Noxafil

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

 



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1. NAME OF THE MEDICINAL PRODUCT

Noxafil 40 mg/mL oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of oral suspension contains 40 mg of posaconazole.

Excipient with known effect:
This medicinal product contains approximately 1.75 g of glucose per 5 mL of suspension. 

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral suspension

White suspension

4. CLINICAL PARTICULARS

4.1 Therapeutic indications 

Noxafil oral suspension is indicated for use in the treatment of the following fungal infections in 
adults (see section 5.1):
- Invasive aspergillosis in patients with disease that is refractory to amphotericin B or 

itraconazole or in patients who are intolerant of these medicinal products;
- Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are 

intolerant of amphotericin B;
- Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole 

or in patients who are intolerant of itraconazole;
- Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole 

or fluconazole or in patients who are intolerant of these medicinal products;
- Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or are 

immunocompromised, in whom response to topical therapy is expected to be poor.

Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days 
of prior therapeutic doses of effective antifungal therapy.

Noxafil oral suspension is also indicated for prophylaxis of invasive fungal infections in the following 
patients:
- Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) 

or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are 
at high risk of developing invasive fungal infections; 

- Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose
immunosuppressive therapy for graft versus host disease and who are at high risk of developing 
invasive fungal infections.

4.2 Posology and method of administration

Non-Interchangeability between Noxafil Tablets and Noxafil Oral Suspension

The tablet and oral suspension are not to be used interchangeably due to the differences between these 

 



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two formulations in frequency of dosing, administration with food and plasma drug concentration 
achieved. Therefore, follow the specific dosage recommendations for each formulation.

Treatment should be initiated by a physician experienced in the management of fungal infections or in 
the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.

Posology
Noxafil is also available as 100 mg gastro-resistant tablet and 300 mg concentrate for solution for 
infusion. Noxafil tablets are the preferred formulation to optimize plasma concentrations and 
generally provide higher plasma drug exposures than Noxafil oral suspension.

Recommended dose is shown in Table 1.

Table 1. Recommended dose according to indication
Indication Dose and duration of therapy

(See section 5.2)
Refractory invasive fungal 
infections (IFI)/patients with IFI 
intolerant to 1st line therapy

200 mg (5 mL) four times a day. Alternatively, patients who can 
tolerate food or a nutritional supplement may take 400 mg (10 mL) 
twice a day during or immediately following a meal or nutritional 
supplement.
Duration of therapy should be based on the severity of the 
underlying disease, recovery from immunosuppression, and 
clinical response.

Oropharyngeal candidiasis Loading dose of 200 mg (5 mL) once a day on the first day, then 
100 mg (2.5 mL) once a day for 13 days.
Each dose of Noxafil should be administered during or 
immediately after a meal, or a nutritional supplement in patients 
who cannot tolerate food to enhance the oral absorption and to 
ensure adequate exposure.

Prophylaxis of invasive fungal 
infections

200 mg (5 mL) three times a day. Each dose of Noxafil should be 
administered during or immediately after a meal, or a nutritional 
supplement in patients who cannot tolerate food to enhance the 
oral absorption and to ensure adequate exposure. The duration of 
therapy is based on recovery from neutropenia or 
immunosuppression. For patients with acute myelogenous 
leukemia or myelodysplastic syndromes, prophylaxis with Noxafil 
should start several days before the anticipated onset of 
neutropenia and continue for 7 days after the neutrophil count rises 
above 500 cells per mm3.

Special populations

Renal impairment 
An effect of renal impairment on the pharmacokinetics of posaconazole is not expected and no dose 
adjustment is recommended (see section 5.2).

Hepatic impairment
Limited data on the effect of hepatic impairment (including Child-Pugh C classification of chronic 
liver disease) on the pharmacokinetics of posaconazole demonstrate an increase in plasma exposure 
compared to subjects with normal hepatic function, but do not suggest that dose adjustment is 
necessary (see sections 4.4 and 5.2). It is recommended to exercise caution due to the potential for 
higher plasma exposure.

 



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Paediatric population
The safety and efficacy of Noxafil in children aged below 18 years have not been established. 
Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology 
can be made.

Method of administration
For oral use

The oral suspension must be shaken well before use.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with ergot alkaloids (see section 4.5).

Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, 
halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal 
products, leading to QTc prolongation and rare occurrences of torsades de pointes (see sections 4.4 
and 4.5).

Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin 
(see section 4.5).

4.4 Special warnings and precautions for use

Hypersensitivity
There is no information regarding cross-sensitivity between posaconazole and other azole antifungal 
agents. Caution should be used when prescribing Noxafil to patients with hypersensitivity to other 
azoles.

Hepatic toxicity
Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin 
and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver 
function tests were generally reversible on discontinuation of therapy and in some instances these 
tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal 
outcomes have been reported. 
Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical 
experience and the possibility that posaconazole plasma levels may be higher in these patients (see 
sections 4.2 and 5.2).

Monitoring of hepatic function
Liver function tests should be evaluated at the start of and during the course of posaconazole therapy.
Patients who develop abnormal liver function tests during Noxafil therapy must be routinely 
monitored for the development of more severe hepatic injury. Patient management should include 
laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). 
Discontinuation of Noxafil should be considered if clinical signs and symptoms are consistent with 
development of liver disease.

QTc prolongation
Some azoles have been associated with prolongation of the QTc interval. Noxafil must not be 
administered with medicinal products that are substrates for CYP3A4 and are known to prolong the 
QTc interval (see sections 4.3 and 4.5). Noxafil should be administered with caution to patients with 
pro-arrhythmic conditions such as:
 Congenital or acquired QTc prolongation
 Cardiomyopathy, especially in the presence of cardiac failure

 



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 Sinus bradycardia
 Existing symptomatic arrhythmias
 Concomitant use with medicinal products known to prolong the QTc interval (other than those 

mentioned in section 4.3).
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should 
be monitored and corrected as necessary before and during posaconazole therapy.

Drug Interactions
Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during 
treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5).

Midazolam and other benzodiazepines
Due to the risk of prolonged sedation and possible respiratory depression co-administration of 
posaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam, 
alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepines 
metabolised by CYP3A4 should be considered (see section 4.5).

Vincristine Toxicity
Concomitant administration of azole antifungals, including posaconazole, with vincristine has been 
associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral 
neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve 
azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including 
vincristine, who have no alternative antifungal treatment options (see section 4.5).

Rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine, 
phenobarbital, primidone), efavirenz and cimetidine
Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use 
with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see 
section 4.5).

Gastrointestinal dysfunction
There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (such as 
severe diarrhoea). Patients who have severe diarrhoea or vomiting should be monitored closely for 
breakthrough fungal infections.

Excipients
This medicinal product contains approximately 1.75 g of glucose per 5 mL of suspension. Patients 
with glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on posaconazole
Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for 
p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, 
clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, 
etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, 
respectively.

Rifabutin
Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area 
under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. 
Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be 
avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of 
posaconazole on rifabutin plasma levels. 

 



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Efavirenz
Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, 
respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to 
the patient outweighs the risk. 

Fosamprenavir
Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma 
concentrations. If concomitant administration is required, close monitoring for breakthrough fungal 
infections is recommended.  Repeat dose administration of fosamprenavir (700 mg twice daily x 
10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 
1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days) by 21 % and 23 %, 
respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with 
ritonavir is unknown.

Phenytoin
Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 % and 50 %, 
respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. 
carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient 
outweighs the risk.

H2 receptor antagonists and proton pump inhibitors
Posaconazole plasma concentrations (Cmax and AUC) were reduced by 39 % when posaconazole was 
administered with cimetidine (400 mg twice a day) due to reduced absorption possibly secondary to a 
decrease in gastric acid production. Co-administration of posaconazole with H2 receptor antagonists 
should be avoided if possible. 
Similarly, administration of 400 mg posaconazole with esomeprazole (40 mg daily) decreased mean 
Cmax and AUC by 46 % and 32 %, respectively, compared to dosing with 400 mg posaconazole alone. 
Co-administration of posaconazole with proton pump inhibitors should be avoided if possible.

Food
The absorption of posaconazole is significantly increased by food (see sections 4.2 and 5.2).

Effects of posaconazole on other medicinal products
Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4 
substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the 
effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co-
administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of 
the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 
substrates that are administered orally, and for which an increase in plasma concentrations may be 
associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate 
and/or adverse reactions should be closely monitored and the dose adjusted as needed. Several of the 
interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole 
occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4 
substrates in patients might be somewhat lower than that observed in healthy volunteers, and is 
expected to be variable between patients due to the variable posaconazole exposure in patients. The 
effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be 
variable within a patient, unless posaconazole is administered in a strictly standardised way with food, 
given the large food effect on posaconazole exposure (see section 5.2).

Terfenadine, astemizole, cisapride, pimozide, halofantrine and quinidine (CYP3A4 substrates)
Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine or 
quinidine is contraindicated. Co-administration may result in increased plasma concentrations of these 
medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see 
section 4.3).

 



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Ergot alkaloids
Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and 
dihydroergotamine), which may lead to ergotism. Co-administration of posaconazole and ergot 
alkaloids is contraindicated (see section 4.3).

HMG-CoA reductase inhibitors metabolised through CYP3A4 (e.g. simvastatin, lovastatin, and 
atorvastatin)
Posaconazole may substantially increase plasma levels of HMG-CoA reductase inhibitors that are 
metabolised by CYP3A4. Treatment with these HMG-CoA reductase inhibitors should be 
discontinued during treatment with posaconazole as increased levels have been associated with 
rhabdomyolysis (see section 4.3).

Vinca alkaloids
Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant 
administration of azole antifungals, including posaconazole, with vincristine has been associated with 
serious adverse reactions (see section 4.4). Posaconazole may increase the plasma concentrations of 
vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, 
reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including 
vincristine, who have no alternative antifungal treatment options.

Rifabutin
Posaconazole increased the Cmax and AUC of rifabutin by 31 % and 72 %, respectively. Concomitant 
use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the 
risk (see also above regarding the effect of rifabutin on plasma levels of posaconazole). If these 
medicinal products are co-administered, careful monitoring of full blood counts and adverse reactions
related to increased rifabutin levels (e.g. uveitis) is recommended.

Sirolimus
Repeat dose administration of posaconazole oral suspension (400 mg twice daily for 16 days) 
increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range 
3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patients 
is unknown, but is expected to be variable due to the variable posaconazole exposure in patients. Co-
administration of posaconazole with sirolimus is not recommended and should be avoided whenever 
possible. If it is considered that co-administration is unavoidable, then it is recommended that the 
dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapy and that 
there should be very frequent monitoring of trough concentrations of sirolimus in whole blood. 
Sirolimus concentrations should be measured upon initiation, during co-administration, and at 
discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should be 
noted that the relationship between sirolimus trough concentration and AUC is changed during co-
administration with posaconazole. As a result, sirolimus trough concentrations that fall within the 
usual therapeutic range may result in sub-therapeutic levels. Therefore trough concentrations that fall 
in the upper part of the usual therapeutic range should be targeted and careful attention should be paid 
to clinical signs and symptoms, laboratory parameters and tissue biopsies.

Ciclosporin
In heart transplant patients on stable doses of ciclosporin, posaconazole oral suspension 200 mg once 
daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin 
levels resulting in serious adverse reactions, including nephrotoxicity and one fatal case of 
leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with 
posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g. 
to about three quarters of the current dose). Thereafter blood levels of ciclosporin should be 
monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, 
and the dose of ciclosporin should be adjusted as necessary.

 



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Tacrolimus
Posaconazole increased Cmax and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121 % 
and 358 %, respectively. Clinically significant interactions resulting in hospitalisation and/or 
posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole 
treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to 
about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored 
carefully during co-administration, and upon discontinuation of posaconazole, and the dose of 
tacrolimus should be adjusted as necessary.

HIV Protease inhibitors
As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase 
plasma levels of these antiretroviral agents. Following co-administration of posaconazole oral 
suspension (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects 
Cmax and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), 
respectively. Following co-administration of posaconazole oral suspension (400 mg twice daily) with 
atazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects Cmax and AUC of 
atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. The 
addition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associated 
with increases in plasma bilirubin levels. Frequent monitoring for adverse reactions and toxicity 
related to antiretroviral agents that are substrates of CYP3A4 is recommended during co-
administration with posaconazole.

Midazolam and other benzodiazepines metabolised by CYP3A4
In a study in healthy volunteers posaconazole oral suspension (200 mg once daily for 10 days) 
increased the exposure (AUC) of intravenous midazolam (0.05 mg/kg) by 83 %. In another study in 
healthy volunteers, repeat dose administration of posaconazole oral suspension (200 mg twice daily 
for 7 days) increased the Cmax and AUC of intravenous midazolam (0.4 mg single dose) by an average 
of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole oral suspension 400 mg twice 
daily for 7 days increased the intravenous midazolam Cmax and AUC by 1.6 and 6.2-fold (range 1.6 to 
7.6-fold), respectively. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg 
single oral dose) by 2.2 and 4.5-fold, respectively. In addition, posaconazole oral suspension (200 mg 
or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 
8-10 hours during co-administration.
Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered 
when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by 
CYP3A4 (e.g. midazolam, triazolam, alprazolam) (see section 4.4).

Calcium channel blockers metabolised through CYP3A4 (e.g. diltiazem, verapamil, nifedipine, 
nisoldipine)
Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is 
recommended during co-administration with posaconazole. Dose adjustment of calcium channel 
blockers may be required.

Digoxin
Administration of other azoles has been associated with increases in digoxin levels. Therefore, 
posaconazole may increase plasma concentration of digoxin and digoxin levels need to be monitored 
when initiating or discontinuing posaconazole treatment.

Sulfonylureas
Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered 
with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.

Paediatric population
Interaction studies have only been performed in adults.

 



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4.6 Fertility, pregnancy and lactation

Pregnancy
There is insufficient information on the use of posaconazole in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Women of childbearing potential have to use effective contraception during treatment. Posaconazole 
must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential 
risk to the foetus.

Breast-feeding
Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of 
posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on 
initiation of treatment with posaconazole.

Fertility
Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (1.7 times the 400-mg 
twice daily regimen based on steady-state plasma concentrations in healthy volunteers) or female rats 
at a dose up to 45 mg/kg (2.2 times the 400-mg twice daily regimen). There is no clinical experience 
assessing the impact of posaconazole on fertility in humans.

4.7 Effects on ability to drive and use machines

Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with 
posaconazole use, which potentially may affect driving/operating machinery, caution needs to be 
used.

4.8 Undesirable effects

Summary of the safety profile

The safety of posaconazole oral suspension has been assessed in > 2,400 patients and healthy 
volunteers enrolled in clinical trials and from post-marketing experience. The most frequently 
reported serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and 
increased bilirubin.
The safety of posaconazole tablet has been assessed in 336 patients and healthy volunteers enrolled in 
clinical trials. The safety profile of tablets was similar to that of the oral suspension.

Tabulated list of adverse reactions
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); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from 
the available data).

 



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Table 2. Adverse reactions by body system and frequency reported in clinical trials and/or post-
marketing use *

Blood and lymphatic system 
disorders

Common: neutropenia

Uncommon: thrombocytopenia, leukopenia, anaemia, eosinophilia, 
lymphadenopathy, splenic infarction

Rare: haemolytic uraemic syndrome, thrombotic thrombocytopenic 
purpura, pancytopenia, coagulopathy, haemorrhage

Immune system disorders
Uncommon: allergic reaction

Rare: hypersensitivity reaction 

Endocrine disorders
Rare:
Not known:

adrenal insufficiency, blood gonadotropin decreased
pseudoaldosteronism

Metabolism and nutrition disorders
Common: electrolyte imbalance, anorexia, decreased appetite, 

hypokalaemia, hypomagnesaemia
Uncommon: hyperglycaemia, hypoglycaemia

Psychiatric disorders
Uncommon:
Rare:

abnormal dreams, confusional state, sleep disorder
psychotic disorder, depression

Nervous system disorders
Common: paresthesia, dizziness, somnolence, headache, dysgeusia

Uncommon: convulsions, neuropathy, hypoaesthesia, tremor, aphasia, 
insomnia

Rare: cerebrovascular accident, encephalopathy, peripheral 
neuropathy, syncope

Eye disorders
Uncommon: blurred vision, photophobia, visual acuity reduced
Rare: diplopia, scotoma

Ear and labyrinth disorder
Rare: hearing impairment

Cardiac disorders
Uncommon: long QT syndrome§, electrocardiogram abnormal§, 

palpitations, bradycardia, supraventricular extrasystoles, 
tachycardia

Rare: torsade de pointes, sudden death, ventricular tachycardia, 
cardio-respiratory arrest, cardiac failure, myocardial infarction

Vascular disorders
Common:
Uncommon:

hypertension
hypotension, vasculitis

Rare: pulmonary embolism, deep vein thrombosis

Respiratory, thoracic and 
mediastinal disorders
Uncommon:

Rare:

cough, epistaxis, hiccups, nasal congestion, pleuritic pain, 
tachypnoea
pulmonary hypertension, interstitial pneumonia, pneumonitis

 



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Gastrointestinal disorders
Very Common:
Common:

nausea
vomiting, abdominal pain, diarrhoea, dyspepsia, dry mouth, 
flatulence, constipation, anorectal discomfort

Uncommon: pancreatitis, abdominal distension, enteritis, epigastric 
discomfort, eructation, gastrooesophageal reflux disease, 
oedema mouth

Rare: gastrointestinal haemorrhage, ileus 

Hepatobiliary disorders
Common: liver function tests raised (ALT increased, AST increased, 

bilirubin increased, alkaline phosphatase increased, GGT 
increased)

Uncommon: hepatocellular damage, hepatitis, jaundice, hepatomegaly, 
cholestasis, hepatic toxicity, hepatic function abnormal

Rare: hepatic failure, hepatitis cholestatic, hepatosplenomegaly, 
liver tenderness, asterixis

Skin and subcutaneous tissue 
disorders
Common: rash, pruritis
Uncommon: mouth ulceration, alopecia, dermatitis, erythema, petechiae
Rare: Stevens Johnson syndrome, vesicular rash

Musculoskeletal and connective 
tissue disorders
Uncommon: back pain, neck pain, musculoskeletal pain, pain in extremity

Renal and urinary disorders 
Uncommon: acute renal failure, renal failure, blood creatinine increased 
Rare: renal tubular acidosis, interstitial nephritis 

Reproductive system and breast 
disorders
Uncommon: menstrual disorder
Rare: breast pain

General disorders and 
administration site conditions
Common: pyrexia (fever), asthenia, fatigue
Uncommon: oedema, pain, chills, malaise, chest discomfort, drug 

intolerance, feeling jittery, mucosal inflammation
Rare: tongue oedema, face oedema

Investigations
Uncommon: altered medicine levels, blood phosphorus decreased, chest 

x-ray abnormal
* Based on adverse reactions observed with the oral suspension, gastro-resistant tablets, and concentrate for solution for 

infusion.
§

See section 4.4.

Description of selected adverse reactions
Hepatobiliary disorders
During post-marketing surveillance of posaconazole oral suspension, severe hepatic injury with fatal 
outcome has been reported (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.

 

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4.9 Overdose

During clinical trials, patients who received posaconazole oral suspension doses up to 1,600 mg/day 
experienced no different adverse reactions from those reported with patients at the lower doses. 
Accidental overdose was noted in one patient who took posaconazole oral suspension 1,200 mg twice 
a day for 3 days. No adverse reactions were noted by the investigator.

Posaconazole is not removed by haemodialysis. There is no special treatment available in the case of 
overdose with posaconazole. Supportive care may be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC04.

Mechanism of action
Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential 
step in ergosterol biosynthesis.

Microbiology
Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus
species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species 
(Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, 
C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea 
pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological data 
suggest that posaconazole is active against Rhizomucor, Mucor, and Rhizopus; however the clinical 
data are currently too limited to assess the efficacy of posaconazole against these causative agents.

Resistance
Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle 
mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.

Epidemiological Cut-off (ECOFF) Values for Aspergillus spp.
The ECOFF values for posaconazole, which distinguish the wild type population from isolates with 
acquired resistance, have been determined by EUCAST methodology.

EUCAST ECOFF values:
 Aspergillus flavus: 0.5 mg/L
 Aspergillus fumigatus: 0.25 mg/L
 Aspergillus nidulans: 0.5 mg/L 
 Aspergillus niger: 0.5 mg/L
 Aspergillus terreus: 0.25 mg/L 

There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do 
not equate to clinical breakpoints.

Breakpoints
EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:
 Candida albicans: S ≤0.06 mg/L, R >0.06 mg/L
 Candida tropicalis: S ≤0.06 mg/L, R >0.06 mg/L
 Candida parapsilosis: S ≤0.06 mg/L, R >0.06 mg/L

There are currently insufficient data to set clinical breakpoints for other Candida species.

 



13

Combination with other antifungal agents
The use of combination antifungal therapies should not decrease the efficacy of either posaconazole 
or the other therapies; however, there is currently no clinical evidence that combination therapy will 
provide an added benefit.

Pharmacokinetic / Pharmacodynamic relationships
A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical 
outcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It is 
particularly important to try to ensure that maximal plasma levels are achieved in patients infected 
with Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens and the effects of food on 
absorption).

Clinical experience

Summary of posaconazole oral suspension studies

Invasive aspergillosis
Oral posaconazole suspension 800 mg/day in divided doses was evaluated for the treatment of 
invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal 
formulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-
comparative salvage therapy trial (Study 0041). Clinical outcomes were compared with those in an 
external control group derived from a retrospective review of medical records. The external control 
group included 86 patients treated with available therapy (as above) mostly at the same time and at the 
same sites as the patients treated with posaconazole. Most of the cases of aspergillosis were 
considered to be refractory to prior therapy in both the posaconazole group (88 %) and in the external 
control group (79 %).

As shown in Table 3, a successful response (complete or partial resolution) at the end of treatment 
was seen in 42 % of posaconazole-treated patients compared to 26 % of the external group. However, 
this was not a prospective, randomised controlled study and so all comparisons with the external 
control group should be viewed with caution.

Table 3. Overall efficacy of posaconazole oral suspension at the end of treatment for invasive 
aspergillosis in comparison to an external control group

Posaconazole oral 
suspension

External control group

Overall Response 45/107 (42 %) 22/86 (26 %)
Success by Species

All mycologically confirmed
Aspergillus spp.1 34/76 (45 %) 19/74 (26 %)
A. fumigatus 12/29 (41 %) 12/34 (35 %)
A. flavus 10/19 (53 %) 3/16 (19 %)
A. terreus 4/14 (29 %) 2/13 (15 %)
A. niger 3/5 (60 %) 2/7 (29 %)

Fusarium spp.
11 of 24 patients who had proven or probable fusariosis were successfully treated with posaconazole 
oral suspension 800 mg/day in divided doses for a median of 124 days and up to 212 days. Among 
eighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole, 
seven patients were classed as responders.

                                                     
1 Includes other less common species or species unknown

 



14

Chromoblastomycosis/Mycetoma
9 of 11 patients were successfully treated with posaconazole oral suspension 800 mg/day in divided 
doses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosis 
due to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.

Coccidioidomycosis
11 of 16 patients were successfully treated (at the end of treatment complete or partial resolution of 
signs and symptoms present at baseline) with posaconazole oral suspension 800 mg/day in divided 
doses for a median of 296 days and up to 460 days.

Treatment of azole-susceptible Oropharyngeal Candidiasis (OPC)
A randomised, evaluator-blind, controlled study was completed in HIV-infected patients with azole-
susceptible oropharyngeal candidiasis (most patients studied had C. albicans isolated at baseline). The 
primary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 days 
of treatment. Patients were treated with posaconazole or fluconazole oral suspension (both 
posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 
100 mg once a day for 13 days).

The clinical response rates from the above study are shown in the Table 4 below.
Posaconazole was shown to be non-inferior to fluconazole for clinical success rates at Day 14 as well 
as 4 weeks after the end of treatment.

Table 4. Clinical success rates in Oropharyngeal Candidiasis
Endpoint Posaconazole Fluconazole
Clinical success rate at Day 14 91.7 % (155/169) 92.5 % (148/160)

Clinical success rate 4 weeks after end of treatment 68.5 % (98/143) 61.8 % (84/136)
Clinical success rate was defined as the number of cases assessed as having a clinical response (cure or improvement) divided
by the total number of cases eligible for analysis.

Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899)
Two randomised, controlled prophylaxis studies were conducted among patients at high risk for 
developing invasive fungal infections.

Study 316 was a randomised, double-blind trial of posaconazole oral suspension (200 mg three times 
a day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell 
transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the 
incidence of proven/probable IFIs at 16 weeks post-randomisation as determined by an independent, 
blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs 
during the on-treatment period (first dose to last dose of study medicinal product + 7 days). The 
majority (377/600, [63 %]) of patients included had Acute Grade 2 or 3 or chronic extensive 
(195/600, [32.5 %]) GVHD at study start. The mean duration of therapy was 80 days for posaconazole 
and 77 days for fluconazole.

Study 1899 was a randomised, evaluator-blinded study of posaconazole oral suspension (200 mg three 
times a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg 
twice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acute 
myelogenous leukaemia or myelodysplastic syndromes. The primary efficacy endpoint was the 
incidence of proven/probable IFIs as determined by an independent, blinded external expert panel 
during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs 
at 100 days post-randomisation. New diagnosis of acute myelogenous leukaemia was the most 
common underlying condition (435/602, [72 %]). The mean duration of therapy was 29 days for 
posaconazole and 25 days for fluconazole/itraconazole.

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 5 
and 6 for results from both studies. There were fewer breakthrough Aspergillus infections in patients 
receiving posaconazole prophylaxis when compared to control patients.

 



15

Table 5. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study Posaconazole oral 
suspension

Controla P-Value

Proportion (%) of patients with proven/probable IFIs

On-treatment periodb

1899d 7/304 (2) 25/298 (8) 0.0009

316e 7/291 (2) 22/288 (8) 0.0038

Fixed-time periodc

1899d 14/304 (5) 33/298 (11) 0.0031

316 d 16/301 (5) 27/299 (9) 0.0740

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the 

period from first dose to last dose of study medicinal product plus 7 days.
c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the 

baseline day to 111 days post-baseline.
d: All randomised 
e: All treated 

Table 6. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study Posaconazole oral 
suspension

Controla

Proportion (%) of patients with proven/probable Aspergillosis

On-treatment periodb

1899d 2/304 (1) 20/298 (7)

316e 3/291 (1) 17/288 (6)

Fixed-time periodc

1899d 4/304 (1) 26/298 (9)

316 d 7/301 (2) 21/299 (7)
FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the 

period from first dose to last dose of study medicinal product plus 7 days.
c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the 

baseline day to 111 days post-baseline.
d: All randomised 
e: All treated 

In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed 
[POS 49/304 (16 %) vs. FLU/ITZ 67/298 (22 %) p= 0.048]. Based on Kaplan-Meier estimates, the 
probability of survival up to day 100 after randomisation, was significantly higher for posaconazole 
recipients; this survival benefit was demonstrated when the analysis considered all causes of death 
(P= 0.0354) as well as IFI-related deaths (P = 0.0209).

In Study 316, overall mortality was similar (POS, 25 %; FLU, 28 %); however, the proportion of IFI-
related deaths was significantly lower in the POS group (4/301) compared with the FLU 
group (12/299; P= 0.0413).

Paediatric population
Sixteen patients 8-17 years of age were treated with posaconazole oral suspension 800 mg/day in a 
study for invasive fungal infections (Study 0041). Based on the available data in 16 of these paediatric 
patients, the safety profile appears to be similar to patients ≥ 18 years of age.

 



16

Additionally, twelve patients 13-17 years of age received posaconazole oral suspension 600 mg/day 
for prophylaxis of invasive fungal infections (Studies 316 and 1899). The safety profile in these 
patients < 18 years of age appears similar to the safety profile observed in adults. Based on 
pharmacokinetic data in 10 of these paediatric patients, the pharmacokinetic profile appears to be 
similar to patients ≥ 18 years of age. In a study (Study 03579) of 136 neutropenic paediatric patients 
11 months – 17 years treated with posaconazole oral suspension at doses up to 18 mg/kg/day divided 
TID, approximately 50% met the pre-specified target (Day 7 Cav between 500 ng/mL-2,500 ng/mL) 
(see section 5.2).

Safety and efficacy in paediatric patients below the age of 18 years have not been established.

Electrocardiogram evaluation
Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during 
administration of posaconazole oral suspension (400 mg twice daily with high fat meals) from 
173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the 
mean QTc (Fridericia) interval from baseline were observed.

5.2 Pharmacokinetic properties

Absorption 
Posaconazole is absorbed with a median tmax of 3 hours (fed patients). The pharmacokinetics of 
posaconazole are linear following single and multiple dose administration of up to 800 mg when taken 
with a high fat meal. No further increases in exposure were observed when doses above 800 mg daily 
were administered to patients and healthy volunteers. In the fasting state, AUC increased less than in 
proportion to dose above 200 mg. In healthy volunteers under fasting conditions, dividing the total 
daily dose (800 mg) into 200 mg four times daily compared to 400 mg twice daily, was shown to 
increase posaconazole exposure by 2.6-fold.

Effect of food on oral absorption in healthy volunteers
The absorption of posaconazole was significantly increased when posaconazole 400 mg (once daily) 
was administered during and immediately after the consumption of a high fat meal (~ 50 grams fat) 
compared to administration before a meal, with Cmax and AUC increasing by approximately 330 % 
and 360 %, respectively. The AUC of posaconazole is: 4 times greater when administered with a high-
fat meal (~ 50 grams fat) and about 2.6 times greater when administered during a non-fat meal or 
nutritional supplement (14 grams fat) relative to the fasted state (see sections 4.2 and 4.5).

Distribution
Posaconazole is slowly absorbed and slowly eliminated with a large apparent volume of distribution 
(1,774 litres) and is highly protein bound (> 98 %), predominantly to serum albumin.

Biotransformation
Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to 
be altered by inhibitors of CYP450 enzymes. Of the circulating metabolites, the majority are 
glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) 
metabolites observed. The excreted metabolites in urine and faeces account for approximately 17 % 
of the administered radiolabelled dose.

Elimination
Posaconazole is slowly eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours). After 
administration of 14C-posaconazole, radioactivity was predominantly recovered in the faeces (77 % of 
the radiolabelled dose) with the major component being parent compound (66 % of the radiolabelled 
dose). Renal clearance is a minor elimination pathway, with 14 % of the radiolabelled dose excreted 
in urine (< 0.2 % of the radiolabelled dose is parent compound). Steady-state is attained following 
7 to 10 days of multiple-dose administration.

 



17

Pharmacokinetics in special populations
Children (< 18 years)
Following administration of 800 mg per day of posaconazole as a divided dose for treatment of 
invasive fungal infections, mean trough plasma concentrations from 12 patients 8 - 17 years of age 
(776 ng/mL) were similar to concentrations from 194 patients 18 - 64 years of age (817 ng/mL). 
Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) 
was comparable among ten adolescents (13-17 years of age) to Cav achieved in adults (≥ 18 years of 
age). In a study of 136 neutropenic paediatric patients 11 months – 17 years treated with posaconazole 
oral suspension at doses up to 18 mg/kg/day divided TID, approximately 50% met the pre-specified 
target (Day 7 Cav between 500 ng/mL-2,500 ng/mL). In general, exposures tended to be higher in the 
older patients (7 to <18 years) than in younger patients (2 to <7 years). 

Gender
The pharmacokinetics of posaconazole are comparable in men and women.

Elderly ( 65 years)
An increase in Cmax (26 %) and AUC (29 %) was observed in elderly subjects (24 subjects  65 years 
of age) relative to younger subjects (24 subjects 18 - 45 years of age). However, in clinical efficacy 
trials, the safety profile of posaconazole between the young and elderly patients was similar.

Race
There was a slight decrease (16 %) in the AUC and Cmax of posaconazole oral suspension in Black 
subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the 
Black and Caucasian subjects was similar.

Weight
Pharmacokinetic modelling with an oral tablet formulation suggests that patients weighing greater 
than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for 
breakthrough fungal infections in patients weighing more than 120 kg. Patients with a low body 
weight (< 60 kg) are more likely to experience higher plasma concentrations of posaconazole and 
should be closely monitored for adverse events.

Renal impairment
Following single-dose administration of posaconazole oral suspension, there was no effect of mild 
and moderate renal impairment (n=18, Cl cr ≥ 20 mL/min/1.73 m

2) on posaconazole pharmacokinetics; 
therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Cl cr
< 20 mL/min/1.73 m2), the AUC of posaconazole was highly variable [> 96 % CV (coefficient of 
variance)] compared to other renal groups [< 40 % CV]. However, as posaconazole is not 
significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of 
posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed 
by haemodialysis.

Hepatic impairment
After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh 
Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six per 
group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with 
normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that 
there is a larger increase in unbound posaconazole exposure than the observed 60 % increase in total 
AUC. The elimination half-life (t1/2) was prolonged from approximately 27 hours up to ~43 hours in 
respective groups. No dose adjustment is recommended for patients with mild to severe hepatic 
impairment but caution is advised due to the potential for higher plasma exposure.

5.3 Preclinical safety data

As observed with other azole antifungal agents, effects related to inhibition of steroid hormone 
synthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effects 

 



18

were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained 
at therapeutic doses in humans. 

Neuronal phospholipidosis occurred in dogs dosed for  3 months at lower systemic exposures than 
those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one 
year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observed 
on the central or peripheral nervous systems at systemic exposures greater than those achieved 
therapeutically.

Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the 
2-year study in rats. These findings are not necessarily indicative of a potential for functional changes 
in humans.

No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety 
pharmacology study in monkeys at systemic exposures 4.6-fold greater than the concentrations 
obtained at therapeutic doses in humans. Echocardiography revealed no indication of cardiac 
decompensation in a repeat dose safety pharmacology study in rats at a systemic exposure 1.4-fold 
greater than that achieved therapeutically. Increased systolic and arterial blood pressures (up to 
29 mm-Hg) were seen in rats and monkeys at systemic exposures 1.4-fold and 4.6-fold greater, 
respectively, than those achieved with the human therapeutic doses.

Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower 
than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and 
malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal 
viability. In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at 
therapeutic doses. As observed with other azole antifungal agents, these effects on reproduction were 
considered to be due to a treatment-related effect on steroidogenesis.

Posaconazole was not genotoxic in in vitro and in vivo studies. Carcinogenicity studies did not reveal 
special hazards for humans.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Polysorbate 80
Simeticone
Sodium benzoate (E211)
Sodium citrate dihydrate
Citric acid monohydrate
Glycerol
Xanthan gum
Liquid glucose
Titanium dioxide (E171)
Artificial cherry flavour containing benzyl alcohol and propylene glycol
Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Unopened container: 3 years

 



19

After first opening the container: 4 weeks

6.4 Special precautions for storage

Do not freeze.

6.5 Nature and contents of container

105 mL of oral suspension in a bottle (glass amber type IV) closed with a plastic child-resistant cap 
(polypropylene) and a measuring spoon (polystyrene) with 2 graduations: 2.5 mL and 5 mL.

6.6 Special precautions for disposal 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

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

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/05/320/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2005
Date of latest renewal: 25 October 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.

 



20

1. NAME OF THE MEDICINAL PRODUCT

Noxafil 100 mg gastro-resistant tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gastro-resistant tablet contains 100 mg of posaconazole.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Gastro-resistant tablet (tablet)
Yellow-coated, capsule-shaped tablet of 17.5 mm length debossed with “100” on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications 

Noxafil gastro-resistant tablets are indicated for use in the treatment of the following fungal infections 
in adults (see section 5.1):
- Invasive aspergillosis in patients with disease that is refractory to amphotericin B or 

itraconazole or in patients who are intolerant of these medicinal products;
- Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are 

intolerant of amphotericin B;
- Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole 

or in patients who are intolerant of itraconazole;
- Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole 

or fluconazole or in patients who are intolerant of these medicinal products.

Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days 
of prior therapeutic doses of effective antifungal therapy.

Noxafil gastro-resistant tablets are also indicated for prophylaxis of invasive fungal infections in the 
following patients:
- Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) 

or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are 
at high risk of developing invasive fungal infections; 

- Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose 
immunosuppressive therapy for graft versus host disease and who are at high risk of developing 
invasive fungal infections.

Please refer to the Summary of Product Characteristics of Noxafil oral suspension for use in 
oropharyngeal candidiasis.

4.2 Posology and method of administration

Non-Interchangeability between Noxafil Tablets and Noxafil Oral Suspension

The tablet and oral suspension are not to be used interchangeably due to the differences between these 
two formulations in frequency of dosing, administration with food and plasma drug concentration 
achieved. Therefore, follow the specific dosage recommendations for each formulation.

 



21

Treatment should be initiated by a physician experienced in the management of fungal infections or in 
the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.

Posology
Noxafil is also available as 40 mg/mL oral suspension and 300 mg concentrate for solution for 
infusion. Noxafil tablets are the preferred formulation to optimize plasma concentrations and 
generally provide higher plasma drug exposures than Noxafil oral suspension.

Recommended dose is shown in Table 1.

Table 1. Recommended dose according to indication
Indication Dose and duration of therapy

(See section 5.2)
Refractory invasive fungal 
infections (IFI)/patients with IFI 
intolerant to 1st line therapy

Loading dose of 300 mg (three 100 mg tablets) twice a day on the 
first day, then 300 mg (three 100 mg tablets) once a day thereafter. 
Each dose may be taken without regard to food intake. Duration of 
therapy should be based on the severity of the underlying disease, 
recovery from immunosuppression, and clinical response. 

Prophylaxis of invasive fungal 
infections

Loading dose of 300 mg (three 100 mg tablets) twice a day on the 
first day, then 300 mg (three 100 mg tablets) once a day thereafter. 
Each dose may be taken without regard to food intake. Duration of 
therapy is based on recovery from neutropenia or 
immunosuppression. For patients with acute myelogenous 
leukemia or myelodysplastic syndromes, prophylaxis with Noxafil 
should start several days before the anticipated onset of 
neutropenia and continue for 7 days after the neutrophil count rises 
above 500 cells per mm3.

Special populations

Renal impairment 
An effect of renal impairment on the pharmacokinetics of posaconazole is not expected and no dose 
adjustment is recommended (see section 5.2).

Hepatic impairment 
Limited data on the effect of hepatic impairment (including Child-Pugh C classification of chronic 
liver disease) on the pharmacokinetics of posaconazole demonstrate an increase in plasma exposure 
compared to subjects with normal hepatic function, but do not suggest that dose adjustment is 
necessary (see sections 4.4 and 5.2). It is recommended to exercise caution due to the potential for 
higher plasma exposure.

Paediatric population
The safety and efficacy of Noxafil in children aged below 18 years have not been established. 
Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology 
can be made.

No data are available for the tablet formulation.

Method of administration
For oral use

Noxafil gastro-resistant tablets may be taken with or without food (see section 5.2). The tablets should 
be swallowed whole with water and should not be crushed, chewed, or broken.

 



22

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with ergot alkaloids (see section 4.5).

Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, 
halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal 
products, leading to QTc prolongation and rare occurrences of torsades de pointes (see sections 4.4 
and 4.5).

Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin 
(see section 4.5).

4.4 Special warnings and precautions for use

Hypersensitivity
There is no information regarding cross-sensitivity between posaconazole and other azole antifungal 
agents. Caution should be used when prescribing Noxafil to patients with hypersensitivity to other 
azoles.

Hepatic toxicity
Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin 
and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver 
function tests were generally reversible on discontinuation of therapy and in some instances these 
tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal 
outcomes have been reported. 
Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical 
experience and the possibility that posaconazole plasma levels may be higher in these patients (see 
sections 4.2 and 5.2).

Monitoring of hepatic function
Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. 
Patients who develop abnormal liver function tests during Noxafil therapy must be routinely 
monitored for the development of more severe hepatic injury. Patient management should include 
laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). 
Discontinuation of Noxafil should be considered if clinical signs and symptoms are consistent with 
development of liver disease.

QTc prolongation
Some azoles have been associated with prolongation of the QTc interval. Noxafil must not be 
administered with medicinal products that are substrates for CYP3A4 and are known to prolong the 
QTc interval (see sections 4.3 and 4.5). Noxafil should be administered with caution to patients with 
pro-arrhythmic conditions such as:
 Congenital or acquired QTc prolongation
 Cardiomyopathy, especially in the presence of cardiac failure
 Sinus bradycardia
 Existing symptomatic arrhythmias
 Concomitant use with medicinal products known to prolong the QTc interval (other than those 

mentioned in section 4.3).
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should 
be monitored and corrected as necessary before and during posaconazole therapy.

 



23

Drug Interactions
Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during 
treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5).

Midazolam and other benzodiazepines
Due to the risk of prolonged sedation and possible respiratory depression co-administration of 
posaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam, 
alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepines 
metabolised by CYP3A4 should be considered (see section 4.5).

Vincristine Toxicity
Concomitant administration of azole antifungals, including posaconazole, with vincristine has been 
associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral 
neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve 
azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including 
vincristine, who have no alternative antifungal treatment options (see section 4.5).

Rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine, 
phenobarbital, primidone), and efavirenz.
Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use 
with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see 
section 4.5).

Plasma exposure
Posaconazole plasma concentrations following administration of posaconazole tablets are generally 
higher than those obtained with posaconazole oral suspension. Posaconazole plasma concentrations 
following administration of posaconazole tablets may increase over time in some patients (see 
section 5.2). Safety data at higher exposure levels achieved with posaconazole tablets are at present 
limited.

Gastrointestinal dysfunction
There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (such as 
severe diarrhoea). Patients who have severe diarrhoea or vomiting should be monitored closely for 
breakthrough fungal infections.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on posaconazole
Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for 
p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, 
clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, 
etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, 
respectively.

Rifabutin
Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area 
under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. 
Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be 
avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of 
posaconazole on rifabutin plasma levels. 

Efavirenz
Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, 
respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to 
the patient outweighs the risk. 

 



24

Fosamprenavir
Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma 
concentrations. If concomitant administration is required, close monitoring for breakthrough fungal 
infections is recommended.  Repeat dose administration of fosamprenavir (700 mg twice daily x 
10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 
1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days) by 21 % and 23 %, 
respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with 
ritonavir is unknown.

Phenytoin
Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 % and 50 %, 
respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. 
carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient 
outweighs the risk.

H2 receptor antagonists and proton pump inhibitors
No clinically relevant effects were observed when posaconazole tablets are concomitantly used with 
antacids, H2-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole 
tablets is required when posaconazole tablets are concomitantly used with antacids, H2-receptor 
antagonists and proton pump inhibitors.

Effects of posaconazole on other medicinal products
Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4 
substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the 
effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co-
administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of 
the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 
substrates that are administered orally, and for which an increase in plasma concentrations may be 
associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate 
and/or adverse reactions should be closely monitored and the dose adjusted as needed. Several of the 
interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole 
occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4 
substrates in patients might be somewhat lower than that observed in healthy volunteers, and is 
expected to be variable between patients due to the variable posaconazole exposure in patients. The 
effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be 
variable within a patient.

Terfenadine, astemizole, cisapride, pimozide, halofantrine and quinidine (CYP3A4 substrates)
Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine or 
quinidine is contraindicated. Co-administration may result in increased plasma concentrations of these 
medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see 
section 4.3).

Ergot alkaloids
Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and 
dihydroergotamine), which may lead to ergotism. Co-administration of posaconazole and ergot 
alkaloids is contraindicated (see section 4.3).

HMG-CoA reductase inhibitors metabolised through CYP3A4 (e.g. simvastatin, lovastatin, and 
atorvastatin)
Posaconazole may substantially increase plasma levels of HMG-CoA reductase inhibitors that are 
metabolised by CYP3A4. Treatment with these HMG-CoA reductase inhibitors should be 
discontinued during treatment with posaconazole as increased levels have been associated with 
rhabdomyolysis (see section 4.3).

 



25

Vinca alkaloids
Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant 
administration of azole antifungals, including posaconazole, with vincristine has been associated with 
serious adverse reactions (see section 4.4). Posaconazole may increase the plasma concentrations of 
vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, 
reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including 
vincristine, who have no alternative antifungal treatment options.

Rifabutin
Posaconazole increased the Cmax and AUC of rifabutin by 31 % and 72 %, respectively. Concomitant 
use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the 
risk (see also above regarding the effect of rifabutin on plasma levels of posaconazole). If these 
medicinal products are co-administered, careful monitoring of full blood counts and adverse reactions 
related to increased rifabutin levels (e.g. uveitis) is recommended.

Sirolimus
Repeat dose administration of posaconazole oral suspension (400 mg twice daily for 16 days) 
increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range 
3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patients 
is unknown, but is expected to be variable due to the variable posaconazole exposure in patients. Co-
administration of posaconazole with sirolimus is not recommended and should be avoided whenever 
possible. If it is considered that co-administration is unavoidable, then it is recommended that the 
dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapy and that 
there should be very frequent monitoring of trough concentrations of sirolimus in whole blood. 
Sirolimus concentrations should be measured upon initiation, during co-administration, and at 
discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should be 
noted that the relationship between sirolimus trough concentration and AUC is changed during co-
administration with posaconazole. As a result, sirolimus trough concentrations that fall within the 
usual therapeutic range may result in sub-therapeutic levels. Therefore, trough concentrations that fall 
in the upper part of the usual therapeutic range should be targeted and careful attention should be paid 
to clinical signs and symptoms, laboratory parameters and tissue biopsies. 

Ciclosporin
In heart transplant patients on stable doses of ciclosporin, posaconazole oral suspension 200 mg once 
daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin 
levels resulting in serious adverse reactions, including nephrotoxicity and one fatal case of 
leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with 
posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g. 
to about three quarters of the current dose). Thereafter blood levels of ciclosporin should be 
monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, 
and the dose of ciclosporin should be adjusted as necessary.

Tacrolimus
Posaconazole increased Cmax and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121 % 
and 358 %, respectively. Clinically significant interactions resulting in hospitalisation and/or 
posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole 
treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to 
about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored 
carefully during co-administration, and upon discontinuation of posaconazole, and the dose of 
tacrolimus should be adjusted as necessary.

HIV Protease inhibitors
As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase 
plasma levels of these antiretroviral agents. Following co-administration of posaconazole oral 
suspension (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects 
Cmax and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), 

 



26

respectively. Following co-administration of posaconazole oral suspension (400 mg twice daily) with 
atazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects Cmax and AUC of 
atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. The 
addition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associated 
with increases in plasma bilirubin levels. Frequent monitoring for adverse reactions and toxicity 
related to antiretroviral agents that are substrates of CYP3A4 is recommended during co-
administration with posaconazole.

Midazolam and other benzodiazepines metabolised by CYP3A4
In a study in healthy volunteers posaconazole oral suspension (200 mg once daily for 10 days) 
increased the exposure (AUC) of intravenous midazolam (0.05 mg/kg) by 83 %. In another study in 
healthy volunteers, repeat dose administration of posaconazole oral suspension (200 mg twice daily 
for 7 days) increased the Cmax and AUC of intravenous midazolam (0.4 mg single dose) by an average 
of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole oral suspension 400 mg twice 
daily for 7 days increased the intravenous midazolam Cmax and AUC by 1.6 and 6.2-fold (range 1.6 to 
7.6-fold), respectively. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg 
single oral dose) by 2.2 and 4.5-fold, respectively. In addition, posaconazole oral suspension (200 mg 
or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 
8-10 hours during co-administration.
Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered 
when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by 
CYP3A4 (e.g. midazolam, triazolam, alprazolam) (see section 4.4).

Calcium channel blockers metabolised through CYP3A4 (e.g. diltiazem, verapamil, nifedipine, 
nisoldipine)
Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is 
recommended during co-administration with posaconazole. Dose adjustment of calcium channel 
blockers may be required.

Digoxin
Administration of other azoles has been associated with increases in digoxin levels. Therefore, 
posaconazole may increase plasma concentration of digoxin and digoxin levels need to be monitored 
when initiating or discontinuing posaconazole treatment.

Sulfonylureas
Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered 
with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.

Paediatric population
Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy
There is insufficient information on the use of posaconazole in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Women of childbearing potential have to use effective contraception during treatment. Posaconazole 
must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential 
risk to the foetus.

Breast-feeding
Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of 
posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on 
initiation of treatment with posaconazole.

 



27

Fertility
Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (3.4 times the 300-mg 
tablet based on steady-state plasma concentrations in patients) or female rats at a dose up to 45 mg/kg 
(2.6 times the 300-mg tablet based on steady-state plasma concentrations in patients). There is no 
clinical experience assessing the impact of posaconazole on fertility in humans.

4.7 Effects on ability to drive and use machines

Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with
posaconazole use, which potentially may affect driving/operating machinery, caution needs to be 
used.

4.8 Undesirable effects

Safety data mainly derive from studies with the oral suspension.

The tablet formulation was investigated in AML and MDS patients and those after HSCT with or at 
risk for Graft versus Host Disease (GvHD) only. Maximum duration of exposure to the tablet 
formulation was shorter than with the oral suspension. Plasma exposure resulting from the tablet 
formulation was higher than observed with the oral suspension. A higher incidence of adverse 
reactions cannot be ruled out.

Summary of the safety profile

Posaconazole tablets 
The safety of posaconazole tablets has been assessed in 230 patients enrolled in the pivotal clinical 
study. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole 
tablets when given as antifungal prophylaxis. Patients were immunocompromised with underlying 
conditions including haematological malignancy, neutropenia post-chemotherapy, GVHD, and post 
HSCT. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 
200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 
1 in each cohort).

Posaconazole tablet and oral suspension safety
The safety of posaconazole oral suspension has been assessed in > 2,400 patients and healthy 
volunteers enrolled in clinical trials and from post-marketing experience. The most frequently 
reported serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and 
increased bilirubin.
The safety of posaconazole tablet has been assessed in 336 patients and healthy volunteers enrolled in 
clinical trials. The safety profile of tablets was similar to that of the oral suspension.

Tabulated list of adverse reactions
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); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from 
the available data).

 



28

Table 2. Adverse reactions by body system and frequency reported in clinical trials and/or post-
marketing use*

Blood and lymphatic system 
disorders

Common: neutropenia

Uncommon: thrombocytopenia, leukopenia, anaemia, eosinophilia, 
lymphadenopathy, splenic infarction

Rare: haemolytic uraemic syndrome, thrombotic thrombocytopenic 
purpura, pancytopenia, coagulopathy, haemorrhage

Immune system disorders
Uncommon: allergic reaction

Rare: hypersensitivity reaction 

Endocrine disorders
Rare:
Not known:

adrenal insufficiency, blood gonadotropin decreased
pseudoaldosteronism

Metabolism and nutrition disorders
Common: electrolyte imbalance, anorexia, decreased appetite, 

hypokalaemia, hypomagnesaemia
Uncommon: hyperglycaemia, hypoglycaemia

Psychiatric disorders
Uncommon:
Rare:

abnormal dreams, confusional state, sleep disorder 
psychotic disorder, depression

Nervous system disorders
Common: paresthesia, dizziness, somnolence, headache, dysgeusia

Uncommon: convulsions, neuropathy, hypoaesthesia, tremor, aphasia, 
insomnia

Rare: cerebrovascular accident, encephalopathy, peripheral 
neuropathy, syncope

Eye disorders
Uncommon: blurred vision, photophobia, visual acuity reduced 
Rare: diplopia, scotoma

Ear and labyrinth disorder
Rare: hearing impairment

Cardiac disorders
Uncommon: long QT syndrome§, electrocardiogram abnormal§, 

palpitations, bradycardia, supraventricular extrasystoles, 
tachycardia

Rare: torsade de pointes, sudden death, ventricular tachycardia, 
cardio-respiratory arrest, cardiac failure, myocardial infarction

Vascular disorders
Common:
Uncommon:

hypertension
hypotension, vasculitis

Rare: pulmonary embolism, deep vein thrombosis

Respiratory, thoracic and 
mediastinal disorders
Uncommon:

Rare:

cough, epistaxis, hiccups, nasal congestion, pleuritic pain, 
tachypnoea
pulmonary hypertension, interstitial pneumonia, pneumonitis

 



29

Gastrointestinal disorders
Very Common:
Common:

nausea
vomiting, abdominal pain, diarrhoea, dyspepsia, dry mouth, 
flatulence, constipation, anorectal discomfort

Uncommon: pancreatitis, abdominal distension, enteritis, epigastric 
discomfort, eructation, gastrooesophageal reflux disease, 
oedema mouth

Rare: gastrointestinal haemorrhage, ileus 

Hepatobiliary disorders
Common: liver function tests raised (ALT increased, AST increased, 

bilirubin increased, alkaline phosphatase increased, GGT 
increased)

Uncommon: hepatocellular damage, hepatitis, jaundice, hepatomegaly, 
cholestasis, hepatic toxicity, hepatic function abnormal

Rare: hepatic failure, hepatitis cholestatic, hepatosplenomegaly, 
liver tenderness, asterixis

Skin and subcutaneous tissue 
disorders
Common: rash, pruritis
Uncommon: mouth ulceration, alopecia, dermatitis, erythema, petechiae
Rare: Stevens Johnson syndrome, vesicular rash

Musculoskeletal and connective 
tissue disorders
Uncommon: back pain, neck pain, musculoskeletal pain, pain in extremity

Renal and urinary disorders 
Uncommon: acute renal failure, renal failure, blood creatinine increased 
Rare: renal tubular acidosis, interstitial nephritis 

Reproductive system and breast 
disorders
Uncommon: menstrual disorder
Rare: breast pain

General disorders and 
administration site conditions
Common: pyrexia (fever), asthenia, fatigue
Uncommon: oedema, pain, chills, malaise, chest discomfort, drug 

intolerance, feeling jittery, mucosal inflammation
Rare: tongue oedema, face oedema

Investigations
Uncommon: altered medicine levels, blood phosphorus decreased, chest x-

ray abnormal 
* Based on adverse reactions observed with the oral suspension, gastro-resistant tablets, and concentrate for solution for 

infusion.
§

See section 4.4.

Description of selected adverse reactions
Hepatobiliary disorders
During post-marketing surveillance of posaconazole oral suspension, severe hepatic injury with fatal 
outcome has been reported (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.

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


30

4.9 Overdose

There is no experience with overdose of posaconazole tablets.

During clinical trials, patients who received posaconazole oral suspension doses up to 1,600 mg/day 
experienced no different adverse reactions from those reported with patients at the lower doses. 
Accidental overdose was noted in one patient who took posaconazole oral suspension 1,200 mg twice 
a day for 3 days. No adverse reactions were noted by the investigator.

Posaconazole is not removed by haemodialysis. There is no special treatment available in the case of 
overdose with posaconazole. Supportive care may be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC04.

Mechanism of action
Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential 
step in ergosterol biosynthesis.

Microbiology
Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus
species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species 
(Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, 
C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea 
pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological data 
suggest that posaconazole is active against Rhizomucor, Mucor, and Rhizopus; however the clinical 
data are currently too limited to assess the efficacy of posaconazole against these causative agents.

Resistance
Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle 
mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.

Epidemiological Cut-off (ECOFF) Values for Aspergillus spp.
The ECOFF values for posaconazole, which distinguish the wild type population from isolates with 
acquired resistance, have been determined by EUCAST methodology.

EUCAST ECOFF values:
 Aspergillus flavus: 0.5 mg/L
 Aspergillus fumigatus: 0.25 mg/L
 Aspergillus nidulans: 0.5 mg/L
 Aspergillus niger: 0.5 mg/L
 Aspergillus terreus: 0.25 mg/L

There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do 
not equate to clinical breakpoints.

Breakpoints
EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:
 Candida albicans: S ≤0.06 mg/L, R >0.06 mg/L
 Candida tropicalis: S ≤0.06 mg/L, R >0.06 mg/L
 Candida parapsilosis: S ≤0.06 mg/L, R >0.06 mg/L

 



31

There are currently insufficient data to set clinical breakpoints for other Candida species.

Combination with other antifungal agents
The use of combination antifungal therapies should not decrease the efficacy of either posaconazole 
or the other therapies; however, there is currently no clinical evidence that combination therapy will 
provide an added benefit.

Clinical experience

Summary of posaconazole tablet bridging study
Study 5615 was a non-comparative multi-center study performed to evaluate the pharmacokinetic 
properties, safety, and tolerability of posaconazole tablet.  Study 5615 was conducted in a similar 
patient population to that previously studied in the pivotal posaconazole oral suspension clinical 
program. The pharmacokinetics and safety data from Study 5615 were bridged to the existing data 
(including efficacy data) with the oral suspension. 

The subject population included: 1) patients with AML or MDS who had recently received 
chemotherapy and had developed or were anticipated to develop significant neutropenia, or 2) patients 
who had undergone a HSCT and were receiving immunosuppressive therapy for prevention or 
treatment of GVHD. Two different dosing groups were evaluated: 200 mg twice daily on Day 1, 
followed by 200 mg once daily thereafter (Part IA) and 300 mg twice daily on Day 1, followed by 
300 mg once daily thereafter (Part 1B and Part 2).

Serial PK samples were collected on Day 1 and at steady-state on Day 8 for all Part 1 subjects and a 
subset of Part 2 subjects. Moreover, sparse PK samples were collected at several days during steady 
state before the next dose (Cmin) for a larger subject population. Based on average Cmin concentrations, 
a predicted average concentration (Cav) could be calculated for 186 subjects dosed with 300 mg. PK 
analysis in patients of Cav found that 81 % of the subjects treated with the 300 mg once daily dose 
attained steady state predicted Cav between 500-2,500 ng/mL. One subject (<1 %) had a predicted 
Cav below 500 ng/mL and 19 % of the subjects had a predicted Cav above 2,500 ng/mL. Subjects 
achieved a mean predicted Cav at steady state of 1,970 ng/mL.

In Table 3 a comparison is shown of exposure (Cav) after administration of posaconazole tablet and 
posaconazole oral suspension at therapeutic doses in patients depicted as quartile analysis. Exposures 
after tablet administration are generally higher than, but overlapping with, exposures after 
administration of posaconazole oral suspension.

 



32

Table 3. Cav quartile analyses of pivotal patient studies with posaconazole tablet and oral suspension
Posaconazole 

tablet
Posaconazole oral suspension

Prophylaxis in 
AML and HSCT

Study 5615

Prophylaxis in 
GVHD

Study 316

Prophylaxis in 
Neutropenia
Study 1899

Treatment  -
Invasive 

Aspergillosis
Study 0041

300 mg once daily  
(Day 1 300 mg 
twice daily)*

200 mg three 
times daily

200 mg three 
times daily

200 mg four times 
daily 

(hospitalized) then 
400 mg twice daily

Quartile pCav Range 
(ng/mL)

Cav Range 
(ng/mL)

Cav Range 
(ng/mL)

Cav Range 
(ng/mL)

Q1 442 – 1,223 22 – 557 90 – 322 55 – 277
Q2 1,240 – 1,710 557 – 915 322 – 490 290 – 544
Q3 1,719 – 2,291 915 – 1,563 490 – 734 550 – 861
Q4 2,304 – 9,523 1,563 – 3,650 734 – 2,200 877 – 2,010
pCav: predicted Cav
Cav = the average concentration when measured at steady state
*20 patients received 200 mg once daily (Day 1 200 mg twice daily)

Summary of posaconazole oral suspension studies

Invasive aspergillosis
Oral posaconazole suspension 800 mg/day in divided doses was evaluated for the treatment of 
invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal 
formulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-
comparative salvage therapy trial (Study 0041). Clinical outcomes were compared with those in an 
external control group derived from a retrospective review of medical records. The external control 
group included 86 patients treated with available therapy (as above) mostly at the same time and at the 
same sites as the patients treated with posaconazole. Most of the cases of aspergillosis were 
considered to be refractory to prior therapy in both the posaconazole group (88 %) and in the external 
control group (79 %).
As shown in Table 4, a successful response (complete or partial resolution) at the end of treatment 
was seen in 42 % of posaconazole-treated patients compared to 26 % of the external group. However, 
this was not a prospective, randomised controlled study and so all comparisons with the external 
control group should be viewed with caution.

Table 4. Overall efficacy of posaconazole oral suspension at the end of treatment for invasive 
aspergillosis in comparison to an external control group 

Posaconazole oral 
suspension

External control group

Overall Response 45/107 (42 %) 22/86 (26 %)
Success by Species

All mycologically confirmed
Aspergillus spp.2 34/76 (45 %) 19/74 (26 %)
A. fumigatus 12/29 (41 %) 12/34 (35 %)
A. flavus 10/19 (53 %) 3/16 (19 %)
A. terreus 4/14 (29 %) 2/13 (15 %)
A. niger 3/5 (60 %) 2/7 (29 %)

Fusarium spp.
11 of 24 patients who had proven or probable fusariosis were successfully treated with posaconazole 
oral suspension 800 mg/day in divided doses for a median of 124 days and up to 212 days. Among 

                                                     
2 Includes other less common species or species unknown

 



33

eighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole, 
seven patients were classed as responders.

Chromoblastomycosis/Mycetoma
9 of 11 patients were successfully treated with posaconazole oral suspension 800 mg/day in divided 
doses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosis 
due to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.

Coccidioidomycosis
11 of 16 patients were successfully treated (at the end of treatment complete or partial resolution of 
signs and symptoms present at baseline) with posaconazole oral suspension 800 mg/day in divided 
doses for a median of 296 days and up to 460 days.

Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899)
Two randomised, controlled prophylaxis studies were conducted among patients at high risk for 
developing invasive fungal infections.

Study 316 was a randomised, double-blind trial of posaconazole oral suspension (200 mg three times 
a day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell 
transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the 
incidence of proven/probable IFIs at 16 weeks post-randomisation as determined by an independent, 
blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs 
during the on-treatment period (first dose to last dose of study medicinal product + 7 days). The 
majority (377/600, [63 %]) of patients included had Acute Grade 2 or 3 or chronic extensive 
(195/600, [32.5 %]) GVHD at study start. The mean duration of therapy was 80 days for posaconazole 
and 77 days for fluconazole.

Study 1899 was a randomised, evaluator-blinded study of posaconazole oral suspension (200 mg three 
times a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg 
twice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acute 
myelogenous leukaemia or myelodysplastic syndromes. The primary efficacy endpoint was the 
incidence of proven/probable IFIs as determined by an independent, blinded external expert panel 
during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs 
at 100 days post-randomisation. New diagnosis of acute myelogenous leukaemia was the most 
common underlying condition (435/602, [72 %]). The mean duration of therapy was 29 days for 
posaconazole and 25 days for fluconazole/itraconazole.

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 5 
and 6 for results from both studies. There were fewer breakthrough Aspergillus infections in patients 
receiving posaconazole prophylaxis when compared to control patients.

Table 5. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study Posaconazole oral 
suspension

Controla P-Value

Proportion (%) of patients with proven/probable IFIs

On-treatment periodb

1899d 7/304 (2) 25/298 (8) 0.0009

316e 7/291 (2) 22/288 (8) 0.0038

Fixed-time periodc

1899d 14/304 (5) 33/298 (11) 0.0031

 



34

Study Posaconazole oral 
suspension

Controla P-Value

Proportion (%) of patients with proven/probable IFIs

316 d 16/301 (5) 27/299 (9) 0.0740

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the 

period from first dose to last dose of study medicinal product plus 7 days.
c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the 

baseline day to 111 days post-baseline.
d: All randomised 
e: All treated 

Table 6. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study Posaconazole oral 
suspension

Controla

Proportion (%) of patients with proven/probable Aspergillosis

On-treatment periodb

1899d 2/304 (1) 20/298 (7)

316e 3/291 (1) 17/288 (6)

Fixed-time periodc

1899d 4/304 (1) 26/298 (9)

316 d 7/301 (2) 21/299 (7)
FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the 

period from first dose to last dose of study medicinal product plus 7 days.
c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the 

baseline day to 111 days post-baseline.
d: All randomised 
e: All treated 

In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed 
[POS 49/304 (16 %) vs. FLU/ITZ 67/298 (22 %) p= 0.048]. Based on Kaplan-Meier estimates, the 
probability of survival up to day 100 after randomisation, was significantly higher for posaconazole 
recipients; this survival benefit was demonstrated when the analysis considered all causes of death 
(P= 0.0354) as well as IFI-related deaths (P = 0.0209).

In Study 316, overall mortality was similar (POS, 25 %; FLU, 28 %); however, the proportion of IFI-
related deaths was significantly lower in the POS group (4/301) compared with the FLU 
group (12/299; P= 0.0413).

Paediatric population
There is no paediatric experience for posaconazole tablets.

Sixteen patients 8-17 years of age were treated with posaconazole oral suspension 800 mg/day in a 
study for invasive fungal infections. Based on the available data in 16 of these paediatric patients, the 
safety profile appears to be similar to patients ≥ 18 years of age.

Additionally, twelve patients 13-17 years of age received posaconazole oral suspension 600 mg/day 
for prophylaxis of invasive fungal infections (Studies 316 and 1899). The safety profile in these 
patients < 18 years of age appears similar to the safety profile observed in adults. Based on 
pharmacokinetic data in 10 of these paediatric patients, the pharmacokinetic profile appears to be 
similar to patients ≥ 18 years of age.

 



35

Safety and efficacy in paediatric patients below the age of 18 years have not been established.

Electrocardiogram evaluation
Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during 
administration of posaconazole oral suspension (400 mg twice daily with high fat meals) from 
173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the 
mean QTc (Fridericia) interval from baseline were observed.

5.2 Pharmacokinetic properties

Pharmacokinetic / Pharmacodynamic relationships
A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical 
outcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It is 
particularly important to try to ensure that maximal plasma levels are achieved in patients infected 
with Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens).

Absorption
Posaconazole tablets are absorbed with a median Tmax of 4 to 5 hours and exhibits dose proportional 
pharmacokinetics after single and multiple dosing up to 300 mg. 

Following a single dose administration of 300 mg posaconazole tablets after a high fat meal to healthy 
volunteers, the AUC0-72 hours and Cmax were higher compared to administration under fasted condition 
(51 % and 16 % for AUC0-72 hours and Cmax respectively).

Posaconazole plasma concentrations following administration of posaconazole tablets may increase 
over time in some patients. The reason for this time-dependency is not completely understood.

Distribution
Posaconazole, after administration of the tablet, has a mean apparent volume of distribution of 394 L 
(42 %), ranging between 294-583 L among the studies in healthy volunteers.

Posaconazole is highly protein bound (> 98 %), predominantly to serum albumin.

Biotransformation
Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to 
be altered by inhibitors of CYP450 enzymes. Of the circulating metabolites, the majority are 
glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) 
metabolites observed. The excreted metabolites in urine and faeces account for approximately 17 % 
of the administered radiolabelled dose.

Elimination
Posaconazole after administration of the tablets, is slowly eliminated with a mean half-life (t½) of 
29 hours (range 26 to 31 hours) and a mean apparent clearance ranging from 7.5 to 11 L/hr. After 
administration of 14C-posaconazole, radioactivity was predominantly recovered in the faeces (77 % of 
the radiolabelled dose) with the major component being parent compound (66 % of the radiolabelled 
dose). Renal clearance is a minor elimination pathway, with 14 % of the radiolabelled dose excreted 
in urine (< 0.2 % of the radiolabelled dose is parent compound). Steady-state plasma concentrations 
are attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1).

Pharmacokinetics in special populations
Children (< 18 years)
There is no paediatric experience with posaconazole tablets.
The pharmacokinetics of posaconazole oral suspension have been evaluated in paediatric patients. 
Following administration of 800 mg per day of posaconazole oral suspension as a divided dose for 
treatment of invasive fungal infections, mean trough plasma concentrations from 12 patients 8 -
17 years of age (776 ng/mL) were similar to concentrations from 194 patients 18 - 64 years of age 

 



36

(817 ng/mL). No pharmacokinetic data are available from paediatric patients less than 8 years of age. 
Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) 
was comparable among ten adolescents (13-17 years of age) to Cav achieved in adults (≥ 18 years of 
age).

Gender
The pharmacokinetics of posaconazole tablets are comparable in men and women.

Elderly
The pharmacokinetics of posaconazole tablets are comparable in young and elderly subjects. No 
overall differences in safety were observed between the geriatric patients and younger patients; 
therefore, no dosage adjustment is recommended for geriatric patients.

Race
There is insufficient data among different races with posaconazole tablets.

There was a slight decrease (16 %) in the AUC and Cmax of posaconazole oral suspension in Black 
subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the 
Black and Caucasian subjects was similar.

Weight
Pharmacokinetic modelling with an oral tablet formulation suggests that patients weighing greater 
than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for 
breakthrough fungal infections in patients weighing more than 120 kg.

Patients, in particular those receiving posaconazole after HSCT, who have a low body weight 
(< 60 kg) are more likely to experience higher plasma concentrations of posaconazole and should be 
closely monitored for adverse events.

Renal impairment
Following single-dose administration of posaconazole oral suspension, there was no effect of mild 
and moderate renal impairment (n=18, Cl cr ≥ 20 mL/min/1.73 m

2) on posaconazole pharmacokinetics; 
therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Cl cr
< 20 mL/min/1.73 m2), the AUC of posaconazole was highly variable [> 96 % CV (coefficient of 
variance)] compared to other renal groups [< 40 % CV]. However, as posaconazole is not 
significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of 
posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed 
by haemodialysis.

Similar recommendations apply to posaconazole tablets; however, a specific study has not been 
conducted with the posaconazole tablets.

Hepatic impairment
After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh 
Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six per 
group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with 
normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that 
there is a larger increase in unbound posaconazole exposure than the observed 60 % increase in total 
AUC. The elimination half-life (t1/2) was prolonged from approximately 27 hours up to ~43 hours in 
respective groups. No dose adjustment is recommended for patients with mild to severe hepatic 
impairment but caution is advised due to the potential for higher plasma exposure.

Similar recommendations apply to posaconazole tablets; however, a specific study has not been 
conducted with the posaconazole tablets.

 



37

5.3 Preclinical safety data

As observed with other azole antifungal agents, effects related to inhibition of steroid hormone 
synthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effects 
were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained 
at therapeutic doses in humans. 

Neuronal phospholipidosis occurred in dogs dosed for  3 months at lower systemic exposures than 
those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one 
year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observed 
on the central or peripheral nervous systems at systemic exposures greater than those achieved 
therapeutically.

Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the 
2-year study in rats. These findings are not necessarily indicative of a potential for functional changes 
in humans.

No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety 
pharmacology study in monkeys at maximal plasma concentrations 8.5-fold greater than the 
concentrations obtained at therapeutic doses in humans. Echocardiography revealed no indication of 
cardiac decompensation in a repeat dose safety pharmacology study in rats at a systemic exposure 
2.1-fold greater than that achieved therapeutically. Increased systolic and arterial blood pressures (up 
to 29 mm-Hg) were seen in rats and monkeys at systemic exposures 2.1-fold and 8.5-fold greater, 
respectively, than those achieved with the human therapeutic doses.

Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower 
than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and 
malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal 
viability. In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at 
therapeutic doses. As observed with other azole antifungal agents, these effects on reproduction were 
considered to be due to a treatment-related effect on steroidogenesis.

Posaconazole was not genotoxic in in vitro and in vivo studies. Carcinogenicity studies did not reveal 
special hazards for humans.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core
Hypromellose acetate succinate
Cellulose, microcrystalline
Hydroxypropylcellulose (E463)
Silica dental type
Croscarmellose sodium
Magnesium stearate

Tablet coat
polyvinyl alcohol
macrogol 3350
titanium dioxide (E171)
talc
iron oxide yellow (E172)

 



38

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Noxafil 100 mg gastro-resistant tablets are packaged in a PVC/ polychlorotrifluoroethylene laminate 
blister with push-through aluminium lidding.

Noxafil gastro-resistant tablets are packaged in a blister in cartons of 24 (2x12) or 96 (8x12) tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

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

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/05/320/002 24 tablets
EU/1/05/320/003 96 tablets

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2005
Date of latest renewal: 25 October 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.

 



39

1. NAME OF THE MEDICINAL PRODUCT

Noxafil 300 mg concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 300 mg of posaconazole.
Each mL contains 18 mg of posaconazole.

Excipient with known effect:
Each vial contains 462 mg (20 mmol) sodium.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion.
Clear, colourless to yellow liquid. 

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Noxafil concentrate for solution for infusion is indicated for use in the treatment of the following 
fungal infections in adults (see section 5.1):
- Invasive aspergillosis in patients with disease that is refractory to amphotericin B or 

itraconazole or in patients who are intolerant of these medicinal products;
- Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are 

intolerant of amphotericin B;
- Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole 

or in patients who are intolerant of itraconazole;
- Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole 

or fluconazole or in patients who are intolerant of these medicinal products.

Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days 
of prior therapeutic doses of effective antifungal therapy.

Noxafil concentrate for solution for infusion is also indicated for prophylaxis of invasive fungal 
infections in the following patients:

- Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) 
or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are 
at high risk of developing invasive fungal infections; 

- Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose 
immunosuppressive therapy for graft versus host disease (GVHD) and who are at high risk of 
developing invasive fungal infections.

Please refer to the Summary of Product Characteristics of Noxafil oral suspension for use in 
oropharyngeal candidiasis.

 



40

4.2 Posology and method of administration

Treatment should be initiated by a physician experienced in the management of fungal infections or in 
the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.

Posology
Noxafil is also available for oral administration (Noxafil 100 mg gastro-resistant tablets and 
40 mg/mL oral suspension). A switch to oral administration is recommended as soon as the patients’ 
condition allows (see section 4.4).

Recommended dose is shown in Table 1.

Table 1. Recommended dose according to indication
Indication Dose and duration of therapy

(See section 5.2)
Refractory invasive fungal 
infections (IFI)/patients with IFI 
intolerant to 1st line therapy

Loading dose of 300 mg Noxafil twice a day on the first day, then 
300 mg once a day thereafter. Duration of therapy should be based 
on the severity of the underlying disease, recovery from 
immunosuppression, and clinical response. 

Prophylaxis of invasive fungal 
infections

Loading dose of 300 mg Noxafil twice a day on the first day, then 
300 mg once a day thereafter. Duration of therapy is based on 
recovery from neutropenia or immunosuppression. For patients 
with AML or MDS, prophylaxis with Noxafil should start several 
days before the anticipated onset of neutropenia and continue for 
7 days after the neutrophil count rises above 500 cells per mm3.

Noxafil should be administered via a central venous line, including a central venous catheter or 
peripherally inserted central catheter (PICC) by slow intravenous infusion over approximately 
90 minutes. Noxafil concentrate for solution for infusion should not be given by bolus administration. 
If a central venous catheter is not available, a single infusion may be administered through a 
peripheral venous catheter. When administered through a peripheral venous catheter, the infusion 
should be administered over approximately 30 minutes (see section 4.8 and 6.6).

Special populations

Renal impairment
In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), 
accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to 
occur. Oral formulations of Noxafil should be used in these patients unless an assessment of the 
benefit/risk to the patient justifies the use of Noxafil concentrate for solution for infusion. Serum 
creatinine levels should be closely monitored in these patients (see section 4.4).

Hepatic impairment
Limited data on the effect of hepatic impairment (including Child-Pugh C classification of chronic 
liver disease) on the pharmacokinetics of posaconazole demonstrate an increase in plasma exposure 
compared to subjects with normal hepatic function, but do not suggest that dose adjustment is 
necessary (see sections 4.4 and 5.2). It is recommended to exercise caution due to the potential for 
higher plasma exposure.

Paediatric population
The safety and efficacy of Noxafil concentrate for solution for infusion in children aged below 
18 years have not been established.
No data are available.

 



41

Noxafil concentrate for solution for infusion should not be used in children aged below 18 years 
because of pre-clinical safety concerns (see section 5.3).

Method of administration
Noxafil concentrate for solution for infusion requires dilution (see section 6.6) prior to administration.  
Noxafil should be administered via a central venous line, including a central venous catheter or 
peripherally inserted central catheter (PICC) by slow intravenous (IV) infusion over approximately 
90 minutes (see sections 4.2, 4.4, and 4.8).
Noxafil concentrate for solution for infusion should not be given by bolus administration.

If a central venous catheter is not available, a single infusion may be administered through a 
peripheral venous catheter. When administered through a peripheral venous catheter, the infusion 
should be administered over approximately 30 minutes to reduce the likelihood of infusion site 
reactions (see section 4.8).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with ergot alkaloids (see section 4.5).

Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, 
halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal 
products, leading to QTc prolongation and rare occurrences of torsades de pointes (see sections 4.4 
and 4.5).

Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin 
(see section 4.5).

4.4 Special warnings and precautions for use

Hypersensitivity
There is no information regarding cross-sensitivity between posaconazole and other azole antifungal 
agents. Caution should be used when prescribing Noxafil to patients with hypersensitivity to other 
azoles.

Hepatic toxicity
Hepatic reactions (e.g. elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical 
hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were 
generally reversible on discontinuation of therapy and in some instances these tests normalised 
without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been 
reported. 

Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical 
experience and the possibility that posaconazole plasma levels may be higher in these patients (see 
sections 4.2 and 5.2).

Monitoring of patients with severe renal impairment
Due to the variability in exposure, patients with severe renal impairment should be monitored closely 
for breakthrough fungal infections (see sections 4.2 and 5.2).

Monitoring of hepatic function
Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. 
Patients who develop abnormal liver function tests during Noxafil therapy must be routinely 
monitored for the development of more severe hepatic injury. Patient management should include 
laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). 

 



42

Discontinuation of Noxafil should be considered if clinical signs and symptoms are consistent with 
development of liver disease.

QTc prolongation
Some azoles have been associated with prolongation of the QTc interval. Noxafil must not be 
administered with medicinal products that are substrates for CYP3A4 and are known to prolong the 
QTc interval (see sections 4.3 and 4.5). Noxafil should be administered with caution to patients with 
pro-arrhythmic conditions such as:
 Congenital or acquired QTc prolongation
 Cardiomyopathy, especially in the presence of cardiac failure
 Sinus bradycardia
 Existing symptomatic arrhythmias
 Concomitant use with medicinal products known to prolong the QTc interval (other than those 

mentioned in section 4.3).
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should 
be monitored and corrected as necessary before and during posaconazole therapy.
In patients, mean maximum plasma concentrations (Cmax) after posaconazole concentrate for solution 
for infusion are 4-fold increased compared to administration of oral suspension. An increased effect 
on the QTc interval cannot be ruled out. Particular caution is advised in such cases where 
posaconazole is administered peripherally, as the recommended infusion time of 30 minutes may 
further increase Cmax.

Drug Interactions
Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during 
treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5).

Midazolam and other benzodiazepines
Due to the risk of prolonged sedation and possible respiratory depression co-administration of 
posaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam, 
alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepines 
metabolised by CYP3A4 should be considered (see section 4.5).

Vincristine toxicity
Concomitant administration of azole antifungals, including posaconazole, with vincristine has been 
associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral 
neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve 
azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including 
vincristine, who have no alternative antifungal treatment options (see section 4.5).

Rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine, 
phenobarbital, primidone), and efavirenz
Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use 
with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see 
section 4.5).

Plasma exposure
Plasma concentrations following administration of posaconazole intravenous concentrate for solution 
for infusion are generally higher than those obtained with posaconazole oral suspension. 
Posaconazole plasma concentrations following administration of posaconazole may increase over time 
in some patients (see section 5.2). Safety data at higher exposure levels achieved with posaconazole 
concentrate for solution for infusion are at present limited.

Thromboembolic events
Thromboembolic events have been identified as a potential risk for posaconazole intravenous 
concentrate for solution for infusion but were not observed in the clinical studies. Thrombophlebitis 

 



43

was observed in clinical trials. Caution is warranted on any sign or symptom of thromboembolic 
events (see sections 4.8 and 5.3).

Sodium content
Each vial of Noxafil contains 462 mg (20 mmol) of sodium. This should be taken into consideration 
for patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

The following information was derived from data with posaconazole oral suspension or early tablet 
formulation. All drug interactions with posaconazole oral suspension, except for those that affect the 
absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole 
concentrate for solution for infusion as well.

Effects of other medicinal products on posaconazole
Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for 
p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, 
clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, 
etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, 
respectively.

Rifabutin
Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area
under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. 
Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be 
avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of 
posaconazole on rifabutin plasma levels. 

Efavirenz
Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, 
respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to 
the patient outweighs the risk. 

Fosamprenavir
Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma 
concentrations. If concomitant administration is required, close monitoring for breakthrough fungal 
infections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x 
10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 
1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days) by 21 % and 23 %, 
respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with 
ritonavir is unknown.

Phenytoin
Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 % and 50 %, 
respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. 
carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient 
outweighs the risk.

Effects of posaconazole on other medicinal products
Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4 
substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the 
effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co-
administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of 
the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 
substrates that are administered orally, and for which an increase in plasma concentrations may be 

 



44

associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate 
and/or adverse reactions should be closely monitored and the dose adjusted as needed. 

Terfenadine, astemizole, cisapride, pimozide, halofantrine and quinidine (CYP3A4 substrates)
Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine or 
quinidine is contraindicated. Co-administration may result in increased plasma concentrations of these 
medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see 
section 4.3).

Ergot alkaloids
Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and 
dihydroergotamine), which may lead to ergotism. Co-administration of posaconazole and ergot 
alkaloids is contraindicated (see section 4.3).

HMG-CoA reductase inhibitors metabolised through CYP3A4 (e.g. simvastatin, lovastatin, and 
atorvastatin)
Posaconazole may substantially increase plasma levels of HMG-CoA reductase inhibitors that are 
metabolised by CYP3A4. Treatment with these HMG-CoA reductase inhibitors should be 
discontinued during treatment with posaconazole as increased levels have been associated with 
rhabdomyolysis (see section 4.3).

Vinca alkaloids
Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant 
administration of azole antifungals, including posaconazole, with vincristine has been associated with 
serious adverse reactions (see section 4.4). Posaconazole may increase the plasma concentrations of 
vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, 
reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including 
vincristine, who have no alternative antifungal treatment options.

Rifabutin
After oral administration, posaconazole increased the Cmax and AUC of rifabutin by 31 % and 72 %, 
respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to 
the patient outweighs the risk (see also above regarding the effect of rifabutin on plasma levels of 
posaconazole). If these medicinal products are co-administered, careful monitoring of full blood 
counts and adverse reactions related to increased rifabutin levels (e.g. uveitis) is recommended.

Sirolimus
Repeat dose administration of oral posaconazole oral suspension (400 mg twice daily for 16 days) 
increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range 
3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patients 
is unknown, but is expected to be variable due to the variable posaconazole exposure in patients. Co-
administration of posaconazole with sirolimus is not recommended and should be avoided whenever 
possible. If it is considered that co-administration is unavoidable, then it is recommended that the 
dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapy and that 
there should be very frequent monitoring of trough concentrations of sirolimus in whole blood. 
Sirolimus concentrations should be measured upon initiation, during co-administration, and at 
discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should be 
noted that the relationship between sirolimus trough concentration and AUC is changed during co-
administration with posaconazole. As a result, sirolimus trough concentrations that fall within the
usual therapeutic range may result in sub-therapeutic levels. Therefore trough concentrations that fall 
in the upper part of the usual therapeutic range should be targeted and careful attention should be paid 
to clinical signs and symptoms, laboratory parameters and tissue biopsies. 

Ciclosporin
In heart transplant patients on stable doses of ciclosporin, posaconazole oral suspension 200 mg once 
daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin 

 



45

levels resulting in serious adverse reactions, including nephrotoxicity and one fatal case of 
leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with 
posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g. 
to about three quarters of the current dose). Thereafter blood levels of ciclosporin should be 
monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, 
and the dose of ciclosporin should be adjusted as necessary.

Tacrolimus
Posaconazole increased Cmax and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121 % 
and 358 %, respectively. Clinically significant interactions resulting in hospitalisation and/or 
posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole 
treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to 
about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored 
carefully during co-administration, and upon discontinuation of posaconazole, and the dