IntronA

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



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1. NAME OF THE MEDICINAL PRODUCT

IntronA 3 million IU/0.5 mL solution for injection or infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of solution for injection or infusion contains 3 million IU of recombinant interferon alfa-2b
produced in E. coli by recombinant DNA technology, in 0.5 mL of solution.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection or infusion.
Clear and colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Chronic hepatitis B
Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral 
replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg), 
elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or 
fibrosis.

Chronic hepatitis C
Before initiating treatment with IntronA, consideration should be given to the results from clinical 
trials comparing IntronA with pegylated interferon (see section 5.1).

Adult patients
IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated 
transaminases without liver decompensation and who are positive for hepatitis C virus RNA 
(HCV-RNA) (see section 4.4).

The best way to use IntronA in this indication is in combination with ribavirin.

Children 3 years of age and older and adolescents
IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of 
age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver 
decompensation, and who are positive for HCV-RNA. 

When deciding not to defer treatment until adulthood, it is important to consider that the combination 
therapy induced a growth inhibition that resulted in reduced final adult height in some patients. 
The decision to treat should be made on a case by case basis (see section 4.4).

Hairy cell leukaemia
Treatment of patients with hairy cell leukaemia.

Chronic myelogenous leukaemia
Monotherapy 
Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic 
myelogenous leukaemia.

 



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Clinical experience indicates that a haematological and cytogenetic major/minor response is 
obtainable in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ 
leukaemic cells in the bone marrow, whereas a minor response is  34 %, but < 90 % Ph+ cells in the 
marrow.

Combination therapy 
The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months 
of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses 
and to significantly prolong the overall survival at three years when compared to interferon alfa-2b 
monotherapy.

Multiple myeloma
As maintenance therapy in patients who have achieved objective remission (more than 50 % reduction 
in myeloma protein) following initial induction chemotherapy.
Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the 
plateau phase; however, effects on overall survival have not been conclusively demonstrated.

Follicular lymphoma
Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction 
chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of 
the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm), 
systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats), 
splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or 
epidural involvement, serous effusion, or leukaemia.

Carcinoid tumour
Treatment of carcinoid tumours with lymph node or liver metastases and with "carcinoid syndrome".

Malignant melanoma
As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic 
recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.

4.2 Posology and method of administration

Treatment must be initiated by a physician experienced in the management of the disease.

Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and 
strength must be selected.

If adverse events develop during the course of treatment with IntronA for any indication, modify the 
dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent 
intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment 
with IntronA. At the discretion of the physician, the patient may self-administer the dose for 
maintenance dose regimens administered subcutaneously.

Chronic hepatitis B
The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a 
week (every other day) for a period of 4 to 6 months.

The administered dose should be reduced by 50 % in case of occurrence of haematological disorders 
(white blood cells < 1,500/mm3, granulocytes < 1,000/mm3, thrombocytes < 100,000/mm3). Treatment 
should be discontinued in case of severe leukopaenia (< 1,200/mm3), severe neutropaenia (< 750/mm3) 
or severe thrombocytopaenia (< 70,000/mm3).

For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment 
(at the maximum tolerated dose), discontinue IntronA therapy.

 



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Chronic hepatitis C
Adults
IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day) 
to adult patients, whether administered as monotherapy or in combination with ribavirin.

Children 3 years of age or older and adolescents
IntronA 3 MIU/m2 is administered subcutaneously 3 times a week (every other day) in combination 
with ribavirin capsules or oral solution administered orally in two divided doses daily with food 
(morning and evening). 

(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for 
combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see 
ribavirin oral solution SPC.)

Relapse patients (adults)
IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are 
available for 6 months of treatment, it is recommended that patients be treated with IntronA in 
combination with ribavirin for 6 months.

Naïve patients (adults)
The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be 
given alone mainly in case of intolerance or contraindication to ribavirin.

- IntronA in combination with ribavirin
Based on the results of clinical trials, in which data are available for 12 months of treatment, it is 
recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.

Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who
exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment 
sample) and high pre-treatment viral load.

Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into 
account in order to extend therapy to 12 months.

During clinical trials, patients who failed to show a virologic response after 6 months of treatment 
(HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-
RNA below lower limit of detection six months after withdrawal of treatment).

- IntronA alone
The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of 
between 12 and 18 months is advised.

It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point 
HCV-RNA status should be determined. Treatment should be continued in patients who exhibit 
negative HCV-RNA.

Naïve patients (children and adolescents)
The efficacy and safety of IntronA in combination with ribavirin has been studied in children and 
adolescents who have not been previously treated for chronic hepatitis C. 

Duration of treatment for children and adolescents
 Genotype 1: The recommended duration of treatment is one year. Patients who fail to achieve 

virological response at 12 weeks are highly unlikely to become sustained virological responders 
(negative predictive value 96 %). Therefore, it is recommended that children and adolescent 
patients receiving IntronA/ribavirin combination be discontinued from therapy if their week 12 
HCV-RNA dropped < 2 log10 compared to pretreatment, or if they have detectable HCV-RNA 
at treatment week 24.

 



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 Genotype 2/3: The recommended duration of treatment is 24 weeks.

Hairy cell leukaemia
The recommended dose is 2 million IU/m2 administered subcutaneously three times a week (every 
other day) for both splenectomised and non-splenectomised patients. For most patients with hairy cell 
leukaemia, normalisation of one or more haematological variables occurs within one to two months of 
IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet 
count and haemoglobin level) may require six months or more. This regimen must be maintained 
unless the disease progresses rapidly or severe intolerance is manifested.

Chronic myelogenous leukaemia
The recommended dose of IntronA is 4 to 5 million IU/m2 administered daily subcutaneously. Some 
patients have been shown to benefit from IntronA 5 million IU/m2 administered daily subcutaneously 
in association with cytarabine (Ara-C) 20 mg/m2 administered daily subcutaneously for 10 days per 
month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled, 
administer the maximum tolerated dose of IntronA (4 to 5 million IU/m2 daily) to maintain 
haematological remission.

IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial 
haematological remission or a clinically meaningful cytoreduction has not been achieved.

Multiple myeloma
Maintenance therapy
In patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following 
initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy, 
subcutaneously, at a dose of 3 million IU/m2 three times a week (every other day).

Follicular lymphoma
Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of 
5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens 
are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide, 
doxorubicin, teniposide and prednisolone).

Carcinoid tumour
The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week 
(every other day). Patients with advanced disease may require a daily dose of 5 million IU. The 
treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long 
as the patient responds to interferon alfa-2b treatment.

Malignant melanoma
As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m2

daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to 
sodium chloride 9 mg/mL (0.9 %) solution for injection and administered as a 20-minute infusion (see 
section 6.6). As maintenance treatment, the recommended dose is 10 million IU/m2 administered 
subcutaneously three days a week (every other day) for 48 weeks.

If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes 
decrease to < 500/mm3 or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to 
> 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates. 
Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after 
dose adjustment or if granulocytes decrease to < 250/mm3 or ALT/AST rises to > 10 x upper limit of
normal, discontinue interferon alfa-2b therapy.

Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at 
the recommended dose, with dose reduction for toxicity as described.

IntronA may be administered using either glass or plastic disposable injection syringes.

 



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4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure, 

recent myocardial infarction, severe arrhythmic disorders. 
- Severe renal or hepatic dysfunction; including that caused by metastases.
- Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).
- Chronic hepatitis with decompensated cirrhosis of the liver.
- Chronic hepatitis in patients who are being or have been treated recently with 

immunosuppressive agents excluding short term corticosteroid withdrawal.
- Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant 

recipients.
- Pre-existing thyroid disease unless it can be controlled with conventional treatment.
- Combination of IntronA with telbivudine.

Children and adolescents
- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal 

ideation or suicide attempt.

Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

4.4 Special warnings and precautions for use

Psychiatric and central nervous system (CNS)
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been 
observed in some patients during IntronA therapy, and even after treatment discontinuation mainly 
during the 6-month follow-up period. Among children and adolescents treated with IntronA in 
combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult 
patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult 
patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes 
directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of 
mental status have been observed with alpha interferons. Patients should be closely monitored for any 
signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of 
these undesirable effects must be borne in mind by the prescribing physician and the need for adequate 
therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal 
or homicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, and 
the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions:
If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe 
psychiatric conditions, this should only be initiated after having ensured appropriate individualised 
diagnostic and therapeutic management of the psychiatric condition.
- The use of interferon alfa-2b in children and adolescents with existence of or history of severe 

psychiatric conditions is contraindicated (see section 4.3).

Patients with substance use/abuse:
HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an 
increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders 
when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, 
the presence of psychiatric co-morbidities and the potential for other substance use should be carefully 
assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach 
including a mental health care provider or addiction specialist should be considered to evaluate, treat and 
follow the patient. Patients should be closely monitored during therapy and even after treatment 

 



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discontinuation. Early intervention for re-emergence or development of psychiatric disorders and 
substance use is recommended.

Children and adolescent population: Growth and development (chronic hepatitis C)
During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to 
48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see 
sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy 
with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile 
decrease in height percentile as compared to baseline) in 21 % of children (n=20) despite being off 
treatment for more than 5 years. Final adult height was available for 14 of those children and 
demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of 
treatment.

Case by case benefit/risk assessment in children 
The expected benefit of treatment should be carefully weighed against the safety findings observed for 
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
- It is important to consider that the combination therapy induced a growth inhibition that resulted 

in reduced final adult height in some patients.
- This risk should be weighed against the disease characteristics of the child, such as evidence

of disease progression (notably fibrosis), co-morbidities that may negatively influence the 
disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV 
genotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the 
risk of growth inhibition. There are no data on long term effects on sexual maturation.

Hypersensitivity reactions
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to 
interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops, 
discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate 
interruption of treatment.

Adverse experiences including prolongation of coagulation markers and liver abnormalities
Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in 
some cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation and 
death in patients with cirrhosis.
Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of 
coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with IntronA must be monitored 
closely and treatment discontinued if signs and symptoms progress.
Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Hypotension
Hypotension may occur during IntronA therapy or up to two days post-therapy and may require 
supportive treatment.

Need for adequate hydration
Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension 
related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.

Pyrexia
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon 
therapy, other causes of persistent pyrexia must be ruled out.

Patients with debilitating medical conditions
IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a 
history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone 

 



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to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g., 
thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Pulmonary conditions
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any 
patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray 
taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function 
impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. 
While this has been reported more often in patients with chronic hepatitis C treated with interferon 
alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. 
Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to 
be associated with resolution of pulmonary adverse events.

Ocular adverse events
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous 
retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after 
treatment with alpha interferons. All patients should have a baseline eye examination. Any patient 
complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms 
during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual 
examinations during IntronA therapy are recommended particularly in patients with disorders that may 
be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA 
should be considered in patients who develop new or worsening ophthalmological disorders.

Obtundation, coma and encephalopathy
More significant obtundation and coma, including cases of encephalopathy, have been observed in 
some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a 
few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high 
doses of IntronA.

Patients with pre-existing cardiac abnormalities
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or 
current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is 
recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced 
stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac 
arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require 
discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac 
disease.

Hypertriglyceridemia
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. 
Monitoring of lipid levels is, therefore, recommended.

Patients with psoriasis and sarcoidosis
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of 
IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies 
the potential risk.

Kidney and liver graft rejection
Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of 
kidney graft rejection. Liver graft rejection has also been reported.

Auto-antibodies and autoimmune disorders
The development of auto-antibodies and autoimmune disorders has been reported during treatment 
with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at 

 



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increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be 
evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also 
section 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic 
hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting 
the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment 
should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Concomitant chemotherapy 
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration), which may be life-threatening or fatal as a result of the concomitantly administered 
medicinal product. The most commonly reported potentially life-threatening or fatal adverse events 
include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of 
the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the 
concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the 
frequency and severity of cutaneous vasculitis may be increased.

Chronic hepatitis C
Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases 
(i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. 
Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to 
commencing treatment.

Monotherapy
Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid 
abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 
2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by 
conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid 
status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C, 
evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that 
time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can 
be maintained in the normal range by medication. Determine TSH levels if, during the course of 
IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the 
presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained 
in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid 
dysfunction occurring during treatment (also see Thyroid supplemental monitoring specific for 
children and adolescents).

Thyroid supplemental monitoring specific for children and adolescents
Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy 
developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease 
below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated 
and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA 
therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid 
dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid 
abnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinically 
appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid 
dysfunction (e.g. TSH).

HCV/HIV Coinfection
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at 
increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to 

 



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HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy 
and zidovudine could be at increased risk of developing anaemia.
Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic 
decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin 
may increase the risk in this patient subset. 

HCV/HBV Coinfection
Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-
infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation 
appears to be low.
All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; 
patients co-infected with hepatitis B and C must then be monitored and managed according to current 
clinical guidelines.

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients 
receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging 
effect on teeth and mucous membranes of the mouth during long-term treatment with the combination 
of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular 
dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they 
should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests 
Standard haematological tests and blood chemistries (complete blood count and differential, platelet 
count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be 
conducted in all patients prior to and periodically during systemic treatment with IntronA.

During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, 
and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to 
greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and 
symptoms of liver failure are observed. During ALT flare, the following liver function tests must be 
monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.

In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and 
differential must be monitored weekly during the induction phase of therapy and monthly during the 
maintenance phase of therapy.

Effect on fertility
Interferon may impair fertility (see section 4.6 and section 5.3).

Important information about some of the ingredients of IntronA 
This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5 mL, i.e., essentially 
"sodium-free".

4.5 Interaction with other medicinal products and other forms of interaction 

Interaction studies have only been performed in adults.

Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with 
IntronA.

Interactions between IntronA and other medicinal products have not been fully evaluated. Caution 
must be exercised when administering IntronA in combination with other potentially 
myelosuppressive agents.

Interferons may affect the oxidative metabolic process. This must be considered during concomitant 
therapy with medicinal products metabolised by this route, such as the xanthine derivatives 

 



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theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline 
levels must be monitored and dose adjusted if necessary.

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration) (see section 4.4).

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon 
alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination 
is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these 
events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SPC). Moreover, the safety and 
efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not 
been demonstrated. Therefore, the combination of IntronA with telbivudine is contraindicated (see 
section 4.3).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females
Women of childbearing potential have to use effective contraception during treatment. Decreased 
serum estradiol and progesterone concentrations have been reported in women treated with human 
leukocyte interferon.

IntronA must be used with caution in fertile men.

Combination therapy with ribavirin 
Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be 
taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in 
combination with ribavirin. Females of childbearing potential must use an effective contraceptive 
during treatment and for 4 months after treatment has been concluded. Male patients or their female 
partners must use an effective contraceptive during treatment and for 7 months after treatment has 
been concluded (see ribavirin SPC).

Pregnancy
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA 
is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin 
Ribavirin therapy is contraindicated in women who are pregnant.

Breast-feeding
It is not known whether the components of this medicinal product are excreted in human milk. 
Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior 
to initiation of treatment.

4.7 Effects on ability to drive and use machines

Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment 
with IntronA, and therefore it is recommended that they avoid driving or operating machinery.

 



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4.8 Undesirable effects

See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in 
combination with ribavirin in patients with chronic hepatitis C.

In clinical trials conducted in a broad range of indications and at a wide range of doses (from 
6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonly 
reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were 
often reversible within 72 hours of interruption or cessation of treatment.

Adults
In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in 
combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three 
times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is 
presented from clinical trials in naïve patients treated for one year. Severity was generally mild to 
moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and 
post-marketing. Within the organ system classes, adverse reactions are listed under headings of 
frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10);
uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported during clinical trials or following the marketing use of 
IntronA alone or in combination with ribavirin

System Organ Class Adverse Reactions
Infections and infestations
Very common:
Common:
Uncommon:
Rarely:
Not known:

Pharyngitis*, infection viral*
Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Bacterial infection
Pneumonia§, sepsis
Hepatitis B reactivation in HCV/HBV co-infected patients

Blood and lymphatic system disorders
Very common:
Common:
Very rarely: 
Not known: 

Leukopaenia
Thrombocytopaenia, lymphadenopathy, lymphopenia
Aplastic anaemia
Pure red cell aplasia, idiopathic thrombocytopenic 
purpura, thrombotic thrombocytopenic purpura 

Immune system disorders§

Very rarely: 
Not known:

Sarcoidosis, exacerbation of sarcoidosis
Systemic lupus erythematosus, vasculitis, rheumatoid 
arthritis (new or aggravated), Vogt-Koyanagi-Harada 
syndrome, acute hypersensitivity reactions including 
urticaria, angioedema, bronchoconstriction, anaphylaxis§

Endocrine disorders
Common:
Very rarely:

Hypothyroidism§, hyperthyroidism§

Diabetes, aggravated diabetes
Metabolism and nutrition disorders
Very common:
Common: 
Very rarely:

Anorexia
Hypocalcaemia, dehydration, hyperuricemia, thirst
Hyperglycaemia, hypertriglyceridaemia§, increased 
appetite

 



13

Psychiatric disorders§

Very common:

Common:
Rarely: 
Very rarely:

Not known:

Depression, insomnia, anxiety, emotional lability*, 
agitation, nervousness
Confusion, sleep disorder, libido decreased
Suicide ideation
Suicide, suicide attempts, aggressive behaviour 
(sometimes directed against others), psychosis including 
hallucinations
Homicidal ideation, mental status change§, mania, bipolar 
disorders

Nervous system disorders§

Very common:
Common:

Uncommon:
Very rarely: 

Not known:

Dizziness, headache, concentration impaired, mouth dry
Tremor, paresthesia, hypoesthesia, migraine, flushing, 
somnolence, taste perversion
Peripheral neuropathy
Cerebrovascular haemorrhage, cerebrovascular ischaemia, 
seizure, impaired consciousness, encephalopathy
Mononeuropathies, coma§

Eye disorders
Very common:
Common:

Rarely:

Not known:

Vision blurred
Conjunctivitis, vision abnormal, lacrimal gland disorder, 
eye pain
Retinal haemorrhages§, retinopathies (including macular 
oedema), retinal artery or vein obstruction§, optic neuritis, 
papilloedema, loss of visual acuity or visual field, cotton-
wool spots§

Serous retinal detachment
Ear and labyrinth
Common:
Very rarely:

Vertigo, tinnitus
Hearing loss, hearing disorder

Cardiac disorders
Common:
Uncommon:
Rarely:
Very rarely:
Not known:

Palpitation, tachycardia
Pericarditis
Cardiomyopathy
Myocardial infarction, cardiac ischaemia 
Congestive heart failure, pericardial effusion, arrhythmia 

Vascular disorders
Common:
Very rarely:

Hypertension
Peripheral ischaemia, hypotension§

Respiratory, thoracic and mediastinal 
disorders
Very common:
Common:

Very rarely: 
Not known:

Dyspnoea*, coughing*
Epistaxis, respiratory disorder, nasal congestion, 
rhinorrhea, cough nonproductive
Pulmonary infiltrates§, pneumonitis§

Pulmonary fibrosis, pulmonary arterial hypertension#

Gastrointestinal disorders
Very common:

Common:

Very rarely:

Not known:

Nausea/vomiting, abdominal pain, diarrhoea, stomatitis, 
dyspepsia
Stomatitis ulcerative, right upper quadrant pain, glossitis, 
gingivitis, constipation, loose stools
Pancreatitis, ischaemic colitis, ulcerative colitis, gingival 
bleeding
Periodontal disorder NOS, dental disorder NOS, tongue 
pigmentation §

 



14

Hepatobiliary disorders
Common:
Very rarely:

Hepatomegaly
Hepatotoxicity, (including fatality)

Skin and subcutaneous tissue 
disorders
Very common:
Common:

Very rarely:

Alopecia, pruritus*, skin dry*, rash*, sweating increased
Psoriasis (new or aggravated)§, rash maculopapular, rash 
erythematous, eczema, erythema, skin disorder
Stevens Johnson syndrome, toxic epidermal necrolysis, 
erythema multiforme

Musculoskeletal and connective tissue 
disorders
Very common: 
Common:
Very rarely:

Myalgia, arthralgia, musculoskeletal pain
Arthritis
Rhabdomyolysis, myositis, leg cramps, back pain

Renal and urinary disorders
Common:
Very rarely:

Micturition frequency
Renal failure, renal insufficiency, nephrotic syndrome

Reproductive system and breast 
disorders
Common: Amenorrhea, breast pain, dysmenorrhea, menorrhagia, 

menstrual disorder, vaginal disorder
General disorders and administration 
site conditions
Very common:

Common:
Very rarely:

Injection site inflammation, injection site reaction*, 
fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia, 
irritability, chest pain, malaise
Injection site pain
Injection site necrosis, face oedema

Investigations
Very common: Weight decrease
*These events were only common with IntronA alone.
§See section 4.4
#Class label for interferon products, see below Pulmonary arterial hypertension.

These undesirable effects have also been reported with IntronA alone.

The undesirable effects seen with hepatitis C are representative of those reported when IntronA is 
administered in other indications, with some anticipated dose-related increases in incidence. For 
example, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences of 
fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-
like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C 
trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of 
patients, respectively), in comparison with the mild to moderate severity usually associated with lower 
doses. Undesirable effects were usually managed by dose adjustment. 

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with 
pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, 
that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients 
without prior evidence of cardiac disease (see section 4.4). 

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 
notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). 
Events were reported at various time points typically several months after starting treatment with 
interferon alfa.

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha 
interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or 

 



15

aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including 
mononeuropathies (see also section 4.4).

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 
10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in 
haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and 
serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase 
in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis 
subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.

Children and adolescent population 
Chronic Hepatitis C - Combination therapy with ribavirin
In clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy due 
to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent 
population studied was similar to that observed in adults, although there is a paediatric- specific 
concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of 
9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during 
treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 
44th percentile, which was below the median of the normative population and less than their mean 
baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height 
percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from 
the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was 
available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 
percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks 
with IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult height 
in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-
term follow-up was most prominent in prepubertal age children (see section 4.4).

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients 
(2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult 
patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, 
anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents 
compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for 
anaemia and neutropaenia.

The adverse reactions listed in Table 2 are based on experience from the two multicentre children and 
adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings 
of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within 
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2 Adverse reactions very commonly and commonly reported during clinical trials in
children and adolescent patients treated with IntronA in combination with ribavirin

System Organ Class Adverse Reactions
Infection and infestations
Very common:
Common:

Viral infection, pharyngitis
Fungal infection, bacterial infection, pulmonary infection, otitis 
media, tooth abscess, herpes simplex, urinary tract infection, 
vaginitis, gastroenteritis

Neoplasms benign, malignant 
and unspecified (including 
cysts and polyps)
Common: Neoplasm (unspecified)

 



16

Blood and lymphatic system 
disorders
Very common:
Common:

Anaemia, neutropaenia
Thrombocytopaenia, lymphadenopathy

Endocrine disorders
Very common:
Common:

Hypothyroidism§, 
Hyperthyroidism§, virilism

Metabolism and nutrition 
disorders
Very common:
Common:

Anorexia
Hypertriglyceridemia§, hyperuricemia, increased appetite

Psychiatric disorders§

Very common:
Common:

Depression, emotional lability, insomnia
Suicidal ideation, aggressive reaction, confusion, behaviour 
disorder, agitation, somnambulism, anxiety, nervousness, sleep 
disorder, abnormal dreaming, apathy

Nervous system disorders§

Very common:
Common:

Headache, dizziness
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, 
hyperaesthesia, concentration impaired, somnolence

Eye disorders
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Vascular disorders
Common: Flushing, pallor
Respiratory, thoracic and 
mediastinal disorders
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal 

irritation, rhinorrhea, sneezing
Gastrointestinal disorders
Very common:
Common:

Diarrhoea, vomiting, nausea, abdominal pain
Mouth ulceration, stomatitis ulcerative, stomatitis, right upper 
quadrant pain, dyspepsia, glossitis, gastroesophageal reflux, rectal 
disorder, gastrointestinal disorder, constipation, loose stools, 
toothache, tooth disorder

Hepatobiliary disorders
Common: Hepatic function abnormal
Skin and subcutaneous tissue 
disorders 
Very common:
Common:

Alopecia, rash
Photosensitivity reaction, maculopapular rash, eczema, acne, skin 
disorder, nail disorder, skin discolouration, pruritus, dry skin, 
erythema, bruise, sweating increased

Musculoskeletal and 
connective tissue disorders
Very common: Arthralgia, myalgia, musculoskeletal pain 
Renal and urinary disorders
Common: Enuresis, micturition disorder, urinary incontinence
Reproductive system and 
breast disorders
Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal 

disorder
Male: testicular pain

 



17

General disorders and 
administration site 
conditions
Very common:

Common:

Injection site inflammation, injection site reaction, fatigue, rigors, 
pyrexia§, influenza-like symptoms§, malaise, irritability
Chest pain, asthenia, oedema, injection site pain

Investigations
Very common: Growth rate decrease (height and/or weight decrease for age)§

Injury and poisoning
Common: Skin laceration
§See section 4.4

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

No case of overdose has been reported that has led to acute clinical manifestations. However, as for 
any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital 
signs and close observation of the patient is indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05

IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant 
DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of 
approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically 
engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b 
protein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activity 
of the recombinant interferon alfa-2b with the activity of the international reference preparation of 
human leukocyte interferon established by the World Health Organisation.

The interferons are a family of small protein molecules with molecular weights of approximately 
15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or 
various synthetic and biological inducers. Three major classes of interferons have been identified: 
alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain 
several different molecular species of interferon. More than 14 genetically distinct human alpha 
interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. 
Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly 
asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species 
specificity. Studies with other interferons have demonstrated species specificity. However, certain 
monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure 
to human type 1 interferons.

The results of several studies suggest that, once bound to the cell membrane, interferon initiates a 
complex sequence of intracellular events that include the induction of certain enzymes. It is thought 

 

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18

that this process, at least in part, is responsible for the various cellular responses to interferon, 
including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and 
such immunomodulating activities as enhancement of the phagocytic activity of macrophages and 
augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities 
may contribute to interferon's therapeutic effects.

Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both 
animal and human cell culture systems as well as human tumour xenografts in animals. It has 
demonstrated significant immunomodulatory activity in vitro.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact 
antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell 
metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are 
unable to leave the cell.

Chronic hepatitis B
Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates 
that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been 
observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity 
and mortality has been observed.

Interferon alfa-2b (6 MIU/m2 3 times a week for 6 months) has been given to children with chronic 
active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover 
children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of 
depression were observed.

Chronic hepatitis C in adult patients
In adult patients receiving interferon in combination with ribavirin, the achieved sustained response 
rate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferon 
with ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with a 
ribavirin dose > 10.6 mg/kg, p < 0.01).

IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical 
trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of 
IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic 
response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C 
confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/mL), a liver 
biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic 
hepatitis, and abnormal serum ALT.

IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with 
ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were 
followed for an additional 6 months after the end of treatment for the determination of sustained 
virologic response. Sustained virologic response rates for treatment groups treated for one year with 
IntronA alone or in combination with ribavirin (from two studies) are shown in Table 3.

Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for 
the treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load are 
prognostic factors which are known to affect response rates. The increased response rate to the 
combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The 
relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most 
difficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).

Response rates in these trials were increased with compliance. Regardless of genotype, patients who 
received IntronA in combination with ribavirin and received  80 % of their treatment had a higher 
sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment 
(56 % vs. 32 % in trial C/I98-580).

 



19

Table 3 Sustained virologic response rates with IntronA + ribavirin (one year of treatment) by 
genotype and viral load

HCV Genotype I
N=503

C95-132/I95-143

I/R
N=505

C95-132/I95-143

I/R
N=505

C/I98-580

All Genotypes 16 % 41 % 47 %

Genotype 1 9 % 29 % 33 %

Genotype 1 
 2 million 
copies/mL

25 % 33 % 45 %

Genotype 1
> 2 million 
copies/mL

3 % 27 % 29 %

Genotype 2/3 31 % 65 % 79 %

I IntronA (3 MIU 3 times a week)
I/R IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)

HCV/HIV Co-infected patients 
Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies, 
patients who received IntronA plus ribavirin, were less likely to respond than patients who received 
pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is 
presented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which 
enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with 
HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus 
ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a 
follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 
95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. 
Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based on 
weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin 
(800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period 
of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL 
(Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

 



20

Table 4 Sustained virological response based on genotype after IntronA in combination with 
ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in 
HCV/HIV co-infected patients

Study 11 Study 22

pegylated 
interferon alfa-
2b  (1.5 µg/kg/

week) + 
ribavirin 
(800 mg)

IntronA 
(3 MIU TIW) +  

ribavirin 
(800 mg)

p 
valuea

pegylated 
interferon 

alfa-2b (100 
or 

150c µg/week) 
+ ribavirin 

(800-
1,200 mg)d

IntronA 
(3 MIU TIW) 

+ ribavirin 
(800-

1,200 mg)d
p 

valueb

All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017

Genotype 1, 
4

17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007

Genotype 2, 
3

44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730

MIU = million international units; TIW = three times a week.
a:  p value based on Cochran-Mantel Haenszel Chi square test.
b:  p value based on chi-square test.
c:  subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week pegylated 

interferon alfa-2b.
d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al.  JAMA 2004; 292(23): 2839-2848.
2 Laguno M, Murillas J, Blanco J.L et al.  AIDS 2004; 18(13): F27-F36.

Relapse patients 
A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA 
monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA 
increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic 
hepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV 
(< 100 copies/mL by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was 
sustained when measured 6 months after the end of treatment.

Long-Term efficacy data
In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-
2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic 
response and assess the impact of continued viral negativity on clinical outcomes. 462 patients 
completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 
492 relapsed during this study. 
The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with 
a 95 % Confidence Interval of [95 %, 99 %]. 
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin) 
results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 
'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients 
with cirrhosis (including hepatocarcinoma).

Chronic hepatitis C in children and adolescent population
Three clinical trials have been conducted in children and adolescents; two with standard interferon and 
ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin 
were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable 
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in 
two multicentre trials and received IntronA 3 MIU/m2 3 times a week plus ribavirin 15 mg/kg per day 

 



21

for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % 
male, 80 % Caucasian, and 78 % genotype 1,64 %  12 years of age. The population enrolled mainly 
consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained 
virological response rates in children and adolescents were similar to those in adults. Due to the lack 
of data in these two multicentre trials for children with severe progression of the disease, and the 
potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b 
needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).

Study results are summarized in Table 5.

Table 5 Sustained virological response in previously untreated children and adolescents

IntronA 3 MIU/m2 3 times a week
+

ribavirin 15 mg/kg/day

Overall Responsea (n=118) 54 (46 %)*

Genotype 1 (n=92) 33 (36 %)*

Genotype 2/3/4 (n=26) 21 (81 %)*

*Number (%) of patients
aDefined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-
up period

Long-term efficacy data 
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C 
patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all 
enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose 
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess 
the impact of continued viral negativity on clinical outcomes for patients who were sustained 
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but 
one of the paediatric subjects remained sustained virologic responders during long-term follow-up 
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for 
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients 
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at 
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in 
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from 
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with 
cirrhosis (including hepatocarcinoma).

Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin
In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic 
hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 g/m2 plus ribavirin 
15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. 
All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received 
treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 
63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate 
hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential 
for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin 
needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs 
section 4.4). The study results are summarized in Table 6.

 



22

Table 6 Sustained virological response rates (na,b (%)) in previously untreated children and 
adolescents by genotype and treatment duration – All subjects

n = 107

24 weeks 48 weeks

All Genotypes 26/27 (96 %) 44/80 (55 %)

Genotype 1 - 38/72 (53 %)

Genotype 2 14/15 (93 %) -

Genotype 3c 12/12 (100 %) 2/3 (67 %)

Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of 

detection=125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with 
genotype 3 and high viral load (≥ 600,000 IU/mL) were to receive 48 weeks of treatment.

5.2 Pharmacokinetic properties

The pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m2

and 10 million IU doses administered subcutaneously, at 5 million IU/m2 administered intramuscularly 
and as a 30-minute intravenous infusion. The mean serum interferon concentrations following 
subcutaneous and intramuscular injections were comparable. Cmax occurred three to 12 hours after the 
lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon 
injections were approximately two to three hours, and six to seven hours, respectively. Serum levels 
were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and 
intramuscular administration resulted in bioavailabilities greater than 100 %.

After intravenous administration, serum interferon levels peaked (135 to 273 IU/mL) by the end of the 
infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular 
administration of medicinal product, becoming undetectable four hours after the infusion. The 
elimination half-life was approximately two hours.

Urine levels of interferon were below the detection limit following each of the three routes of 
administration.

Interferon neutralising factor assays were performed on serum samples of patients who received 
IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies 
which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors 
developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %. 
The detectable titres are low in almost all cases and have not been regularly associated with loss of 
response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was 
observed apparently due to the low titres.

Children and adolescent population
Multiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children and 
adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 7. The 
pharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children or 
adolescents.

 



23

Table 7 Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and 
ribavirincapsules when administered to children or adolescents with chronic hepatitis 
C

Parameter Ribavirin
15 mg/kg/day as 2 divided doses

(n = 17)

IntronA
3 MIU/m2 3 times a week

(n = 54)
Tmax (hr) 1.9 (83) 5.9 (36)

Cmax (ng/mL) 3,275 (25) 51 (48)
AUC* 29,774 (26) 622 (48)

Apparent clearance L/hr/kg 0.27 (27) Not done
*AUC12 (ng.hr/mL) for ribavirin; AUC0-24 (IU.hr/mL) for IntronA

Transfer into seminal fluid
Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is 
approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female 
partner after sexual intercourse with a treated patient has been estimated and remains extremely 
limited compared to therapeutic plasma concentration of ribavirin.

5.3 Preclinical safety data

Although interferon is generally recognised as being species specific, toxicity studies in animals were 
conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no 
evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with 
20 x 106 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in 
monkeys given 100 x 106 IU/kg/day for 3 months.

In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been 
observed (see section 4.4).

Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic 
in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in 
offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macaca 
mulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose 
of 2 million IU/m2. Abortion was observed in all dose groups (7.5 million, 15 million and 
30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups 
(corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of 
2 million IU/m2). High doses of other forms of interferons alpha and beta are known to produce dose-
related anovulatory and abortifacient effects in rhesus monkeys.

Mutagenicity studies with interferon alfa-2b revealed no adverse events.

IntronA plus ribavirin
No studies have been conducted in juvenile animals to examine the effects of treatment with interferon 
alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results 
have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with 
ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with 
ribavirin).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium phosphate anhydrous 
Sodium dihydrogen phosphate monohydrate 
Edetate disodium 

 



24

Sodium chloride 
M-cresol 
Polysorbate 80 
Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6.

6.3 Shelf life

18 months.
Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the product is not used during the seven-day period, it cannot be put back in the 
refrigerator for a new storage period and must be discarded.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). 
Do not freeze. 
For storage conditions of the medicinal product, see section 6.3.

6.5 Nature and contents of container

0.5 mL of solution (corresponding to 3 MIU) is contained in a single dose vial (type I glass) with a 
stopper (halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene).

IntronA is supplied as:
- Pack of 1 vial
- Pack of 1 vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing swab
- Pack of 6 vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing swabs
- Pack of 12 vials, 12 injection syringes of 1 mL, 12 injection needles and 12 cleansing swabs
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Not all dose forms and strengths are appropriate for some indications. Please make sure to select an 
appropriate dose form and strength.

IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriate 
doses from the vial with a sterile injection syringe.

Detailed instructions for the subcutaneous use of the product are provided with the package leaflet 
(refer to “How to self inject IntronA”).

Preparation of IntronA for intravenous infusion: The infusion is to be prepared immediately prior to 
use. Any size vial may be used to measure the required dose; however, final concentration of 
interferon in sodium chloride solution must be not less than 0.3 million IU/mL. The appropriate dose 
of IntronA is withdrawn from the vial(s), added to 50 mL of 9 mg/mL (0.9 %) sodium chloride 
solution for injection in a PVC bag or glass bottle for intravenous use and administered over 
20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

 



25

As with all parenteral medicinal products, prior to administration inspect IntronA, solution for 
injection or infusion, visually for particulate matter and discolouration. The solution should be clear 
and colourless.

Any unused medicinal product must be discarded after withdrawal of the dose and in accordance with 
local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBERS

EU/1/99/127/011
EU/1/99/127/012
EU/1/99/127/013
EU/1/99/127/014

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 March 2000
Date of latest renewal: 9 March 2010

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



26

1. NAME OF THE MEDICINAL PRODUCT

IntronA 5 million IU/0.5 mL solution for injection or infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of solution for injection or infusion contains 5 million IU of recombinant interferon alfa-2b
produced in E. coli by recombinant DNA technology, in 0.5 mL of solution.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection or infusion.
Clear and colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Chronic hepatitis B
Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral 
replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg), 
elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or 
fibrosis.

Chronic hepatitis C 
Before initiating treatment with IntronA, consideration should be given to the results from clinical 
trials comparing IntronA with pegylated interferon (see section 5.1).

Adult patients 
IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated 
transaminases without liver decompensation and who are positive for hepatitis C virus RNA 
(HCV-RNA) (see section 4.4).

The best way to use IntronA in this indication is in combination with ribavirin.

Children 3 years of age and older and adolescents
IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of 
age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver 
decompensation, and who are positive for HCV-RNA. 

When deciding not to defer treatment until adulthood, it is important to consider that the combination 
therapy induced a growth inhibition that resulted in reduced final adult height in some patients. 
The decision to treat should be made on a case by case basis (see section 4.4).

Hairy cell leukaemia
Treatment of patients with hairy cell leukaemia.

Chronic myelogenous leukaemia
Monotherapy 
Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic 
myelogenous leukaemia.

 



27

Clinical experience indicates that a haematological and cytogenetic major/minor response is 
obtainable in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ 
leukaemic cells in the bone marrow, whereas a minor response is  34 %, but < 90 % Ph+ cells in the 
marrow.

Combination therapy 
The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months 
of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses 
and to significantly prolong the overall survival at three years when compared to interferon alfa-2b 
monotherapy.

Multiple myeloma
As maintenance therapy in patients who have achieved objective remission (more than 50 % reduction 
in myeloma protein) following initial induction chemotherapy.
Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the 
plateau phase; however, effects on overall survival have not been conclusively demonstrated.

Follicular lymphoma
Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction 
chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of 
the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm), 
systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats), 
splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or 
epidural involvement, serous effusion, or leukaemia.

Carcinoid tumour
Treatment of carcinoid tumours with lymph node or liver metastases and with "carcinoid syndrome".

Malignant melanoma
As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic 
recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.

4.2 Posology and method of administration

Treatment must be initiated by a physician experienced in the management of the disease.

Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and 
strength must be selected.

If adverse events develop during the course of treatment with IntronA for any indication, modify the 
dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent 
intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment 
with IntronA. At the discretion of the physician, the patient may self-administer the dose for 
maintenance dose regimens administered subcutaneously.

Chronic hepatitis B
The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a 
week (every other day) for a period of 4 to 6 months.

The administered dose should be reduced by 50 % in case of occurrence of haematological disorders 
(white blood cells < 1,500/mm3, granulocytes < 1,000/mm3, thrombocytes < 100,000/mm3). Treatment 
should be discontinued in case of severe leukopaenia (< 1,200/mm3), severe neutropaenia (< 750/mm3) 
or severe thrombocytopaenia (< 70,000/mm3).

For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment 
(at the maximum tolerated dose), discontinue IntronA therapy.

 



28

Chronic hepatitis C
Adults
IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day) 
to adult patients, whether administered as monotherapy or in combination with ribavirin.

Children 3 years of age or older and adolescents
IntronA 3 MIU/m2 is administered subcutaneously 3 times a week (every other day) in combination 
with ribavirin capsules or oral solution administered orally in two divided doses daily with food 
(morning and evening). 

(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for 
combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see 
ribavirin oral solution SPC.)

Relapse patients (adults)
IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are 
available for 6 months of treatment, it is recommended that patients be treated with IntronA in 
combination with ribavirin for 6 months.

Naïve patients (adults)
The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be 
given alone mainly in case of intolerance or contraindication to ribavirin.

- IntronA in combination with ribavirin
Based on the results of clinical trials, in which data are available for 12 months of treatment, it is 
recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.

Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who 
exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment 
sample) and high pre-treatment viral load.

Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into 
account in order to extend therapy to 12 months.

During clinical trials, patients who failed to show a virologic response after 6 months of treatment 
(HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-
RNA below lower limit of detection six months after withdrawal of treatment).

- IntronA alone
The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of 
between 12 and 18 months is advised.

It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point
HCV-RNA status should be determined. Treatment should be continued in patients who exhibit 
negative HCV-RNA.

Naïve patients (children and adolescents)
The efficacy and safety of IntronA in combination with ribavirin has been studied in children and 
adolescents who have not been previously treated for chronic hepatitis C. 

Duration of treatment for children and adolescents
 Genotype 1: The recommended duration of treatment is one year. Patients who fail to achieve 

virological response at 12 weeks are highly unlikely to become sustained virological responders 
(negative predictive value 96 %). Therefore, it is recommended that children and adolescent 
patients receiving IntronA/ribavirin combination be discontinued from therapy if their week 12 
HCV-RNA dropped < 2 log10 compared to pretreatment, or if they have detectable HCV-RNA 
at treatment week 24.

 



29

 Genotype 2/3: The recommended duration of treatment is 24 weeks.

Hairy cell leukaemia
The recommended dose is 2 million IU/m2 administered subcutaneously three times a week (every 
other day) for both splenectomised and non-splenectomised patients. For most patients with hairy cell 
leukaemia, normalisation of one or more haematological variables occurs within one to two months of
IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet 
count and haemoglobin level) may require six months or more. This regimen must be maintained 
unless the disease progresses rapidly or severe intolerance is manifested.

Chronic myelogenous leukaemia
The recommended dose of IntronA is 4 to 5 million IU/m2 administered daily subcutaneously. Some 
patients have been shown to benefit from IntronA 5 million IU/m2 administered daily subcutaneously 
in association with cytarabine (Ara-C) 20 mg/m2 administered daily subcutaneously for 10 days per 
month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled, 
administer the maximum tolerated dose of IntronA (4 to 5 million IU/m2 daily) to maintain 
haematological remission.

IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial 
haematological remission or a clinically meaningful cytoreduction has not been achieved.

Multiple myeloma
Maintenance therapy 
In patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following 
initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy, 
subcutaneously, at a dose of 3 million IU/m2 three times a week (every other day).

Follicular lymphoma
Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of 
5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens 
are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide, 
doxorubicin, teniposide and prednisolone).

Carcinoid tumour
The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week 
(every other day). Patients with advanced disease may require a daily dose of 5 million IU. The 
treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long 
as the patient responds to interferon alfa-2b treatment.

Malignant melanoma
As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m2

daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to 
sodium chloride 9 mg/mL (0.9 %) solution for injection and administered as a 20-minute infusion (see 
section 6.6). As maintenance treatment, the recommended dose is 10 million IU/m2 administered 
subcutaneously three days a week (every other day) for 48 weeks.

If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes 
decrease to < 500/mm3 or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to 
> 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates. 
Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after 
dose adjustment or if granulocytes decrease to < 250/mm3 or ALT/AST rises to > 10 x upper limit of 
normal, discontinue interferon alfa-2b therapy.

Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at 
the recommended dose, with dose reduction for toxicity as described.

IntronA may be administered using either glass or plastic disposable injection syringes.

 



30

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure, 

recent myocardial infarction, severe arrhythmic disorders. 
- Severe renal or hepatic dysfunction; including that caused by metastases.
- Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).
- Chronic hepatitis with decompensated cirrhosis of the liver.
- Chronic hepatitis in patients who are being or have been treated recently with 

immunosuppressive agents excluding short term corticosteroid withdrawal.
- Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant 

recipients.
- Pre-existing thyroid disease unless it can be controlled with conventional treatment.
- Combination of IntronA with telbivudine.

Children and adolescents
- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal 

ideation or suicide attempt.

Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

4.4 Special warnings and precautions for use

Psychiatric and central nervous system (CNS)
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been 
observed in some patients during IntronA therapy, and even after treatment discontinuation mainly 
during the 6-month follow-up period. Among children and adolescents treated with IntronA in 
combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult 
patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult 
patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes 
directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of 
mental status have been observed with alpha interferons. Patients should be closely monitored for any 
signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of 
these undesirable effects must be borne in mind by the prescribing physician and the need for adequate 
therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal 
or homicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, and 
the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions:
If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe 
psychiatric conditions, this should only be initiated after having ensured appropriate individualised 
diagnostic and therapeutic management of the psychiatric condition.
- The use of interferon alfa-2b in children and adolescents with existence of or history of severe 

psychiatric conditions is contraindicated (see section 4.3).

Patients with substance use/abuse:
HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an 
increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders 
when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, 
the presence of psychiatric co-morbidities and the potential for other substance use should be carefully 
assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach 
including a mental health care provider or addiction specialist should be considered to evaluate, treat and 
follow the patient. Patients should be closely monitored during therapy and even after treatment 

 



31

discontinuation. Early intervention for re-emergence or development of psychiatric disorders and 
substance use is recommended.

Children and adolescent population: Growth and development (chronic hepatitis C)
During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to 
48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see 
sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy 
with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile 
decrease in height percentile as compared to baseline) in 21 % of children (n=20) despite being off 
treatment for more than 5 years. Final adult height was available for 14 of those children and 
demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of 
treatment.

Case by case benefit/risk assessment in children 
The expected benefit of treatment should be carefully weighed against the safety findings observed for 
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
- It is important to consider that the combination therapy induced a growth inhibition that resulted 

in reduced final adult height in some patients.
- This risk should be weighed against the disease characteristics of the child, such as evidence

of disease progression (notably fibrosis), co-morbidities that may negatively influence the 
disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV 
genotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the 
risk of growth inhibition. There are no data on long term effects on sexual maturation.

Hypersensitivity reactions
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to 
interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops, 
discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate 
interruption of treatment.

Adverse experiences including prolongation of coagulation markers and liver abnormalities
Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in 
some cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation and 
death in patients with cirrhosis.
Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of 
coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with IntronA must be monitored 
closely and treatment discontinued if signs and symptoms progress.
Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Hypotension
Hypotension may occur during IntronA therapy or up to two days post-therapy and may require 
supportive treatment.

Need for adequate hydration
Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension 
related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.

Pyrexia
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon 
therapy, other causes of persistent pyrexia must be ruled out.

Patients with debilitating medical conditions
IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a 
history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone 

 



32

to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g., 
thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Pulmonary conditions
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any 
patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray 
taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function 
impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. 
While this has been reported more often in patients with chronic hepatitis C treated with interferon 
alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. 
Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to 
be associated with resolution of pulmonary adverse events.

Ocular adverse events
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous 
retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after 
treatment with alpha interferons. All patients should have a baseline eye examination. Any patient 
complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms 
during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual 
examinations during IntronA therapy are recommended particularly in patients with disorders that may 
be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA 
should be considered in patients who develop new or worsening ophthalmological disorders.

Obtundation, coma and encephalopathy
More significant obtundation and coma, including cases of encephalopathy, have been observed in 
some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a 
few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high 
doses of IntronA.

Patients with pre-existing cardiac abnormalities
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or 
current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is 
recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced 
stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac 
arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require 
discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac 
disease.

Hypertriglyceridemia
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. 
Monitoring of lipid levels is, therefore, recommended.

Patients with psoriasis and sarcoidosis
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of 
IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies 
the potential risk.

Kidney and liver graft rejection
Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of 
kidney graft rejection. Liver graft rejection has also been reported.

Auto-antibodies and autoimmune disorders
The development of auto-antibodies and autoimmune disorders has been reported during treatment 
with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at 

 



33

increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be 
evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also 
section 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic 
hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting 
the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment 
should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Concomitant chemotherapy 
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration), which may be life-threatening or fatal as a result of the concomitantly administered 
medicinal product. The most commonly reported potentially life-threatening or fatal adverse events 
include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of 
the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the 
concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the 
frequency and severity of cutaneous vasculitis may be increased.

Chronic hepatitis C
Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases 
(i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. 
Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to 
commencing treatment.

Monotherapy 
Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid 
abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 
2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by 
conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid 
status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C, 
evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that 
time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can 
be maintained in the normal range by medication. Determine TSH levels if, during the course of 
IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the 
presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained 
in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid 
dysfunction occurring during treatment (also see Thyroid supplemental monitoring specific for 
children and adolescents).

Thyroid supplemental monitoring specific for children and adolescents
Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy 
developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease 
below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated 
and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA 
therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid 
dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid 
abnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinically 
appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid 
dysfunction (e.g. TSH).

HCV/HIV Coinfection
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at 
increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to 

 



34

HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy 
and zidovudine could be at increased risk of developing anaemia.
Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic 
decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin 
may increase the risk in this patient subset. 

HCV/HBV Coinfection
Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-
infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation 
appears to be low.
All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; 
patients co-infected with hepatitis B and C must then be monitored and managed according to current 
clinical guidelines.

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients 
receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging 
effect on teeth and mucous membranes of the mouth during long-term treatment with the combination 
of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular 
dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they 
should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests 
Standard haematological tests and blood chemistries (complete blood count and differential, platelet 
count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be 
conducted in all patients prior to and periodically during systemic treatment with IntronA.

During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, 
and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to 
greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and 
symptoms of liver failure are observed. During ALT flare, the following liver function tests must be 
monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.

In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and 
differential must be monitored weekly during the induction phase of therapy and monthly during the 
maintenance phase of therapy.

Effect on fertility
Interferon may impair fertility (see section 4.6 and section 5.3).

Important information about some of the ingredients of IntronA 
This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5 mL, i.e., essentially 
"sodium-free".

4.5 Interaction with other medicinal products and other forms of interaction 

Interaction studies have only been performed in adults.

Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with 
IntronA.

Interactions between IntronA and other medicinal products have not been fully evaluated. Caution 
must be exercised when administering IntronA in combination with other potentially 
myelosuppressive agents.

Interferons may affect the oxidative metabolic process. This must be considered during concomitant 
therapy with medicinal products metabolised by this route, such as the xanthine derivatives 

 



35

theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline 
levels must be monitored and dose adjusted if necessary.

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration) (see section 4.4).

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon 
alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination 
is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these 
events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SPC). Moreover, the safety and 
efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not 
been demonstrated. Therefore, the combination of IntronA with telbivudine is contraindicated (see 
section 4.3).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females
Women of childbearing potential have to use effective contraception during treatment. Decreased 
serum estradiol and progesterone concentrations have been reported in women treated with human 
leukocyte interferon.

IntronA must be used with caution in fertile men.

Combination therapy with ribavirin 
Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be 
taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in 
combination with ribavirin. Females of childbearing potential must use an effective contraceptive 
during treatment and for 4 months after treatment has been concluded. Male patients or their female 
partners must use an effective contraceptive during treatment and for 7 months after treatment has 
been concluded (see ribavirin SPC).

Pregnancy
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA 
is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin 
Ribavirin therapy is contraindicated in women who are pregnant.

Breast-feeding
It is not known whether the components of this medicinal product are excreted in human milk. 
Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior 
to initiation of treatment.

4.7 Effects on ability to drive and use machines

Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment 
with IntronA, and therefore it is recommended that they avoid driving or operating machinery.

 



36

4.8 Undesirable effects

See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in 
combination with ribavirin in patients with chronic hepatitis C.

In clinical trials conducted in a broad range of indications and at a wide range of doses (from 
6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonly 
reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were 
often reversible within 72 hours of interruption or cessation of treatment.

Adults
In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in 
combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three 
times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is 
presented from clinical trials in naïve patients treated for one year. Severity was generally mild to 
moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and 
post-marketing. Within the organ system classes, adverse reactions are listed under headings of 
frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10);
uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported during clinical trials or following the marketing use of 
IntronA alone or in combination with ribavirin

System Organ Class Adverse Reactions
Infections and infestations
Very common:
Common:
Uncommon:
Rarely:
Not known:

Pharyngitis*, infection viral*
Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Bacterial infection
Pneumonia§, sepsis
Hepatitis B reactivation in HCV/HBV co-infected patients

Blood and lymphatic system disorders
Very common:
Common:
Very rarely: 
Not known: 

Leukopaenia
Thrombocytopaenia, lymphadenopathy, lymphopenia
Aplastic anaemia
Pure red cell aplasia, idiopathic thrombocytopenic 
purpura, thrombotic thrombocytopenic purpura 

Immune system disorders§

Very rarely: 
Not known:

Sarcoidosis, exacerbation of sarcoidosis
Systemic lupus erythematosus, vasculitis, rheumatoid 
arthritis (new or aggravated), Vogt-Koyanagi-Harada 
syndrome, acute hypersensitivity reactions including 
urticaria, angioedema, bronchoconstriction, anaphylaxis§

Endocrine disorders
Common:
Very rarely:

Hypothyroidism§, hyperthyroidism§

Diabetes, aggravated diabetes
Metabolism and nutrition disorders
Very common:
Common: 
Very rarely:

Anorexia
Hypocalcaemia, dehydration, hyperuricemia, thirst
Hyperglycaemia, hypertriglyceridaemia§, increased 
appetite

 



37

Psychiatric disorders§

Very common:

Common:
Rarely: 
Very rarely:

Not known:

Depression, insomnia, anxiety, emotional lability*, 
agitation, nervousness
Confusion, sleep disorder, libido decreased
Suicide ideation
Suicide, suicide attempts, aggressive behaviour 
(sometimes directed against others), psychosis including 
hallucinations
Homicidal ideation, mental status change§, mania, bipolar 
disorders

Nervous system disorders§

Very common:
Common:

Uncommon:
Very rarely: 

Not known:

Dizziness, headache, concentration impaired, mouth dry
Tremor, paresthesia, hypoesthesia, migraine, flushing, 
somnolence, taste perversion
Peripheral neuropathy
Cerebrovascular haemorrhage, cerebrovascular ischaemia, 
seizure, impaired consciousness, encephalopathy
Mononeuropathies, coma§

Eye disorders
Very common:
Common:

Rarely:

Not known:

Vision blurred
Conjunctivitis, vision abnormal, lacrimal gland disorder, 
eye pain
Retinal haemorrhages§, retinopathies (including macular 
oedema), retinal artery or vein obstruction§, optic neuritis, 
papilloedema, loss of visual acuity or visual field, cotton-
wool spots§

Serous retinal detachment
Ear and labyrinth
Common:
Very rarely:

Vertigo, tinnitus
Hearing loss, hearing disorder

Cardiac disorders
Common:
Uncommon:
Rarely:
Very rarely:
Not known:

Palpitation, tachycardia
Pericarditis
Cardiomyopathy
Myocardial infarction, cardiac ischaemia 
Congestive heart failure, pericardial effusion, arrhythmia 

Vascular disorders
Common:
Very rarely:

Hypertension
Peripheral ischaemia, hypotension§

Respiratory, thoracic and mediastinal 
disorders
Very common:
Common:

Very rarely: 
Not known:

Dyspnoea*, coughing*
Epistaxis, respiratory disorder, nasal congestion, 
rhinorrhea, cough nonproductive
Pulmonary infiltrates§, pneumonitis§

Pulmonary fibrosis, pulmonary arterial hypertension#

Gastrointestinal disorders
Very common:

Common:

Very rarely:

Not known:

Nausea/vomiting, abdominal pain, diarrhoea, stomatitis, 
dyspepsia
Stomatitis ulcerative, right upper quadrant pain, glossitis, 
gingivitis, constipation, loose stools
Pancreatitis, ischaemic colitis, ulcerative colitis, gingival 
bleeding
Periodontal disorder NOS, dental disorder NOS, tongue 
pigmentation §

 



38

Hepatobiliary disorders
Common:
Very rarely:

Hepatomegaly
Hepatotoxicity, (including fatality)

Skin and subcutaneous tissue 
disorders
Very common:
Common:

Very rarely:

Alopecia, pruritus*, skin dry*, rash*, sweating increased
Psoriasis (new or aggravated)§, rash maculopapular, rash 
erythematous, eczema, erythema, skin disorder
Stevens Johnson syndrome, toxic epidermal necrolysis, 
erythema multiforme

Musculoskeletal and connective tissue 
disorders
Very common: 
Common:
Very rarely:

Myalgia, arthralgia, musculoskeletal pain
Arthritis
Rhabdomyolysis, myositis, leg cramps, back pain

Renal and urinary disorders
Common:
Very rarely:

Micturition frequency
Renal failure, renal insufficiency, nephrotic syndrome

Reproductive system and breast 
disorders
Common: Amenorrhea, breast pain, dysmenorrhea, menorrhagia, 

menstrual disorder, vaginal disorder
General disorders and administration 
site conditions
Very common:

Common:
Very rarely:

Injection site inflammation, injection site reaction*, 
fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia, 
irritability, chest pain, malaise
Injection site pain
Injection site necrosis, face oedema

Investigations
Very common: Weight decrease
*These events were only common with IntronA alone.
§See section 4.4
#Class label for interferon products, see below Pulmonary arterial hypertension.

These undesirable effects have also been reported with IntronA alone.

The undesirable effects seen with hepatitis C are representative of those reported when IntronA is 
administered in other indications, with some anticipated dose-related increases in incidence. For 
example, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences of 
fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-
like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C 
trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of 
patients, respectively), in comparison with the mild to moderate severity usually associated with lower 
doses. Undesirable effects were usually managed by dose adjustment. 

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with 
pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, 
that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients 
without prior evidence of cardiac disease (see section 4.4). 

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 
notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). 
Events were reported at various time points typically several months after starting treatment with 
interferon alfa.

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha 
interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or 

 



39

aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including 
mononeuropathies (see also section 4.4).

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 
10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in 
haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and 
serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase 
in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis 
subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.

Children and adolescent population 
Chronic Hepatitis C - Combination therapy with ribavirin
In clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy due 
to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent 
population studied was similar to that observed in adults, although there is a paediatric- specific 
concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of 
9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during 
treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 
44th percentile, which was below the median of the normative population and less than their mean 
baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height 
percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from 
the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was 
available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 
percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks 
with IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult height 
in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-
term follow-up was most prominent in prepubertal age children (see section 4.4).

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients 
(2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult 
patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, 
anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents 
compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for 
anaemia and neutropaenia.

The adverse reactions listed in Table 2 are based on experience from the two multicentre children and 
adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings 
of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within 
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2 Adverse reactions very commonly and commonly reported during clinical trials in
children and adolescent patients treated with IntronA in combination with ribavirin

System Organ Class Adverse Reactions
Infection and infestations
Very common:
Common:

Viral infection, pharyngitis
Fungal infection, bacterial infection, pulmonary infection, otitis 
media, tooth abscess, herpes simplex, urinary tract infection, 
vaginitis, gastroenteritis

Neoplasms benign, malignant 
and unspecified (including 
cysts and polyps)
Common: Neoplasm (unspecified)

 



40

Blood and lymphatic system 
disorders
Very common:
Common:

Anaemia, neutropaenia
Thrombocytopaenia, lymphadenopathy

Endocrine disorders
Very common:
Common:

Hypothyroidism§, 
Hyperthyroidism§, virilism

Metabolism and nutrition 
disorders
Very common:
Common:

Anorexia
Hypertriglyceridemia§, hyperuricemia, increased appetite

Psychiatric disorders§

Very common:
Common:

Depression, emotional lability, insomnia
Suicidal ideation, aggressive reaction, confusion, behaviour 
disorder, agitation, somnambulism, anxiety, nervousness, sleep 
disorder, abnormal dreaming, apathy

Nervous system disorders§

Very common:
Common:

Headache, dizziness
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, 
hyperaesthesia, concentration impaired, somnolence

Eye disorders
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Vascular disorders
Common: Flushing, pallor
Respiratory, thoracic and 
mediastinal disorders
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal 

irritation, rhinorrhea, sneezing
Gastrointestinal disorders
Very common:
Common:

Diarrhoea, vomiting, nausea, abdominal pain
Mouth ulceration, stomatitis ulcerative, stomatitis, right upper 
quadrant pain, dyspepsia, glossitis, gastroesophageal reflux, rectal 
disorder, gastrointestinal disorder, constipation, loose stools, 
toothache, tooth disorder

Hepatobiliary disorders
Common: Hepatic function abnormal
Skin and subcutaneous tissue 
disorders 
Very common:
Common:

Alopecia, rash
Photosensitivity reaction, maculopapular rash, eczema, acne, skin 
disorder, nail disorder, skin discolouration, pruritus, dry skin, 
erythema, bruise, sweating increased

Musculoskeletal and 
connective tissue disorders
Very common: Arthralgia, myalgia, musculoskeletal pain 
Renal and urinary disorders
Common: Enuresis, micturition disorder, urinary incontinence
Reproductive system and 
breast disorders
Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal 

disorder
Male: testicular pain

 



41

General disorders and 
administration site 
conditions
Very common:

Common:

Injection site inflammation, injection site reaction, fatigue, rigors, 
pyrexia§, influenza-like symptoms§, malaise, irritability
Chest pain, asthenia, oedema, injection site pain

Investigations
Very common: Growth rate decrease (height and/or weight decrease for age)§

Injury and poisoning
Common: Skin laceration
§See section 4.4

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

No case of overdose has been reported that has led to acute clinical manifestations. However, as for 
any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital 
signs and close observation of the patient is indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05

IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant 
DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of 
approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically 
engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b 
protein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activity 
of the recombinant interferon alfa-2b with the activity of the international reference preparation of 
human leukocyte interferon established by the World Health Organisation.

The interferons are a family of small protein molecules with molecular weights of approximately 
15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or 
various synthetic and biological inducers. Three major classes of interferons have been identified: 
alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain 
several different molecular species of interferon. More than 14 genetically distinct human alpha 
interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. 
Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly 
asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species 
specificity. Studies with other interferons have demonstrated species specificity. However, certain 
monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure 
to human type 1 interferons.

The results of several studies suggest that, once bound to the cell membrane, interferon initiates a 
complex sequence of intracellular events that include the induction of certain enzymes. It is thought 

 

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42

that this process, at least in part, is responsible for the various cellular responses to interferon, 
including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and 
such immunomodulating activities as enhancement of the phagocytic activity of macrophages and 
augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities 
may contribute to interferon's therapeutic effects.

Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both 
animal and human cell culture systems as well as human tumour xenografts in animals. It has 
demonstrated significant immunomodulatory activity in vitro.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact 
antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell 
metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are 
unable to leave the cell.

Chronic hepatitis B
Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates 
that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been 
observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity 
and mortality has been observed.

Interferon alfa-2b (6 MIU/m2 3 times a week for 6 months) has been given to children with chronic 
active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover 
children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of 
depression were observed.

Chronic hepatitis C in adult patients
In adult patients receiving interferon in combination with ribavirin, the achieved sustained response 
rate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferon 
with ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with a 
ribavirin dose > 10.6 mg/kg, p < 0.01).

IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical 
trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of 
IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic 
response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C 
confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/mL), a liver 
biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic 
hepatitis, and abnormal serum ALT.

IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with 
ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were 
followed for an additional 6 months after the end of treatment for the determination of sustained 
virologic response. Sustained virologic response rates for treatment groups treated for one year with 
IntronA alone or in combination with ribavirin (from two studies) are shown in Table 3.

Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for 
the treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load are 
prognostic factors which are known to affect response rates. The increased response rate to the 
combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The 
relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most 
difficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).

Response rates in these trials were increased with compliance. Regardless of genotype, patients who 
received IntronA in combination with ribavirin and received  80 % of their treatment had a higher 
sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment 
(56 % vs. 32 % in trial C/I98-580).

 



43

Table 3 Sustained virologic response rates with IntronA + ribavirin (one year of treatment) by 
genotype and viral load

HCV Genotype I
N=503

C95-132/I95-143

I/R
N=505

C95-132/I95-143

I/R
N=505

C/I98-580

All Genotypes 16 % 41 % 47 %

Genotype 1 9 % 29 % 33 %

Genotype 1 
 2 million 
copies/mL

25 % 33 % 45 %

Genotype 1
> 2 million 
copies/mL

3 % 27 % 29 %

Genotype 2/3 31 % 65 % 79 %

I IntronA (3 MIU 3 times a week)
I/R IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)

HCV/HIV Co-infected patients 
Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies, 
patients who received IntronA plus ribavirin, were less likely to respond than patients who received 
pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is 
presented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which 
enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with 
HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus 
ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a 
follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 
95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. 
Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based on 
weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin 
(800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period 
of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL 
(Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

 



44

Table 4 Sustained virological response based on genotype after IntronA in combination with 
ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in 
HCV/HIV co-infected patients

Study 11 Study 22

pegylated 
interferon alfa-
2b  (1.5 µg/kg/

week) + 
ribavirin 
(800 mg)

IntronA 
(3 MIU TIW) +  

ribavirin 
(800 mg)

p 
valuea

pegylated 
interferon 

alfa-2b (100 
or 

150c µg/week) 
+ ribavirin 

(800-
1,200 mg)d

IntronA 
(3 MIU TIW) 

+ ribavirin 
(800-

1,200 mg)d
p 

valueb

All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017

Genotype 1, 
4

17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007

Genotype 2, 
3

44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730

MIU = million international units; TIW = three times a week.
a:  p value based on Cochran-Mantel Haenszel Chi square test.
b:  p value based on chi-square test.
c:  subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week pegylated 

interferon alfa-2b.
d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al.  JAMA 2004; 292(23): 2839-2848.
2 Laguno M, Murillas J, Blanco J.L et al.  AIDS 2004; 18(13): F27-F36.

Relapse patients 
A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA 
monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA 
increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic 
hepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV 
(< 100 copies/mL by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was 
sustained when measured 6 months after the end of treatment.

Long-Term efficacy data
In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-
2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic 
response and assess the impact of continued viral negativity on clinical outcomes. 462 patients 
completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 
492 relapsed during this study. 
The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with 
a 95 % Confidence Interval of [95 %, 99 %].
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin) 
results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 
'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients 
with cirrhosis (including hepatocarcinoma).

Chronic hepatitis C in children and adolescent population
Three clinical trials have been conducted in children and adolescents; two with standard interferon and 
ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin 
were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable 
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in 
two multicentre trials and received IntronA 3 MIU/m2 3 times a week plus ribavirin 15 mg/kg per day 

 



45

for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % 
male, 80 % Caucasian, and 78 % genotype 1,64 %  12 years of age. The population enrolled mainly 
consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained 
virological response rates in children and adolescents were similar to those in adults. Due to the lack 
of data in these two multicentre trials for children with severe progression of the disease, and the 
potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b 
needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).

Study results are summarized in Table 5.

Table 5 Sustained virological response in previously untreated children and adolescents

IntronA 3 MIU/m2 3 times a week
+

ribavirin 15 mg/kg/day

Overall Responsea (n=118) 54 (46 %)*

Genotype 1 (n=92) 33 (36 %)*

Genotype 2/3/4 (n=26) 21 (81 %)*

*Number (%) of patients
a Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during 
follow-up period

Long-term efficacy data 
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C 
patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all 
enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose 
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess 
the impact of continued viral negativity on clinical outcomes for patients who were sustained 
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but 
one of the paediatric subjects remained sustained virologic responders during long-term follow-up 
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for 
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients 
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at 
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in 
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from 
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with 
cirrhosis (including hepatocarcinoma).

Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin
In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic 
hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 g/m2 plus ribavirin 
15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. 
All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received 
treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 
63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate 
hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential 
for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin 
needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs 
section 4.4). The study results are summarized in Table 6.

 



46

Table 6 Sustained virological response rates (na,b (%)) in previously untreated children and 
adolescents by genotype and treatment duration – All subjects

n = 107

24 weeks 48 weeks

All Genotypes 26/27 (96 %) 44/80 (55 %)

Genotype 1 - 38/72 (53 %)

Genotype 2 14/15 (93 %) -

Genotype 3c 12/12 (100 %) 2/3 (67 %)

Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of 

detection=125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with 
genotype 3 and high viral load (≥ 600,000 IU/mL) were to receive 48 weeks of treatment.

5.2 Pharmacokinetic properties

The pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m2

and 10 million IU doses administered subcutaneously, at 5 million IU/m2 administered intramuscularly 
and as a 30-minute intravenous infusion. The mean serum interferon concentrations following 
subcutaneous and intramuscular injections were comparable. Cmax occurred three to 12 hours after the 
lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon 
injections were approximately two to three hours, and six to seven hours, respectively. Serum levels 
were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and 
intramuscular administration resulted in bioavailabilities greater than 100 %.

After intravenous administration, serum interferon levels peaked (135 to 273 IU/mL) by the end of the 
infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular 
administration of medicinal product, becoming undetectable four hours after the infusion. The 
elimination half-life was approximately two hours.

Urine levels of interferon were below the detection limit following each of the three routes of 
administration.

Interferon neutralising factor assays were performed on serum samples of patients who received 
IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies 
which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors 
developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %. 
The detectable titres are low in almost all cases and have not been regularly associated with loss of 
response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was 
observed apparently due to the low titres.

Children and adolescent population
Multiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children and 
adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 7. The 
pharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children or 
adolescents.

 



47

Table 7 Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and ribavirin 
capsules when administered to children or adolescents with chronic hepatitis C

Parameter Ribavirin
15 mg/kg/day as 2 divided doses

(n = 17)

IntronA
3 MIU/m2 3 times a week

(n = 54)
Tmax (hr) 1.9 (83) 5.9 (36)

Cmax (ng/mL) 3,275 (25) 51 (48)
AUC* 29,774 (26) 622 (48)

Apparent clearance L/hr/kg 0.27 (27) Not done
*AUC12 (ng.hr/mL) for ribavirin; AUC0-24 (IU.hr/mL) for IntronA

Transfer into seminal fluid
Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is 
approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female 
partner after sexual intercourse with a treated patient has been estimated and remains extremely 
limited compared to therapeutic plasma concentration of ribavirin.

5.3 Preclinical safety data

Although interferon is generally recognised as being species specific, toxicity studies in animals were 
conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no 
evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with 
20 x 106 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in 
monkeys given 100 x 106 IU/kg/day for 3 months.

In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been 
observed (see section 4.4).

Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic 
in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in 
offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macaca 
mulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose 
of 2 million IU/m2. Abortion was observed in all dose groups (7.5 million, 15 million and
30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups 
(corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of 
2 million IU/m2). High doses of other forms of interferons alpha and beta are known to produce dose-
related anovulatory and abortifacient effects in rhesus monkeys.

Mutagenicity studies with interferon alfa-2b revealed no adverse events.

IntronA plus ribavirin
No studies have been conducted in juvenile animals to examine the effects of treatment with interferon 
alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results 
have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with 
ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with 
ribavirin).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium phosphate anhydrous 
Sodium dihydrogen phosphate monohydrate 
Edetate disodium 
Sodium chloride 

 



48

M-cresol 
Polysorbate 80 
Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6.

6.3 Shelf life

18 months.
Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the product is not used during the seven-day period, it cannot be put back in the 
refrigerator for a new storage period and must be discarded.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). 
Do not freeze. 
For storage conditions of the medicinal product, see section 6.3.

6.5 Nature and contents of container

0.5 mL of solution (corresponding to 5 MIU) is contained in a single dose vial (type I glass) with a 
stopper (halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene).

IntronA is supplied as:
- Pack of 1 vial
- Pack of 1 vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing swab
- Pack of 6 vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing swabs
- Pack of 12 vials, 12 injection syringes of 1 mL, 12 injection needles and 12 cleansing swabs
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Not all dose forms and strengths are appropriate for some indications. Please make sure to select an 
appropriate dose form and strength.

IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriate 
doses from the vial with a sterile injection syringe.

Detailed instructions for the subcutaneous use of the product are provided with the package leaflet 
(refer to “How to self inject IntronA”).

Preparation of IntronA for intravenous infusion: The infusion is to be prepared immediately prior to 
use. Any size vial may be used to measure the required dose; however, final concentration of 
interferon in sodium chloride solution must be not less than 0.3 million IU/mL. The appropriate dose 
of IntronA is withdrawn from the vial(s), added to 50 mL of 9 mg/mL (0.9 %) sodium chloride 
solution for injection in a PVC bag or glass bottle for intravenous use and administered over 
20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

 



49

As with all parenteral medicinal products, prior to administration inspect IntronA, solution for 
injection or infusion, visually for particulate matter and discolouration. The solution should be clear 
and colourless.

Any unused medicinal product must be discarded after withdrawal of the dose and in accordance with 
local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBERS

EU/1/99/127/015
EU/1/99/127/016
EU/1/99/127/017
EU/1/99/127/018

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 March 2000
Date of latest renewal: 9 March 2010

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



50

1. NAME OF THE MEDICINAL PRODUCT

IntronA 10 million IU/mL solution for injection or infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of solution for injection or infusion contains 10 million IU of recombinant interferon alfa-2b
produced in E. coli by recombinant DNA technology, in 1 mL of solution.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection or infusion.
Clear and colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Chronic hepatitis B
Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral 
replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg), 
elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or 
fibrosis.

Chronic hepatitis C 
Before initiating treatment with IntronA, consideration should be given to the results from clinical 
trials comparing IntronA with pegylated interferon (see section 5.1).

Adult patients 
IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated 
transaminases without liver decompensation and who are positive for hepatitis C virus RNA 
(HCV-RNA) (see section 4.4).

The best way to use IntronA in this indication is in combination with ribavirin.

Children 3 years of age and older and adolescents
IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of 
age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver 
decompensation, and who are positive for HCV-RNA. 

When deciding not to defer treatment until adulthood, it is important to consider that the combination 
therapy induced a growth inhibition that resulted in reduced final adult height in some patients. 
The decision to treat should be made on a case by case basis (see section 4.4).

Hairy cell leukaemia
Treatment of patients with hairy cell leukaemia.

Chronic myelogenous leukaemia
Monotherapy 
Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic 
myelogenous leukaemia.

 



51

Clinical experience indicates that a haematological and cytogenetic major/minor response is 
obtainable in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ 
leukaemic cells in the bone marrow, whereas a minor response is  34 %, but < 90 % Ph+ cells in the 
marrow.

Combination therapy 
The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months 
of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses 
and to significantly prolong the overall survival at three years when compared to interferon alfa-2b 
monotherapy.

Multiple myeloma
As maintenance therapy in patients who have achieved objective remission (more than 50 % reduction 
in myeloma protein) following initial induction chemotherapy.
Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the 
plateau phase; however, effects on overall survival have not been conclusively demonstrated.

Follicular lymphoma
Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction 
chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of 
the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm), 
systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats), 
splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or 
epidural involvement, serous effusion, or leukaemia.

Carcinoid tumour
Treatment of carcinoid tumours with lymph node or liver metastases and with "carcinoid syndrome".

Malignant melanoma
As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic 
recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.

4.2 Posology and method of administration

Treatment must be initiated by a physician experienced in the management of the disease.

Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and 
strength must be selected.

If adverse events develop during the course of treatment with IntronA for any indication, modify the 
dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent 
intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment 
with IntronA. At the discretion of the physician, the patient may self-administer the dose for 
maintenance dose regimens administered subcutaneously.

Chronic hepatitis B
The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a 
week (every other day) for a period of 4 to 6 months.

The administered dose should be reduced by 50 % in case of occurrence of haematological disorders 
(white blood cells < 1,500/mm3, granulocytes < 1,000/mm3, thrombocytes < 100,000/mm3). Treatment 
should be discontinued in case of severe leukopaenia (< 1,200/mm3), severe neutropaenia (< 750/mm3) 
or severe thrombocytopaenia (< 70,000/mm3).

For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment 
(at the maximum tolerated dose), discontinue IntronA therapy.

 



52

Chronic hepatitis C
Adults
IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day) 
to adult patients, whether administered as monotherapy or in combination with ribavirin.

Children 3 years of age or older and adolescents
IntronA 3 MIU/m2 is administered subcutaneously 3 times a week (every other day) in combination 
with ribavirin capsules or oral solution administered orally in two divided doses daily with food 
(morning and evening). 

(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for 
combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see 
ribavirin oral solution SPC.)

Relapse patients (adults)
IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are 
available for 6 months of treatment, it is recommended that patients be treated with IntronA in 
combination with ribavirin for 6 months.

Naïve patients (adults)
The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be 
given alone mainly in case of intolerance or contraindication to ribavirin.

- IntronA in combination with ribavirin
Based on the results of clinical trials, in which data are available for 12 months of treatment, it is 
recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.

Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who 
exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment 
sample) and high pre-treatment viral load.

Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into 
account in order to extend therapy to 12 months.

During clinical trials, patients who failed to show a virologic response after 6 months of treatment 
(HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-
RNA below lower limit of detection six months after withdrawal of treatment).

- IntronA alone
The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of 
between 12 and 18 months is advised.

It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point 
HCV-RNA status should be determined. Treatment should be continued in patients who exhibit 
negative HCV-RNA.

Naïve patients (children and adolescents)
The efficacy and safety of IntronA in combination with ribavirin has been studied in children and 
adolescents who have not been previously treated for chronic hepatitis C. 

Duration of treatment for children and adolescents
 Genotype 1: The recommended duration of treatment is one year. Patients who fail to achieve 

virological response at 12 weeks are highly unlikely to become sustained virological responders 
(negative predictive value 96 %). Therefore, it is recommended that children and adolescent 
patients receiving IntronA/ribavirin combination be discontinued from therapy if their week 12 
HCV-RNA dropped < 2 log10 compared to pretreatment, or if they have detectable HCV-RNA 
at treatment week 24.

 



53

 Genotype 2/3: The recommended duration of treatment is 24 weeks.

Hairy cell leukaemia
The recommended dose is 2 million IU/m2 administered subcutaneously three times a week (every 
other day) for both splenectomised and non-splenectomised patients. For most patients with hairy cell 
leukaemia, normalisation of one or more haematological variables occurs within one to two months of 
IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet 
count and haemoglobin level) may require six months or more. This regimen must be maintained 
unless the disease progresses rapidly or severe intolerance is manifested.

Chronic myelogenous leukaemia
The recommended dose of IntronA is 4 to 5 million IU/m2 administered daily subcutaneously. Some 
patients have been shown to benefit from IntronA 5 million IU/m2 administered daily subcutaneously 
in association with cytarabine (Ara-C) 20 mg/m2 administered daily subcutaneously for 10 days per 
month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled, 
administer the maximum tolerated dose of IntronA (4 to 5 million IU/m2 daily) to maintain 
haematological remission.

IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial 
haematological remission or a clinically meaningful cytoreduction has not been achieved.

Multiple myeloma
Maintenance therapy 
In patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following 
initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy, 
subcutaneously, at a dose of 3 million IU/m2 three times a week (every other day).

Follicular lymphoma
Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of 
5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens 
are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide, 
doxorubicin, teniposide and prednisolone).

Carcinoid tumour
The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week 
(every other day). Patients with advanced disease may require a daily dose of 5 million IU. The 
treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long 
as the patient responds to interferon alfa-2b treatment.

Malignant melanoma
As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m2

daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to 
sodium chloride 9 mg/mL (0.9 %) solution for injection and administered as a 20-minute infusion (see 
section 6.6). As maintenance treatment, the recommended dose is 10 million IU/m2 administered 
subcutaneously three days a week (every other day) for 48 weeks.

If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes 
decrease to < 500/mm3 or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to 
> 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates. 
Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after 
dose adjustment or if granulocytes decrease to < 250/mm3 or ALT/AST rises to > 10 x upper limit of 
normal, discontinue interferon alfa-2b therapy.

Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at 
the recommended dose, with dose reduction for toxicity as described.

IntronA may be administered using either glass or plastic disposable injection syringes.

 



54

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure, 

recent myocardial infarction, severe arrhythmic disorders. 
- Severe renal or hepatic dysfunction; including that caused by metastases.
- Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).
- Chronic hepatitis with decompensated cirrhosis of the liver.
- Chronic hepatitis in patients who are being or have been treated recently with 

immunosuppressive agents excluding short term corticosteroid withdrawal.
- Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant 

recipients.
- Pre-existing thyroid disease unless it can be controlled with conventional treatment.
- Combination of IntronA with telbivudine.

Children and adolescents
- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal 

ideation or suicide attempt.

Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

4.4 Special warnings and precautions for use

Psychiatric and central nervous system (CNS)
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been 
observed in some patients during IntronA therapy, and even after treatment discontinuation mainly 
during the 6-month follow-up period. Among children and adolescents treated with IntronA in 
combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult 
patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult 
patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes 
directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of 
mental status have been observed with alpha interferons. Patients should be closely monitored for any 
signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of 
these undesirable effects must be borne in mind by the prescribing physician and the need for adequate 
therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal 
or homicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, and 
the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions:
If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe 
psychiatric conditions, this should only be initiated after having ensured appropriate individualised 
diagnostic and therapeutic management of the psychiatric condition.
- The use of interferon alfa-2b in children and adolescents with existence of or history of severe 

psychiatric conditions is contraindicated (see section 4.3).

Patients with substance use/abuse:
HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an 
increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders 
when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, 
the presence of psychiatric co-morbidities and the potential for other substance use should be carefully 
assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach 
including a mental health care provider or addiction specialist should be considered to evaluate, treat and 
follow the patient. Patients should be closely monitored during therapy and even after treatment 

 



55

discontinuation. Early intervention for re-emergence or development of psychiatric disorders and 
substance use is recommended.

Children and adolescent population: Growth and development (chronic hepatitis C)
During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to 
48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see 
sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy 
with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile 
decrease in height percentile as compared to baseline) in 21 % of children (n=20) despite being off 
treatment for more than 5 years. Final adult height was available for 14 of those children and 
demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of 
treatment.

Case by case benefit/risk assessment in children 
The expected benefit of treatment should be carefully weighed against the safety findings observed for 
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
- It is important to consider that the combination therapy induced a growth inhibition that resulted 

in reduced final adult height in some patients.
- This risk should be weighed against the disease characteristics of the child, such as evidence

of disease progression (notably fibrosis), co-morbidities that may negatively influence the 
disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV 
genotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the 
risk of growth inhibition. There are no data on long term effects on sexual maturation.

Hypersensitivity reactions
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to 
interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops, 
discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate 
interruption of treatment.

Adverse experiences including prolongation of coagulation markers and liver abnormalities
Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in 
some cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation and 
death in patients with cirrhosis.
Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of 
coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with IntronA must be monitored 
closely and treatment discontinued if signs and symptoms progress.
Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Hypotension
Hypotension may occur during IntronA therapy or up to two days post-therapy and may require 
supportive treatment.

Need for adequate hydration
Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension 
related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.

Pyrexia
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon 
therapy, other causes of persistent pyrexia must be ruled out.

Patients with debilitating medical conditions
IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a 
history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone 

 



56

to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g., 
thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Pulmonary conditions
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any 
patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray 
taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function 
impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. 
While this has been reported more often in patients with chronic hepatitis C treated with interferon 
alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. 
Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to 
be associated with resolution of pulmonary adverse events.

Ocular adverse events
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous 
retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after 
treatment with alpha interferons. All patients should have a baseline eye examination. Any patient 
complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms 
during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual 
examinations during IntronA therapy are recommended particularly in patients with disorders that may 
be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA 
should be considered in patients who develop new or worsening ophthalmological disorders.

Obtundation, coma and encephalopathy
More significant obtundation and coma, including cases of encephalopathy, have been observed in 
some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a 
few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high 
doses of IntronA.

Patients with pre-existing cardiac abnormalities
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or 
current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is 
recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced 
stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac 
arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require 
discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac 
disease.

Hypertriglyceridemia
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. 
Monitoring of lipid levels is, therefore, recommended.

Patients with psoriasis and sarcoidosis
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of 
IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies 
the potential risk.

Kidney and liver graft rejection
Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of 
kidney graft rejection. Liver graft rejection has also been reported.

Auto-antibodies and autoimmune disorders
The development of auto-antibodies and autoimmune disorders has been reported during treatment 
with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at 

 



57

increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be 
evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also 
section 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic 
hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting 
the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment 
should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Concomitant chemotherapy 
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration), which may be life-threatening or fatal as a result of the concomitantly administered 
medicinal product. The most commonly reported potentially life-threatening or fatal adverse events 
include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of 
the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the 
concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the 
frequency and severity of cutaneous vasculitis may be increased.

Chronic hepatitis C
Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases 
(i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. 
Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to 
commencing treatment.

Monotherapy 
Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid 
abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 
2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by 
conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid 
status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C, 
evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that 
time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can 
be maintained in the normal range by medication. Determine TSH levels if, during the course of 
IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the 
presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained 
in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid 
dysfunction occurring during treatment (also see Thyroid supplemental monitoring specific for 
children and adolescents).

Thyroid supplemental monitoring specific for children and adolescents
Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy 
developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease 
below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated 
and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA 
therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid 
dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid 
abnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinically 
appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid 
dysfunction (e.g. TSH).

HCV/HIV Coinfection
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at 
increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to 

 



58

HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy 
and zidovudine could be at increased risk of developing anaemia.
Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic 
decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin 
may increase the risk in this patient subset. 

HCV/HBV Coinfection
Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-
infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation 
appears to be low.
All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; 
patients co-infected with hepatitis B and C must then be monitored and managed according to current 
clinical guidelines.

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients 
receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging 
effect on teeth and mucous membranes of the mouth during long-term treatment with the combination 
of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular 
dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they 
should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests 
Standard haematological tests and blood chemistries (complete blood count and differential, platelet 
count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be 
conducted in all patients prior to and periodically during systemic treatment with IntronA.

During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, 
and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to 
greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and 
symptoms of liver failure are observed. During ALT flare, the following liver function tests must be 
monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.

In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and 
differential must be monitored weekly during the induction phase of therapy and monthly during the 
maintenance phase of therapy.

Effect on fertility
Interferon may impair fertility (see section 4.6 and section 5.3).

Important information about some of the ingredients of IntronA 
This medicinal product contains less than 1 mmol sodium (23 mg) per 1 mL, i.e., essentially "sodium-
free".

4.5 Interaction with other medicinal products and other forms of interaction 

Interaction studies have only been performed in adults.

Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with 
IntronA.

Interactions between IntronA and other medicinal products have not been fully evaluated. Caution 
must be exercised when administering IntronA in combination with other potentially 
myelosuppressive agents.

Interferons may affect the oxidative metabolic process. This must be considered during concomitant 
therapy with medicinal products metabolised by this route, such as the xanthine derivatives 

 



59

theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline 
levels must be monitored and dose adjusted if necessary.

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration) (see section 4.4).

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon 
alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination 
is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these 
events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SPC). Moreover, the safety and 
efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not 
been demonstrated. Therefore, the combination of IntronA with telbivudine is contraindicated (see 
section 4.3).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females
Women of childbearing potential have to use effective contraception during treatment. Decreased 
serum estradiol and progesterone concentrations have been reported in women treated with human 
leukocyte interferon.

IntronA must be used with caution in fertile men.

Combination therapy with ribavirin 
Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be 
taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in 
combination with ribavirin. Females of childbearing potential must use an effective contraceptive 
during treatment and for 4 months after treatment has been concluded. Male patients or their female 
partners must use an effective contraceptive during treatment and for 7 months after treatment has 
been concluded (see ribavirin SPC).

Pregnancy
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA 
is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin 
Ribavirin therapy is contraindicated in women who are pregnant.

Breast-feeding
It is not known whether the components of this medicinal product are excreted in human milk. 
Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior 
to initiation of treatment.

4.7 Effects on ability to drive and use machines

Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment 
with IntronA, and therefore it is recommended that they avoid driving or operating machinery.

 



60

4.8 Undesirable effects

See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in 
combination with ribavirin in patients with chronic hepatitis C.

In clinical trials conducted in a broad range of indications and at a wide range of doses (from 
6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonly 
reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were 
often reversible within 72 hours of interruption or cessation of treatment.

Adults
In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in 
combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three 
times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is 
presented from clinical trials in naïve patients treated for one year. Severity was generally mild to 
moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and 
post-marketing. Within the organ system classes, adverse reactions are listed under headings of 
frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10);
uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported during clinical trials or following the marketing use of 
IntronA alone or in combination with ribavirin

System Organ Class Adverse Reactions
Infections and infestations
Very common:
Common:
Uncommon:
Rarely:
Not known:

Pharyngitis*, infection viral*
Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Bacterial infection
Pneumonia§, sepsis
Hepatitis B reactivation in HCV/HBV co-infected patients

Blood and lymphatic system disorders
Very common:
Common:
Very rarely: 
Not known: 

Leukopaenia
Thrombocytopaenia, lymphadenopathy, lymphopenia
Aplastic anaemia
Pure red cell aplasia, idiopathic thrombocytopenic 
purpura, thrombotic thrombocytopenic purpura 

Immune system disorders§

Very rarely: 
Not known:

Sarcoidosis, exacerbation of sarcoidosis
Systemic lupus erythematosus, vasculitis, rheumatoid 
arthritis (new or aggravated), Vogt-Koyanagi-Harada 
syndrome, acute hypersensitivity reactions including 
urticaria, angioedema, bronchoconstriction, anaphylaxis§

Endocrine disorders
Common:
Very rarely:

Hypothyroidism§, hyperthyroidism§

Diabetes, aggravated diabetes
Metabolism and nutrition disorders
Very common:
Common: 
Very rarely:

Anorexia
Hypocalcaemia, dehydration, hyperuricemia, thirst
Hyperglycaemia, hypertriglyceridaemia§, increased 
appetite

 



61

Psychiatric disorders§

Very common:

Common:
Rarely: 
Very rarely:

Not known:

Depression, insomnia, anxiety, emotional lability*, 
agitation, nervousness
Confusion, sleep disorder, libido decreased
Suicide ideation
Suicide, suicide attempts, aggressive behaviour 
(sometimes directed against others), psychosis including 
hallucinations
Homicidal ideation, mental status change§, mania, bipolar 
disorders

Nervous system disorders§

Very common:
Common:

Uncommon:
Very rarely: 

Not known:

Dizziness, headache, concentration impaired, mouth dry
Tremor, paresthesia, hypoesthesia, migraine, flushing, 
somnolence, taste perversion
Peripheral neuropathy
Cerebrovascular haemorrhage, cerebrovascular ischaemia, 
seizure, impaired consciousness, encephalopathy
Mononeuropathies, coma§

Eye disorders
Very common:
Common:

Rarely: 

Not known:

Vision blurred
Conjunctivitis, vision abnormal, lacrimal gland disorder, 
eye pain
Retinal haemorrhages§, retinopathies (including macular 
oedema), retinal artery or vein obstruction§, optic neuritis, 
papilloedema, loss of visual acuity or visual field, cotton-
wool spots§

Serous retinal detachment
Ear and labyrinth
Common:
Very rarely:

Vertigo, tinnitus
Hearing loss, hearing disorder

Cardiac disorders
Common:
Uncommon:
Rarely:
Very rarely:
Not known:

Palpitation, tachycardia
Pericarditis
Cardiomyopathy
Myocardial infarction, cardiac ischaemia 
Congestive heart failure, pericardial effusion, arrhythmia 

Vascular disorders
Common:
Very rarely:

Hypertension
Peripheral ischaemia, hypotension§

Respiratory, thoracic and mediastinal 
disorders
Very common:
Common:

Very rarely: 
Not known:

Dyspnoea*, coughing*
Epistaxis, respiratory disorder, nasal congestion, 
rhinorrhea, cough nonproductive
Pulmonary infiltrates§, pneumonitis§

Pulmonary fibrosis, pulmonary arterial hypertension#

Gastrointestinal disorders
Very common:

Common:

Very rarely:

Not known:

Nausea/vomiting, abdominal pain, diarrhoea, stomatitis, 
dyspepsia
Stomatitis ulcerative, right upper quadrant pain, glossitis, 
gingivitis, constipation, loose stools
Pancreatitis, ischaemic colitis, ulcerative colitis, gingival 
bleeding
Periodontal disorder NOS, dental disorder NOS, tongue 
pigmentation §

 



62

Hepatobiliary disorders
Common:
Very rarely:

Hepatomegaly
Hepatotoxicity, (including fatality)

Skin and subcutaneous tissue 
disorders
Very common:
Common:

Very rarely:

Alopecia, pruritus*, skin dry*, rash*, sweating increased
Psoriasis (new or aggravated)§, rash maculopapular, rash 
erythematous, eczema, erythema, skin disorder
Stevens Johnson syndrome, toxic epidermal necrolysis, 
erythema multiforme

Musculoskeletal and connective tissue 
disorders
Very common: 
Common:
Very rarely:

Myalgia, arthralgia, musculoskeletal pain
Arthritis
Rhabdomyolysis, myositis, leg cramps, back pain

Renal and urinary disorders
Common:
Very rarely:

Micturition frequency
Renal failure, renal insufficiency, nephrotic syndrome

Reproductive system and breast 
disorders
Common: Amenorrhea, breast pain, dysmenorrhea, menorrhagia, 

menstrual disorder, vaginal disorder
General disorders and administration 
site conditions
Very common:

Common:
Very rarely:

Injection site inflammation, injection site reaction*, 
fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia, 
irritability, chest pain, malaise
Injection site pain
Injection site necrosis, face oedema

Investigations
Very common: Weight decrease
*These events were only common with IntronA alone.
§See section 4.4
#Class label for interferon products, see below Pulmonary arterial hypertension.

These undesirable effects have also been reported with IntronA alone.

The undesirable effects seen with hepatitis C are representative of those reported when IntronA is 
administered in other indications, with some anticipated dose-related increases in incidence. For 
example, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences of 
fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-
like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C 
trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of 
patients, respectively), in comparison with the mild to moderate severity usually associated with lower 
doses. Undesirable effects were usually managed by dose adjustment. 

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with 
pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, 
that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients 
without prior evidence of cardiac disease (see section 4.4). 

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 
notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). 
Events were reported at various time points typically several months after starting treatment with 
interferon alfa.

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha 
interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or 

 



63

aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including 
mononeuropathies (see also section 4.4).

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 
10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in 
haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and 
serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase 
in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis 
subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.

Children and adolescent population 
Chronic Hepatitis C - Combination therapy with ribavirin
In clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy due 
to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent 
population studied was similar to that observed in adults, although there is a paediatric- specific 
concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of 
9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during 
treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 
44th percentile, which was below the median of the normative population and less than their mean 
baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height 
percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from 
the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was 
available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 
percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks 
with IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult height 
in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-
term follow-up was most prominent in prepubertal age children (see section 4.4).

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients 
(2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult 
patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, 
anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents 
compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for 
anaemia and neutropaenia.

The adverse reactions listed in Table 2 are based on experience from the two multicentre children and 
adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings 
of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within 
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2 Adverse reactions very commonly and commonly reported during clinical trials in
children and adolescent patients treated with IntronA in combination with ribavirin

System Organ Class Adverse Reactions
Infection and infestations
Very common:
Common:

Viral infection, pharyngitis
Fungal infection, bacterial infection, pulmonary infection, otitis 
media, tooth abscess, herpes simplex, urinary tract infection, 
vaginitis, gastroenteritis

Neoplasms benign, malignant 
and unspecified (including 
cysts and polyps)
Common: Neoplasm (unspecified)

 



64

Blood and lymphatic system 
disorders
Very common:
Common:

Anaemia, neutropaenia
Thrombocytopaenia, lymphadenopathy

Endocrine disorders
Very common:
Common:

Hypothyroidism§, 
Hyperthyroidism§, virilism

Metabolism and nutrition 
disorders
Very common:
Common:

Anorexia
Hypertriglyceridemia§, hyperuricemia, increased appetite

Psychiatric disorders§

Very common:
Common:

Depression, emotional lability, insomnia
Suicidal ideation, aggressive reaction, confusion, behaviour 
disorder, agitation, somnambulism, anxiety, nervousness, sleep 
disorder, abnormal dreaming, apathy

Nervous system disorders§

Very common:
Common:

Headache, dizziness
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, 
hyperaesthesia, concentration impaired, somnolence

Eye disorders
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Vascular disorders
Common: Flushing, pallor
Respiratory, thoracic and 
mediastinal disorders
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal 

irritation, rhinorrhea, sneezing
Gastrointestinal disorders
Very common:
Common:

Diarrhoea, vomiting, nausea, abdominal pain
Mouth ulceration, stomatitis ulcerative, stomatitis, right upper 
quadrant pain, dyspepsia, glossitis, gastroesophageal reflux, rectal 
disorder, gastrointestinal disorder, constipation, loose stools, 
toothache, tooth disorder

Hepatobiliary disorders
Common: Hepatic function abnormal
Skin and subcutaneous tissue 
disorders 
Very common:
Common:

Alopecia, rash
Photosensitivity reaction, maculopapular rash, eczema, acne, skin 
disorder, nail disorder, skin discolouration, pruritus, dry skin, 
erythema, bruise, sweating increased

Musculoskeletal and 
connective tissue disorders
Very common: Arthralgia, myalgia, musculoskeletal pain 
Renal and urinary disorders
Common: Enuresis, micturition disorder, urinary incontinence
Reproductive system and 
breast disorders
Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal 

disorder
Male: testicular pain

 



65

General disorders and 
administration site 
conditions
Very common:

Common:

Injection site inflammation, injection site reaction, fatigue, rigors, 
pyrexia§, influenza-like symptoms§, malaise, irritability
Chest pain, asthenia, oedema, injection site pain

Investigations
Very common: Growth rate decrease (height and/or weight decrease for age)§

Injury and poisoning
Common: Skin laceration
§See section 4.4

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

No case of overdose has been reported that has led to acute clinical manifestations. However, as for 
any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital 
signs and close observation of the patient is indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05

IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant 
DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of 
approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically 
engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b 
protein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activity 
of the recombinant interferon alfa-2b with the activity of the international reference preparation of 
human leukocyte interferon established by the World Health Organisation.

The interferons are a family of small protein molecules with molecular weights of approximately 
15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or 
various synthetic and biological inducers. Three major classes of interferons have been identified: 
alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain 
several different molecular species of interferon. More than 14 genetically distinct human alpha 
interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. 
Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly 
asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species 
specificity. Studies with other interferons have demonstrated species specificity. However, certain 
monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure 
to human type 1 interferons.

The results of several studies suggest that, once bound to the cell membrane, interferon initiates a 
complex sequence of intracellular events that include the induction of certain enzymes. It is thought 

 

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66

that this process, at least in part, is responsible for the various cellular responses to interferon, 
including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and 
such immunomodulating activities as enhancement of the phagocytic activity of macrophages and 
augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities 
may contribute to interferon's therapeutic effects.

Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both 
animal and human cell culture systems as well as human tumour xenografts in animals. It has 
demonstrated significant immunomodulatory activity in vitro.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact 
antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell 
metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are 
unable to leave the cell.

Chronic hepatitis B
Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates 
that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been 
observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity 
and mortality has been observed.

Interferon alfa-2b (6 MIU/m2 3 times a week for 6 months) has been given to children with chronic 
active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover 
children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of 
depression were observed.

Chronic hepatitis C in adult patients
In adult patients receiving interferon in combination with ribavirin, the achieved sustained response 
rate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferon 
with ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with a 
ribavirin dose > 10.6 mg/kg, p < 0.01).

IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical 
trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of 
IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic 
response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C 
confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/mL), a liver 
biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic 
hepatitis, and abnormal serum ALT.

IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with 
ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were 
followed for an additional 6 months after the end of treatment for the determination of sustained 
virologic response. Sustained virologic response rates for treatment groups treated for one year with
IntronA alone or in combination with ribavirin (from two studies) are shown in Table 3.

Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for 
the treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load are 
prognostic factors which are known to affect response rates. The increased response rate to the 
combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The 
relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most 
difficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).

Response rates in these trials were increased with compliance. Regardless of genotype, patients who 
received IntronA in combination with ribavirin and received  80 % of their treatment had a higher 
sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment 
(56 % vs. 32 % in trial C/I98-580).

 



67

Table 3 Sustained virologic response rates with IntronA + ribavirin (one year of treatment) by 
genotype and viral load

HCV Genotype I
N=503

C95-132/I95-143

I/R
N=505

C95-132/I95-143

I/R
N=505

C/I98-580

All Genotypes 16 % 41 % 47 %

Genotype 1 9 % 29 % 33 %

Genotype 1 
 2 million 
copies/mL

25 % 33 % 45 %

Genotype 1
> 2 million 
copies/mL

3 % 27 % 29 %

Genotype 2/3 31 % 65 % 79 %

I IntronA (3 MIU 3 times a week)
I/R IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)

HCV/HIV Co-infected patients 
Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies, 
patients who received IntronA plus ribavirin, were less likely to respond than patients who received 
pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is 
presented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which 
enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with 
HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus 
ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a 
follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 
95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. 
Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based on 
weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin 
(800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period 
of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL 
(Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

 



68

Table 4 Sustained virological response based on genotype after IntronA in combination with 
ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in 
HCV/HIV co-infected patients

Study 11 Study 22

pegylated 
interferon alfa-
2b  (1.5 µg/kg/

week) + 
ribavirin 
(800 mg)

IntronA 
(3 MIU TIW) +  

ribavirin 
(800 mg)

p 
valuea

pegylated 
interferon 

alfa-2b (100 
or 

150c µg/week) 
+ ribavirin 

(800-
1,200 mg)d

IntronA 
(3 MIU TIW) 

+ ribavirin 
(800-

1,200 mg)d
p 

valueb

All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017

Genotype 1, 
4

17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007

Genotype 2, 
3

44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730

MIU = million international units; TIW = three times a week.
a:  p value based on Cochran-Mantel Haenszel Chi square test.
b:  p value based on chi-square test.
c:  subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week pegylated 

interferon alfa-2b.
d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al.  JAMA 2004; 292(23): 2839-2848.
2 Laguno M, Murillas J, Blanco J.L et al.  AIDS 2004; 18(13): F27-F36.

Relapse patients 
A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA 
monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA 
increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic 
hepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV 
(< 100 copies/mL by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was 
sustained when measured 6 months after the end of treatment.

Long-Term efficacy data
In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-
2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic 
response and assess the impact of continued viral negativity on clinical outcomes. 462 patients 
completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 
492 relapsed during this study. 
The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with 
a 95 % Confidence Interval of [95 %, 99 %]. 
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin) 
results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 
'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients 
with cirrhosis (including hepatocarcinoma).

Chronic hepatitis C in children and adolescent population
Three clinical trials have been conducted in children and adolescents; two with standard interferon and 
ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin 
were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable 
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in 
two multicentre trials and received IntronA 3 MIU/m2 3 times a week plus ribavirin 15 mg/kg per day 

 



69

for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % 
male, 80 % Caucasian, and 78 % genotype 1,64 %  12 years of age. The population enrolled mainly 
consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained 
virological response rates in children and adolescents were similar to those in adults. Due to the lack 
of data in these two multicentre trials for children with severe progression of the disease, and the 
potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b 
needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).

Study results are summarized in Table 5.

Table 5 Sustained virological response in previously untreated children and adolescents

IntronA 3 MIU/m2 3 times a week
+

ribavirin 15 mg/kg/day

Overall Responsea (n=118) 54 (46 %)*

Genotype 1 (n=92) 33 (36 %)*

Genotype 2/3/4 (n=26) 21 (81 %)*

*Number (%) of patients
a Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during 
follow-up period

Long-term efficacy data 
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C 
patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all 
enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose 
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess 
the impact of continued viral negativity on clinical outcomes for patients who were sustained 
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but 
one of the paediatric subjects remained sustained virologic responders during long-term follow-up 
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for 
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients 
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at 
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in 
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from 
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with 
cirrhosis (including hepatocarcinoma).

Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin
In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic 
hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 g/m2 plus ribavirin 
15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. 
All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received 
treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 
63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate 
hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential 
for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin 
needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs 
section 4.4). The study results are summarized in Table 6.

 



70

Table 6 Sustained virological response rates (na,b (%)) in previously untreated children and 
adolescents by genotype and treatment duration – All subjects

n = 107

24 weeks 48 weeks

All Genotypes 26/27 (96 %) 44/80 (55 %)

Genotype 1 - 38/72 (53 %)

Genotype 2 14/15 (93 %) -

Genotype 3c 12/12 (100 %) 2/3 (67 %)

Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of 

detection=125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with 
genotype 3 and high viral load (≥ 600,000 IU/mL) were to receive 48 weeks of treatment.

5.2 Pharmacokinetic properties

The pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m2

and 10 million IU doses administered subcutaneously, at 5 million IU/m2 administered intramuscularly 
and as a 30-minute intravenous infusion. The mean serum interferon concentrations following 
subcutaneous and intramuscular injections were comparable. Cmax occurred three to 12 hours after the 
lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon 
injections were approximately two to three hours, and six to seven hours, respectively. Serum levels 
were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and 
intramuscular administration resulted in bioavailabilities greater than 100 %.

After intravenous administration, serum interferon levels peaked (135 to 273 IU/mL) by the end of the 
infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular 
administration of medicinal product, becoming undetectable four hours after the infusion. The 
elimination half-life was approximately two hours.

Urine levels of interferon were below the detection limit following each of the three routes of 
administration.

Interferon neutralising factor assays were performed on serum samples of patients who received 
IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies 
which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors 
developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %. 
The detectable titres are low in almost all cases and have not been regularly associated with loss of 
response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was 
observed apparently due to the low titres.

Children and adolescent population
Multiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children and 
adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 7. The 
pharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children or 
adolescents.

 



71

Table 7 Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and ribavirin 
capsules when administered to children or adolescents with chronic hepatitis C

Parameter Ribavirin
15 mg/kg/day as 2 divided doses

(n = 17)

IntronA
3 MIU/m2 3 times a week

(n = 54)
Tmax (hr) 1.9 (83) 5.9 (36)

Cmax (ng/mL) 3,275 (25) 51 (48)
AUC* 29,774 (26) 622 (48)

Apparent clearance L/hr/kg 0.27 (27) Not done
*AUC12 (ng.hr/mL) for ribavirin; AUC0-24 (IU.hr/mL) for IntronA

Transfer into seminal fluid
Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is 
approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female 
partner after sexual intercourse with a treated patient has been estimated and remains extremely 
limited compared to therapeutic plasma concentration of ribavirin.

5.3 Preclinical safety data

Although interferon is generally recognised as being species specific, toxicity studies in animals were 
conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no 
evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with 
20 x 106 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in 
monkeys given 100 x 106 IU/kg/day for 3 months.

In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been 
observed (see section 4.4).

Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic 
in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in 
offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macaca 
mulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose 
of 2 million IU/m2. Abortion was observed in all dose groups (7.5 million, 15 million and 
30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups 
(corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of 
2 million IU/m2). High doses of other forms of interferons alpha and beta are known to produce dose-
related anovulatory and abortifacient effects in rhesus monkeys.

Mutagenicity studies with interferon alfa-2b revealed no adverse events.

IntronA plus ribavirin
No studies have been conducted in juvenile animals to examine the effects of treatment with interferon 
alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results 
have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with 
ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with 
ribavirin).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium phosphate anhydrous 
Sodium dihydrogen phosphate monohydrate 
Edetate disodium 
Sodium chloride 

 



72

M-cresol 
Polysorbate 80
Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6.

6.3 Shelf life

18 months.
Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the product is not used during the seven-day period, it cannot be put back in the 
refrigerator for a new storage period and must be discarded.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). 
Do not freeze. 
For storage conditions of the medicinal product, see section 6.3.

6.5 Nature and contents of container

1 mL of solution (corresponding to 10 MIU) is contained in a single dose vial (type I glass) with a 
stopper (halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene).

IntronA is supplied as:
- Pack of 1 vial
- Pack of 1 vial, 1 injection syringe of 2 mL, 1 injection needle and 1 cleansing swab
- Pack of 6 vials, 6 injection syringes of 2 mL, 6 injection needles and 6 cleansing swabs
- Pack of 12 vials, 12 injection syringes of 2 mL, 12 injection needles and 12 cleansing swabs
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Not all dose forms and strengths are appropriate for some indications. Please make sure to select an 
appropriate dose form and strength.

IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriate 
doses from the vial with a sterile injection syringe.

Detailed instructions for the subcutaneous use of the product are provided with the package leaflet 
(refer to “How to self inject IntronA”).

Preparation of IntronA for intravenous infusion: The infusion is to be prepared immediately prior to 
use. Any size vial may be used to measure the required dose; however, final concentration of 
interferon in sodium chloride solution must be not less than 0.3 million IU/mL. The appropriate dose 
of IntronA is withdrawn from the vial(s), added to 50 mL of 9 mg/mL (0.9 %) sodium chloride 
solution for injection in a PVC bag or glass bottle for intravenous use and administered over 
20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

 



73

As with all parenteral medicinal products, prior to administration inspect IntronA, solution for 
injection or infusion, visually for particulate matter and discolouration. The solution should be clear 
and colourless.

Any unused medicinal product must be discarded after withdrawal of the dose and in accordance with 
local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBERS

EU/1/99/127/019
EU/1/99/127/020
EU/1/99/127/021
EU/1/99/127/022

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 March 2000
Date of latest renewal: 9 March 2010

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



74

1. NAME OF THE MEDICINAL PRODUCT

IntronA 18 million IU/3 mL solution for injection or infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of solution for injection or infusion contains 18 million IU of recombinant interferon alfa-2b
produced in E. coli by recombinant DNA technology, in 3 mL of solution.

One mL of solution contains 6 million IU of interferon alfa-2b.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection or infusion.
Clear and colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Chronic hepatitis B
Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral 
replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg), 
elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or 
fibrosis.

Chronic hepatitis C 
Before initiating treatment with IntronA, consideration should be given to the results from clinical 
trials comparing IntronA with pegylated interferon (see section 5.1).

Adult patients 
IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated 
transaminases without liver decompensation and who are positive for hepatitis C virus RNA 
(HCV-RNA) (see section 4.4).

The best way to use IntronA in this indication is in combination with ribavirin.

Children 3 years of age and older and adolescents
IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of 
age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver 
decompensation, and who are positive for HCV-RNA. 

When deciding not to defer treatment until adulthood, it is important to consider that the combination 
therapy induced a growth inhibition that resulted in reduced final adult height in some patients. 
The decision to treat should be made on a case by case basis (see section 4.4).

Hairy cell leukaemia
Treatment of patients with hairy cell leukaemia.

 



75

Chronic myelogenous leukaemia
Monotherapy 
Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic 
myelogenous leukaemia.
Clinical experience indicates that a haematological and cytogenetic major/minor response is 
obtainable in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ 
leukaemic cells in the bone marrow, whereas a minor response is  34 %, but < 90 % Ph+ cells in the 
marrow.

Combination therapy 
The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months 
of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses 
and to significantly prolong the overall survival at three years when compared to interferon alfa-2b 
monotherapy.

Multiple myeloma
As maintenance therapy in patients who have achieved objective remission (more than 50 % reduction 
in myeloma protein) following initial induction chemotherapy.
Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the 
plateau phase; however, effects on overall survival have not been conclusively demonstrated.

Follicular lymphoma
Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction 
chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of 
the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm), 
systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats), 
splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or 
epidural involvement, serous effusion, or leukaemia.

Carcinoid tumour
Treatment of carcinoid tumours with lymph node or liver metastases and with "carcinoid syndrome".

Malignant melanoma
As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic 
recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.

4.2 Posology and method of administration

Treatment must be initiated by a physician experienced in the management of the disease.

Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and 
strength must be selected.

If adverse events develop during the course of treatment with IntronA for any indication, modify the 
dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent 
intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment 
with IntronA. At the discretion of the physician, the patient may self-administer the dose for 
maintenance dose regimens administered subcutaneously.

Chronic hepatitis B
The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a 
week (every other day) for a period of 4 to 6 months.

The administered dose should be reduced by 50 % in case of occurrence of haematological disorders 
(white blood cells < 1,500/mm3, granulocytes < 1,000/mm3, thrombocytes < 100,000/mm3). Treatment 
should be discontinued in case of severe leukopaenia (< 1,200/mm3), severe neutropaenia (< 750/mm3) 
or severe thrombocytopaenia (< 70,000/mm3).

 



76

For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment 
(at the maximum tolerated dose), discontinue IntronA therapy.

Chronic hepatitis C
Adults
IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day) 
to adult patients, whether administered as monotherapy or in combination with ribavirin.

Children 3 years of age or older and adolescents
IntronA 3 MIU/m2 is administered subcutaneously 3 times a week (every other day) in combination 
with ribavirin capsules or oral solution administered orally in two divided doses daily with food 
(morning and evening). 

(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for 
combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see 
ribavirin oral solution SPC.)

Relapse patients (adults)
IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are 
available for 6 months of treatment, it is recommended that patients be treated with IntronA in 
combination with ribavirin for 6 months.

Naïve patients (adults)
The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be 
given alone mainly in case of intolerance or contraindication to ribavirin.

- IntronA in combination with ribavirin
Based on the results of clinical trials, in which data are available for 12 months of treatment, it is 
recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.

Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who 
exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment 
sample) and high pre-treatment viral load.

Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into 
account in order to extend therapy to 12 months.

During clinical trials, patients who failed to show a virologic response after 6 months of treatment 
(HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-
RNA below lower limit of detection six months after withdrawal of treatment).

- IntronA alone
The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of 
between 12 and 18 months is advised.

It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point 
HCV-RNA status should be determined. Treatment should be continued in patients who exhibit 
negative HCV-RNA.

Naïve patients (children and adolescents)
The efficacy and safety of IntronA in combination with ribavirin has been studied in children and 
adolescents who have not been previously treated for chronic hepatitis C. 

Duration of treatment for children and adolescents
 Genotype 1: The recommended duration of treatment is one year. Patients who fail to achieve 

virological response at 12 weeks are highly unlikely to become sustained virological responders 

 



77

(negative predictive value 96 %). Therefore, it is recommended that children and adolescent 
patients receiving IntronA/ribavirin combination be discontinued from therapy if their week 12 
HCV-RNA dropped < 2 log10 compared to pretreatment, or if they have detectable HCV-RNA 
at treatment week 24.

 Genotype 2/3: The recommended duration of treatment is 24 weeks.

Hairy cell leukaemia
The recommended dose is 2 million IU/m2 administered subcutaneously three times a week (every 
other day) for both splenectomised and non-splenectomised patients. For most patients with hairy cell 
leukaemia, normalisation of one or more haematological variables occurs within one to two months of 
IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet 
count and haemoglobin level) may require six months or more. This regimen must be maintained 
unless the disease progresses rapidly or severe intolerance is manifested.

Chronic myelogenous leukaemia
The recommended dose of IntronA is 4 to 5 million IU/m2 administered daily subcutaneously. Some 
patients have been shown to benefit from IntronA 5 million IU/m2 administered daily subcutaneously 
in association with cytarabine (Ara-C) 20 mg/m2 administered daily subcutaneously for 10 days per 
month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled, 
administer the maximum tolerated dose of IntronA (4 to 5 million IU/m2 daily) to maintain 
haematological remission.

IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial 
haematological remission or a clinically meaningful cytoreduction has not been achieved.

Multiple myeloma
Maintenance therapy 
In patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following 
initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy, 
subcutaneously, at a dose of 3 million IU/m2 three times a week (every other day).

Follicular lymphoma
Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of 
5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens 
are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide, 
doxorubicin, teniposide and prednisolone).

Carcinoid tumour
The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week 
(every other day). Patients with advanced disease may require a daily dose of 5 million IU. The 
treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long 
as the patient responds to interferon alfa-2b treatment.

Malignant melanoma
As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m2

daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to 
sodium chloride 9 mg/mL (0.9 %) solution for injection and administered as a 20-minute infusion (see 
section 6.6). As maintenance treatment, the recommended dose is 10 million IU/m2 administered 
subcutaneously three days a week (every other day) for 48 weeks.

If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes 
decrease to < 500/mm3 or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to 
> 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates. 
Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after 
dose adjustment or if granulocytes decrease to < 250/mm3 or ALT/AST rises to > 10 x upper limit of 
normal, discontinue interferon alfa-2b therapy.

 



78

Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at 
the recommended dose, with dose reduction for toxicity as described.

IntronA may be administered using either glass or plastic disposable injection syringes.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure, 

recent myocardial infarction, severe arrhythmic disorders. 
- Severe renal or hepatic dysfunction; including that caused by metastases.
- Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).
- Chronic hepatitis with decompensated cirrhosis of the liver.
- Chronic hepatitis in patients who are being or have been treated recently with 

immunosuppressive agents excluding short term corticosteroid withdrawal.
- Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant 

recipients.
- Pre-existing thyroid disease unless it can be controlled with conventional treatment.
- Combination of IntronA with telbivudine.

Children and adolescents
- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal 

ideation or suicide attempt.

Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

4.4 Special warnings and precautions for use

Psychiatric and central nervous system (CNS)
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been 
observed in some patients during IntronA therapy, and even after treatment discontinuation mainly 
during the 6-month follow-up period. Among children and adolescents treated with IntronA in 
combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult 
patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult 
patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes 
directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of 
mental status have been observed with alpha interferons. Patients should be closely monitored for any 
signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of
these undesirable effects must be borne in mind by the prescribing physician and the need for adequate 
therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal 
or homicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, and 
the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions:
If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe 
psychiatric conditions, this should only be initiated after having ensured appropriate individualised 
diagnostic and therapeutic management of the psychiatric condition.
- The use of interferon alfa-2b in children and adolescents with existence of or history of severe 

psychiatric conditions is contraindicated (see section 4.3).

Patients with substance use/abuse:
HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an 
increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders 
when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, 

 



79

the presence of psychiatric co-morbidities and the potential for other substance use should be carefully 
assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach 
including a mental health care provider or addiction specialist should be considered to evaluate, treat and 
follow the patient. Patients should be closely monitored during therapy and even after treatment 
discontinuation. Early intervention for re-emergence or development of psychiatric disorders and 
substance use is recommended.

Children and adolescent population: Growth and development (chronic hepatitis C)
During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to 
48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see 
sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy 
with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile 
decrease in height percentile as compared to baseline) in 21 % of children (n=20) despite being off 
treatment for more than 5 years. Final adult height was available for 14 of those children and 
demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of 
treatment.

Case by case benefit/risk assessment in children 
The expected benefit of treatment should be carefully weighed against the safety findings observed for 
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
- It is important to consider that the combination therapy induced a growth inhibition that resulted 

in reduced final adult height in some patients.
- This risk should be weighed against the disease characteristics of the child, such as evidence

of disease progression (notably fibrosis), co-morbidities that may negatively influence the 
disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV 
genotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the 
risk of growth inhibition. There are no data on long term effects on sexual maturation.

Hypersensitivity reactions
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to 
interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops, 
discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate 
interruption of treatment.

Adverse experiences including prolongation of coagulation markers and liver abnormalities
Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in 
some cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation and 
death in patients with cirrhosis.
Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of 
coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with IntronA must be monitored 
closely and treatment discontinued if signs and symptoms progress.
Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Hypotension
Hypotension may occur during IntronA therapy or up to two days post-therapy and may require 
supportive treatment.

Need for adequate hydration
Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension 
related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.

Pyrexia
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon 
therapy, other causes of persistent pyrexia must be ruled out.

 



80

Patients with debilitating medical conditions
IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a 
history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone 
to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g., 
thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Pulmonary conditions
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any 
patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray 
taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function 
impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. 
While this has been reported more often in patients with chronic hepatitis C treated with interferon 
alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. 
Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to 
be associated with resolution of pulmonary adverse events.

Ocular adverse events
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous 
retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after 
treatment with alpha interferons. All patients should have a baseline eye examination. Any patient 
complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms 
during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual 
examinations during IntronA therapy are recommended particularly in patients with disorders that may 
be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA 
should be considered in patients who develop new or worsening ophthalmological disorders.

Obtundation, coma and encephalopathy
More significant obtundation and coma, including cases of encephalopathy, have been observed in 
some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a 
few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high 
doses of IntronA.

Patients with pre-existing cardiac abnormalities
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or 
current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is 
recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced 
stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac 
arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require 
discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac 
disease.

Hypertriglyceridemia
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. 
Monitoring of lipid levels is, therefore, recommended.

Patients with psoriasis and sarcoidosis
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of 
IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies 
the potential risk.

Kidney and liver graft rejection
Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of 
kidney graft rejection. Liver graft rejection has also been reported.

 



81

Auto-antibodies and autoimmune disorders
The development of auto-antibodies and autoimmune disorders has been reported during treatment 
with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at 
increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be 
evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also 
section 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic 
hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting 
the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment 
should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Concomitant chemotherapy 
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration), which may be life-threatening or fatal as a result of the concomitantly administered 
medicinal product. The most commonly reported potentially life-threatening or fatal adverse events 
include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of 
the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the 
concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the 
frequency and severity of cutaneous vasculitis may be increased.

Chronic hepatitis C
Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases 
(i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. 
Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to 
commencing treatment.

Monotherapy 
Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid 
abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 
2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by 
conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid 
status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C, 
evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that 
time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can 
be maintained in the normal range by medication. Determine TSH levels if, during the course of 
IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the 
presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained 
in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid 
dysfunction occurring during treatment (also see Thyroid supplemental monitoring specific for 
children and adolescents).

Thyroid supplemental monitoring specific for children and adolescents
Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy 
developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease 
below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated 
and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA 
therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid 
dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid 
abnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinically 
appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid 
dysfunction (e.g. TSH).

 



82

HCV/HIV Coinfection
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at 
increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to 
HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy 
and zidovudine could be at increased risk of developing anaemia.
Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic 
decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin 
may increase the risk in this patient subset. 

HCV/HBV Coinfection
Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-
infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation 
appears to be low.
All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; 
patients co-infected with hepatitis B and C must then be monitored and managed according to current 
clinical guidelines.

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients 
receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging 
effect on teeth and mucous membranes of the mouth during long-term treatment with the combination 
of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular 
dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they 
should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests 
Standard haematological tests and blood chemistries (complete blood count and differential, platelet 
count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be 
conducted in all patients prior to and periodically during systemic treatment with IntronA.

During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, 
and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to 
greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and 
symptoms of liver failure are observed. During ALT flare, the following liver function tests must be 
monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.

In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and 
differential must be monitored weekly during the induction phase of therapy and monthly during the 
maintenance phase of therapy.

Effect on fertility
Interferon may impair fertility (see section 4.6 and section 5.3).

Important information about some of the ingredients of IntronA 
This medicinal product contains less than 1 mmol sodium (23 mg) per 3 mL, i.e., essentially "sodium-
free".

4.5 Interaction with other medicinal products and other forms of interaction 

Interaction studies have only been performed in adults.

Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with 
IntronA.

 



83

Interactions between IntronA and other medicinal products have not been fully evaluated. Caution 
must be exercised when administering IntronA in combination with other potentially 
myelosuppressive agents.

Interferons may affect the oxidative metabolic process. This must be considered during concomitant 
therapy with medicinal products metabolised by this route, such as the xanthine derivatives 
theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline 
levels must be monitored and dose adjusted if necessary.

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration) (see section 4.4).

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon 
alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination 
is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these 
events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SPC). Moreover, the safety and 
efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not 
been demonstrated. Therefore, the combination of IntronA with telbivudine is contraindicated (see 
section 4.3).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females
Women of childbearing potential have to use effective contraception during treatment. Decreased 
serum estradiol and progesterone concentrations have been reported in women treated with human 
leukocyte interferon.

IntronA must be used with caution in fertile men.

Combination therapy with ribavirin 
Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be 
taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in 
combination with ribavirin. Females of childbearing potential must use an effective contraceptive 
during treatment and for 4 months after treatment has been concluded. Male patients or their female 
partners must use an effective contraceptive during treatment and for 7 months after treatment has 
been concluded (see ribavirin SPC).

Pregnancy
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA 
is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin 
Ribavirin therapy is contraindicated in women who are pregnant.

 



84

Breast-feeding
It is not known whether the components of this medicinal product are excreted in human milk. 
Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior 
to initiation of treatment.

4.7 Effects on ability to drive and use machines

Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment 
with IntronA, and therefore it is recommended that they avoid driving or operating machinery.

4.8 Undesirable effects

See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in 
combination with ribavirin in patients with chronic hepatitis C.

In clinical trials conducted in a broad range of indications and at a wide range of doses (from 
6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonly 
reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were 
often reversible within 72 hours of interruption or cessation of treatment.

Adults
In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in 
combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three 
times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is 
presented from clinical trials in naïve patients treated for one year. Severity was generally mild to 
moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and 
post-marketing. Within the organ system classes, adverse reactions are listed under headings of 
frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10);
uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported during clinical trials or following the marketing use of 
IntronA alone or in combination with ribavirin

System Organ Class Adverse Reactions
Infections and infestations
Very common:
Common:
Uncommon:
Rarely:
Not known:

Pharyngitis*, infection viral*
Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Bacterial infection
Pneumonia§, sepsis
Hepatitis B reactivation in HCV/HBV co-infected patients

Blood and lymphatic system disorders
Very common:
Common:
Very rarely: 
Not known: 

Leukopaenia
Thrombocytopaenia, lymphadenopathy, lymphopenia
Aplastic anaemia
Pure red cell aplasia, idiopathic thrombocytopenic 
purpura, thrombotic thrombocytopenic purpura 

Immune system disorders§

Very rarely: 
Not known:

Sarcoidosis, exacerbation of sarcoidosis
Systemic lupus erythematosus, vasculitis, rheumatoid 
arthritis (new or aggravated), Vogt-Koyanagi-Harada 
syndrome, acute hypersensitivity reactions including 
urticaria, angioedema, bronchoconstriction, anaphylaxis§

Endocrine disorders
Common:
Very rarely:

Hypothyroidism§, hyperthyroidism§

Diabetes, aggravated diabetes

 



85

Metabolism and nutrition disorders
Very common:
Common: 
Very rarely:

Anorexia
Hypocalcaemia, dehydration, hyperuricemia, thirst
Hyperglycaemia, hypertriglyceridaemia§, increased 
appetite

Psychiatric disorders§

Very common:

Common:
Rarely: 
Very rarely:

Not known:

Depression, insomnia, anxiety, emotional lability*, 
agitation, nervousness
Confusion, sleep disorder, libido decreased
Suicide ideation
Suicide, suicide attempts, aggressive behaviour 
(sometimes directed against others), psychosis including 
hallucinations
Homicidal ideation, mental status change§, mania, bipolar 
disorders

Nervous system disorders§

Very common:
Common:

Uncommon:
Very rarely: 

Not known:

Dizziness, headache, concentration impaired, mouth dry
Tremor, paresthesia, hypoesthesia, migraine, flushing, 
somnolence, taste perversion
Peripheral neuropathy
Cerebrovascular haemorrhage, cerebrovascular ischaemia, 
seizure, impaired consciousness, encephalopathy
Mononeuropathies, coma§

Eye disorders
Very common:
Common:

Rarely:

Not known:

Vision blurred
Conjunctivitis, vision abnormal, lacrimal gland disorder, 
eye pain
Retinal haemorrhages§, retinopathies (including macular 
oedema), retinal artery or vein obstruction§, optic neuritis, 
papilloedema, loss of visual acuity or visual field, cotton-
wool spots§

Serous retinal detachment
Ear and labyrinth
Common:
Very rarely:

Vertigo, tinnitus
Hearing loss, hearing disorder

Cardiac disorders
Common:
Uncommon:
Rarely:
Very rarely:
Not known:

Palpitation, tachycardia
Pericarditis
Cardiomyopathy
Myocardial infarction, cardiac ischaemia 
Congestive heart failure, pericardial effusion, arrhythmia

Vascular disorders
Common:
Very rarely:

Hypertension
Peripheral ischaemia, hypotension§

Respiratory, thoracic and mediastinal 
disorders
Very common:
Common:

Very rarely:
Not known:

Dyspnoea*, coughing*
Epistaxis, respiratory disorder, nasal congestion, 
rhinorrhea, cough nonproductive
Pulmonary infiltrates§, pneumonitis§

Pulmonary fibrosis, pulmonary arterial hypertension#

 



86

Gastrointestinal disorders
Very common:

Common:

Very rarely:

Not known:

Nausea/vomiting, abdominal pain, diarrhoea, stomatitis, 
dyspepsia
Stomatitis ulcerative, right upper quadrant pain, glossitis, 
gingivitis, constipation, loose stools
Pancreatitis, ischaemic colitis, ulcerative colitis, gingival 
bleeding
Periodontal disorder NOS, dental disorder NOS, tongue 
pigmentation §

Hepatobiliary disorders
Common:
Very rarely:

Hepatomegaly
Hepatotoxicity, (including fatality)

Skin and subcutaneous tissue 
disorders
Very common:
Common:

Very rarely:

Alopecia, pruritus*, skin dry*, rash*, sweating increased
Psoriasis (new or aggravated)§, rash maculopapular, rash 
erythematous, eczema, erythema, skin disorder
Stevens Johnson syndrome, toxic epidermal necrolysis, 
erythema multiforme

Musculoskeletal and connective tissue 
disorders
Very common: 
Common:
Very rarely:

Myalgia, arthralgia, musculoskeletal pain
Arthritis
Rhabdomyolysis, myositis, leg cramps, back pain

Renal and urinary disorders
Common:
Very rarely:

Micturition frequency
Renal failure, renal insufficiency, nephrotic syndrome

Reproductive system and breast 
disorders
Common: Amenorrhea, breast pain, dysmenorrhea, menorrhagia, 

menstrual disorder, vaginal disorder
General disorders and administration 
site conditions
Very common:

Common:
Very rarely:

Injection site inflammation, injection site reaction*, 
fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia, 
irritability, chest pain, malaise
Injection site pain
Injection site necrosis, face oedema

Investigations
Very common: Weight decrease
*These events were only common with IntronA alone.
§See section 4.4
#Class label for interferon products, see below Pulmonary arterial hypertension.

These undesirable effects have also been reported with IntronA alone.

The undesirable effects seen with hepatitis C are representative of those reported when IntronA is 
administered in other indications, with some anticipated dose-related increases in incidence. For 
example, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences of 
fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-
like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C 
trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of 
patients, respectively), in comparison with the mild to moderate severity usually associated with lower 
doses. Undesirable effects were usually managed by dose adjustment. 

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with 
pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, 

 



87

that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients 
without prior evidence of cardiac disease (see section 4.4). 

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 
notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). 
Events were reported at various time points typically several months after starting treatment with 
interferon alfa.

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha 
interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or 
aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including 
mononeuropathies (see also section 4.4).

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 
10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in 
haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and 
serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase 
in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis 
subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.

Children and adolescent population 
Chronic Hepatitis C - Combination therapy with ribavirin
In clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy due 
to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent 
population studied was similar to that observed in adults, although there is a paediatric- specific 
concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of 
9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during 
treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 
44th percentile, which was below the median of the normative population and less than their mean 
baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height 
percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from 
the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was 
available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 
percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks 
with IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult height 
in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-
term follow-up was most prominent in prepubertal age children (see section 4.4).

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients 
(2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult 
patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, 
anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents 
compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for 
anaemia and neutropaenia.

The adverse reactions listed in Table 2 are based on experience from the two multicentre children and 
adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings 
of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within 
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 



88

Table 2 Adverse reactions very commonly and commonly reported during clinical trials in
children and adolescent patients treated with IntronA in combination with ribavirin

System Organ Class Adverse Reactions
Infection and infestations
Very common:
Common:

Viral infection, pharyngitis
Fungal infection, bacterial infection, pulmonary infection, otitis 
media, tooth abscess, herpes simplex, urinary tract infection, 
vaginitis, gastroenteritis

Neoplasms benign, malignant 
and unspecified (including 
cysts and polyps)
Common: Neoplasm (unspecified)
Blood and lymphatic system 
disorders
Very common:
Common:

Anaemia, neutropaenia
Thrombocytopaenia, lymphadenopathy

Endocrine disorders
Very common:
Common:

Hypothyroidism§, 
Hyperthyroidism§, virilism

Metabolism and nutrition 
disorders
Very common:
Common:

Anorexia
Hypertriglyceridemia§, hyperuricemia, increased appetite

Psychiatric disorders§

Very common:
Common:

Depression, emotional lability, insomnia
Suicidal ideation, aggressive reaction, confusion, behaviour 
disorder, agitation, somnambulism, anxiety, nervousness, sleep 
disorder, abnormal dreaming, apathy

Nervous system disorders§

Very common:
Common:

Headache, dizziness
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, 
hyperaesthesia, concentration impaired, somnolence

Eye disorders
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Vascular disorders
Common: Flushing, pallor
Respiratory, thoracic and 
mediastinal disorders
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal 

irritation, rhinorrhea, sneezing
Gastrointestinal disorders
Very common:
Common:

Diarrhoea, vomiting, nausea, abdominal pain
Mouth ulceration, stomatitis ulcerative, stomatitis, right upper 
quadrant pain, dyspepsia, glossitis, gastroesophageal reflux, rectal 
disorder, gastrointestinal disorder, constipation, loose stools, 
toothache, tooth disorder

Hepatobiliary disorders
Common: Hepatic function abnormal
Skin and subcutaneous tissue 
disorders 
Very common:
Common:

Alopecia, rash
Photosensitivity reaction, maculopapular rash, eczema, acne, skin 
disorder, nail disorder, skin discolouration, pruritus, dry skin, 
erythema, bruise, sweating increased

 



89

Musculoskeletal and 
connective tissue disorders
Very common: Arthralgia, myalgia, musculoskeletal pain 
Renal and urinary disorders
Common: Enuresis, micturition disorder, urinary incontinence
Reproductive system and 
breast disorders
Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal 

disorder
Male: testicular pain

General disorders and 
administration site 
conditions
Very common:

Common:

Injection site inflammation, injection site reaction, fatigue, rigors, 
pyrexia§, influenza-like symptoms§, malaise, irritability
Chest pain, asthenia, oedema, injection site pain

Investigations
Very common: Growth rate decrease (height and/or weight decrease for age)§

Injury and poisoning
Common: Skin laceration
§See section 4.4

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

No case of overdose has been reported that has led to acute clinical manifestations. However, as for 
any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital 
signs and close observation of the patient is indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05

IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant 
DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of 
approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically 
engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b 
protein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activity 
of the recombinant interferon alfa-2b with the activity of the international reference preparation of 
human leukocyte interferon established by the World Health Organisation.

The interferons are a family of small protein molecules with molecular weights of approximately 
15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or 
various synthetic and biological inducers. Three major classes of interferons have been identified: 
alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain 
several different molecular species of interferon. More than 14 genetically distinct human alpha 
interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.

 

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90

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. 
Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly 
asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species 
specificity. Studies with other interferons have demonstrated species specificity. However, certain 
monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure 
to human type 1 interferons.

The results of several studies suggest that, once bound to the cell membrane, interferon initiates a 
complex sequence of intracellular events that include the induction of certain enzymes. It is thought 
that this process, at least in part, is responsible for the various cellular responses to interferon, 
including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and 
such immunomodulating activities as enhancement of the phagocytic activity of macrophages and 
augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities 
may contribute to interferon's therapeutic effects.

Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both 
animal and human cell culture systems as well as human tumour xenografts in animals. It has 
demonstrated significant immunomodulatory activity in vitro.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact 
antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell 
metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are 
unable to leave the cell.

Chronic hepatitis B
Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates 
that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been 
observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity 
and mortality has been observed.

Interferon alfa-2b (6 MIU/m2 3 times a week for 6 months) has been given to children with chronic 
active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover 
children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of 
depression were observed.

Chronic hepatitis C in adult patients
In adult patients receiving interferon in combination with ribavirin, the achieved sustained response 
rate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferon 
with ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with a 
ribavirin dose > 10.6 mg/kg, p < 0.01).

IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical 
trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of 
IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic 
response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C 
confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/mL), a liver 
biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic 
hepatitis, and abnormal serum ALT.

IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with 
ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were 
followed for an additional 6 months after the end of treatment for the determination of sustained 
virologic response. Sustained virologic response rates for treatment groups treated for one year with 
IntronA alone or in combination with ribavirin (from two studies) are shown in Table 3.

 



91

Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for 
the treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load are 
prognostic factors which are known to affect response rates. The increased response rate to the 
combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The 
relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most 
difficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).

Response rates in these trials were increased with compliance. Regardless of genotype, patients who 
received IntronA in combination with ribavirin and received  80 % of their treatment had a higher 
sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment 
(56 % vs. 32 % in trial C/I98-580).

Table 3 Sustained virologic response rates with IntronA + ribavirin (one year of treatment) by 
genotype and viral load

HCV Genotype I
N=503

C95-132/I95-143

I/R
N=505

C95-132/I95-143

I/R
N=505

C/I98-580

All Genotypes 16 % 41 % 47 %

Genotype 1 9 % 29 % 33 %

Genotype 1 
 2 million 
copies/mL

25 % 33 % 45 %

Genotype 1
> 2 million 
copies/mL

3 % 27 % 29 %

Genotype 2/3 31 % 65 % 79 %

I IntronA (3 MIU 3 times a week)
I/R IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)

HCV/HIV Co-infected patients 
Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies, 
patients who received IntronA plus ribavirin, were less likely to respond than patients who received 
pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is 
presented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which 
enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with 
HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus 
ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a 
follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 
95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. 
Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based on 
weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin 
(800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period 
of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL 
(Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

 



92

Table 4 Sustained virological response based on genotype after IntronA in combination with 
ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in 
HCV/HIV co-infected patients

Study 11 Study 22

pegylated 
interferon alfa-
2b  (1.5 µg/kg/

week) + 
ribavirin 
(800 mg)

IntronA 
(3 MIU TIW) +  

ribavirin 
(800 mg)

p 
valuea

pegylated 
interferon 

alfa-2b (100 
or 

150c µg/week) 
+ ribavirin 

(800-
1,200 mg)d

IntronA 
(3 MIU TIW) 

+ ribavirin 
(800-

1,200 mg)d
p 

valueb

All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017

Genotype 1, 
4

17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007

Genotype 2, 
3

44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730

MIU = million international units; TIW = three times a week.
a:  p value based on Cochran-Mantel Haenszel Chi square test.
b:  p value based on chi-square test.
c:  subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week pegylated 

interferon alfa-2b.
d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al.  JAMA 2004; 292(23): 2839-2848.
2 Laguno M, Murillas J, Blanco J.L et al.  AIDS 2004; 18(13): F27-F36.

Relapse patients 
A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA 
monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA 
increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic 
hepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV 
(< 100 copies/mL by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was 
sustained when measured 6 months after the end of treatment.

Long-Term efficacy data
In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-
2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic 
response and assess the impact of continued viral negativity on clinical outcomes. 462 patients 
completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 
492 relapsed during this study. 
The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with 
a 95 % Confidence Interval of [95 %, 99 %]. 
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin) 
results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 
'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients 
with cirrhosis (including hepatocarcinoma).

Chronic hepatitis C in children and adolescent population
Three clinical trials have been conducted in children and adolescents; two with standard interferon and 
ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin 
were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable 
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in 
two multicentre trials and received IntronA 3 MIU/m2 3 times a week plus ribavirin 15 mg/kg per day 

 



93

for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % 
male, 80 % Caucasian, and 78 % genotype 1,64 %  12 years of age. The population enrolled mainly 
consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained 
virological response rates in children and adolescents were similar to those in adults. Due to the lack 
of data in these two multicentre trials for children with severe progression of the disease, and the 
potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b 
needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).

Study results are summarized in Table 5.

Table 5 Sustained virological response in previously untreated children and adolescents

IntronA 3 MIU/m2 3 times a week
+

ribavirin 15 mg/kg/day

Overall Responsea (n=118) 54 (46 %)*

Genotype 1 (n=92) 33 (36 %)*

Genotype 2/3/4 (n=26) 21 (81 %)*

*Number (%) of patients
a Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during 
follow-up period

Long-term efficacy data 
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C 
patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all 
enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose 
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess 
the impact of continued viral negativity on clinical outcomes for patients who were sustained 
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but 
one of the paediatric subjects remained sustained virologic responders during long-term follow-up 
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for 
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients 
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at 
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in 
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from 
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with 
cirrhosis (including hepatocarcinoma).

Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin
In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic 
hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 g/m2 plus ribavirin 
15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. 
All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received 
treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 
63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate 
hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential 
for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin 
needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs 
section 4.4). The study results are summarized in Table 6.

 



94

Table 6 Sustained virological response rates (na,b (%)) in previously untreated children and 
adolescents by genotype and treatment duration – All subjects

n = 107

24 weeks 48 weeks

All Genotypes 26/27 (96 %) 44/80 (55 %)

Genotype 1 - 38/72 (53 %)

Genotype 2 14/15 (93 %) -

Genotype 3c 12/12 (100 %) 2/3 (67 %)

Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of 

detection=125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with 
genotype 3 and high viral load (≥ 600,000 IU/mL) were to receive 48 weeks of treatment.

5.2 Pharmacokinetic properties

The pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m2

and 10 million IU doses administered subcutaneously, at 5 million IU/m2 administered intramuscularly 
and as a 30-minute intravenous infusion. The mean serum interferon concentrations following 
subcutaneous and intramuscular injections were comparable. Cmax occurred three to 12 hours after the 
lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon 
injections were approximately two to three hours, and six to seven hours, respectively. Serum levels 
were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and 
intramuscular administration resulted in bioavailabilities greater than 100 %.

After intravenous administration, serum interferon levels peaked (135 to 273 IU/mL) by the end of the 
infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular 
administration of medicinal product, becoming undetectable four hours after the infusion. The 
elimination half-life was approximately two hours.

Urine levels of interferon were below the detection limit following each of the three routes of 
administration.

Interferon neutralising factor assays were performed on serum samples of patients who received 
IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies 
which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors 
developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %. 
The detectable titres are low in almost all cases and have not been regularly associated with loss of 
response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was 
observed apparently due to the low titres.

Children and adolescent population
Multiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children and 
adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 7. The 
pharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children or 
adolescents.

 



95

Table 7 Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and ribavirin 
capsules when administered to children or adolescents with chronic hepatitis C

Parameter Ribavirin
15 mg/kg/day as 2 divided doses

(n = 17)

IntronA
3 MIU/m2 3 times a week

(n = 54)
Tmax (hr) 1.9 (83) 5.9 (36)

Cmax (ng/mL) 3,275 (25) 51 (48)
AUC* 29,774 (26) 622 (48)

Apparent clearance L/hr/kg 0.27 (27) Not done
*AUC12 (ng.hr/mL) for ribavirin; AUC0-24 (IU.hr/mL) for IntronA

Transfer into seminal fluid
Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is 
approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female 
partner after sexual intercourse with a treated patient has been estimated and remains extremely 
limited compared to therapeutic plasma concentration of ribavirin.

5.3 Preclinical safety data

Although interferon is generally recognised as being species specific, toxicity studies in animals were 
conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no 
evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with 
20 x 106 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in 
monkeys given 100 x 106 IU/kg/day for 3 months.

In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been 
observed (see section 4.4).

Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic 
in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in 
offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macaca 
mulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose 
of 2 million IU/m2. Abortion was observed in all dose groups (7.5 million, 15 million and 
30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups 
(corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of 
2 million IU/m2). High doses of other forms of interferons alpha and beta are known to produce dose-
related anovulatory and abortifacient effects in rhesus monkeys.

Mutagenicity studies with interferon alfa-2b revealed no adverse events.

IntronA plus ribavirin
No studies have been conducted in juvenile animals to examine the effects of treatment with interferon 
alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results 
have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with 
ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with 
ribavirin).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium phosphate anhydrous 
Sodium dihydrogen phosphate monohydrate 
Edetate disodium 
Sodium chloride 

 



96

M-cresol 
Polysorbate 80
Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6.

6.3 Shelf life

2 years.

After first opening the container: Chemical and physical in-use stability has been demonstrated for 
28 days at 2ºC – 8ºC.
From a microbiological point of view, once opened, the product may be stored for a maximum of 
28 days at 2ºC – 8ºC. Other in-use storage times and conditions are the responsibility of the user.
Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the product is not used during the seven-day period, it cannot be put back in the 
refrigerator for a new storage period and must be discarded.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C). 
Do not freeze. 
For storage conditions of the medicinal product, see section 6.3.

6.5 Nature and contents of container

3 mL of solution (corresponding to 18 MIU) is contained in a multidose vial (type I glass) with a 
stopper (halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene).

IntronA is supplied as:
- Pack of 1 vial
- Pack of 1 vial, 6 injection syringes of 1 mL, 6 injection needles and 12 cleansing swabs
- Pack of 1 vial, 6 injection syringes with attached needle and needle protection device of 1 mL 

and 12 cleansing swabs
- Pack of 2 vials
- Pack of 2 vials, 12 injection syringes of 1 mL, 12 injection needles and 24 cleansing swabs
- Pack of 2 vials, 12 injection syringes with attached needle and needle protection device of 1 mL 

and 24 cleansing swabs
- Pack of 12 vials
- Pack of 12 vials, 72 injection syringes of 1 mL, 72 injection needles and 144 cleansing swabs
- Pack of 12 vials, 72 injection syringes with attached needle and needle protection device of 

1 mL and 144 cleansing swabs
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Not all dose forms and strengths are appropriate for some indications. Please make sure to select an 
appropriate dose form and strength.

IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriate 
doses from the vial with a sterile injection syringe.

 



97

Detailed instructions for the subcutaneous use of the product are provided with the package leaflet 
(refer to “How to self inject IntronA”).

Preparation of IntronA for intravenous infusion: The infusion is to be prepared immediately prior to 
use. Any size vial may be used to measure the required dose; however, final concentration of 
interferon in sodium chloride solution must be not less than 0.3 million IU/mL. The appropriate dose 
of IntronA is withdrawn from the vial(s), added to 50 mL of 9 mg/mL (0.9 %) sodium chloride 
solution for injection in a PVC bag or glass bottle for intravenous use and administered over 
20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

As with all parenteral medicinal products, prior to administration inspect IntronA, solution for 
injection or infusion, visually for particulate matter and discolouration. The solution should be clear 
and colourless.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBERS

EU/1/99/127/023
EU/1/99/127/024
EU/1/99/127/025
EU/1/99/127/026
EU/1/99/127/041
EU/1/99/127/042
EU/1/99/127/045
EU/1/99/127/046
EU/1/99/127/047

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 March 2000
Date of latest renewal: 9 March 2010

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



98

1. NAME OF THE MEDICINAL PRODUCT

IntronA 25 million IU/2.5 mL solution for injection or infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of solution for injection or infusion contains 25 million IU of recombinant interferon alfa-2b
produced in E. coli by recombinant DNA technology, in 2.5 mL of solution.

One mL of solution contains 10 million IU of interferon alfa-2b.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection or infusion.
Clear and colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Chronic hepatitis B
Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral 
replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg), 
elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or 
fibrosis.

Chronic hepatitis C 
Before initiating treatment with IntronA, consideration should be given to the results from clinical 
trials comparing IntronA with pegylated interferon (see section 5.1).

Adult patients 
IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated 
transaminases without liver decompensation and who are positive for hepatitis C virus RNA 
(HCV-RNA) (see section 4.4).

The best way to use IntronA in this indication is in combination with ribavirin.

Children 3 years of age and older and adolescents
IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of 
age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver 
decompensation, and who are positive for HCV-RNA. 

When deciding not to defer treatment until adulthood, it is important to consider that the combination 
therapy induced a growth inhibition that resulted in reduced final adult height in some patients. 
The decision to treat should be made on a case by case basis (see section 4.4).

Hairy cell leukaemia
Treatment of patients with hairy cell leukaemia.

 



99

Chronic myelogenous leukaemia
Monotherapy 
Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic 
myelogenous leukaemia.
Clinical experience indicates that a haematological and cytogenetic major/minor response is 
obtainable in the majority of patients treated. A major cytogenetic response is defined by < 34 % Ph+ 
leukaemic cells in the bone marrow, whereas a minor response is  34 %, but < 90 % Ph+ cells in the 
marrow.

Combination therapy 
The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months 
of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses 
and to significantly prolong the overall survival at three years when compared to interferon alfa-2b 
monotherapy.

Multiple myeloma
As maintenance therapy in patients who have achieved objective remission (more than 50 % reduction 
in myeloma protein) following initial induction chemotherapy.
Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the 
plateau phase; however, effects on overall survival have not been conclusively demonstrated.

Follicular lymphoma
Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction 
chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of 
the following: bulky tumour mass (> 7 cm), involvement of three or more nodal sites (each > 3 cm), 
systemic symptoms (weight loss > 10 %, pyrexia > 38°C for more than 8 days, or nocturnal sweats), 
splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or 
epidural involvement, serous effusion, or leukaemia.

Carcinoid tumour
Treatment of carcinoid tumours with lymph node or liver metastases and with "carcinoid syndrome".

Malignant melanoma
As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic 
recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.

4.2 Posology and method of administration

Treatment must be initiated by a physician experienced in the management of the disease.

Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and 
strength must be selected.

If adverse events develop during the course of treatment with IntronA for any indication, modify the 
dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent 
intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment 
with IntronA. At the discretion of the physician, the patient may self-administer the dose for 
maintenance dose regimens administered subcutaneously.

Chronic hepatitis B
The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a 
week (every other day) for a period of 4 to 6 months.

The administered dose should be reduced by 50 % in case of occurrence of haematological disorders 
(white blood cells < 1,500/mm3, granulocytes < 1,000/mm3, thrombocytes < 100,000/mm3). Treatment 
should be discontinued in case of severe leukopaenia (< 1,200/mm3), severe neutropaenia (< 750/mm3) 
or severe thrombocytopaenia (< 70,000/mm3).

 



100

For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment 
(at the maximum tolerated dose), discontinue IntronA therapy.

Chronic hepatitis C
Adults
IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day) 
to adult patients, whether administered as monotherapy or in combination with ribavirin.

Children 3 years of age or older and adolescents
IntronA 3 MIU/m2 is administered subcutaneously 3 times a week (every other day) in combination 
with ribavirin capsules or oral solution administered orally in two divided doses daily with food 
(morning and evening). 

(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for 
combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see 
ribavirin oral solution SPC.)

Relapse patients (adults)
IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are 
available for 6 months of treatment, it is recommended that patients be treated with IntronA in 
combination with ribavirin for 6 months.

Naïve patients (adults)
The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be 
given alone mainly in case of intolerance or contraindication to ribavirin.

- IntronA in combination with ribavirin
Based on the results of clinical trials, in which data are available for 12 months of treatment, it is 
recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.

Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who 
exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment 
sample) and high pre-treatment viral load.

Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into 
account in order to extend therapy to 12 months.

During clinical trials, patients who failed to show a virologic response after 6 months of treatment 
(HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV-
RNA below lower limit of detection six months after withdrawal of treatment).

- IntronA alone
The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of 
between 12 and 18 months is advised.

It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point 
HCV-RNA status should be determined. Treatment should be continued in patients who exhibit 
negative HCV-RNA.

Naïve patients (children and adolescents)
The efficacy and safety of IntronA in combination with ribavirin has been studied in children and 
adolescents who have not been previously treated for chronic hepatitis C. 

Duration of treatment for children and adolescents
 Genotype 1: The recommended duration of treatment is one year. Patients who fail to achieve 

virological response at 12 weeks are highly unlikely to become sustained virological responders 

 



101

(negative predictive value 96 %). Therefore, it is recommended that children and adolescent 
patients receiving IntronA/ribavirin combination be discontinued from therapy if their week 12 
HCV-RNA dropped < 2 log10 compared to pretreatment, or if they have detectable HCV-RNA 
at treatment week 24.

 Genotype 2/3: The recommended duration of treatment is 24 weeks.

Hairy cell leukaemia
The recommended dose is 2 million IU/m2 administered subcutaneously three times a week (every 
other day) for both splenectomised and non-splenectomised patients. For most patients with hairy cell 
leukaemia, normalisation of one or more haematological variables occurs within one to two months of 
IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet 
count and haemoglobin level) may require six months or more. This regimen must be maintained 
unless the disease progresses rapidly or severe intolerance is manifested.

Chronic myelogenous leukaemia
The recommended dose of IntronA is 4 to 5 million IU/m2 administered daily subcutaneously. Some 
patients have been shown to benefit from IntronA 5 million IU/m2 administered daily subcutaneously 
in association with cytarabine (Ara-C) 20 mg/m2 administered daily subcutaneously for 10 days per 
month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled, 
administer the maximum tolerated dose of IntronA (4 to 5 million IU/m2 daily) to maintain 
haematological remission.

IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial 
haematological remission or a clinically meaningful cytoreduction has not been achieved.

Multiple myeloma
Maintenance therapy 
In patients who are in the plateau phase (more than 50 % reduction of myeloma protein) following 
initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy, 
subcutaneously, at a dose of 3 million IU/m2 three times a week (every other day).

Follicular lymphoma
Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of 
5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens 
are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide, 
doxorubicin, teniposide and prednisolone).

Carcinoid tumour
The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week 
(every other day). Patients with advanced disease may require a daily dose of 5 million IU. The 
treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long 
as the patient responds to interferon alfa-2b treatment.

Malignant melanoma
As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m2

daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to 
sodium chloride 9 mg/mL (0.9 %) solution for injection and administered as a 20-minute infusion (see 
section 6.6). As maintenance treatment, the recommended dose is 10 million IU/m2 administered 
subcutaneously three days a week (every other day) for 48 weeks.

If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes 
decrease to < 500/mm3 or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to 
> 5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates. 
Interferon alfa-2b treatment is to be restarted at 50 % of the previous dose. If intolerance persists after 
dose adjustment or if granulocytes decrease to < 250/mm3 or ALT/AST rises to > 10 x upper limit of 
normal, discontinue interferon alfa-2b therapy.

 



102

Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at 
the recommended dose, with dose reduction for toxicity as described.

IntronA may be administered using either glass or plastic disposable injection syringes.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure, 

recent myocardial infarction, severe arrhythmic disorders. 
- Severe renal or hepatic dysfunction; including that caused by metastases.
- Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).
- Chronic hepatitis with decompensated cirrhosis of the liver.
- Chronic hepatitis in patients who are being or have been treated recently with 

immunosuppressive agents excluding short term corticosteroid withdrawal.
- Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant 

recipients.
- Pre-existing thyroid disease unless it can be controlled with conventional treatment.
- Combination of IntronA with telbivudine.

Children and adolescents
- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal 

ideation or suicide attempt.

Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

4.4 Special warnings and precautions for use

Psychiatric and central nervous system (CNS)
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been 
observed in some patients during IntronA therapy, and even after treatment discontinuation mainly 
during the 6-month follow-up period. Among children and adolescents treated with IntronA in 
combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult 
patients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adult 
patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes 
directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of 
mental status have been observed with alpha interferons. Patients should be closely monitored for any 
signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of 
these undesirable effects must be borne in mind by the prescribing physician and the need for adequate 
therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal 
or homicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, and 
the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions:
If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severe 
psychiatric conditions, this should only be initiated after having ensured appropriate individualised 
diagnostic and therapeutic management of the psychiatric condition.
- The use of interferon alfa-2b in children and adolescents with existence of or history of severe 
psychiatric conditions is contraindicated (see section 4.3).

Patients with substance use/abuse:
HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an 
increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders 
when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, 

 



103

the presence of psychiatric co-morbidities and the potential for other substance use should be carefully 
assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach 
including a mental health care provider or addiction specialist should be considered to evaluate, treat and 
follow the patient. Patients should be closely monitored during therapy and even after treatment 
discontinuation. Early intervention for re-emergence or development of psychiatric disorders and 
substance use is recommended.

Children and adolescent population: Growth and development (chronic hepatitis C)
During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to 
48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see 
sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy 
with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile 
decrease in height percentile as compared to baseline) in 21 % of children (n=20) despite being off 
treatment for more than 5 years. Final adult height was available for 14 of those children and 
demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of 
treatment.

Case by case benefit/risk assessment in children 
The expected benefit of treatment should be carefully weighed against the safety findings observed for 
children and adolescents in the clinical trials (see sections 4.8 and 5.1).
- It is important to consider that the combination therapy induced a growth inhibition that resulted 

in reduced final adult height in some patients.
- This risk should be weighed against the disease characteristics of the child, such as evidence

of disease progression (notably fibrosis), co-morbidities that may negatively influence the 
disease progression (such as HIV co-infection), as well as prognostic factors of response, (HCV 
genotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the 
risk of growth inhibition. There are no data on long term effects on sexual maturation.

Hypersensitivity reactions
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to 
interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops, 
discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate 
interruption of treatment.

Adverse experiences including prolongation of coagulation markers and liver abnormalities
Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in 
some cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation and 
death in patients with cirrhosis.
Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of 
coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with IntronA must be monitored 
closely and treatment discontinued if signs and symptoms progress.
Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Hypotension
Hypotension may occur during IntronA therapy or up to two days post-therapy and may require 
supportive treatment.

Need for adequate hydration
Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension 
related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.

Pyrexia
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon 
therapy, other causes of persistent pyrexia must be ruled out.

 



104

Patients with debilitating medical conditions
IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a 
history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone 
to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g., 
thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Pulmonary conditions
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Any 
patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray 
taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function 
impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. 
While this has been reported more often in patients with chronic hepatitis C treated with interferon 
alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. 
Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to 
be associated with resolution of pulmonary adverse events.

Ocular adverse events
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous 
retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after 
treatment with alpha interferons. All patients should have a baseline eye examination. Any patient 
complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms 
during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual 
examinations during IntronA therapy are recommended particularly in patients with disorders that may 
be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA 
should be considered in patients who develop new or worsening ophthalmological disorders.

Obtundation, coma and encephalopathy
More significant obtundation and coma, including cases of encephalopathy, have been observed in 
some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a 
few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high 
doses of IntronA.

Patients with pre-existing cardiac abnormalities
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or 
current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is 
recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced 
stages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiac 
arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require 
discontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiac 
disease.

Hypertriglyceridemia
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. 
Monitoring of lipid levels is, therefore, recommended.

Patients with psoriasis and sarcoidosis
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of 
IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies 
the potential risk.

Kidney and liver graft rejection
Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of 
kidney graft rejection. Liver graft rejection has also been reported.

 



105

Auto-antibodies and autoimmune disorders
The development of auto-antibodies and autoimmune disorders has been reported during treatment 
with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at 
increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be 
evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also 
section 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic 
hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting 
the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment 
should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Concomitant chemotherapy 
Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration), which may be life-threatening or fatal as a result of the concomitantly administered 
medicinal product. The most commonly reported potentially life-threatening or fatal adverse events 
include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of 
the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the 
concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the 
frequency and severity of cutaneous vasculitis may be increased.

Chronic hepatitis C
Combination therapy with ribavirin 
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases 
(i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. 
Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to 
commencing treatment.

Monotherapy 
Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid 
abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 
2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by 
conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid 
status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C, 
evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that 
time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can 
be maintained in the normal range by medication. Determine TSH levels if, during the course of 
IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the 
presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained 
in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid 
dysfunction occurring during treatment (also see Thyroid supplemental monitoring specific for 
children and adolescents).

Thyroid supplemental monitoring specific for children and adolescents
Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapy 
developed increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decrease 
below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated 
and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA 
therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid 
dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid 
abnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinically 
appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid 
dysfunction (e.g. TSH).

 



106

HCV/HIV Coinfection
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at 
increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to 
HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy 
and zidovudine could be at increased risk of developing anaemia.
Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic 
decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin 
may increase the risk in this patient subset. 

HCV/HBV Coinfection
Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-
infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation 
appears to be low.
All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; 
patients co-infected with hepatitis B and C must then be monitored and managed according to current 
clinical guidelines.

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients 
receiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging 
effect on teeth and mucous membranes of the mouth during long-term treatment with the combination 
of IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular 
dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they 
should be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests 
Standard haematological tests and blood chemistries (complete blood count and differential, platelet 
count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be 
conducted in all patients prior to and periodically during systemic treatment with IntronA.

During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, 
and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to 
greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and 
symptoms of liver failure are observed. During ALT flare, the following liver function tests must be 
monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.

In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and 
differential must be monitored weekly during the induction phase of therapy and monthly during the 
maintenance phase of therapy.

Effect on fertility
Interferon may impair fertility (see section 4.6 and section 5.3).

Important information about some of the ingredients of IntronA 
This medicinal product contains less than 1 mmol sodium (23 mg) per 2.5 mL, i.e., essentially 
"sodium-free".

4.5 Interaction with other medicinal products and other forms of interaction 

Interaction studies have only been performed in adults.

Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with 
IntronA.

 



107

Interactions between IntronA and other medicinal products have not been fully evaluated. Caution 
must be exercised when administering IntronA in combination with other potentially 
myelosuppressive agents.

Interferons may affect the oxidative metabolic process. This must be considered during concomitant 
therapy with medicinal products metabolised by this route, such as the xanthine derivatives 
theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline 
levels must be monitored and dose adjusted if necessary.

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been 
observed rarely in interferon alpha treated patients, including those treated with IntronA. The 
aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, 
a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, 
cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and 
duration) (see section 4.4).

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with 
chronic hepatitis C.

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon 
alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination 
is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these 
events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SPC). Moreover, the safety and 
efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not 
been demonstrated. Therefore, the combination of IntronA with telbivudine is contraindicated (see 
section 4.3).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females
Women of childbearing potential have to use effective contraception during treatment. Decreased 
serum estradiol and progesterone concentrations have been reported in women treated with human 
leukocyte interferon.

IntronA must be used with caution in fertile men.

Combination therapy with ribavirin 
Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be 
taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in 
combination with ribavirin. Females of childbearing potential must use an effective contraceptive 
during treatment and for 4 months after treatment has been concluded. Male patients or their female 
partners must use an effective contraceptive during treatment and for 7 months after treatment has 
been concluded (see ribavirin SPC).

Pregnancy
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA 
is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin 
Ribavirin therapy is contraindicated in women who are pregnant.

 



108

Breast-feeding
It is not known whether the components of this medicinal product are excreted in human milk. 
Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior 
to initiation of treatment.

4.7 Effects on ability to drive and use machines

Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment 
with IntronA, and therefore it is recommended that they avoid driving or operating machinery.

4.8 Undesirable effects

See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in 
combination with ribavirin in patients with chronic hepatitis C.

In clinical trials conducted in a broad range of indications and at a wide range of doses (from 
6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonly 
reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were 
often reversible within 72 hours of interruption or cessation of treatment.

Adults
In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in 
combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three 
times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is 
presented from clinical trials in naïve patients treated for one year. Severity was generally mild to 
moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and 
post-marketing. Within the organ system classes, adverse reactions are listed under headings of 
frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10);
uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. 
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported during clinical trials or following the marketing use of 
IntronA alone or in combination with ribavirin

System Organ Class Adverse Reactions
Infections and infestations
Very common:
Common:
Uncommon:
Rarely:
Not known:

Pharyngitis*, infection viral*
Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Bacterial infection
Pneumonia§, sepsis
Hepatitis B reactivation in HCV/HBV co-infected patients

Blood and lymphatic system disorders
Very common:
Common:
Very rarely: 
Not known: 

Leukopaenia
Thrombocytopaenia, lymphadenopathy, lymphopenia
Aplastic anaemia
Pure red cell aplasia, idiopathic thrombocytopenic 
purpura, thrombotic thrombocytopenic purpura 

Immune system disorders§

Very rarely: 
Not known:

Sarcoidosis, exacerbation of sarcoidosis
Systemic lupus erythematosus, vasculitis, rheumatoid 
arthritis (new or aggravated), Vogt-Koyanagi-Harada 
syndrome, acute hypersensitivity reactions including 
urticaria, angioedema, bronchoconstriction, anaphylaxis§

Endocrine disorders
Common:
Very rarely:

Hypothyroidism§, hyperthyroidism§

Diabetes, aggravated diabetes

 



109

Metabolism and nutrition disorders
Very common:
Common: 
Very rarely:

Anorexia
Hypocalcaemia, dehydration, hyperuricemia, thirst
Hyperglycaemia, hypertriglyceridaemia§, increased 
appetite

Psychiatric disorders§

Very common:

Common:
Rarely: 
Very rarely:

Not known:

Depression, insomnia, anxiety, emotional lability*, 
agitation, nervousness
Confusion, sleep disorder, libido decreased
Suicide ideation
Suicide, suicide attempts, aggressive behaviour 
(sometimes directed against others), psychosis including 
hallucinations
Homicidal ideation, mental status change§, mania, bipolar 
disorders

Nervous system disorders§

Very common:
Common:

Uncommon:
Very rarely: 

Not known:

Dizziness, headache, concentration impaired, mouth dry
Tremor, paresthesia, hypoesthesia, migraine, flushing, 
somnolence, taste perversion
Peripheral neuropathy
Cerebrovascular haemorrhage, cerebrovascular ischaemia, 
seizure, impaired consciousness, encephalopathy
Mononeuropathies, coma§

Eye disorders
Very common:
Common:

Rarely:

Not known:

Vision blurred
Conjunctivitis, vision abnormal, lacrimal gland disorder, 
eye pain
Retinal haemorrhages§, retinopathies (including macular 
oedema), retinal artery or vein obstruction§, optic neuritis, 
papilloedema, loss of visual acuity or visual field, cotton-
wool spots§

Serous retinal detachment
Ear and labyrinth
Common:
Very rarely:

Vertigo, tinnitus
Hearing loss, hearing disorder

Cardiac disorders
Common:
Uncommon:
Rarely:
Very rarely:
Not known:

Palpitation, tachycardia
Pericarditis
Cardiomyopathy
Myocardial infarction, cardiac ischaemia 
Congestive heart failure, pericardial effusion, arrhythmia 

Vascular disorders
Common:
Very rarely:

Hypertension
Peripheral ischaemia, hypotension§

Respiratory, thoracic and mediastinal 
disorders
Very common:
Common:

Very rarely:
Not known:

Dyspnoea*, coughing*
Epistaxis, respiratory disorder, nasal congestion, 
rhinorrhea, cough nonproductive
Pulmonary infiltrates§, pneumonitis§

Pulmonary fibrosis, pulmonary arterial hypertension#

 



110

Gastrointestinal disorders
Very common:

Common:

Very rarely:

Not known:

Nausea/vomiting, abdominal pain, diarrhoea, stomatitis, 
dyspepsia
Stomatitis ulcerative, right upper quadrant pain, glossitis, 
gingivitis, constipation, loose stools
Pancreatitis, ischaemic colitis, ulcerative colitis, gingival 
bleeding
Periodontal disorder NOS, dental disorder NOS, tongue 
pigmentation §

Hepatobiliary disorders
Common:
Very rarely:

Hepatomegaly
Hepatotoxicity, (including fatality)

Skin and subcutaneous tissue 
disorders
Very common:
Common:

Very rarely:

Alopecia, pruritus*, skin dry*, rash*, sweating increased
Psoriasis (new or aggravated)§, rash maculopapular, rash 
erythematous, eczema, erythema, skin disorder
Stevens Johnson syndrome, toxic epidermal necrolysis, 
erythema multiforme

Musculoskeletal and connective tissue 
disorders
Very common: 
Common:
Very rarely:

Myalgia, arthralgia, musculoskeletal pain
Arthritis
Rhabdomyolysis, myositis, leg cramps, back pain

Renal and urinary disorders
Common:
Very rarely:

Micturition frequency
Renal failure, renal insufficiency, nephrotic syndrome

Reproductive system and breast 
disorders
Common: Amenorrhea, breast pain, dysmenorrhea, menorrhagia, 

menstrual disorder, vaginal disorder
General disorders and administration 
site conditions
Very common:

Common:
Very rarely:

Injection site inflammation, injection site reaction*, 
fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia, 
irritability, chest pain, malaise
Injection site pain
Injection site necrosis, face oedema

Investigations
Very common: Weight decrease
*These events were only common with IntronA alone.
§See section 4.4
#Class label for interferon products, see below Pulmonary arterial hypertension.

These undesirable effects have also been reported with IntronA alone.

The undesirable effects seen with hepatitis C are representative of those reported when IntronA is 
administered in other indications, with some anticipated dose-related increases in incidence. For 
example, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences of 
fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-
like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C 
trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of 
patients, respectively), in comparison with the mild to moderate severity usually associated with lower 
doses. Undesirable effects were usually managed by dose adjustment. 

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with 
pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, 

 



111

that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients 
without prior evidence of cardiac disease (see section 4.4). 

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 
notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). 
Events were reported at various time points typically several months after starting treatment with 
interferon alfa.

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha 
interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or 
aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including 
mononeuropathies (see also section 4.4).

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 
10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in 
haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and 
serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase 
in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis 
subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.

Children and adolescent population 
Chronic Hepatitis C - Combination therapy with ribavirin
In clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy due 
to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent 
population studied was similar to that observed in adults, although there is a paediatric- specific 
concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of 
9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during 
treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 
44th percentile, which was below the median of the normative population and less than their mean 
baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height 
percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from 
the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was 
available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 
percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks 
with IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult height 
in some patients. In particular, decrease in mean height percentile from baseline to the end of the long-
term follow-up was most prominent in prepubertal age children (see section 4.4).

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients 
(2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adult 
patients, children and adolescents also experienced other psychiatric adverse events (e.g., depression, 
emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, 
anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents 
compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for 
anaemia and neutropaenia.

The adverse reactions listed in Table 2 are based on experience from the two multicentre children and 
adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings 
of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within 
each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 



112

Table 2 Adverse reactions very commonly and commonly reported during clinical trials in
children and adolescent patients treated with IntronA in combination with ribavirin

System Organ Class Adverse Reactions
Infection and infestations
Very common:
Common:

Viral infection, pharyngitis
Fungal infection, bacterial infection, pulmonary infection, otitis 
media, tooth abscess, herpes simplex, urinary tract infection, 
vaginitis, gastroenteritis

Neoplasms benign, malignant 
and unspecified (including 
cysts and polyps)
Common: Neoplasm (unspecified)
Blood and lymphatic system 
disorders
Very common:
Common:

Anaemia, neutropaenia
Thrombocytopaenia, lymphadenopathy

Endocrine disorders
Very common:
Common:

Hypothyroidism§, 
Hyperthyroidism§, virilism

Metabolism and nutrition 
disorders
Very common:
Common:

Anorexia
Hypertriglyceridemia§, hyperuricemia, increased appetite

Psychiatric disorders§

Very common:
Common:

Depression, emotional lability, insomnia
Suicidal ideation, aggressive reaction, confusion, behaviour 
disorder, agitation, somnambulism, anxiety, nervousness, sleep 
disorder, abnormal dreaming, apathy

Nervous system disorders§

Very common:
Common:

Headache, dizziness
Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, 
hyperaesthesia, concentration impaired, somnolence

Eye disorders
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Vascular disorders
Common: Flushing, pallor
Respiratory, thoracic and 
mediastinal disorders
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal 

irritation, rhinorrhea, sneezing
Gastrointestinal disorders
Very common:
Common:

Diarrhoea, vomiting, nausea, abdominal pain
Mouth ulceration, stomatitis ulcerative, stomatitis, right upper 
quadrant pain, dyspepsia, glossitis, gastroesophageal reflux, rectal 
disorder, gastrointestinal disorder, constipation, loose stools, 
toothache, tooth disorder

Hepatobiliary disorders
Common: Hepatic function abnormal
Skin and subcutaneous tissue 
disorders 
Very common:
Common:

Alopecia, rash
Photosensitivity reaction, maculopapular rash, eczema, acne, skin 
disorder, nail disorder, skin discolouration, pruritus, dry skin, 
erythema, bruise, sweating increased

 



113

Musculoskeletal and 
connective tissue disorders
Very common: Arthralgia, myalgia, musculoskeletal pain 
Renal and urinary disorders
Common: Enuresis, micturition disorder, urinary incontinence
Reproductive system and 
breast disorders
Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal 

disorder
Male: testicular pain

General disorders and 
administration site 
conditions
Very common:

Common:

Injection site inflammation, injection site reaction, fatigue, rigors, 
pyrexia§, influenza-like symptoms§, malaise, irritability
Chest pain, asthenia, oedema, injection site pain

Investigations
Very common: Growth rate decrease (height and/or weight decrease for age)§

Injury and poisoning
Common: Skin laceration
§See section 4.4

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

No case of overdose has been reported that has led to acute clinical manifestations. However, as for 
any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital 
signs and close observation of the patient is indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05

IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant 
DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight of 
approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically 
engineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2b 
protein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activity 
of the recombinant interferon alfa-2b with the activity of the international reference preparation of 
human leukocyte interferon established by the World Health Organisation.

The interferons are a family of small protein molecules with molecular weights of approximately 
15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or 
various synthetic and biological inducers. Three major classes of interferons have been identified: 
alpha, beta and gamma. These three main classes are themselves not homogeneous and may contain 
several different molecular species of interferon. More than 14 genetically distinct human alpha 
interferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.

 

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114

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. 
Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highly 
asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species 
specificity. Studies with other interferons have demonstrated species specificity. However, certain 
monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure 
to human type 1 interferons.

The results of several studies suggest that, once bound to the cell membrane, interferon initiates a 
complex sequence of intracellular events that include the induction of certain enzymes. It is thought 
that this process, at least in part, is responsible for the various cellular responses to interferon, 
including inhibition of virus replication in virus-infected cells, suppression of cell proliferation and 
such immunomodulating activities as enhancement of the phagocytic activity of macrophages and 
augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities 
may contribute to interferon's therapeutic effects.

Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing both 
animal and human cell culture systems as well as human tumour xenografts in animals. It has 
demonstrated significant immunomodulatory activity in vitro.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact 
antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell 
metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are 
unable to leave the cell.

Chronic hepatitis B
Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicates 
that therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has been 
observed. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidity 
and mortality has been observed.

Interferon alfa-2b (6 MIU/m2 3 times a week for 6 months) has been given to children with chronic 
active hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreover 
children treated with interferon alfa-2b experienced a reduced rate of growth and some cases of 
depression were observed.

Chronic hepatitis C in adult patients
In adult patients receiving interferon in combination with ribavirin, the achieved sustained response 
rate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferon 
with ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with a 
ribavirin dose > 10.6 mg/kg, p < 0.01).

IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical 
trials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of 
IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologic 
response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C 
confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/mL), a liver 
biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic 
hepatitis, and abnormal serum ALT.

IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with 
ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were 
followed for an additional 6 months after the end of treatment for the determination of sustained 
virologic response. Sustained virologic response rates for treatment groups treated for one year with 
IntronA alone or in combination with ribavirin (from two studies) are shown in Table 3.

 



115

Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold for 
the treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load are 
prognostic factors which are known to affect response rates. The increased response rate to the 
combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The 
relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most 
difficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).

Response rates in these trials were increased with compliance. Regardless of genotype, patients who 
received IntronA in combination with ribavirin and received  80 % of their treatment had a higher 
sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment 
(56 % vs. 32 % in trial C/I98-580).

Table 3 Sustained virologic response rates with IntronA + ribavirin (one year of treatment) by 
genotype and viral load

HCV Genotype I
N=503

C95-132/I95-143

I/R
N=505

C95-132/I95-143

I/R
N=505

C/I98-580

All Genotypes 16 % 41 % 47 %

Genotype 1 9 % 29 % 33 %

Genotype 1 
 2 million 
copies/mL

25 % 33 % 45 %

Genotype 1
> 2 million 
copies/mL

3 % 27 % 29 %

Genotype 2/3 31 % 65 % 79 %

I IntronA (3 MIU 3 times a week)
I/R IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)

HCV/HIV Co-infected patients 
Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies, 
patients who received IntronA plus ribavirin, were less likely to respond than patients who received 
pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is 
presented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which 
enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with 
HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plus 
ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a 
follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 
95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. 
Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based on 
weight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin 
(800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up period 
of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL 
(Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

 



116

Table 4 Sustained virological response based on genotype after IntronA in combination with 
ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in 
HCV/HIV co-infected patients

Study 11 Study 22

pegylated 
interferon alfa-
2b  (1.5 µg/kg/

week) + 
ribavirin 
(800 mg)

IntronA 
(3 MIU TIW) +  

ribavirin 
(800 mg)

p 
valuea

pegylated 
interferon 

alfa-2b (100 
or 

150c µg/week) 
+ ribavirin 

(800-
1,200 mg)d

IntronA 
(3 MIU TIW) 

+ ribavirin 
(800-

1,200 mg)d
p 

valueb

All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017

Genotype 1, 
4

17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007

Genotype 2, 
3

44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730

MIU = million international units; TIW = three times a week.
a:  p value based on Cochran-Mantel Haenszel Chi square test.
b:  p value based on chi-square test.
c:  subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week pegylated 

interferon alfa-2b.
d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al.  JAMA 2004; 292(23): 2839-2848.
2 Laguno M, Murillas J, Blanco J.L et al.  AIDS 2004; 18(13): F27-F36.

Relapse patients 
A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronA 
monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA 
increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic 
hepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV 
(< 100 copies/mL by PCR), improvement in hepatic inflammation, and normalisation of ALT, and was 
sustained when measured 6 months after the end of treatment.

Long-Term efficacy data
In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-
2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic 
response and assess the impact of continued viral negativity on clinical outcomes. 462 patients 
completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 
492 relapsed during this study. 
The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with 
a 95 % Confidence Interval of [95 %, 99 %]. 
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin) 
results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 
'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients 
with cirrhosis (including hepatocarcinoma).

Chronic hepatitis C in children and adolescent population

Three clinical trials have been conducted in children and adolescents; two with standard interferon and 
ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin 
were less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable 
HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled in 
two multicentre trials and received IntronA 3 MIU/m2 3 times a week plus ribavirin 15 mg/kg per day 

 



117

for 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 % 
male, 80 % Caucasian, and 78 % genotype 1,64 %  12 years of age. The population enrolled mainly 
consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained 
virological response rates in children and adolescents were similar to those in adults. Due to the lack 
of data in these two multicentre trials for children with severe progression of the disease, and the 
potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b 
needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).

Study results are summarized in Table 5.

Table 5 Sustained virological response in previously untreated children and adolescents

IntronA 3 MIU/m2 3 times a week
+

ribavirin 15 mg/kg/day

Overall Responsea (n=118) 54 (46 %)*

Genotype 1 (n=92) 33 (36 %)*

Genotype 2/3/4 (n=26) 21 (81 %)*

*Number (%) of patients
a Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during 
follow-up period

Long-term efficacy data 
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C 
patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all 
enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose 
of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess 
the impact of continued viral negativity on clinical outcomes for patients who were sustained 
responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but 
one of the paediatric subjects remained sustained virologic responders during long-term follow-up 
after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for 
continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients 
treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at 
follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results in 
long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from 
chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with 
cirrhosis (including hepatocarcinoma).

Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin
In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronic 
hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 g/m2 plus ribavirin 
15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. 
All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received 
treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 
63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate 
hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential 
for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin 
needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs 
section 4.4). The study results are summarized in Table 6.

 



118

Table 6 Sustained virological response rates (na,b (%)) in previously untreated children and 
adolescents by genotype and treatment duration – All subjects

n = 107

24 weeks 48 weeks

All Genotypes 26/27 (96 %) 44/80 (55 %)

Genotype 1 - 38/72 (53 %)

Genotype 2 14/15 (93 %) -

Genotype 3c 12/12 (100 %) 2/3 (67 %)

Genotype 4 - 4/5 (80 %)
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of 

detection=125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those with 
genotype 3 and high viral load (≥ 600,000 IU/mL) were to receive 48 weeks of treatment.

5.2 Pharmacokinetic properties

The pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m2

and 10 million IU doses administered subcutaneously, at 5 million IU/m2 administered intramuscularly 
and as a 30-minute intravenous infusion. The mean serum interferon concentrations following 
subcutaneous and intramuscular injections were comparable. Cmax occurred three to 12 hours after the 
lower dose and six to eight hours after the higher dose. The elimination half-lives of interferon 
injections were approximately two to three hours, and six to seven hours, respectively. Serum levels 
were below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous and 
intramuscular administration resulted in bioavailabilities greater than 100 %.

After intravenous administration, serum interferon levels peaked (135 to 273 IU/mL) by the end of the 
infusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscular 
administration of medicinal product, becoming undetectable four hours after the infusion. The 
elimination half-life was approximately two hours.

Urine levels of interferon were below the detection limit following each of the three routes of 
administration.

Interferon neutralising factor assays were performed on serum samples of patients who received 
IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies 
which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors 
developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %. 
The detectable titres are low in almost all cases and have not been regularly associated with loss of 
response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was 
observed apparently due to the low titres.

Children and adolescent population
Multiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children and 
adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 7. The 
pharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children or 
adolescents.

 



119

Table 7 Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and ribavirin 
capsules when administered to children or adolescents with chronic hepatitis C

Parameter Ribavirin
15 mg/kg/day as 2 divided doses

(n = 17)

IntronA
3 MIU/m2 3 times a week

(n = 54)
Tmax (hr) 1.9 (83) 5.9 (36)

Cmax (ng/mL) 3,275 (25) 51 (48)
AUC* 29,774 (26) 622 (48)

Apparent clearance L/hr/kg 0.27 (27) Not done
*AUC12 (ng.hr/mL) for ribavirin; AUC0-24 (IU.hr/mL) for IntronA

Transfer into seminal fluid
Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is 
approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female 
partner after sexual intercourse with a treated patient has been estimated and remains extremely 
limited compared to therapeutic plasma concentration of ribavirin.

5.3 Preclinical safety data

Although interferon is generally recognised as being species specific, toxicity studies in animals were 
conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no 
evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with 
20 x 106 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in 
monkeys given 100 x 106 IU/kg/day for 3 months.

In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have been 
observed (see section 4.4).

Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic 
in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in 
offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macaca 
mulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose 
of 2 million IU/m2. Abortion was observed in all dose groups (7.5 million, 15 million and 
30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups 
(corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of 
2 million IU/m2). High doses of other forms of interferons alpha and beta are known to produce dose-
related anovulatory and abortifacient effects in rhesus monkeys.

Mutagenicity studies with interferon alfa-2b revealed no adverse events.

IntronA plus ribavirin 
No studies have been conducted in juvenile animals to examine the effects of treatment with interferon 
alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results 
have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with 
ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with 
ribavirin).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium phosphate anhydrous 
Sodium dihydrogen phosphate monohydrate 
Edetate disodium 
Sodium chloride 

 



120

M-cresol 
Polysorbate 80
Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6.

6.3 Shelf life

2 years

After first opening the container: Chemical and physical in-use stability has been demonstrated for 
28 days at 2ºC – 8ºC.
From a microbiological point of view, once opened, the product may be stored for a maximum of 
28 days at 2ºC – 8ºC. Other in-use storage times and conditions are the responsibility of the user.
Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the product is not used during the seven-day period, it cannot be put back in the 
refrigerator for a new storage period and must be discarded.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).
Do not freeze.
For storage conditions of the medicinal product, see section 6.3.

6.5 Nature and contents of container

2.5 mL of solution (corresponding to 25 MIU) is contained in a multidose vial (type I glass) with a 
stopper (halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene).

IntronA is supplied as:
- Pack of 1 vial
- Pack of 1 vial, 6 injection syringes of 1 mL, 6 injection needles and 12 cleansing swabs
- Pack of 1 vial, 6 injection syringes with attached needle and needle protection device of 1 mL 

and 12 cleansing swabs
- Pack of 1 vial, 6 injection syringes with attached needle of 1 mL and 12 cleansing swabs
- Pack of 2 vials
- Pack of 2 vials, 12 injection syringes of 1 mL, 12 injection needles and 24 cleansing swabs
- Pack of 2 vials, 12 injection syringes with attached needle and needle protection device of 1 mL 

and 24 cleansing swabs
- Pack of 2 vials, 12 injection syringes with attached needle of 1 mL and 24 cleansing swabs
- Pack of 12 vials
- Pack of 12 vials, 72 injection syringes of 1 mL, 72 injection needles and 144 cleansing swabs
- Pack of 12 vials, 72 injection syringes with attached needle and needle protection device of 

1 mL and 144 cleansing swabs
- Pack of 12 vials, 72 injection syringes with attached needle of 1 mL and 144 cleansing swabs
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Not all dose forms and strengths are appropriate for some indications. Please make sure to select an 
appropriate dose form and strength.

 



121

IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriate 
doses from the vial with a sterile injection syringe.

Detailed instructions for the subcutaneous use of the product are provided with the package leaflet 
(refer to “How to self inject IntronA”).

Preparation of IntronA for intravenous infusion: The infusion is to be prepared immediately prior to 
use. Any size vial may be used to measure the required dose; however, final concentration of 
interferon in sodium chloride solution must be not less than 0.3 million IU/mL. The appropriate dose 
of IntronA is withdrawn from the vial(s), added to 50 mL of 9 mg/mL (0.9 %) sodium chloride 
solution for injection in a PVC bag or glass bottle for intravenous use and administered over 
20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

As with all parenteral medicinal products, prior to administration inspect IntronA, solution for 
injection or infusion, visually for particulate matter and discolouration. The solution should be clear 
and colourless.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

8. MARKETING AUTHORISATION NUMBERS

EU/1/99/127/027
EU/1/99/127/028
EU/1/99/127/029
EU/1/99/127/030
EU/1/99/127/043
EU/1/99/127/044
EU/1/99/127/048
EU/1/99/127/049
EU/1/99/127/050
EU/1/99/127/051
EU/1/99/127/052
EU/1/99/127/053

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 March 2000
Date of latest renewal: 9 March 2010

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

 



122

ANNEX II

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT

 



123

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer of the biological active substance

MSD International GmbH T/A MSD Ireland (Brinny)
Brinny
Innishannon –
Co. Cork
Ireland

Name and address of the manufacturer responsible for batch release

SP Labo N.V.
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.

 



124

ANNEX III

LABELLING AND PACKAGE LEAFLET

 



125

A. LABELLING

 



126

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

Outer carton

1. NAME OF THE MEDICINAL PRODUCT

IntronA 3 million IU/0.5 mL solution for injection or infusion
interferon alfa-2b

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One vial contains 3 million IU of interferon alfa-2b in 0.5 mL of solution.

3. LIST OF EXCIPIENTS

Excipients: disodium phosphate anhydrous, sodium dihydrogen phosphate monohydrate, edetate 
disodium, sodium chloride, m-cresol, polysorbate 80 and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

3 million IU/0.5 mL solution for injection or infusion
1 single dose vial
1 single dose vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing swab
6 single dose vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing swabs
12 single dose vials, 12 injection syringes of 1 mL, 12 injection needles and 12 cleansing swabs

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous or intravenous use.
Dilute prior to intravenous use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. Do not freeze.

 



127

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

After withdrawal of the dose, any remaining solution must be discarded.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/127/011 1 single dose vial
EU/1/99/127/012 1 single dose vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing 
swab
EU/1/99/127/013 6 single dose vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing 
swabs
EU/1/99/127/014 12 single dose vials, 12 injection syringes of 1 mL, 12 injection needles and 
12 cleansing swabs

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

IntronA 3 MIU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

 



128

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial label

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

IntronA 3 million IU/0.5 mL solution for injection or infusion
interferon alfa-2b
SC/IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

3 million IU/0.5 mL

6. OTHER

 



129

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

Outer carton

1. NAME OF THE MEDICINAL PRODUCT

IntronA 5 million IU/0.5 mL solution for injection or infusion
interferon alfa-2b

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One vial contains 5 million IU of interferon alfa-2b in 0.5 mL of solution.

3. LIST OF EXCIPIENTS

Excipients: disodium phosphate anhydrous, sodium dihydrogen phosphate monohydrate, edetate 
disodium, sodium chloride, m-cresol, polysorbate 80 and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

5 million IU/0.5 mL solution for injection or infusion
1 single dose vial
1 single dose vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing swab
6 single dose vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing swabs
12 single dose vials, 12 injection syringes of 1 mL, 12 injection needles and 12 cleansing swabs

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous or intravenous use.
Dilute prior to intravenous use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. Do not freeze.

 



130

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

After withdrawal of the dose, any remaining solution must be discarded.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/127/015 1 single dose vial
EU/1/99/127/016 1 single dose vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing 
swab
EU/1/99/127/017 6 single dose vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing 
swabs
EU/1/99/127/018 12 single dose vials, 12 injection syringes of 1 mL, 12 injection needles and 
12 cleansing swabs

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

IntronA 5 MIU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

 



131

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial label

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

IntronA 5 million IU/0.5 mL solution for injection or infusion
interferon alfa-2b
SC/IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

5 million IU/0.5 mL

6. OTHER

 



132

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

Outer carton

1. NAME OF THE MEDICINAL PRODUCT

IntronA 10 million IU/mL solution for injection or infusion
interferon alfa-2b

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One vial contains 10 million IU of interferon alfa-2b in 1 mL of solution.

3. LIST OF EXCIPIENTS

Excipients: disodium phosphate anhydrous, sodium dihydrogen phosphate monohydrate, edetate 
disodium, sodium chloride, m-cresol, polysorbate 80 and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

10 million IU/mL solution for injection or infusion
1 single dose vial
1 single dose vial, 1 injection syringe of 2 mL, 1 injection needle and 1 cleansing swab
6 single dose vials, 6 injection syringes of 2 mL, 6 injection needles and 6 cleansing swabs
12 single dose vials, 12 injection syringes of 2 mL, 12 injection needles and 12 cleansing swabs

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous or intravenous use.
Dilute prior to intravenous use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. Do not freeze.

 



133

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

After withdrawal of the dose, any remaining solution must be discarded.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/127/019 1 single dose vial
EU/1/99/127/020 1 single dose vial, 1 injection syringe of 2 mL, 1 injection needle and 1 cleansing 
swab
EU/1/99/127/021 6 single dose vials, 6 injection syringes of 2 mL, 6 injection needles and 6 cleansing 
swabs
EU/1/99/127/022 12 single dose vials, 12 injection syringes of 2 mL, 12 injection needles and 
12 cleansing swabs

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

IntronA 10 MIU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

 



134

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial label

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

IntronA 10 million IU/mL solution for injection or infusion
interferon alfa-2b
SC/IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

10 million IU/mL

6. OTHER

 



135

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

Outer carton

1. NAME OF THE MEDICINAL PRODUCT

IntronA 18 million IU/3 mL solution for injection or infusion
interferon alfa-2b

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One vial contains 18 million IU of interferon alfa-2b in 3 mL of solution.

3. LIST OF EXCIPIENTS

Excipients: disodium phosphate anhydrous, sodium dihydrogen phosphate monohydrate, edetate 
disodium, sodium chloride, m-cresol, polysorbate 80 and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

18 million IU/3 mL solution for injection or infusion
1 multiple dose vial
1 multiple dose vial, 6 injection syringes of 1 mL, 6 injection needles and 12 cleansing swabs
1 multiple dose vial, 6 injection syringes with attached needle and needle protection device of 1 mL 
and 12 cleansing swabs
2 multiple dose vials
2 multiple dose vials, 12 injection syringes of 1 mL, 12 injection needles and 24 cleansing swabs
2 multiple dose vials, 12 injection syringes with attached needle and needle protection device of 1 mL 
and 24 cleansing swabs
12 multiple dose vials
12 multiple dose vials, 72 injection syringes of 1 mL, 72 injection needles and 144 cleansing swabs
12 multiple dose vials, 72 injection syringes with attached needle and needle protection device of 
1 mL and 144 cleansing swabs

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous or intravenous use.
Dilute prior to intravenous use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

 



136

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/127/023 1 multiple dose vial
EU/1/99/127/024 1 multiple dose vial 6 injection syringes of 1 mL, 6 injection needles and 
12 cleansing swabs
EU/1/99/127/045 1 multiple dose vial, 6 injection syringes with attached needle and needle protection 
device of 1 mL and 12 cleansing swabs
EU/1/99/127/025 2 multiple dose vials
EU/1/99/127/041 2 multiple dose vials, 12 injection syringes of 1 mL, 12 injection needles and 
24 cleansing swabs
EU/1/99/127/046 2 multiple dose vial, 12 injection syringes with attached needle and needle 
protection device of 1 mL and 24 cleansing swabs
EU/1/99/127/026 12 multiple dose vials
EU/1/99/127/042 12 multiple dose vials, 72 injection syringes of 1 mL, 72 injection needles and 
144 cleansing swabs
EU/1/99/127/047 12 multiple dose vial, 72 injection syringes with attached needle and needle 
protection device of 1 mL and 144 cleansing swabs

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

 



137

16. INFORMATION IN BRAILLE

IntronA 18 MIU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

 



138

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial label

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

IntronA 18 million IU/3 mL solution for injection or infusion
interferon alfa-2b
SC/IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

18 million IU/3 mL

6. OTHER

 



139

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

Outer carton

1. NAME OF THE MEDICINAL PRODUCT

IntronA 25 million IU/2.5 mL solution for injection or infusion
interferon alfa-2b

2. STATEMENT OF ACTIVE SUBSTANCE(S)

One vial contains 25 million IU of interferon alfa-2b in 2.5 mL of solution.

3. LIST OF EXCIPIENTS

Excipients: disodium phosphate anhydrous, sodium dihydrogen phosphate monohydrate, edetate 
disodium, sodium chloride, m-cresol, polysorbate 80 and water for injections.

4. PHARMACEUTICAL FORM AND CONTENTS

25 million IU/2.5 mL solution for injection or infusion
1 multiple dose vial
1 multiple dose vial, 6 injection syringes of 1 mL, 6 injection needles and 12 cleansing swabs
1 multiple dose vial, 6 injection syringes with attached needle and needle protection device of 1 mL 
and 12 cleansing swabs
1 multiple dose vial, 6 injection syringes with attached needle of 1 mL and 12 cleansing swabs
2 multiple dose vials
2 multiple dose vials, 12 injection syringes of 1 mL, 12 injection needles and 24 cleansing swabs
2 multiple dose vial, 12 injection syringes with attached needle and needle protection device of 1 mL 
and 24 cleansing swabs
2 multiple dose vial, 12 injection syringes with attached needle of 1 mL and 24 cleansing swabs
12 multiple dose vials
12 multiple dose vials, 72 injection syringes of 1 mL, 72 injection needles and 144 cleansing swabs
12 multiple dose vial, 72 injection syringes with attached needle and needle protection device of 1 mL 
and 144 cleansing swabs
12 multiple dose vial, 72 injection syringes with attached needle of 1 mL and 144 cleansing swabs

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Subcutaneous or intravenous use.
Dilute prior to intravenous use.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

 



140

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator. Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/99/127/027 1 multiple dose vial
EU/1/99/127/028 1 multiple dose vial, 6 injection syringes of 1 mL, 6 injection needles and 
12 cleansing swabs
EU/1/99/127/048 1 multiple dose vial, 6 injection syringes with attached needle and needle protection 
device of 1 mL and 12 cleansing swabs
EU/1/99/127/051 1 multiple dose vial, 6 injection syringes with attached needle of 1 mL and 
12 cleansing swabs
EU/1/99/127/029 2 multiple dose vials
EU/1/99/127/043 2 multiple dose vials, 12 injection syringes of 1 mL, 12 injection needles and 
24 cleansing swabs
EU/1/99/127/049 2 multiple dose vial, 12 injection syringes with attached needle and needle 
protection device of 1 mL and 24 cleansing swabs
EU/1/99/127/052 2 multiple dose vial, 12 injection syringes with attached needle of 1 mL and 
24 cleansing swabs
EU/1/99/127/030 12 multiple dose vials
EU/1/99/127/044 12 multiple dose vials, 72 injection syringes of 1 mL, 72 injection needles and 
144 cleansing swabs
EU/1/99/127/050 12 multiple dose vial, 72 injection syringes with attached needle and needle 
protection device of 1 mL and 144 cleansing swabs
EU/1/99/127/053 12 multiple dose vial, 72 injection syringes with attached needle of 1 mL and 
144 cleansing swabs

13. BATCH NUMBER

Lot

 



141

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

IntronA 25 MIU

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:
SN:
NN:

 



142

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

Vial label

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

IntronA 25 million IU/2.5 mL solution for injection or infusion
interferon alfa-2b
SC/IV

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

25 million IU/2.5 mL

6. OTHER

 



143

B. PACKAGE LEAFLET

 



144

Package leaflet: Information for the user

IntronA 3 million IU/0.5 mL solution for injection or infusion
Interferon alfa-2b

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What IntronA is and what it is used for
2. What you need to know before you use IntronA
3. How to use IntronA
4. Possible side effects
5. How to store IntronA
6. Contents of the pack and other information

1. What IntronA is and what it is used for

IntronA (interferon alfa-2b) modifies the response of the body's immune system to help fight infections 
and severe diseases. 

IntronA is used in adult patients to treat certain disorders that affect the blood, bone marrow, lymph 
glands, or skin and may extend into the body. Included are hairy cell leukaemia, chronic myelogenous 
leukaemia, multiple myeloma, follicular lymphoma, carcinoid tumour, and malignant melanoma. 

IntronA is also used in adult patients for the treatment of chronic hepatitis B or C, which are viral 
infections of the liver.

IntronA is used in combination with ribavirin in children 3 years of age and older and adolescents who 
have previously untreated chronic hepatitis C.

2. What you need to know before you use IntronA

Do not use IntronA
- if you are allergic to interferon or any of the other ingredients of this medicine (listed in 

section 6).
- if you have severe heart disease.
- if you have poor kidney or liver function.
- if you have advanced decompensated (uncontrolled) liver disease.
- if you have hepatitis and have been treated recently with medicines that suppress the immune 

system (other than short-term treatment with cortisone-type medicine).
- if you have a history of seizures (convulsions).
- if you have a history of autoimmune disease, or have had an organ transplant and are taking 

medicine that suppresses your immune system (your immune system helps protect you from 
infection).

- if you have thyroid disease that is not well controlled.
- if you are being treated with telbivudine (see section "Other medicines and IntronA").

 



145

Children and adolescents:
- if you have had serious nervous or mental problems, such as severe depression or thoughts of 

suicide.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using IntronA
- if you are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”).
- if you are being treated for mental illness or had treatment in the past for any other nervous or 

mental disorder, including depression (such as feelings of sadness, dejection) or suicidal or 
homicidal behaviour (see section 4 “Possible side effects”). The use of interferon alfa-2b in 
children and adolescents with existence of or history of severe psychiatric conditions is 
contraindicated (see section “Do not use IntronA”). 

- if you have cirrhosis or other liver problems (other than hepatitis B or C).
- if you have psoriasis, it may get worse during treatment with IntronA.
- when receiving IntronA, you may temporarily have a greater risk of getting an infection. Check 

with your doctor if you think you are getting an infection.
- if you develop symptoms associated with a cold or other respiratory infection, such as fever, cough, 

or any difficulty in breathing, tell your doctor.
- if you notice unusual bleeding or bruising check with your doctor immediately.
- if you develop symptoms of a severe allergic reaction (such as difficulty in breathing, wheezing, or 

hives) while on this medicine seek medical help immediately.
- if you are also being treated for HIV (see section “Other medicines and IntronA”).
- if you have a current or previous infection with the hepatitis B virus, since your doctor may 

want to monitor you more closely.
- if you have received an organ transplant, either kidney or liver, interferon treatment may increase 

the risk of rejection. Be sure to discuss this with your doctor.

Dental and gum disorders, which may lead to loss of teeth, have been reported in patients receiving 
IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on 
teeth and membranes of the mouth during long-term treatment with the combination of IntronA with 
ribavirin. You should brush your teeth thoroughly twice daily and have regular dental examinations. In 
addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth 
thoroughly afterwards.

Tell your doctor if you have ever had a heart attack or a heart problem; if you have a history of 
breathing irregularities or pneumonia, problems with blood clotting, liver condition, thyroid problems, 
diabetes, or high or low blood pressure.

Tell your doctor if you have ever been treated for depression or any other psychiatric disorder; confusion; 
unconsciousness; thoughts of suicide or attempted suicide, or have a history of substance abuse (e.g., 
alcohol or drugs).

Be sure to tell your doctor if you are taking the Chinese herbal medicine shosaikoto.

Other medicines and IntronA
IntronA will add to the effects of substances that slow down your nervous system, possibly causing 
drowsiness. Therefore, check with your doctor or pharmacist about drinking alcoholic beverages, or 
taking sleeping pills, sedatives or strong pain medicines. 

Tell your doctor if you are taking theophylline or aminophylline for asthma, and about all other 
medicines you are taking, or have taken recently, even those not prescribed, as the dose of some 
medicines may have to be adjusted while you are treated with IntronA.

Patients who also have HIV infection: Lactic acidosis and worsening liver function are side effects 
associated with Highly Active Anti-Retroviral Therapy (HAART), an HIV treatment. If you are 
receiving HAART, the addition of IntronA and ribavirin may increase your risk of lactic acidosis and 
of liver failure. Your doctor will monitor you for signs and symptoms of these conditions (Please be 

 



146

sure to read the ribavirin Patient Leaflet also). Additionally, patients treated with IntronA and ribavirin 
combination therapy and zidovudine could be at increased risk of developing anaemia (low number of 
red blood cells).

If you take telbivudine with a pegylated interferon alfa-2a or any type of injectable interferon product, 
your risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations in the 
arms and/or legs) is higher. These events may also be more severe. Therefore, the combination of 
IntronA with telbivudine is contraindicated.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription.

IntronA with food and drink and alcohol
While being treated with IntronA, your doctor may want you to drink extra fluids to help prevent low 
blood pressure.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. In studies in pregnant animals, 
interferons have sometimes caused miscarriage. The effect on human pregnancy is not known.
If you are prescribed IntronA in combination with ribavirin, ribavirin can be very damaging to an 
unborn baby, thus both female and male patients must take special precautions in their sexual activity 
if there is any chance for pregnancy to occur:
- if you are a girl or a woman of childbearing age, you must have a negative pregnancy test before 
treatment, each month during treatment, and for the 4 months after treatment is stopped. You must use 
an effective contraceptive during the time you are taking ribavirin and for 4 months after stopping 
treatment. This can be discussed with your doctor.
- if you are a man who is taking ribavirin, do not have sex with a pregnant woman unless you use a 
condom. This will lessen the chance for ribavirin to be left in the woman’s body. If your female 
partner is not pregnant now but is of childbearing age, she must be tested for pregnancy each month 
during treatment and for the 7 months after treatment has stopped. This can be discussed with your 
doctor. If you are a male patient, you a or your partner must use an effective contraceptive during the 
time you are taking ribavirin and for 7 months after stopping treatment. This can be discussed with 
your doctor.

It is not known whether this medicine is present in human milk. Therefore, do not breast-feed an infant 
if you are taking IntronA. In combination therapy with ribavirin, take notice of the respective 
informing texts of ribavirin containing medicinal products.

Driving and using machines
Do not drive or use machines if you become drowsy, tired, or confused from using this medicine.

IntronA contains less than 1 mmol sodium (23 mg) per 0.5 mL, i.e., essentially "sodium-free".

3. How to use IntronA

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure. Your doctor has prescribed IntronA specifically for you and your current 
condition; do not share this medicine with anyone else.

Your doctor has determined the exact dosage for administration of IntronA according to your individual 
needs. The dosage will vary according to the disease being treated.

If you are injecting IntronA yourself, please be sure that the dose that has been prescribed for you is 
clearly provided with the package of medicine you receive. Dosages that are to be administered 3 times a 
week are best given every other day.

 



147

The usual starting dose for each condition follows; however, individual doses may vary, and the doctor 
may change your dose based on your specific needs:

Chronic hepatitis B: 5 to 10 million IU 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic hepatitis C: Adults - 3 million IU 3 times a week (every other day) injected subcutaneously 
(under the skin) in combination with ribavirin or alone. Children 3 years of age and older and 
adolescents - 3 million IU/m2 3 times a week (every other day) injected subcutaneously (under the skin) 
in combination with ribavirin (Please also see ribavirin package leaflet).

Hairy Cell Leukaemia: 2 million IU/m2, 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic Myelogenous Leukaemia: 4-5 million IU/m2 daily injected subcutaneously (under the skin).

Multiple myeloma: 3 million IU/m2, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Follicular lymphoma: Adjunctively with chemotherapy, 5 million IU 3 times a week (every other day) 
injected subcutaneously (under the skin).

Carcinoid tumour: 5 million IU, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Malignant melanoma, induction therapy: 20 million IU/m2, intravenously, given daily for 5 days a week 
for a 4 week period. Maintenance treatment: 10 million IU/m2, 3 times a week (every other day) injected 
subcutaneously (under the skin).

Your doctor may prescribe a different dose of IntronA alone or in combination with other medicines (e.g., 
cytarabine, ribavirin). If you are prescribed IntronA in combination with another medicine, please refer 
also to the Package Leaflet of the medicine to be used in combination. Your doctor will determine the 
exact dosage schedule and regimen according to your needs. If you have the impression that the effect of 
IntronA is too strong or too weak, talk to your doctor or pharmacist.

Subcutaneous use:
IntronA is usually intended for subcutaneous use. This means that IntronA is injected with a short needle 
into the fatty tissue just under the skin. If you are injecting this medicine yourself, you will be instructed 
how to prepare and give the injection. Detailed instructions for subcutaneous administration are provided 
with this leaflet (see section “HOW TO SELF INJECT INTRONA” at the end of the leaflet).

Intravenous infusion:
The infusion must be prepared immediately prior to use. Any size vial may be used to measure the 
required dose; however, final concentration of interferon in sodium chloride solution must be not less 
than 0.3 million IU/mL. The appropriate dose of IntronA is withdrawn from the vial(s), added to 
50 mL of 9 mg/mL (0.9 %) sodium chloride solution for injection in a PVC bag or glass bottle for 
intravenous use and administered over 20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

One dose of IntronA is given on each scheduled day. IntronA is given either daily (5 or 7 times a week), 
or three times a week, every other day, for example on Monday, Wednesday, and Friday. Interferons may 
cause unusual tiredness; if you are injecting this medicine yourself, or giving it to a child, use it at 
bedtime.

 



148

Use IntronA exactly as prescribed by your doctor. Do not exceed the recommended dosage, and take 
IntronA for as long as prescribed.

If you use more IntronA than you should
Contact your doctor or healthcare professional as soon as possible.

If you forget to use IntronA
If you are self-administering treatment, or if you are the caregiver of a child taking IntronA in 
combination with ribavirin, inject the recommended dose as soon as you remember and continue 
treatment as usual. Do not take a double dose to make up for a forgotten dose. If you are scheduled to 
inject this medicine every day, and you accidentally missed a full day’s dose, continue treatment at the 
usual dose the following day. Contact your doctor or pharmacist if needed.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Although 
not all of these side effects may occur, they may need medical attention if they do.

Psychiatric and central nervous system: 
Some people get depressed when taking IntronA alone or in combination treatment with ribavirin, and 
in some cases people had thoughts about threatening the life of others, suicidal thoughts or aggressive 
behaviour (sometimes directed against others). Some patients have actually committed suicide. Be sure 
to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or 
change in your behaviour. You may want to consider asking a family member or close friend to help 
you stay alert to signs of depression or changes in your behaviour.

Children and adolescents are particularly prone to develop depression when being treated with 
IntronA and ribavirin. Immediately contact the doctor or seek emergency treatment if they display any 
unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or others.

Growth and development (children and adolescents): 
During the one year of treatment with IntronA in combination with ribavirin, some children and 
adolescents did not grow or gain weight as much as expected. Some children did not reach their 
projected height within 10-12 years after completing treatment.

If any of the following side effects happen, stop taking IntronA and tell your doctor immediately or go 
to the casualty department at your nearest hospital:
- swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 

swallowing or breathing; hives; fainting.
These are all very serious side effects. If you have them, you may have had a serious allergic reaction 
to IntronA. You may need urgent medical attention or hospitalisation. These very serious side effects 
are very rare.

Check with your doctor immediately if any of the following side effects occur:
- chest pain or persistent and severe cough; irregular or rapid heartbeat; shortness of breath, 

confusion, difficulty remaining alert, numbness or tingling sensation or pain in hands or feet; 
seizure (convulsions); trouble sleeping, thinking or concentrating; altered mental state; suicidal 
thoughts, suicide attempt, changed behaviour or aggressive behaviour (sometimes directed 
against others), hallucinations; severe stomach pain; black or tar like stools; blood in stool or 
urine, severe nosebleed; waxy pallor, high sugar level in blood, fever or chills beginning after a 
few weeks of treatment, lower back or side pain, difficult urination, problems with your eyes or 
your eyesight or hearing, loss of hearing, severe or painful reddening or sores on your skin or 
mucous membrane.

These may signal serious side effects that may need urgent medical attention. Your doctor will test 
your blood to ensure that your white blood cell (cells that fight infection) and red blood cell (cells that 
carry iron and oxygen) counts, platelets (blood clotting cells) and other laboratory values are at 

 



149

acceptable levels. Moderate and usually reversible reduction in all three blood elements-white blood 
cells, red blood cells and platelets, has been reported.

At the beginning of treatment with IntronA, you may experience a flu-like reaction, with fever, 
fatigue, headache, muscle ache, joint pain and chills/rigors. Your doctor may recommend that you take 
paracetamol if you develop these symptoms.

Possible side effects listed below are grouped by frequency of occurrence:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)
Not known (frequency cannot be estimated from the available data)

The following side effects have been reported:

Very commonly reported side effects: 
pain, swelling and redness or skin damage at site of injection, hair loss, dizziness, changes in appetite, 
stomach or abdominal pains, diarrhoea, nausea (feeling sick), viral infection, depression, emotional 
lability, insomnia, anxiety, sore throat and painful swallowing, fatigue, chills/rigors, fever, flu-like 
reaction, feeling of general discomfort, headaches, weight loss, vomiting, irritability, weakness, mood 
swings, coughing (sometimes severe), shortness of breath, itching, dry skin, rash, sudden and severe 
muscle pain, joint pain, musculoskeletal pain, changes in laboratory blood values including decreased 
white blood cell count. Some children have had a decrease in their rate of growth (height and weight).

Commonly reported side effects:
thirst, dehydration, high blood pressure, migraines, swollen glands, flushing, menstrual problems, 
decreased sexual drive, vaginal problem, breast pain, pain in testicle, problems with thyroid gland, red 
gums, dry mouth, red or sore mouth or tongue, tooth ache or tooth disorder, herpes simplex (fever 
blisters), taste change, upset stomach, dyspepsia (heartburn), constipation, enlargement of liver (liver 
problems, sometimes severe), loose stools, bedwetting in children, inflammation of the sinuses, 
bronchitis, eye pain, problem with your tear ducts, conjunctivitis (“pink eye”), agitation, sleepiness, 
sleepwalking, problem with behaviour, nervousness, stuffy or runny nose, sneezing, rapid breathing, 
pale or reddened skin, bruising, problem with skin or nails, psoriasis (new or worsened), increased 
sweating, increased need to pass urine, fine shaking movements, decreased sensitivity to touch, 
arthritis. 

Uncommonly reported side effects:
bacterial infection, feeling of pins and needles, and pericarditis (inflammation of the lining of the 
heart).

Rarely reported side effects:
pneumonia.

Very rarely reported side effects:
low blood pressure, puffy face, diabetes, leg cramps, back pain, kidney problems, nerve damage, 
bleeding gums, aplastic anaemia. Pure red cell aplasia, a condition where the body stopped or reduced 
the production of red blood cells, has been reported. This causes severe anaemia, symptoms of which 
would include unusual tiredness and a lack of energy.
Very rarely sarcoidosis, (a disease characterised by persistent fever, weight loss, joint pain and 
swelling, skin lesions and swollen glands) has been reported. Loss of consciousness has occurred very 
rarely, mostly in elderly patients treated at high doses. Cases of stroke (cerebrovascular events) have 
been reported. Check with your doctor immediately if you have any of these symptoms. 

 



150

Not known side effects:
Periodontal (affecting gums) and dental disorders, change in colour of the tongue, altered mental 
status, loss of consciousness, acute hypersensitivity reactions including urticaria (hives), angioedema 
(swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 
swallowing or breathing), bronchoconstriction and anaphylaxis (a severe, whole-body allergic 
reaction) have been reported, but their frequency is unknown. 
Additionally, Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the 
eyes, skin and the membranes of the ears, brain and spinal cord), thoughts about threatening the life of
others, mania (excessive or unreasonable enthusiasm), bipolar disorders (mood disorders characterized by 
alternating episodes of sadness and excitement), congestive heart failure, pericardial effusion (a fluid 
collection that develops between the pericardium (the lining of the heart) and the heart itself), pulmonary 
fibrosis (scarring of the lungs), and hepatitis B reactivation in HCV/HBV co-infected patients 
(recurrence of hepatitis B disease) have been reported with IntronA use.

Pulmonary arterial hypertension – a disease of severe narrowing of the blood vessels in the lungs 
resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This 
may occur in particular in patients with risk factors such as HIV infection or severe liver problems 
(cirrhosis). The side effect may develop at various time points during treatment, typically several 
months after starting treatment with IntronA.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can also help provide more information on the 
safety of this medicine.

5. How to store IntronA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to 
the last day of that month.

Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
For short term travelling, the solution can be kept out of the refrigerator at or below 25°C for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the medicine is not used during the seven-day period, it should be discarded.

Do not use this medicine if you notice changes in the appearance of IntronA.

Any unused medicine must be discarded after withdrawal of the dose.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What IntronA contains

- The active substance is recombinant interferon alfa-2b. Each vial contains 3 million IU in 
0.5 mL of solution.

- The other ingredients are disodium phosphate anhydrous, sodium dihydrogen phosphate 
monohydrate, edetate disodium, sodium chloride, m-cresol, polysorbate 80 and water for 
injections.

 

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151

What IntronA looks like and contents of the pack

IntronA is presented as a solution for injection or infusion.
The clear and colourless solution is contained in a glass vial.

IntronA is available in four different pack sizes:
- Pack of 1 vial
- Pack of 1 vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing swab
- Pack of 6 vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing swabs
- Pack of 12 vials, 12 injection syringes of 1 mL, 12 injection needles and 12 cleansing swabs
Not all pack sizes may be marketed.

Marketing Authorisation Holder: Manufacturer:
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

SP Labo N.V.
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 44824000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com 

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland 
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eλλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

 



152

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: +33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda.
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201
msd_slovenia@merck.com

Ísland
Vistor hf.
Simi: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 80000 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in. 

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

 

mailto:inform_pt@merck.com


153

HOW TO SELF INJECT INTRONA
Syringe with an unattached needle

The following instructions explain how to inject IntronA yourself. Please read the instructions 
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and 
requirement of self-injection.

Preparation
Collect necessary items before you begin:
- a vial of IntronA solution for injection;
- a syringe (for example 1 mL);
- a needle for the subcutaneous injection (for example 0.4 x 13 mm [27 gauge 0.5 inch]);
- a cleansing swab.
Wash your hands carefully.

Measuring the dose of IntronA
Remove the cap from the vial. Clean the rubber stopper on the top of the vial containing the IntronA 
solution with a cleansing swab.
Remove the syringe from the wrapping. Do not touch the tip of the syringe. Take the needle and place 
it firmly onto the tip of the syringe.
Remove the needle guard without touching the needle, and fill the syringe with air by pulling the 
plunger to the level that represents your dose as prescribed by your doctor.
Hold the IntronA vial upright without touching the cleaned top of the vial with your hands.
Insert the needle into the vial containing the IntronA solution and inject air into the vial.
Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the IntronA 
solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw 
the correct dose as prescribed by your doctor into the syringe.
Remove the needle from the vial and check for air bubbles in the syringe. If you see any bubbles, pull 
the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles 
disappear. Push up the plunger slowly back to the correct dose. Replace the needle guard and place the 
syringe with the needle on a flat surface.

Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe 
between your palms. Examine the solution prior to administration: it should be clear and colourless. 
Do not use if discolouration or particulate matter is present. You are now ready to inject the dose.

Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and 
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use 
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or 
outer surface of the arm for injection.
Change your injection site each time.

Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the 
needle guard. With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you 
would a pencil. Insert the needle into the pinched skin at an angle of 45° to 90°. Inject the solution by 
pushing the plunger all the way down gently. Pull the needle straight out of the skin. Press the 
injection site with a small bandage or sterile gauze if necessary for several seconds. Do not massage 
the injection site. If there is bleeding, cover with an adhesive bandage.
The vial and injection materials intended for single use must be discarded. Dispose of the syringe and 
needle safely in a closed container.

 



154

Package leaflet: Information for the user

IntronA 5 million IU/0.5 mL solution for injection or infusion
Interferon alfa-2b

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What IntronA is and what it is used for
2. What you need to know before you use IntronA
3. How to use IntronA
4. Possible side effects
5. How to store IntronA
6. Contents of the pack and other information

1. What IntronA is and what it is used for

IntronA (interferon alfa-2b) modifies the response of the body's immune system to help fight infections 
and severe diseases. 

IntronA is used in adult patients to treat certain disorders that affect the blood, bone marrow, lymph 
glands, or skin and may extend into the body. Included are hairy cell leukaemia, chronic myelogenous 
leukaemia, multiple myeloma, follicular lymphoma, carcinoid tumour, and malignant melanoma. 

IntronA is also used in adult patients for the treatment of chronic hepatitis B or C, which are viral 
infections of the liver.

IntronA is used in combination with ribavirin in children 3 years of age and older and adolescents who 
have previously untreated chronic hepatitis C.

2. What you need to know before you use IntronA

Do not use IntronA
- if you are allergic  to interferon or any of the other ingredients of this medicine (listed in 

section 6).
- if you have severe heart disease.
- if you have poor kidney or liver function.
- if you have advanced decompensated (uncontrolled) liver disease.
- if you have hepatitis and have been treated recently with medicines that suppress the immune 

system (other than short-term treatment with cortisone-type medicine).
- if you have a history of seizures (convulsions).
- if you have a history of autoimmune disease, or have had an organ transplant and are taking 

medicine that suppresses your immune system (your immune system helps protect you from 
infection).

- if you have thyroid disease that is not well controlled.
- if you are being treated with telbivudine (see section "Other medicines and IntronA").

 



155

Children and adolescents:
- if you have had serious nervous or mental problems, such as severe depression or thoughts of 

suicide.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using IntronA
- if you are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”).
- if you are being treated for mental illness or had treatment in the past for any other nervous or 

mental disorder, including depression (such as feelings of sadness, dejection) or suicidal or 
homicidal behaviour (see section 4 “Possible side effects”). The use of interferon alfa-2b in 
children and adolescents with existence of or history of severe psychiatric conditions is 
contraindicated (see section “Do not use IntronA”). 

- if you have cirrhosis or other liver problems (other than hepatitis B or C).
- if you have psoriasis, it may get worse during treatment with IntronA.
- when receiving IntronA, you may temporarily have a greater risk of getting an infection. Check 

with your doctor if you think you are getting an infection.
- if you develop symptoms associated with a cold or other respiratory infection, such as fever, cough, 

or any difficulty in breathing, tell your doctor.
- if you notice unusual bleeding or bruising check with your doctor immediately.
- if you develop symptoms of a severe allergic reaction (such as difficulty in breathing, wheezing, or 

hives) while on this medicine seek medical help immediately.
- if you are also being treated for HIV (see section “Other medicines and IntronA”).
- if you have a current or previous infection with the hepatitis B virus, since your doctor may

want to monitor you more closely.
- if you have received an organ transplant, either kidney or liver, interferon treatment may increase 

the risk of rejection. Be sure to discuss this with your doctor.

Dental and gum disorders, which may lead to loss of teeth, have been reported in patients receiving 
IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on 
teeth and membranes of the mouth during long-term treatment with the combination of IntronA with 
ribavirin. You should brush your teeth thoroughly twice daily and have regular dental examinations. In 
addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth 
thoroughly afterwards.

Tell your doctor if you have ever had a heart attack or a heart problem; if you have a history of 
breathing irregularities or pneumonia, problems with blood clotting, liver condition, thyroid problems, 
diabetes, or high or low blood pressure.

Tell your doctor if you have ever been treated for depression or any other psychiatric disorder; confusion; 
unconsciousness; thoughts of suicide or attempted suicide, or have a history of substance abuse (e.g., 
alcohol or drugs).

Be sure to tell your doctor if you are taking the Chinese herbal medicine shosaikoto.

Other medicines and IntronA
IntronA will add to the effects of substances that slow down your nervous system, possibly causing 
drowsiness. Therefore, check with your doctor or pharmacist about drinking alcoholic beverages, or 
taking sleeping pills, sedatives or strong pain medicines.

Tell your doctor if you are taking theophylline or aminophylline for asthma, and about all other 
medicines you are taking, or have taken recently, even those not prescribed, as the dose of some 
medicines may have to be adjusted while you are treated with IntronA.

Patients who also have HIV infection: Lactic acidosis and worsening liver function are side effects 
associated with Highly Active Anti-Retroviral Therapy (HAART), an HIV treatment. If you are 
receiving HAART, the addition of IntronA and ribavirin may increase your risk of lactic acidosis and 
of liver failure. Your doctor will monitor you for signs and symptoms of these conditions (Please be 

 



156

sure to read the ribavirin Patient Leaflet also). Additionally, patients treated with IntronA and ribavirin 
combination therapy and zidovudine could be at increased risk of developing anaemia (low number of 
red blood cells).

If you take telbivudine with a pegylated interferon alfa-2a or any type of injectable interferon product, 
your risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations in the 
arms and/or legs) is higher. These events may also be more severe. Therefore, the combination of 
IntronA with telbivudine is contraindicated.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription.

IntronA with food and drink and alcohol
While being treated with IntronA, your doctor may want you to drink extra fluids to help prevent low 
blood pressure.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. In studies in pregnant animals, 
interferons have sometimes caused miscarriage. The effect on human pregnancy is not known.
If you are prescribed IntronA in combination with ribavirin, ribavirin can be very damaging to an 
unborn baby, thus both female and male patients must take special precautions in their sexual activity 
if there is any chance for pregnancy to occur:
- if you are a girl or a woman of childbearing age, you must have a negative pregnancy test before 
treatment, each month during treatment, and for the 4 months after treatment is stopped. You must use 
an effective contraceptive during the time you are taking ribavirin and for 4 months after stopping 
treatment. This can be discussed with your doctor.
- if you are a man who is taking ribavirin, do not have sex with a pregnant woman unless you use a 
condom. This will lessen the chance for ribavirin to be left in the woman’s body. If your female 
partner is not pregnant now but is of childbearing age, she must be tested for pregnancy each month 
during treatment and for the 7 months after treatment has stopped. This can be discussed with your 
doctor. If you are a male patient, you or your partner must use an effective contraceptive during the 
time you are taking ribavirin and for 7 months after stopping treatment. This can be discussed with 
your doctor.

It is not known whether this medicine is present in human milk. Therefore, do not breast-feed an infant 
if you are taking IntronA. In combination therapy with ribavirin, take notice of the respective 
informing texts of ribavirin containing medicinal products.

Driving and using machines
Do not drive or use machines if you become drowsy, tired, or confused from using this medicine.

IntronA contains less than 1 mmol sodium (23 mg) per 0.5 mL, i.e., essentially "sodium-free".

3. How to use IntronA

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure. Your doctor has prescribed IntronA specifically for you and your current 
condition; do not share this medicine with anyone else.

Your doctor has determined the exact dosage for administration of IntronA according to your individual 
needs. The dosage will vary according to the disease being treated.

If you are injecting IntronA yourself, please be sure that the dose that has been prescribed for you is 
clearly provided with the package of medicine you receive. Dosages that are to be administered 3 times a 
week are best given every other day.

 



157

The usual starting dose for each condition follows; however, individual doses may vary, and the doctor 
may change your dose based on your specific needs:

Chronic hepatitis B: 5 to 10 million IU 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic hepatitis C: Adults - 3 million IU 3 times a week (every other day) injected subcutaneously 
(under the skin) in combination with ribavirin or alone. Children 3 years of age and older and 
adolescents - 3 million IU/m2 3 times a week (every other day) injected subcutaneously (under the skin) 
in combination with ribavirin (Please also see ribavirin package leaflet).

Hairy Cell Leukaemia: 2 million IU/m2, 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic Myelogenous Leukaemia: 4-5 million IU/m2 daily injected subcutaneously (under the skin).

Multiple myeloma: 3 million IU/m2, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Follicular lymphoma: Adjunctively with chemotherapy, 5 million IU 3 times a week (every other day) 
injected subcutaneously (under the skin).

Carcinoid tumour: 5 million IU, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Malignant melanoma, induction therapy: 20 million IU/m2, intravenously, given daily for 5 days a week 
for a 4 week period. Maintenance treatment: 10 million IU/m2, 3 times a week (every other day) injected 
subcutaneously (under the skin).

Your doctor may prescribe a different dose of IntronA alone or in combination with other medicines (e.g., 
cytarabine, ribavirin). If you are prescribed IntronA in combination with another medicine, please refer 
also to the Package Leaflet of the medicine to be used in combination. Your doctor will determine the 
exact dosage schedule and regimen according to your needs. If you have the impression that the effect of 
IntronA is too strong or too weak, talk to your doctor or pharmacist.

Subcutaneous use:
IntronA is usually intended for subcutaneous use. This means that IntronA is injected with a short needle
into the fatty tissue just under the skin. If you are injecting this medicine yourself, you will be instructed 
how to prepare and give the injection. Detailed instructions for subcutaneous administration are provided 
with this leaflet (see section “HOW TO SELF INJECT INTRONA” at the end of the leaflet).

Intravenous infusion:
The infusion must be prepared immediately prior to use. Any size vial may be used to measure the 
required dose; however, final concentration of interferon in sodium chloride solution must be not less 
than 0.3 million IU/mL. The appropriate dose of IntronA is withdrawn from the vial(s), added to 
50 mL of 9 mg/mL (0.9 %) sodium chloride solution for injection in a PVC bag or glass bottle for 
intravenous use and administered over 20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

One dose of IntronA is given on each scheduled day. IntronA is given either daily (5 or 7 times a week), 
or three times a week, every other day, for example on Monday, Wednesday, and Friday. Interferons may 
cause unusual tiredness; if you are injecting this medicine yourself, or giving it to a child, use it at 
bedtime.

 



158

Use IntronA exactly as prescribed by your doctor. Do not exceed the recommended dosage, and take 
IntronA for as long as prescribed.

If you use more IntronA than you should
Contact your doctor or healthcare professional as soon as possible.

If you forget to use IntronA
If you are self-administering treatment, or if you are the caregiver of a child taking IntronA in
combination with ribavirin, inject the recommended dose as soon as you remember and continue 
treatment as usual. Do not take a double dose to make up for a forgotten dose. If you are scheduled to 
inject this medicine every day, and you accidentally missed a full day’s dose, continue treatment at the 
usual dose the following day. Contact your doctor or pharmacist if needed.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Although 
not all of these side effects may occur, they may need medical attention if they do.

Psychiatric and central nervous system: 
Some people get depressed when taking IntronA alone or in combination treatment with ribavirin, and 
in some cases people had thoughts about threatening the life of others, suicidal thoughts or aggressive 
behaviour (sometimes directed against others). Some patients have actually committed suicide. Be sure 
to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or 
change in your behaviour. You may want to consider asking a family member or close friend to help 
you stay alert to signs of depression or changes in your behaviour.

Children and adolescents are particularly prone to develop depression when being treated with 
IntronA and ribavirin. Immediately contact the doctor or seek emergency treatment if they display any 
unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or others.

Growth and development (children and adolescents): 
During the one year of treatment with IntronA in combination with ribavirin, some children and 
adolescents did not grow or gain weight as much as expected. Some children did not reach their 
projected height within 10-12 years after completing treatment.

If any of the following side effects happen, stop taking IntronA and tell your doctor immediately or go 
to the casualty department at your nearest hospital:
- swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 

swallowing or breathing; hives; fainting.
These are all very serious side effects. If you have them, you may have had a serious allergic reaction 
to IntronA. You may need urgent medical attention or hospitalisation. These very serious side effects 
are very rare.

Check with your doctor immediately if any of the following side effects occur:
- chest pain or persistent and severe cough; irregular or rapid heartbeat; shortness of breath, 

confusion, difficulty remaining alert, numbness or tingling sensation or pain in hands or feet; 
seizure (convulsions); trouble sleeping, thinking or concentrating; altered mental state; suicidal 
thoughts, suicide attempt, changed behaviour or aggressive behaviour (sometimes directed 
against others), hallucinations; severe stomach pain; black or tar like stools; blood in stool or 
urine, severe nosebleed; waxy pallor, high sugar level in blood, fever or chills beginning after a 
few weeks of treatment, lower back or side pain, difficult urination, problems with your eyes or 
your eyesight or hearing, loss of hearing, severe or painful reddening or sores on your skin or 
mucous membrane.

These may signal serious side effects that may need urgent medical attention. Your doctor will test 
your blood to ensure that your white blood cell (cells that fight infection) and red blood cell (cells that 

 



159

carry iron and oxygen) counts, platelets (blood clotting cells) and other laboratory values are at 
acceptable levels. Moderate and usually reversible reduction in all three blood elements-white blood 
cells, red blood cells and platelets, has been reported.

At the beginning of treatment with IntronA, you may experience a flu-like reaction, with fever, 
fatigue, headache, muscle ache, joint pain and chills/rigors. Your doctor may recommend that you take 
paracetamol if you develop these symptoms.

Possible side effects listed below are grouped by frequency of occurrence:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)
Not known (frequency cannot be estimated from the available data)

The following side effects have been reported:

Very commonly reported side effects: 
pain, swelling and redness or skin damage at site of injection, hair loss, dizziness, changes in appetite, 
stomach or abdominal pains, diarrhoea, nausea (feeling sick), viral infection, depression, emotional 
lability, insomnia, anxiety, sore throat and painful swallowing, fatigue, chills/rigors, fever, flu-like 
reaction, feeling of general discomfort, headaches, weight loss, vomiting, irritability, weakness, mood 
swings, coughing (sometimes severe), shortness of breath, itching, dry skin, rash, sudden and severe 
muscle pain, joint pain, musculoskeletal pain, changes in laboratory blood values including decreased 
white blood cell count. Some children have had a decrease in their rate of growth (height and weight).

Commonly reported side effects:
thirst, dehydration, high blood pressure, migraines, swollen glands, flushing, menstrual problems, 
decreased sexual drive, vaginal problem, breast pain, pain in testicle, problems with thyroid gland, red 
gums, dry mouth, red or sore mouth or tongue, tooth ache or tooth disorder, herpes simplex (fever 
blisters), taste change, upset stomach, dyspepsia (heartburn), constipation, enlargement of liver (liver 
problems, sometimes severe), loose stools, bedwetting in children, inflammation of the sinuses, 
bronchitis, eye pain, problem with your tear ducts, conjunctivitis (“pink eye”), agitation, sleepiness, 
sleepwalking, problem with behaviour, nervousness, stuffy or runny nose, sneezing, rapid breathing, 
pale or reddened skin, bruising, problem with skin or nails, psoriasis (new or worsened), increased 
sweating, increased need to pass urine, fine shaking movements, decreased sensitivity to touch, 
arthritis. 

Uncommonly reported side effects:
bacterial infection, feeling of pins and needles, and pericarditis (inflammation of the lining of the 
heart).

Rarely reported side effects:
pneumonia.

Very rarely reported side effects:
low blood pressure, puffy face, diabetes, leg cramps, back pain, kidney problems, nerve damage, 
bleeding gums, aplastic anaemia. Pure red cell aplasia, a condition where the body stopped or reduced 
the production of red blood cells, has been reported. This causes severe anaemia, symptoms of which 
would include unusual tiredness and a lack of energy.
Very rarely sarcoidosis, (a disease characterised by persistent fever, weight loss, joint pain and 
swelling, skin lesions and swollen glands) has been reported. Loss of consciousness has occurred very 
rarely, mostly in elderly patients treated at high doses. Cases of stroke (cerebrovascular events) have 
been reported. Check with your doctor immediately if you have any of these symptoms. 

 



160

Not known side effects:
Periodontal (affecting gums) and dental disorders, change in colour of the tongue, altered mental 
status, loss of consciousness, acute hypersensitivity reactions including urticaria (hives), angioedema 
(swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 
swallowing or breathing), bronchoconstriction and anaphylaxis (a severe, whole-body allergic 
reaction) have been reported, but their frequency is unknown. 
Additionally, Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the 
eyes, skin and the membranes of the ears, brain and spinal cord), thoughts about threatening the life of
others, mania (excessive or unreasonable enthusiasm), bipolar disorders (mood disorders characterized by 
alternating episodes of sadness and excitement), congestive heart failure, pericardial effusion (a fluid 
collection that develops between the pericardium (the lining of the heart) and the heart itself), pulmonary 
fibrosis (scarring of the lungs), and hepatitis B reactivation in HCV/HBV co-infected patients 
(recurrence of hepatitis B disease) have been reported with IntronA use.

Pulmonary arterial hypertension – a disease of severe narrowing of the blood vessels in the lungs 
resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This 
may occur in particular in patients with risk factors such as HIV infection or severe liver problems 
(cirrhosis). The side effect may develop at various time points during treatment, typically several 
months after starting treatment with IntronA.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can also help provide more information on the 
safety of this medicine.

5. How to store IntronA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to 
the last day of that month.

Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
For short term travelling, the solution can be kept out of the refrigerator at or below 25°C for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the medicine is not used during the seven-day period, it should be discarded.

Do not use this medicine if you notice changes in the appearance of IntronA.

Any unused medicine must be discarded after withdrawal of the dose.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What IntronA contains

- The active substance is recombinant interferon alfa-2b. Each vial contains 5 million IU in 
0.5 mL of solution.

- The other ingredients are disodium phosphate anhydrous, sodium dihydrogen phosphate 
monohydrate, edetate disodium, sodium chloride, m-cresol, polysorbate 80 and water for 
injections.

 

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161

What IntronA looks like and contents of the pack

IntronA is presented as a solution for injection or infusion.
The clear and colourless solution is contained in a glass vial.

IntronA is available in four different pack sizes:
- Pack of 1 vial
- Pack of 1 vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing swab
- Pack of 6 vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing swabs
- Pack of 12 vials, 12 injection syringes of 1 mL, 12 injection needles and 12 cleansing swabs
Not all pack sizes may be marketed.

Marketing Authorisation Holder: Manufacturer:
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

SP Labo N.V.
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 44824000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com 

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland 
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eλλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

 



162

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: +33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda.
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201
msd_slovenia@merck.com

Ísland
Vistor hf.
Simi: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 80000 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in.

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

 

mailto:inform_pt@merck.com


163

HOW TO SELF INJECT INTRONA
Syringe with an unattached needle

The following instructions explain how to inject IntronA yourself. Please read the instructions 
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and 
requirement of self-injection.

Preparation
Collect necessary items before you begin:
- a vial of IntronA solution for injection;
- a syringe (for example 1 mL);
- a needle for the subcutaneous injection (for example 0.4 x 13 mm [27 gauge 0.5 inch]);
- a cleansing swab.
Wash your hands carefully.

Measuring the dose of IntronA
Remove the cap from the vial. Clean the rubber stopper on the top of the vial containing the IntronA 
solution with a cleansing swab.
Remove the syringe from the wrapping. Do not touch the tip of the syringe. Take the needle and place 
it firmly onto the tip of the syringe.
Remove the needle guard without touching the needle, and fill the syringe with air by pulling the 
plunger to the level that represents your dose as prescribed by your doctor.
Hold the IntronA vial upright without touching the cleaned top of the vial with your hands.
Insert the needle into the vial containing the IntronA solution and inject air into the vial.
Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the IntronA 
solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw 
the correct dose as prescribed by your doctor into the syringe.
Remove the needle from the vial and check for air bubbles in the syringe. If you see any bubbles, pull 
the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles 
disappear. Push up the plunger slowly back to the correct dose. Replace the needle guard and place the 
syringe with the needle on a flat surface.

Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe 
between your palms. Examine the solution prior to administration: it should be clear and colourless. 
Do not use if discolouration or particulate matter is present. You are now ready to inject the dose.

Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and 
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use 
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or 
outer surface of the arm for injection.
Change your injection site each time.

Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the 
needle guard. With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you 
would a pencil. Insert the needle into the pinched skin at an angle of 45° to 90°. Inject the solution by 
pushing the plunger all the way down gently. Pull the needle straight out of the skin. Press the 
injection site with a small bandage or sterile gauze if necessary for several seconds. Do not massage 
the injection site. If there is bleeding, cover with an adhesive bandage.
The vial and injection materials intended for single use must be discarded. Dispose of the syringe and 
needle safely in a closed container.

 



164

Package leaflet: Information for the user

IntronA 10 million IU/mL solution for injection or infusion
Interferon alfa-2b

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What IntronA is and what it is used for
2. What you need to know before you use IntronA
3. How to use IntronA
4. Possible side effects
5. How to store IntronA
6. Contents of the pack and other information

1. What IntronA is and what it is used for

IntronA (interferon alfa-2b) modifies the response of the body's immune system to help fight infections 
and severe diseases. 

IntronA is used in adult patients to treat certain disorders that affect the blood, bone marrow, lymph 
glands, or skin and may extend into the body. Included are hairy cell leukaemia, chronic myelogenous 
leukaemia, multiple myeloma, follicular lymphoma, carcinoid tumour, and malignant melanoma. 

IntronA is also used in adult patients for the treatment of chronic hepatitis B or C, which are viral 
infections of the liver.

IntronA is used in combination with ribavirin in children 3 years of age and older and adolescents who 
have previously untreated chronic hepatitis C.

2. What you need to know before you use IntronA

Do not use IntronA
- if you are allergic to interferon or any of the other ingredients of this medicine (listed in 

section 6).
- if you have severe heart disease.
- if you have poor kidney or liver function.
- if you have advanced decompensated (uncontrolled) liver disease.
- if you have hepatitis and have been treated recently with medicines that suppress the immune 

system (other than short-term treatment with cortisone-type medicine).
- if you have a history of seizures (convulsions).
- if you have a history of autoimmune disease, or have had an organ transplant and are taking 

medicine that suppresses your immune system (your immune system helps protect you from 
infection).

- if you have thyroid disease that is not well controlled.
- if you are being treated with telbivudine (see section "Other medicines and IntronA").

 



165

Children and adolescents:
- if you have had serious nervous or mental problems, such as severe depression or thoughts of 

suicide.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using IntronA
- if you are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”). 
- if you are being treated for mental illness or had treatment in the past for any other nervous or 

mental disorder, including depression (such as feelings of sadness, dejection) or suicidal or 
homicidal behaviour (see section 4 “Possible side effects”). The use of interferon alfa-2b in 
children and adolescents with existence of or history of severe psychiatric conditions is 
contraindicated (see section “Do not use IntronA”). 

- if you have cirrhosis or other liver problems (other than hepatitis B or C).
- if you have psoriasis, it may get worse during treatment with IntronA.
- when receiving IntronA, you may temporarily have a greater risk of getting an infection. Check 

with your doctor if you think you are getting an infection.
- if you develop symptoms associated with a cold or other respiratory infection, such as fever, cough, 

or any difficulty in breathing, tell your doctor.
- if you notice unusual bleeding or bruising check with your doctor immediately.
- if you develop symptoms of a severe allergic reaction (such as difficulty in breathing, wheezing, or 

hives) while on this medicine seek medical help immediately.
- if you are also being treated for HIV (see section “Other medicines and IntronA”).
- if you have a current or previous infection with the hepatitis B virus, since your doctor may 

want to monitor you more closely.
- if you have received an organ transplant, either kidney or liver, interferon treatment may increase 

the risk of rejection. Be sure to discuss this with your doctor.

Dental and gum disorders, which may lead to loss of teeth, have been reported in patients receiving 
IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on 
teeth and membranes of the mouth during long-term treatment with the combination of IntronA with 
ribavirin. You should brush your teeth thoroughly twice daily and have regular dental examinations. In 
addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth 
thoroughly afterwards.

Tell your doctor if you have ever had a heart attack or a heart problem; if you have a history of 
breathing irregularities or pneumonia, problems with blood clotting, liver condition, thyroid problems, 
diabetes, or high or low blood pressure.

Tell your doctor if you have ever been treated for depression or any other psychiatric disorder; confusion; 
unconsciousness; thoughts of suicide or attempted suicide, or have a history of substance abuse (e.g., 
alcohol or drugs).

Be sure to tell your doctor if you are taking the Chinese herbal medicine shosaikoto.

Other medicines and IntronA
IntronA will add to the effects of substances that slow down your nervous system, possibly causing 
drowsiness. Therefore, check with your doctor or pharmacist about drinking alcoholic beverages, or 
taking sleeping pills, sedatives or strong pain medicines.

Tell your doctor if you are taking theophylline or aminophylline for asthma, and about all other 
medicines you are taking, or have taken recently, even those not prescribed, as the dose of some 
medicines may have to be adjusted while you are treated with IntronA.

Patients who also have HIV infection: Lactic acidosis and worsening liver function are side effects 
associated with Highly Active Anti-Retroviral Therapy (HAART), an HIV treatment. If you are 
receiving HAART, the addition of IntronA and ribavirin may increase your risk of lactic acidosis and 
of liver failure. Your doctor will monitor you for signs and symptoms of these conditions (Please be 

 



166

sure to read the ribavirin Patient Leaflet also). Additionally, patients treated with IntronA and ribavirin 
combination therapy and zidovudine could be at increased risk of developing anaemia (low number of 
red blood cells).

If you take telbivudine with a pegylated interferon alfa-2a or any type of injectable interferon product, 
your risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations in the 
arms and/or legs) is higher. These events may also be more severe. Therefore, the combination of 
IntronA with telbivudine is contraindicated.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription.

IntronA with food and drink and alcohol
While being treated with IntronA, your doctor may want you to drink extra fluids to help prevent low 
blood pressure.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. In studies in pregnant animals, 
interferons have sometimes caused miscarriage. The effect on human pregnancy is not known.
If you are prescribed IntronA in combination with ribavirin, ribavirin can be very damaging to an 
unborn baby, thus both female and male patients must take special precautions in their sexual activity 
if there is any chance for pregnancy to occur:
- if you are a girl or a woman of childbearing age, you must have a negative pregnancy test before 
treatment, each month during treatment, and for the 4 months after treatment is stopped. You must use 
an effective contraceptive during the time you are taking ribavirin and for 4 months after stopping 
treatment. This can be discussed with your doctor.
- if you are a man who is taking ribavirin, do not have sex with a pregnant woman unless you use a 
condom. This will lessen the chance for ribavirin to be left in the woman’s body. If your female 
partner is not pregnant now but is of childbearing age, she must be tested for pregnancy each month 
during treatment and for the 7 months after treatment has stopped. This can be discussed with your 
doctor. If you are a male patient, you or your partner must use an effective contraceptive during the 
time you are taking ribavirin and for 7 months after stopping treatment. This can be discussed with 
your doctor.

It is not known whether this medicine is present in human milk. Therefore, do not breast-feed an infant 
if you are taking IntronA. In combination therapy with ribavirin, take notice of the respective 
informing texts of ribavirin containing medicinal products.

Driving and using machines
Do not drive or use machines if you become drowsy, tired, or confused from using this medicine.

IntronA contains less than 1 mmol sodium (23 mg) per 1 mL, i.e., essentially "sodium-free".

3. How to use IntronA

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure. Your doctor has prescribed IntronA specifically for you and your current 
condition; do not share this medicine with anyone else.

Your doctor has determined the exact dosage for administration of IntronA according to your individual 
needs. The dosage will vary according to the disease being treated.

If you are injecting IntronA yourself, please be sure that the dose that has been prescribed for you is 
clearly provided with the package of medicine you receive. Dosages that are to be administered 3 times a 
week are best given every other day.

 



167

The usual starting dose for each condition follows; however, individual doses may vary, and the doctor 
may change your dose based on your specific needs:

Chronic hepatitis B: 5 to 10 million IU 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic hepatitis C: Adults - 3 million IU 3 times a week (every other day) injected subcutaneously 
(under the skin) in combination with ribavirin or alone. Children 3 years of age and older and 
adolescents - 3 million IU/m2 3 times a week (every other day) injected subcutaneously (under the skin) 
in combination with ribavirin (Please also see ribavirin package leaflet).

Hairy Cell Leukaemia: 2 million IU/m2, 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic Myelogenous Leukaemia: 4-5 million IU/m2 daily injected subcutaneously (under the skin).

Multiple myeloma: 3 million IU/m2, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Follicular lymphoma: Adjunctively with chemotherapy, 5 million IU 3 times a week (every other day) 
injected subcutaneously (under the skin).

Carcinoid tumour: 5 million IU, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Malignant melanoma, induction therapy: 20 million IU/m2, intravenously, given daily for 5 days a week 
for a 4 week period. Maintenance treatment: 10 million IU/m2, 3 times a week (every other day) injected 
subcutaneously (under the skin).

Your doctor may prescribe a different dose of IntronA alone or in combination with other medicines (e.g., 
cytarabine, ribavirin). If you are prescribed IntronA in combination with another medicine, please refer 
also to the Package Leaflet of the medicine to be used in combination. Your doctor will determine the 
exact dosage schedule and regimen according to your needs. If you have the impression that the effect of 
IntronA is too strong or too weak, talk to your doctor or pharmacist.

Subcutaneous use:
IntronA is usually intended for subcutaneous use. This means that IntronA is injected with a short needle 
into the fatty tissue just under the skin. If you are injecting this medicine yourself, you will be instructed 
how to prepare and give the injection. Detailed instructions for subcutaneous administration are provided 
with this leaflet (see section “HOW TO SELF INJECT INTRONA” at the end of the leaflet).

Intravenous infusion:
The infusion must be prepared immediately prior to use. Any size vial may be used to measure the 
required dose; however, final concentration of interferon in sodium chloride solution must be not less 
than 0.3 million IU/mL. The appropriate dose of IntronA is withdrawn from the vial(s), added to 
50 mL of 9 mg/mL (0.9 %) sodium chloride solution for injection in a PVC bag or glass bottle for 
intravenous use and administered over 20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

One dose of IntronA is given on each scheduled day. IntronA is given either daily (5 or 7 times a week), 
or three times a week, every other day, for example on Monday, Wednesday, and Friday. Interferons may 
cause unusual tiredness; if you are injecting this medicine yourself, or giving it to a child, use it at 
bedtime.

 



168

Use IntronA exactly as prescribed by your doctor. Do not exceed the recommended dosage, and take 
IntronA for as long as prescribed.

If you use more IntronA than you should
Contact your doctor or healthcare professional as soon as possible.

If you forget to use IntronA
If you are self-administering treatment, or if you are the caregiver of a child taking IntronA in 
combination with ribavirin, inject the recommended dose as soon as you remember and continue 
treatment as usual. Do not take a double dose to make up for a forgotten dose. If you are scheduled to 
inject this medicine every day, and you accidentally missed a full day’s dose, continue treatment at the 
usual dose the following day. Contact your doctor or pharmacist if needed.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Although 
not all of these side effects may occur, they may need medical attention if they do.

Psychiatric and central nervous system: 
Some people get depressed when taking IntronA alone or in combination treatment with ribavirin, and 
in some cases people had thoughts about threatening the life of others, suicidal thoughts or aggressive 
behaviour (sometimes directed against others). Some patients have actually committed suicide. Be sure 
to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or 
change in your behaviour. You may want to consider asking a family member or close friend to help 
you stay alert to signs of depression or changes in your behaviour.

Children and adolescents are particularly prone to develop depression when being treated with 
IntronA and ribavirin. Immediately contact the doctor or seek emergency treatment if they display any 
unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or others.

Growth and development (children and adolescents): 
During the one year of treatment with IntronA in combination with ribavirin, some children and 
adolescents did not grow or gain weight as much as expected. Some children did not reach their 
projected height within 10-12 years after completing treatment.

If any of the following side effects happen, stop taking IntronA and tell your doctor immediately or go 
to the casualty department at your nearest hospital:
- swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 

swallowing or breathing; hives; fainting.
These are all very serious side effects. If you have them, you may have had a serious allergic reaction 
to IntronA. You may need urgent medical attention or hospitalisation. These very serious side effects 
are very rare.

Check with your doctor immediately if any of the following side effects occur:
- chest pain or persistent and severe cough; irregular or rapid heartbeat; shortness of breath, 

confusion, difficulty remaining alert, numbness or tingling sensation or pain in hands or feet; 
seizure (convulsions); trouble sleeping, thinking or concentrating; altered mental state; suicidal 
thoughts, suicide attempt, changed behaviour or aggressive behaviour (sometimes directed 
against others), hallucinations; severe stomach pain; black or tar like stools; blood in stool or 
urine, severe nosebleed; waxy pallor, high sugar level in blood, fever or chills beginning after a 
few weeks of treatment, lower back or side pain, difficult urination, problems with your eyes or 
your eyesight or hearing, loss of hearing, severe or painful reddening or sores on your skin or 
mucous membrane.

These may signal serious side effects that may need urgent medical attention. Your doctor will test 
your blood to ensure that your white blood cell (cells that fight infection) and red blood cell (cells that 
carry iron and oxygen) counts, platelets (blood clotting cells) and other laboratory values are at 

 



169

acceptable levels. Moderate and usually reversible reduction in all three blood elements-white blood 
cells, red blood cells and platelets, has been reported.

At the beginning of treatment with IntronA, you may experience a flu-like reaction, with fever, 
fatigue, headache, muscle ache, joint pain and chills/rigors. Your doctor may recommend that you take 
paracetamol if you develop these symptoms.

Possible side effects listed below are grouped by frequency of occurrence:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)
Not known (frequency cannot be estimated from the available data)

The following side effects have been reported:

Very commonly reported side effects: 
pain, swelling and redness or skin damage at site of injection, hair loss, dizziness, changes in appetite, 
stomach or abdominal pains, diarrhoea, nausea (feeling sick), viral infection, depression, emotional 
lability, insomnia, anxiety, sore throat and painful swallowing, fatigue, chills/rigors, fever, flu-like 
reaction, feeling of general discomfort, headaches, weight loss, vomiting, irritability, weakness, mood 
swings, coughing (sometimes severe), shortness of breath, itching, dry skin, rash, sudden and severe 
muscle pain, joint pain, musculoskeletal pain, changes in laboratory blood values including decreased 
white blood cell count. Some children have had a decrease in their rate of growth (height and weight).

Commonly reported side effects:
thirst, dehydration, high blood pressure, migraines, swollen glands, flushing, menstrual problems, 
decreased sexual drive, vaginal problem, breast pain, pain in testicle, problems with thyroid gland, red 
gums, dry mouth, red or sore mouth or tongue, tooth ache or tooth disorder, herpes simplex (fever 
blisters), taste change, upset stomach, dyspepsia (heartburn), constipation, enlargement of liver (liver 
problems, sometimes severe), loose stools, bedwetting in children, inflammation of the sinuses, 
bronchitis, eye pain, problem with your tear ducts, conjunctivitis (“pink eye”), agitation, sleepiness, 
sleepwalking, problem with behaviour, nervousness, stuffy or runny nose, sneezing, rapid breathing, 
pale or reddened skin, bruising, problem with skin or nails, psoriasis (new or worsened), increased 
sweating, increased need to pass urine, fine shaking movements, decreased sensitivity to touch, 
arthritis. 

Uncommonly reported side effects:
bacterial infection, feeling of pins and needles, and pericarditis (inflammation of the lining of the 
heart).

Rarely reported side effects:
pneumonia.

Very rarely reported side effects:
low blood pressure, puffy face, diabetes, leg cramps, back pain, kidney problems, nerve damage, 
bleeding gums, aplastic anaemia. Pure red cell aplasia, a condition where the body stopped or reduced 
the production of red blood cells, has been reported. This causes severe anaemia, symptoms of which 
would include unusual tiredness and a lack of energy.
Very rarely sarcoidosis, (a disease characterised by persistent fever, weight loss, joint pain and 
swelling, skin lesions and swollen glands) has been reported. Loss of consciousness has occurred very 
rarely, mostly in elderly patients treated at high doses. Cases of stroke (cerebrovascular events) have 
been reported. Check with your doctor immediately if you have any of these symptoms. 

 



170

Not known side effects:
Periodontal (affecting gums) and dental disorders, change in colour of the tongue, altered mental 
status, loss of consciousness, acute hypersensitivity reactions including urticaria (hives), angioedema 
(swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 
swallowing or breathing), bronchoconstriction and anaphylaxis (a severe, whole-body allergic 
reaction) have been reported, but their frequency is unknown. 
Additionally, Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the 
eyes, skin and the membranes of the ears, brain and spinal cord), thoughts about threatening the life of
others, mania (excessive or unreasonable enthusiasm), bipolar disorders (mood disorders characterized by 
alternating episodes of sadness and excitement), congestive heart failure, pericardial effusion (a fluid 
collection that develops between the pericardium (the lining of the heart) and the heart itself), pulmonary 
fibrosis (scarring of the lungs), and hepatitis B reactivation in HCV/HBV co-infected patients 
(recurrence of hepatitis B disease) have been reported with IntronA use.

Pulmonary arterial hypertension – a disease of severe narrowing of the blood vessels in the lungs 
resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This 
may occur in particular in patients with risk factors such as HIV infection or severe liver problems 
(cirrhosis). The side effect may develop at various time points during treatment, typically several 
months after starting treatment with IntronA.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can also help provide more information on the 
safety of this medicine.

5. How to store IntronA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to 
the last day of that month.

Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
For short term travelling, the solution can be kept out of the refrigerator at or below 25°C for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-
day period. If the medicine is not used during the seven-day period, it should be discarded.

Do not use this medicine if you notice changes in the appearance of IntronA.

Any unused medicine must be discarded after withdrawal of the dose.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What IntronA contains

- The active substance is recombinant interferon alfa-2b. Each vial contains 10 million IU in 
1 mL of solution.

- The other ingredients are disodium phosphate anhydrous, sodium dihydrogen phosphate 
monohydrate, edetate disodium, sodium chloride, m-cresol, polysorbate 80 and water for 
injections.

 

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171

What IntronA looks like and contents of the pack

IntronA is presented as a solution for injection or infusion.
The clear and colourless solution is contained in a glass vial.

IntronA is available in four different pack sizes:
- Pack of 1 vial
- Pack of 1 vial, 1 injection syringe of 2 mL, 1 injection needle and 1 cleansing swab
- Pack of 6 vials, 6 injection syringes of 2 mL, 6 injection needles and 6 cleansing swabs
- Pack of 12 vials, 12 injection syringes of 2 mL, 12 injection needles and 12 cleansing swabs
Not all pack sizes may be marketed.

Marketing Authorisation Holder: Manufacturer:
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

SP Labo N.V.
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 44824000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com 

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland 
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eλλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

 



172

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: +33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda.
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201
msd_slovenia@merck.com

Ísland
Vistor hf.
Simi: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 80000 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in. 

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

 

mailto:inform_pt@merck.com


173

HOW TO SELF INJECT INTRONA
Syringe with an unattached needle

The following instructions explain how to inject IntronA yourself. Please read the instructions 
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and 
requirement of self-injection.

Preparation
Collect necessary items before you begin:
- a vial of IntronA solution for injection;
- a syringe (for example 2 mL);
- a needle for the subcutaneous injection (for example 0.4 x 13 mm [27 gauge 0.5 inch]);
- a cleansing swab.
Wash your hands carefully.

Measuring the dose of IntronA
Remove the cap from the vial. Clean the rubber stopper on the top of the vial containing the IntronA 
solution with a cleansing swab.
Remove the syringe from the wrapping. Do not touch the tip of the syringe. Take the needle and place 
it firmly onto the tip of the syringe.
Remove the needle guard without touching the needle, and fill the syringe with air by pulling the 
plunger to the level that represents your dose as prescribed by your doctor.
Hold the IntronA vial upright without touching the cleaned top of the vial with your hands.
Insert the needle into the vial containing the IntronA solution and inject air into the vial.
Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the IntronA 
solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw 
the correct dose as prescribed by your doctor into the syringe.
Remove the needle from the vial and check for air bubbles in the syringe. If you see any bubbles, pull 
the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles 
disappear. Push up the plunger slowly back to the correct dose. Replace the needle guard and place the 
syringe with the needle on a flat surface.

Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe 
between your palms. Examine the solution prior to administration: it should be clear and colourless. 
Do not use if discolouration or particulate matter is present. You are now ready to inject the dose.

Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and 
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use 
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or 
outer surface of the arm for injection.
Change your injection site each time.

Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the 
needle guard. With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you 
would a pencil. Insert the needle into the pinched skin at an angle of 45° to 90°. Inject the solution by 
pushing the plunger all the way down gently. Pull the needle straight out of the skin. Press the 
injection site with a small bandage or sterile gauze if necessary for several seconds. Do not massage 
the injection site. If there is bleeding, cover with an adhesive bandage.
The vial and injection materials intended for single use must be discarded. Dispose of the syringe and 
needle safely in a closed container.

 



174

Package leaflet: Information for the user

IntronA 18 million IU/3 mL solution for injection or infusion
Interferon alfa-2b

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What IntronA is and what it is used for
2. What you need to know before you use IntronA
3. How to use IntronA
4. Possible side effects
5. How to store IntronA
6. Contents of the pack and other information

1. What IntronA is and what it is used for

IntronA (interferon alfa-2b) modifies the response of the body's immune system to help fight infections 
and severe diseases. 

IntronA is used in adult patients to treat certain disorders that affect the blood, bone marrow, lymph 
glands, or skin and may extend into the body. Included are hairy cell leukaemia, chronic myelogenous 
leukaemia, multiple myeloma, follicular lymphoma, carcinoid tumour, and malignant melanoma. 

IntronA is also used in adult patients for the treatment of chronic hepatitis B or C, which are viral 
infections of the liver.

IntronA is used in combination with ribavirin in children 3 years of age and older and adolescents who 
have previously untreated chronic hepatitis C.

2. What you need to know before you use IntronA

Do not use IntronA
- if you are allergic  to interferon or any of the other ingredients of this medicine (listed in 

section 6).
- if you have severe heart disease.
- if you have poor kidney or liver function.
- if you have advanced decompensated (uncontrolled) liver disease.
- if you have hepatitis and have been treated recently with medicines that suppress the immune 

system (other than short-term treatment with cortisone-type medicine).
- if you have a history of seizures (convulsions).
- if you have a history of autoimmune disease, or have had an organ transplant and are taking 

medicine that suppresses your immune system (your immune system helps protect you from 
infection).

- if you have thyroid disease that is not well controlled.
- if you are being treated with telbivudine (see section "Other medicines and IntronA").

 



175

Children and adolescents:
- if you have had serious nervous or mental problems, such as severe depression or thoughts of 

suicide.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using IntronA
- if you are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”). 
- if you are being treated for mental illness or had treatment in the past for any other nervous or 

mental disorder, including depression (such as feelings of sadness, dejection) or suicidal or 
homicidal behaviour (see section 4 “Possible side effects”). The use of interferon alfa-2b in 
children and adolescents with existence of or history of severe psychiatric conditions is 
contraindicated (see section “Do not use IntronA”). 

- if you have cirrhosis or other liver problems (other than hepatitis B or C).
- if you have psoriasis, it may get worse during treatment with IntronA.
- when receiving IntronA, you may temporarily have a greater risk of getting an infection. Check 

with your doctor if you think you are getting an infection.
- if you develop symptoms associated with a cold or other respiratory infection, such as fever, cough, 

or any difficulty in breathing, tell your doctor.
- if you notice unusual bleeding or bruising check with your doctor immediately.
- if you develop symptoms of a severe allergic reaction (such as difficulty in breathing, wheezing, or 

hives) while on this medicine seek medical help immediately.
- if you are also being treated for HIV (see section “Other medicines and IntronA”).
- if you have a current or previous infection with the hepatitis B virus, since your doctor may 

want to monitor you more closely.
- if you have received an organ transplant, either kidney or liver, interferon treatment may increase 

the risk of rejection. Be sure to discuss this with your doctor.

Dental and gum disorders, which may lead to loss of teeth, have been reported in patients receiving 
IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on 
teeth and membranes of the mouth during long-term treatment with the combination of IntronA with 
ribavirin. You should brush your teeth thoroughly twice daily and have regular dental examinations. In 
addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth 
thoroughly afterwards.

Tell your doctor if you have ever had a heart attack or a heart problem; if you have a history of 
breathing irregularities or pneumonia, problems with blood clotting, liver condition, thyroid problems, 
diabetes, or high or low blood pressure.

Tell your doctor if you have ever been treated for depression or any other psychiatric disorder; confusion; 
unconsciousness; thoughts of suicide or attempted suicide, or have a history of substance abuse (e.g., 
alcohol or drugs).

Be sure to tell your doctor if you are taking the Chinese herbal medicine shosaikoto.

Other medicines and IntronA
IntronA will add to the effects of substances that slow down your nervous system, possibly causing 
drowsiness. Therefore, check with your doctor or pharmacist about drinking alcoholic beverages, or 
taking sleeping pills, sedatives or strong pain medicines.

Tell your doctor if you are taking theophylline or aminophylline for asthma, and about all other 
medicines you are taking, or have taken recently, even those not prescribed, as the dose of some 
medicines may have to be adjusted while you are treated with IntronA.

Patients who also have HIV infection: Lactic acidosis and worsening liver function are side effects 
associated with Highly Active Anti-Retroviral Therapy (HAART), an HIV treatment. If you are 
receiving HAART, the addition of IntronA and ribavirin may increase your risk of lactic acidosis and 
of liver failure. Your doctor will monitor you for signs and symptoms of these conditions (Please be 

 



176

sure to read the ribavirin Patient Leaflet also). Additionally, patients treated with IntronA and ribavirin 
combination therapy and zidovudine could be at increased risk of developing anaemia (low number of 
red blood cells).

If you take telbivudine with a pegylated interferon alfa-2a or any type of injectable interferon product, 
your risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations in the 
arms and/or legs) is higher. These events may also be more severe. Therefore, the combination of 
IntronA with telbivudine is contraindicated.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription.

IntronA with food and drink and alcohol
While being treated with IntronA, your doctor may want you to drink extra fluids to help prevent low 
blood pressure.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. In studies in pregnant animals, 
interferons have sometimes caused miscarriage. The effect on human pregnancy is not known.
If you are prescribed IntronA in combination with ribavirin, ribavirin can be very damaging to an 
unborn baby, thus both female and male patients must take special precautions in their sexual activity 
if there is any chance for pregnancy to occur:
- if you are a girl or a woman of childbearing age, you must have a negative pregnancy test before 
treatment, each month during treatment, and for the 4 months after treatment is stopped. You must use 
an effective contraceptive during the time you are taking ribavirin and for 4 months after stopping 
treatment. This can be discussed with your doctor.
- if you are a man who is taking ribavirin, do not have sex with a pregnant woman unless you use a 
condom. This will lessen the chance for ribavirin to be left in the woman’s body. If your female 
partner is not pregnant now but is of childbearing age, she must be tested for pregnancy each month 
during treatment and for the 7 months after treatment has stopped. This can be discussed with your 
doctor. If you are a male patient, you or your partner must use an effective contraceptive during the 
time you are taking ribavirin and for 7 months after stopping treatment. This can be discussed with 
your doctor.

It is not known whether this medicine is present in human milk. Therefore, do not breast-feed an infant 
if you are taking IntronA. In combination therapy with ribavirin, take notice of the respective 
informing texts of ribavirin containing medicinal products.

Driving and using machines
Do not drive or use machines if you become drowsy, tired, or confused from using this medicine.

IntronA contains less than 1 mmol sodium (23 mg) per 3 mL, i.e., essentially "sodium-free".

3. How to use IntronA

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure. Your doctor has prescribed IntronA specifically for you and your current 
condition; do not share this medicine with anyone else.

Your doctor has determined the exact dosage for administration of IntronA according to your individual 
needs. The dosage will vary according to the disease being treated.

If you are injecting IntronA yourself, please be sure that the dose that has been prescribed for you is 
clearly provided with the package of medicine you receive. Dosages that are to be administered 3 times a 
week are best given every other day.

 



177

The usual starting dose for each condition follows; however, individual doses may vary, and the doctor 
may change your dose based on your specific needs:

Chronic hepatitis B: 5 to 10 million IU 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic hepatitis C: Adults - 3 million IU 3 times a week (every other day) injected subcutaneously 
(under the skin) in combination with ribavirin or alone. Children 3 years of age and older and 
adolescents - 3 million IU/m2 3 times a week (every other day) injected subcutaneously (under the skin) 
in combination with ribavirin (Please also see ribavirin package leaflet).

Hairy Cell Leukaemia: 2 million IU/m2, 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic Myelogenous Leukaemia: 4-5 million IU/m2 daily injected subcutaneously (under the skin).

Multiple myeloma: 3 million IU/m2, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Follicular lymphoma: Adjunctively with chemotherapy, 5 million IU 3 times a week (every other day) 
injected subcutaneously (under the skin).

Carcinoid tumour: 5 million IU, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Malignant melanoma, induction therapy: 20 million IU/m2, intravenously, given daily for 5 days a week 
for a 4 week period. Maintenance treatment: 10 million IU/m2, 3 times a week (every other day) injected 
subcutaneously (under the skin).

Your doctor may prescribe a different dose of IntronA alone or in combination with other medicines (e.g., 
cytarabine, ribavirin). If you are prescribed IntronA in combination with another medicine, please refer 
also to the Package Leaflet of the medicine to be used in combination. Your doctor will determine the 
exact dosage schedule and regimen according to your needs. If you have the impression that the effect of 
IntronA is too strong or too weak, talk to your doctor or pharmacist.

Subcutaneous use:
IntronA is usually intended for subcutaneous use. This means that IntronA is injected with a short needle 
into the fatty tissue just under the skin. If you are injecting this medicine yourself, you will be instructed 
how to prepare and give the injection. Detailed instructions for subcutaneous administration are provided 
with this leaflet (see section “HOW TO SELF INJECT INTRONA” at the end of the leaflet).

Intravenous infusion:
The infusion must be prepared immediately prior to use. Any size vial may be used to measure the 
required dose; however, final concentration of interferon in sodium chloride solution must be not less 
than 0.3 million IU/mL. The appropriate dose of IntronA is withdrawn from the vial(s), added to 
50 mL of 9 mg/mL (0.9 %) sodium chloride solution for injection in a PVC bag or glass bottle for 
intravenous use and administered over 20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

One dose of IntronA is given on each scheduled day. IntronA is given either daily (5 or 7 times a week), 
or three times a week, every other day, for example on Monday, Wednesday, and Friday. Interferons may 
cause unusual tiredness; if you are injecting this medicine yourself, or giving it to a child, use it at 
bedtime.

 



178

Use IntronA exactly as prescribed by your doctor. Do not exceed the recommended dosage, and take 
IntronA for as long as prescribed.

If you use more IntronA than you should
Contact your doctor or healthcare professional as soon as possible.

If you forget to use IntronA
If you are self-administering treatment, or if you are the caregiver of a child taking IntronA in 
combination with ribavirin, inject the recommended dose as soon as you remember and continue 
treatment as usual. Do not take a double dose to make up for a forgotten dose. If you are scheduled to 
inject this medicine every day, and you accidentally missed a full day’s dose, continue treatment at the 
usual dose the following day. Contact your doctor or pharmacist if needed.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Although 
not all of these side effects may occur, they may need medical attention if they do.

Psychiatric and central nervous system:
Some people get depressed when taking IntronA alone or in combination treatment with ribavirin, and 
in some cases people had thoughts about threatening the life of others, suicidal thoughts or aggressive 
behaviour (sometimes directed against others). Some patients have actually committed suicide. Be sure 
to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or 
change in your behaviour. You may want to consider asking a family member or close friend to help 
you stay alert to signs of depression or changes in your behaviour.

Children and adolescents are particularly prone to develop depression when being treated with 
IntronA and ribavirin. Immediately contact the doctor or seek emergency treatment if they display any 
unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or others.

Growth and development (children and adolescents): 
During the one year of treatment with IntronA in combination with ribavirin, some children and 
adolescents did not grow or gain weight as much as expected. Some children did not reach their 
projected height within 10-12 years after completing treatment.

If any of the following side effects happen, stop taking IntronA and tell your doctor immediately or go 
to the casualty department at your nearest hospital:
- swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 

swallowing or breathing; hives; fainting.
These are all very serious side effects. If you have them, you may have had a serious allergic reaction 
to IntronA. You may need urgent medical attention or hospitalisation. These very serious side effects 
are very rare.

Check with your doctor immediately if any of the following side effects occur:
- chest pain or persistent and severe cough; irregular or rapid heartbeat; shortness of breath, 

confusion, difficulty remaining alert, numbness or tingling sensation or pain in hands or feet; 
seizure (convulsions); trouble sleeping, thinking or concentrating; altered mental state; suicidal 
thoughts, suicide attempt, changed behaviour or aggressive behaviour (sometimes directed 
against others), hallucinations; severe stomach pain; black or tar like stools; blood in stool or 
urine, severe nosebleed; waxy pallor, high sugar level in blood, fever or chills beginning after a 
few weeks of treatment, lower back or side pain, difficult urination, problems with your eyes or 
your eyesight or hearing, loss of hearing, severe or painful reddening or sores on your skin or 
mucous membrane.

These may signal serious side effects that may need urgent medical attention. Your doctor will test 
your blood to ensure that your white blood cell (cells that fight infection) and red blood cell (cells that 
carry iron and oxygen) counts, platelets (blood clotting cells) and other laboratory values are at 

 



179

acceptable levels. Moderate and usually reversible reduction in all three blood elements-white blood 
cells, red blood cells and platelets, has been reported.

At the beginning of treatment with IntronA, you may experience a flu-like reaction, with fever, 
fatigue, headache, muscle ache, joint pain and chills/rigors. Your doctor may recommend that you take 
paracetamol if you develop these symptoms.

Possible side effects listed below are grouped by frequency of occurrence:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)
Not known (frequency cannot be estimated from the available data)

The following side effects have been reported:

Very commonly reported side effects: 
pain, swelling and redness or skin damage at site of injection, hair loss, dizziness, changes in appetite, 
stomach or abdominal pains, diarrhoea, nausea (feeling sick), viral infection, depression, emotional 
lability, insomnia, anxiety, sore throat and painful swallowing, fatigue, chills/rigors, fever, flu-like 
reaction, feeling of general discomfort, headaches, weight loss, vomiting, irritability, weakness, mood 
swings, coughing (sometimes severe), shortness of breath, itching, dry skin, rash, sudden and severe 
muscle pain, joint pain, musculoskeletal pain, changes in laboratory blood values including decreased 
white blood cell count. Some children have had a decrease in their rate of growth (height and weight).

Commonly reported side effects:
thirst, dehydration, high blood pressure, migraines, swollen glands, flushing, menstrual problems, 
decreased sexual drive, vaginal problem, breast pain, pain in testicle, problems with thyroid gland, red 
gums, dry mouth, red or sore mouth or tongue, tooth ache or tooth disorder, herpes simplex (fever 
blisters), taste change, upset stomach, dyspepsia (heartburn), constipation, enlargement of liver (liver 
problems, sometimes severe), loose stools, bedwetting in children, inflammation of the sinuses, 
bronchitis, eye pain, problem with your tear ducts, conjunctivitis (“pink eye”), agitation, sleepiness, 
sleepwalking, problem with behaviour, nervousness, stuffy or runny nose, sneezing, rapid breathing, 
pale or reddened skin, bruising, problem with skin or nails, psoriasis (new or worsened), increased 
sweating, increased need to pass urine, fine shaking movements, decreased sensitivity to touch, 
arthritis. 

Uncommonly reported side effects:
bacterial infection, feeling of pins and needles, and pericarditis (inflammation of the lining of the 
heart).

Rarely reported side effects:
pneumonia.

Very rarely reported side effects:
low blood pressure, puffy face, diabetes, leg cramps, back pain, kidney problems, nerve damage, 
bleeding gums, aplastic anaemia. Pure red cell aplasia, a condition where the body stopped or reduced 
the production of red blood cells, has been reported. This causes severe anaemia, symptoms of which 
would include unusual tiredness and a lack of energy.
Very rarely sarcoidosis, (a disease characterised by persistent fever, weight loss, joint pain and 
swelling, skin lesions and swollen glands) has been reported. Loss of consciousness has occurred very 
rarely, mostly in elderly patients treated at high doses. Cases of stroke (cerebrovascular events) have 
been reported. Check with your doctor immediately if you have any of these symptoms. 

 



180

Not known side effects:
Periodontal (affecting gums) and dental disorders, change in colour of the tongue, altered mental 
status, loss of consciousness, acute hypersensitivity reactions including urticaria (hives), angioedema 
(swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 
swallowing or breathing), bronchoconstriction and anaphylaxis (a severe, whole-body allergic 
reaction) have been reported, but their frequency is unknown. 
Additionally, Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the 
eyes, skin and the membranes of the ears, brain and spinal cord), thoughts about threatening the life of
others, mania (excessive or unreasonable enthusiasm), bipolar disorders (mood disorders characterized by
alternating episodes of sadness and excitement), congestive heart failure, pericardial effusion (a fluid 
collection that develops between the pericardium (the lining of the heart) and the heart itself), pulmonary 
fibrosis (scarring of the lungs), and hepatitis B reactivation in HCV/HBV co-infected patients 
(recurrence of hepatitis B disease) have been reported with IntronA use.

Pulmonary arterial hypertension – a disease of severe narrowing of the blood vessels in the lungs 
resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This 
may occur in particular in patients with risk factors such as HIV infection or severe liver problems 
(cirrhosis). The side effect may develop at various time points during treatment, typically several 
months after starting treatment with IntronA.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can also help provide more information on the 
safety of this medicine.

5. How to store IntronA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to 
the last day of that month.

Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
For short term travelling, the solution can be kept out of the refrigerator at or below 25°C for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this
seven-day period. If the medicine is not used during the seven-day period, it should be discarded.

Once opened, the medicine may be stored for a maximum of 28 days at 2ºC – 8ºC.

Do not use this medicine if you notice changes in the appearance of IntronA.

6. Contents of the pack and other information

What IntronA contains

- The active substance is recombinant interferon alfa-2b Each vial contains 18 million IU in 3 mL 
of solution.

- The other ingredients are disodium phosphate anhydrous, sodium dihydrogen phosphate 
monohydrate, edetate disodium, sodium chloride, m-cresol, polysorbate 80 and water for 
injections.

- One mL of solution contains 6 million IU of interferon alfa-2b.

 

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181

What IntronA looks like and contents of the pack

IntronA is presented as a solution for injection or infusion.
The clear and colourless solution is contained in a glass vial.

IntronA is available in nine different pack sizes:
- Pack of 1 vial
- Pack of 1 vial, 6 injection syringes of 1 mL, 6 injection needles and 12 cleansing swabs
- Pack of 1 vial, 6 injection syringes with attached needle and needle protection device of 1 mL 

and 12 cleansing swabs
- Pack of 2 vials
- Pack of 2 vials, 12 injection syringes of 1 mL, 12 injection needles and 24 cleansing swabs
- Pack of 2 vials, 12 injection syringes with attached needle and needle protection device of 1 mL 

and 24 cleansing swabs
- Pack of 12 vials
- Pack of 12 vials, 72 injection syringes of 1 mL, 72 injection needles and 144 cleansing swabs
- Pack of 12 vials, 72 injection syringes with attached needle and needle protection device of 

1 mL and 144 cleansing swabs
Not all pack sizes may be marketed.

Marketing Authorisation Holder: Manufacturer:
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

SP Labo N.V.
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 44824000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com 

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland 
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

 



182

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eλλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: +33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda.
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201
msd_slovenia@merck.com

Ísland
Vistor hf.
Simi: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 80000 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in. 

 

mailto:inform_pt@merck.com


183

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

 



184

HOW TO SELF INJECT INTRONA
Syringe with an unattached needle

The following instructions explain how to inject IntronA yourself. Please read the instructions 
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and 
requirement of self-injection.

Preparation
Collect necessary items before you begin:
- a vial of IntronA solution for injection;
- a syringe (for example 1 mL);
- a needle for the subcutaneous injection (for example 0.4 x 13 mm [27 gauge 0.5 inch]);
- a cleansing swab.
Wash your hands carefully.

Measuring the dose of IntronA
Remove the cap from the vial. If this is a multidose vial, you will only have to remove the cap when 
preparing the first dose. Clean the rubber stopper on the top of the vial containing the IntronA solution 
with a cleansing swab.
Remove the syringe from the wrapping. Do not touch the tip of the syringe. Take the needle and place 
it firmly onto the tip of the syringe.
Remove the needle guard without touching the needle, and fill the syringe with air by pulling the 
plunger to the level that represents your dose as prescribed by your doctor.
Hold the IntronA vial upright without touching the cleaned top of the vial with your hands.
Insert the needle into the vial containing the IntronA solution and inject air into the vial.
Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the IntronA 
solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw 
the correct dose as prescribed by your doctor into the syringe.
Remove the needle from the vial and check for air bubbles in the syringe. If you see any bubbles, pull 
the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles 
disappear. Push up the plunger slowly back to the correct dose. 

Volume to be withdrawn according to the dose:

Volume 
(mL)

Corresponding dose (million IU) using IntronA 
18 million IU/3 mL solution for injection or 
infusion

0.25

0.5

1

1.5

2

2.5

3

1.5

3

6

9

12

15

18

 



185

Replace the needle guard and place the syringe with the needle on a flat surface.

Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe 
between your palms. Examine the solution prior to administration: it should be clear and colourless. 
Do not use if discolouration or particulate matter is present. You are now ready to inject the dose.

Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and 
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use 
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or 
outer surface of the arm for injection.
Change your injection site each time.

Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the 
needle guard. With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you 
would a pencil. Insert the needle into the pinched skin at an angle of 45° to 90°. Inject the solution by 
pushing the plunger all the way down gently. Pull the needle straight out of the skin. Press the 
injection site with a small bandage or sterile gauze if necessary for several seconds. Do not massage 
the injection site. If there is bleeding, cover with an adhesive bandage.
The vial and injection materials intended for single use must be discarded. Dispose of the syringe and 
needle safely in a closed container. For multidose vials, be sure to return the vial to the refrigerator.

 



186

HOW TO SELF INJECT INTRONA
Syringe with an attached needle and a needle protection device

The following instructions explain how to inject IntronA yourself. Please read the instructions 
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and 
requirement of self-injection.

Preparation
Collect necessary items before you begin:
- a vial of IntronA solution for injection;
- a 1 mL syringe with an attached needle and a needle protection device (BD SafetyGlide 

syringe);
- a cleansing swab.
Wash your hands carefully.

Measuring the dose of IntronA
Remove the cap from the vial. If this is a multidose vial, you will only have to remove the cap when 
preparing the first dose. Clean the rubber stopper on the top of the vial containing the IntronA solution 
with a cleansing swab.
Remove the syringe from the wrapping. Rotate the needle protection device for bevel orientation or 
scale readability.
Remove the needle guard without touching the needle, and fill the syringe with air by pulling the 
plunger to the level that represents your dose as prescribed by your doctor.
Hold the IntronA vial upright without touching the cleaned top of the vial with your hands.
Insert the needle into the vial containing the IntronA solution and inject air into the vial.
Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the IntronA 
solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw 
the correct dose as prescribed by your doctor into the syringe (Diagram A).

Diagram A

Remove the needle from the vial and check for air bubbles in the syringe. If you see any bubbles, pull 
the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles 
disappear. Push up the plunger slowly back to the correct dose. 

 



187

Volume to be withdrawn according to the dose:

Volume 
(mL)

Corresponding dose (million IU) using IntronA 
18 million IU/3 mL solution for injection or 
infusion

0.25

0.5

1

1.5

2

2.5

3

1.5

3

6

9

12

15

18

Replace the needle guard and place the syringe with the needle on a flat surface.

Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe 
between your palms. Examine the solution prior to administration: it should be clear and colourless. 
Do not use if discolouration or particulate matter is present. You are now ready to inject the dose.

Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and 
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use 
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or 
outer surface of the arm for injection.
Change your injection site each time.

Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the 
needle guard. For user convenience, the needle protection device can be rotated for ease of injection 
(Diagram B).

Diagram B

 



188

With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you would a 
pencil. Insert the needle into the pinched skin at an angle of 45° to 90°. Inject the solution by pushing 
the plunger all the way down gently (Diagram C).

Diagram C

Pull the needle straight out of the skin. Press the injection site with a small bandage or sterile gauze if 
necessary for several seconds. Do not massage the injection site. If there is bleeding, cover with an 
adhesive bandage.

The vial and injection materials intended for single use must be discarded. Activate Safety Mechanism 
of the syringe after removal from the injection site by moving the pushrod completely forward until 
the pushrod is fully extended and the needle tip is covered (Diagram D). Visually confirm the pushrod 
has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an 
approved sharps collector. Dispose of the syringe with attached needle safely in a closed container. 
For multidose vials, be sure to return the vial to the refrigerator.

Diagram D

Authorized Representative:
BD, Laagstraat 57, B-9140
Temse, Belgium

 



189

Package leaflet: Information for the user

IntronA 25 million IU/2.5 mL solution for injection or infusion
Interferon alfa-2b

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet
1. What IntronA is and what it is used for
2. What you need to know before you use IntronA
3. How to use IntronA
4. Possible side effects
5. How to store IntronA
6. Contents of the pack and other information

1. What IntronA is and what it is used for

IntronA (interferon alfa-2b) modifies the response of the body's immune system to help fight infections 
and severe diseases. 

IntronA is used in adult patients to treat certain disorders that affect the blood, bone marrow, lymph 
glands, or skin and may extend into the body. Included are hairy cell leukaemia, chronic myelogenous 
leukaemia, multiple myeloma, follicular lymphoma, carcinoid tumour, and malignant melanoma.

IntronA is also used in adult patients for the treatment of chronic hepatitis B or C, which are viral 
infections of the liver.

IntronA is used in combination with ribavirin in children 3 years of age and older and adolescents who 
have previously untreated chronic hepatitis C.

2. What you need to know before you use IntronA

Do not use IntronA
- if you are allergic  to interferon or any of the other ingredients of this medicine (listed in 

section 6).
- if you have severe heart disease.
- if you have poor kidney or liver function.
- if you have advanced decompensated (uncontrolled) liver disease.
- if you have hepatitis and have been treated recently with medicines that suppress the immune 

system (other than short-term treatment with cortisone-type medicine).
- if you have a history of seizures (convulsions).
- if you have a history of autoimmune disease, or have had an organ transplant and are taking 

medicine that suppresses your immune system (your immune system helps protect you from 
infection).

- if you have thyroid disease that is not well controlled.
- if you are being treated with telbivudine (see section "Other medicines and IntronA").

 



190

Children and adolescents:
- if you have had serious nervous or mental problems, such as severe depression or thoughts of 

suicide.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before using IntronA
- if you are pregnant or planning to become pregnant (see section “Pregnancy and breast-feeding”). 
- if you are being treated for mental illness or had treatment in the past for any other nervous or 

mental disorder, including depression (such as feelings of sadness, dejection) or suicidal or 
homicidal behaviour (see section 4 “Possible side effects”). The use of interferon alfa-2b in 
children and adolescents with existence of or history of severe psychiatric conditions is 
contraindicated (see section “Do not use IntronA”). 

- if you have cirrhosis or other liver problems (other than hepatitis B or C).
- if you have psoriasis, it may get worse during treatment with IntronA.
- when receiving IntronA, you may temporarily have a greater risk of getting an infection. Check 

with your doctor if you think you are getting an infection.
- if you develop symptoms associated with a cold or other respiratory infection, such as fever, cough, 

or any difficulty in breathing, tell your doctor.
- if you notice unusual bleeding or bruising check with your doctor immediately.
- if you develop symptoms of a severe allergic reaction (such as difficulty in breathing, wheezing, or 

hives) while on this medicine seek medical help immediately.
- if you are also being treated for HIV (see section “Other medicines and IntronA”).
- if you have a current or previous infection with the hepatitis B virus, since your doctor may 

want to monitor you more closely.
- if you have received an organ transplant, either kidney or liver, interferon treatment may increase 

the risk of rejection. Be sure to discuss this with your doctor.

Dental and gum disorders, which may lead to loss of teeth, have been reported in patients receiving 
IntronA and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on 
teeth and membranes of the mouth during long-term treatment with the combination of IntronA with 
ribavirin. You should brush your teeth thoroughly twice daily and have regular dental examinations. In 
addition some patients may experience vomiting. If you have this reaction, be sure to rinse your mouth 
thoroughly afterwards.

Tell your doctor if you have ever had a heart attack or a heart problem; if you have a history of 
breathing irregularities or pneumonia, problems with blood clotting, liver condition, thyroid problems, 
diabetes, or high or low blood pressure.

Tell your doctor if you have ever been treated for depression or any other psychiatric disorder; confusion; 
unconsciousness; thoughts of suicide or attempted suicide, or have a history of substance abuse (e.g., 
alcohol or drugs).

Be sure to tell your doctor if you are taking the Chinese herbal medicine shosaikoto.

Other medicines and IntronA
IntronA will add to the effects of substances that slow down your nervous system, possibly causing 
drowsiness. Therefore, check with your doctor or pharmacist about drinking alcoholic beverages, or 
taking sleeping pills, sedatives or strong pain medicines.

Tell your doctor if you are taking theophylline or aminophylline for asthma, and about all other 
medicines you are taking, or have taken recently, even those not prescribed, as the dose of some 
medicines may have to be adjusted while you are treated with IntronA.

Patients who also have HIV infection: Lactic acidosis and worsening liver function are side effects 
associated with Highly Active Anti-Retroviral Therapy (HAART), an HIV treatment. If you are 
receiving HAART, the addition of IntronA and ribavirin may increase your risk of lactic acidosis and 
of liver failure. Your doctor will monitor you for signs and symptoms of these conditions (Please be 

 



191

sure to read the ribavirin Patient Leaflet also). Additionally, patients treated with IntronA and ribavirin 
combination therapy and zidovudine could be at increased risk of developing anaemia (low number of 
red blood cells).

If you take telbivudine with a pegylated interferon alfa-2a or any type of injectable interferon product, 
your risk of developing peripheral neuropathy (numbness, tingling and/or burning sensations in the 
arms and/or legs) is higher. These events may also be more severe. Therefore, the combination of 
IntronA with telbivudine is contraindicated.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription.

IntronA with food and drink and alcohol
While being treated with IntronA, your doctor may want you to drink extra fluids to help prevent low 
blood pressure.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. In studies in pregnant animals, 
interferons have sometimes caused miscarriage. The effect on human pregnancy is not known.
If you are prescribed IntronA in combination with ribavirin, ribavirin can be very damaging to an 
unborn baby, thus both female and male patients must take special precautions in their sexual activity 
if there is any chance for pregnancy to occur:
- if you are a girl or a woman of childbearing age, you must have a negative pregnancy test before 
treatment, each month during treatment, and for the 4 months after treatment is stopped. You must use 
an effective contraceptive during the time you are taking ribavirin and for 4 months after stopping 
treatment. This can be discussed with your doctor.
- if you are a man who is taking ribavirin, do not have sex with a pregnant woman unless you use a 
condom. This will lessen the chance for ribavirin to be left in the woman’s body. If your female 
partner is not pregnant now but is of childbearing age, she must be tested for pregnancy each month 
during treatment and for the 7 months after treatment has stopped. This can be discussed with your 
doctor. If you are a male patient, you or your partner must use an effective contraceptive during the 
time you are taking ribavirin and for 7 months after stopping treatment. This can be discussed with 
your doctor.

It is not known whether this medicine is present in human milk. Therefore, do not breast-feed an infant 
if you are taking IntronA. In combination therapy with ribavirin, take notice of the respective 
informing texts of ribavirin containing medicinal products.

Driving and using machines
Do not drive or use machines if you become drowsy, tired, or confused from using this medicine.

IntronA contains less than 1 mmol sodium (23 mg) per 2.5 mL, i.e., essentially "sodium-free".

3. How to use IntronA

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or 
pharmacist if you are not sure. Your doctor has prescribed IntronA specifically for you and your current 
condition; do not share this medicine with anyone else.

Your doctor has determined the exact dosage for administration of IntronA according to your individual 
needs. The dosage will vary according to the disease being treated.

If you are injecting IntronA yourself, please be sure that the dose that has been prescribed for you is 
clearly provided with the package of medicine you receive. Dosages that are to be administered 3 times a 
week are best given every other day.

 



192

The usual starting dose for each condition follows; however, individual doses may vary, and the doctor 
may change your dose based on your specific needs:

Chronic hepatitis B: 5 to 10 million IU 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic hepatitis C: Adults - 3 million IU 3 times a week (every other day) injected subcutaneously 
(under the skin) in combination with ribavirin or alone. Children 3 years of age and older and 
adolescents - 3 million IU/m2 3 times a week (every other day) injected subcutaneously (under the skin) 
in combination with ribavirin (Please also see ribavirin package leaflet).

Hairy Cell Leukaemia: 2 million IU/m2, 3 times a week (every other day) injected subcutaneously (under 
the skin).

Chronic Myelogenous Leukaemia: 4-5 million IU/m2 daily injected subcutaneously (under the skin).

Multiple myeloma: 3 million IU/m2, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Follicular lymphoma: Adjunctively with chemotherapy, 5 million IU 3 times a week (every other day) 
injected subcutaneously (under the skin).

Carcinoid tumour: 5 million IU, 3 times a week (every other day) injected subcutaneously (under the 
skin).

Malignant melanoma, induction therapy: 20 million IU/m2, intravenously, given daily for 5 days a week 
for a 4 week period. Maintenance treatment: 10 million IU/m2, 3 times a week (every other day) injected 
subcutaneously (under the skin).

Your doctor may prescribe a different dose of IntronA alone or in combination with other medicines (e.g., 
cytarabine, ribavirin). If you are prescribed IntronA in combination with another medicine, please refer 
also to the Package Leaflet of the medicine to be used in combination. Your doctor will determine the 
exact dosage schedule and regimen according to your needs. If you have the impression that the effect of 
IntronA is too strong or too weak, talk to your doctor or pharmacist.

Subcutaneous use:
IntronA is usually intended for subcutaneous use. This means that IntronA is injected with a short needle 
into the fatty tissue just under the skin. If you are injecting this medicine yourself, you will be instructed 
how to prepare and give the injection. Detailed instructions for subcutaneous administration are provided 
with this leaflet (see section “HOW TO SELF INJECT INTRONA” at the end of the leaflet).

Intravenous infusion:
The infusion must be prepared immediately prior to use. Any size vial may be used to measure the 
required dose; however, final concentration of interferon in sodium chloride solution must be not less 
than 0.3 million IU/mL. The appropriate dose of IntronA is withdrawn from the vial(s), added to 
50 mL of 9 mg/mL (0.9 %) sodium chloride solution for injection in a PVC bag or glass bottle for 
intravenous use and administered over 20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

One dose of IntronA is given on each scheduled day. IntronA is given either daily (5 or 7 times a week), 
or three times a week, every other day, for example on Monday, Wednesday, and Friday. Interferons may 
cause unusual tiredness; if you are injecting this medicine yourself, or giving it to a child, use it at 
bedtime.

 



193

Use IntronA exactly as prescribed by your doctor. Do not exceed the recommended dosage, and take 
IntronA for as long as prescribed.

If you use more IntronA than you should
Contact your doctor or healthcare professional as soon as possible.

If you forget to use IntronA
If you are self-administering treatment, or if you are the caregiver of a child taking IntronA in 
combination with ribavirin, inject the recommended dose as soon as you remember and continue 
treatment as usual. Do not take a double dose to make up for a forgotten dose. If you are scheduled to 
inject this medicine every day, and you accidentally missed a full day’s dose, continue treatment at the 
usual dose the following day. Contact your doctor or pharmacist if needed.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Although 
not all of these side effects may occur, they may need medical attention if they do.

Psychiatric and central nervous system:
Some people get depressed when taking IntronA alone or in combination treatment with ribavirin, and 
in some cases people had thoughts about threatening the life of others, suicidal thoughts or aggressive 
behaviour (sometimes directed against others). Some patients have actually committed suicide. Be sure 
to seek emergency care if you notice that you are becoming depressed or have suicidal thoughts or 
change in your behaviour. You may want to consider asking a family member or close friend to help 
you stay alert to signs of depression or changes in your behaviour.

Children and adolescents are particularly prone to develop depression when being treated with 
IntronA and ribavirin. Immediately contact the doctor or seek emergency treatment if they display any 
unusual behavioural symptoms, feel depressed, or feel they want to harm themselves or others.

Growth and development (children and adolescents): 
During the one year of treatment with IntronA in combination with ribavirin, some children and 
adolescents did not grow or gain weight as much as expected. Some children did not reach their 
projected height within 10-12 years after completing treatment.

If any of the following side effects happen, stop taking IntronA and tell your doctor immediately or go 
to the casualty department at your nearest hospital:
- swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 

swallowing or breathing; hives; fainting.
These are all very serious side effects. If you have them, you may have had a serious allergic reaction 
to IntronA. You may need urgent medical attention or hospitalisation. These very serious side effects 
are very rare.

Check with your doctor immediately if any of the following side effects occur:
- chest pain or persistent and severe cough; irregular or rapid heartbeat; shortness of breath, 

confusion, difficulty remaining alert, numbness or tingling sensation or pain in hands or feet; 
seizure (convulsions); trouble sleeping, thinking or concentrating; altered mental state; suicidal 
thoughts, suicide attempt, changed behaviour or aggressive behaviour (sometimes directed 
against others), hallucinations; severe stomach pain; black or tar like stools; blood in stool or 
urine, severe nosebleed; waxy pallor, high sugar level in blood, fever or chills beginning after a 
few weeks of treatment, lower back or side pain, difficult urination, problems with your eyes or 
your eyesight or hearing, loss of hearing, severe or painful reddening or sores on your skin or 
mucous membrane.

These may signal serious side effects that may need urgent medical attention. Your doctor will test 
your blood to ensure that your white blood cell (cells that fight infection) and red blood cell (cells that 
carry iron and oxygen) counts, platelets (blood clotting cells) and other laboratory values are at 

 



194

acceptable levels. Moderate and usually reversible reduction in all three blood elements-white blood 
cells, red blood cells and platelets, has been reported.

At the beginning of treatment with IntronA, you may experience a flu-like reaction, with fever, 
fatigue, headache, muscle ache, joint pain and chills/rigors. Your doctor may recommend that you take 
paracetamol if you develop these symptoms.

Possible side effects listed below are grouped by frequency of occurrence:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)
Not known (frequency cannot be estimated from the available data)

The following side effects have been reported:

Very commonly reported side effects: 
pain, swelling and redness or skin damage at site of injection, hair loss, dizziness, changes in appetite, 
stomach or abdominal pains, diarrhoea, nausea (feeling sick), viral infection, depression, emotional 
lability, insomnia, anxiety, sore throat and painful swallowing, fatigue, chills/rigors, fever, flu-like 
reaction, feeling of general discomfort, headaches, weight loss, vomiting, irritability, weakness, mood 
swings, coughing (sometimes severe), shortness of breath, itching, dry skin, rash, sudden and severe 
muscle pain, joint pain, musculoskeletal pain, changes in laboratory blood values including decreased 
white blood cell count. Some children have had a decrease in their rate of growth (height and weight).

Commonly reported side effects:
thirst, dehydration, high blood pressure, migraines, swollen glands, flushing, menstrual problems, 
decreased sexual drive, vaginal problem, breast pain, pain in testicle, problems with thyroid gland, red 
gums, dry mouth, red or sore mouth or tongue, tooth ache or tooth disorder, herpes simplex (fever 
blisters), taste change, upset stomach, dyspepsia (heartburn), constipation, enlargement of liver (liver 
problems, sometimes severe), loose stools, bedwetting in children, inflammation of the sinuses, 
bronchitis, eye pain, problem with your tear ducts, conjunctivitis (“pink eye”), agitation, sleepiness, 
sleepwalking, problem with behaviour, nervousness, stuffy or runny nose, sneezing, rapid breathing, 
pale or reddened skin, bruising, problem with skin or nails, psoriasis (new or worsened), increased 
sweating, increased need to pass urine, fine shaking movements, decreased sensitivity to touch, 
arthritis. 

Uncommonly reported side effects:
bacterial infection, feeling of pins and needles, and pericarditis (inflammation of the lining of the 
heart).

Rarely reported side effects:
pneumonia.

Very rarely reported side effects:
low blood pressure, puffy face, diabetes, leg cramps, back pain, kidney problems, nerve damage, 
bleeding gums, aplastic anaemia. Pure red cell aplasia, a condition where the body stopped or reduced 
the production of red blood cells, has been reported. This causes severe anaemia, symptoms of which 
would include unusual tiredness and a lack of energy.
Very rarely sarcoidosis, (a disease characterised by persistent fever, weight loss, joint pain and 
swelling, skin lesions and swollen glands) has been reported. Loss of consciousness has occurred very 
rarely, mostly in elderly patients treated at high doses. Cases of stroke (cerebrovascular events) have 
been reported. Check with your doctor immediately if you have any of these symptoms. 

 



195

Not known side effects:
Periodontal (affecting gums) and dental disorders, change in colour of the tongue, altered mental 
status, loss of consciousness, acute hypersensitivity reactions including urticaria (hives), angioedema 
(swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause difficulty in 
swallowing or breathing), bronchoconstriction and anaphylaxis (a severe, whole-body allergic 
reaction) have been reported, but their frequency is unknown. 
Additionally, Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the 
eyes, skin and the membranes of the ears, brain and spinal cord), thoughts about threatening the life of
others, mania (excessive or unreasonable enthusiasm), bipolar disorders (mood disorders characterized by 
alternating episodes of sadness and excitement), congestive heart failure, pericardial effusion (a fluid 
collection that develops between the pericardium (the lining of the heart) and the heart itself), pulmonary 
fibrosis (scarring of the lungs), and hepatitis B reactivation in HCV/HBV co-infected patients 
(recurrence of hepatitis B disease) have been reported with IntronA use.

Pulmonary arterial hypertension – a disease of severe narrowing of the blood vessels in the lungs 
resulting in high blood pressure in the blood vessels that carry blood from the heart to the lungs. This 
may occur in particular in patients with risk factors such as HIV infection or severe liver problems 
(cirrhosis). The side effect may develop at various time points during treatment, typically several 
months after starting treatment with IntronA.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can also help provide more information on the 
safety of this medicine.

5. How to store IntronA

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package. The expiry date refers to 
the last day of that month.

Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
For short term travelling, the solution can be kept out of the refrigerator at or below 25°C for a period 
up to seven days before use. IntronA can be put back in the refrigerator at any time during this 
seven-day period. If the medicine is not used during the seven-day period, it should be discarded.

Once opened, the medicine may be stored for a maximum of 28 days at 2ºC – 8ºC.

Do not use this medicine if you notice changes in the appearance of IntronA.

6. Contents of the pack and other information

What IntronA contains

- The active substance is recombinant interferon alfa-2b Each vial contains 25 million IU in 
2.5 mL of solution.

- The other ingredients are disodium phosphate anhydrous, sodium dihydrogen phosphate 
monohydrate, edetate disodium, sodium chloride, m-cresol, polysorbate 80 and water for 
injections.

- One mL of solution contains 10 million IU of interferon alfa-2b

 

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196

What IntronA looks like and contents of the pack

IntronA is presented as a solution for injection or infusion.
The clear and colourless solution is contained in a glass vial.

IntronA is available in twelve different pack sizes:
- Pack of 1 vial
- Pack of 1 vial, 6 injection syringes of 1 mL, 6 injection needles and 12 cleansing swabs
- Pack of 1 vial, 6 injection syringes with attached needle and needle protection device of 1 mL 

and 12 cleansing swabs
- Pack of 1 vial, 6 injection syringes with attached needle of 1 mL and 12 cleansing swabs
- Pack of 2 vials
- Pack of 2 vials, 12 injection syringes of 1 mL, 12 injection needles and 24 cleansing swabs
- Pack of 2 vials, 12 injection syringes with attached needle and needle protection device of 1 mL 

and 24 cleansing swabs
- Pack of 2 vials, 12 injection syringes with attached needle of 1 mL and 24 cleansing swabs
- Pack of 12 vials
- Pack of 12 vials, 72 injection syringes of 1 mL, 72 injection needles and 144 cleansing swabs
- Pack of 12 vials, 72 injection syringes with attached needle and needle protection device of 

1 mL and 144 cleansing swabs
- Pack of 12 vials, 72 injection syringes with attached needle of 1 mL and 144 cleansing swabs
Not all pack sizes may be marketed.

Marketing Authorisation Holder: Manufacturer:
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

SP Labo N.V.
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

Belgique/België/Belgien 
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3737
info-msdbg@merck.com

Luxembourg/Luxemburg
MSD Belgium BVBA/SPRL
Tél/Tel: +32(0)27766211
dpoc_belux@merck.com

Česká republika
Merck Sharp & Dohme s.r.o.
Tel.: +420 233 010 111
dpoc_czechslovak@merck.com

Magyarország
MSD Pharma Hungary Kft.
Tel.: +36 1 888 53 00
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: +45 44824000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: 8007 4433 (+356 99917558)
malta_info@merck.com 

Deutschland
MSD SHARP & DOHME GMBH
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612)
e-mail@msd.de

Nederland 
Merck Sharp & Dohme B.V.
Tel: 0800 9999000 (+31 23 5153153)
medicalinfo.nl@merck.com

 



197

Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 6144 200
msdeesti@merck.com

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eλλάδα
MSD Α.Φ.Β.Ε.Ε.
Τηλ: +30 210 98 97 300
dpoc_greece@merck.com

Österreich
Merck Sharp & Dohme Ges.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

España
Merck Sharp & Dohme de España, S.A.
Tel: +34 91 321 06 00
msd_info@merck.com

Polska
MSD Polska Sp. z o.o.
Tel: +48 22 549 51 00
msdpolska@merck.com

France
MSD France
Tél: +33 (0) 1 80 46 40 40

Portugal
Merck Sharp & Dohme, Lda.
Tel: +351 21 4465700
inform_pt@merck.com

Hrvatska
Merck Sharp & Dohme d.o.o.
Tel: + 385 1 6611 333
croatia_info@merck.com

România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp & Dohme Ireland (Human Health) 
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, inovativna zdravila 
d.o.o. 
Tel: + 386 1 5204201
msd_slovenia@merck.com

Ísland
Vistor hf.
Simi: +354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel.: +421 2 58282010
dpoc_czechslovak@merck.com

Ιtalia
MSD Italia S.r.l.
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: 80000 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

This leaflet was last revised in. 

 

mailto:inform_pt@merck.com


198

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.

This leaflet is available in all EU/EEA languages on the European Medicines Agency website.

 



199

HOW TO SELF INJECT INTRONA
Syringe with an unattached needle

The following instructions explain how to inject IntronA yourself. Please read the instructions 
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and 
requirement of self-injection.

Preparation
Collect necessary items before you begin:
- a vial of IntronA solution for injection;
- a syringe (for example 1 mL);
- a needle for the subcutaneous injection (for example 0.4 x 13 mm [27 gauge 0.5 inch]);
- a cleansing swab.
Wash your hands carefully.

Measuring the dose of IntronA
Remove the cap from the vial. If this is a multidose vial, you will only have to remove the cap when 
preparing the first dose. Clean the rubber stopper on the top of the vial containing the IntronA solution 
with a cleansing swab.
Remove the syringe from the wrapping. Do not touch the tip of the syringe. Take the needle and place 
it firmly onto the tip of the syringe.
Remove the needle guard without touching the needle, and fill the syringe with air by pulling the 
plunger to the level that represents your dose as prescribed by your doctor.
Hold the IntronA vial upright without touching the cleaned top of the vial with your hands.
Insert the needle into the vial containing the IntronA solution and inject air into the vial.
Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the IntronA 
solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw 
the correct dose as prescribed by your doctor into the syringe.
Remove the needle from the vial and check for air bubbles in the syringe. If you see any bubbles, pull 
the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles 
disappear. Push up the plunger slowly back to the correct dose. 

Volume to be withdrawn according to the dose:

Volume 
(mL)

Corresponding dose (million IU) using IntronA 
25 million IU/2.5 mL solution for injection or 

infusion

0.25

0.5

1

1.5

2

2.5

2.5

5

10

15

20

25

Replace the needle guard and place the syringe with the needle on a flat surface.

 



200

Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe 
between your palms. Examine the solution prior to administration: it should be clear and colourless. 
Do not use if discolouration or particulate matter is present. You are now ready to inject the dose.

Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and 
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use 
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or 
outer surface of the arm for injection.
Change your injection site each time.

Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the 
needle guard. With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you 
would a pencil. Insert the needle into the pinched skin at an angle of 45° to 90°. Inject the solution by 
pushing the plunger all the way down gently. Pull the needle straight out of the skin. Press the 
injection site with a small bandage or sterile gauze if necessary for several seconds. Do not massage 
the injection site. If there is bleeding, cover with an adhesive bandage.
The vial and injection materials intended for single use must be discarded. Dispose of the syringe and 
needle safely in a closed container. For multidose vials, be sure to return the vial to the refrigerator.

 



201

HOW TO SELF INJECT INTRONA
Syringe with an attached needle

The following instructions explain how to inject IntronA yourself. Please read the instructions 
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and 
requirement of self-injection.

Preparation
Collect necessary items before you begin:
- a vial of IntronA solution for injection;
- a syringe with an attached needle for subcutaneous injection;
- a cleansing swab.
Wash your hands carefully.

Measuring the dose of IntronA
Remove the cap from the vial. If this is a multidose vial, you will only have to remove the cap when 
preparing the first dose. Clean the rubber stopper on the top of the vial containing the IntronA solution 
with a cleansing swab.
Remove the syringe from the wrapping. Ensure that needle with needle guard is firmly attached to the 
syringe by pushing while turning the needle guard. 
Remove the needle guard without touching the needle, and fill the syringe with air by pulling the 
plunger to the level that represents your dose as prescribed by your doctor.
Hold the IntronA vial upright without touching the cleaned top of the vial with your hands.
Insert the needle into the vial containing the IntronA solution and inject air into the vial.
Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the IntronA 
solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw 
the correct dose as prescribed by your doctor into the syringe.
Remove the needle from the vial and check for air bubbles in the syringe. If you see any bubbles, pull 
the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles 
disappear. Push up the plunger slowly back to the correct dose.

Volume to be withdrawn according to the dose:

Volume 
(mL)

Corresponding dose (million IU) using IntronA 
25 million IU/2.5 mL solution for injection or 
infusion

0.25

0.5

1

1.5

2

2.5

2.5

5

10

15

20

25

Replace the needle guard and place the syringe with the needle on a flat surface.

 



202

Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe 
between your palms. Examine the solution prior to administration: it should be clear and colourless. 
Do not use if discolouration or particulate matter is present. You are now ready to inject the dose.

Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and 
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use 
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or 
outer surface of the arm for injection.
Change your injection site each time.

Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the 
needle guard. With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you 
would a pencil. Insert the needle into the pinched skin at an angle of 45° to 90°. Inject the solution by 
pushing the plunger all the way down gently. Pull the needle straight out of the skin. Press the 
injection site with a small bandage or sterile gauze if necessary for several seconds. Do not massage 
the injection site. If there is bleeding, cover with an adhesive bandage.
The vial and injection materials intended for single use must be discarded. Dispose of the syringe with 
attached needle safely in a closed container. For multidose vials, be sure to return the vial to the 
refrigerator.

 



203

HOW TO SELF INJECT INTRONA
Syringe with an attached needle and a needle protection device

The following instructions explain how to inject IntronA yourself. Please read the instructions 
carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-
inject IntronA. Do not attempt to inject yourself unless you are sure you understand the procedure and 
requirement of self-injection.

Preparation
Collect necessary items before you begin:
- a vial of IntronA solution for injection;
- a 1 mL syringe with an attached needle and a needle protection device (BD SafetyGlide 

syringe);
- a cleansing swab.
Wash your hands carefully.

Measuring the dose of IntronA
Remove the cap from the vial. If this is a multidose vial, you will only have to remove the cap when 
preparing the first dose. Clean the rubber stopper on the top of the vial containing the IntronA solution 
with a cleansing swab.
Remove the syringe from the wrapping. Rotate the needle protection device for bevel orientation or 
scale readability.
Remove the needle guard without touching the needle, and fill the syringe with air by pulling the 
plunger to the level that represents your dose as prescribed by your doctor.
Hold the IntronA vial upright without touching the cleaned top of the vial with your hands.
Insert the needle into the vial containing the IntronA solution and inject air into the vial.
Turn the vial and the syringe upside down in one hand. Be sure the tip of needle is in the IntronA 
solution. Your other hand will be free to move the plunger. Pull back on the plunger slowly to draw 
the correct dose as prescribed by your doctor into the syringe (Diagram A).

Diagram A

Remove the needle from the vial and check for air bubbles in the syringe. If you see any bubbles, pull 
the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles 
disappear. Push up the plunger slowly back to the correct dose. 

 



204

Volume to be withdrawn according to the dose:

Volume 
(mL)

Corresponding dose (million IU) using IntronA 
25 million IU/2.5 mL solution for injection or 
infusion

0.25

0.5

1

1.5

2

2.5

2.5

5

10

15

20

25

Replace the needle guard and place the syringe with the needle on a flat surface.

Be sure the solution is at room temperature up to 25°C. If the solution is cold, warm the syringe 
between your palms. Examine the solution prior to administration: it should be clear and colourless. 
Do not use if discolouration or particulate matter is present. You are now ready to inject the dose.

Injecting the solution
Select the injection site. The best sites for injection are tissues with a layer of fat between skin and 
muscle: thigh, outer surface of the upper arm (you may need the assistance of another person to use 
this site), abdomen (except the navel or waistline). If you are exceptionally thin, use only the thigh or 
outer surface of the arm for injection.
Change your injection site each time.

Cleanse and disinfect the skin where the injection is to be made. Wait for the area to dry. Remove the 
needle guard. For user convenience, the needle protection device can be rotated for ease of injection 
(Diagram B).

Diagram B

 



205

With one hand, pinch a fold of loose skin. With your other hand hold the syringe as you would a 
pencil. Insert the needle into the pinched skin at an angle of 45° to 90°. Inject the solution by pushing 
the plunger all the way down gently (Diagram C).

Diagram C

Pull the needle straight out of the skin. Press the injection site with a small bandage or sterile gauze if 
necessary for several seconds. Do not massage the injection site. If there is bleeding, cover with an 
adhesive bandage.

The vial and injection materials intended for single use must be discarded. Activate Safety Mechanism 
of the syringe after removal from the injection site by moving the pushrod completely forward until 
the pushrod is fully extended and the needle tip is covered (Diagram D). Visually confirm the pushrod 
has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an 
approved sharps collector. Dispose of the syringe with attached needle safely in a closed container. 
For multidose vials, be sure to return the vial to the refrigerator.

Diagram D

Authorized Representative:
BD, Laagstraat 57, B-9140
Temse, Belgium

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET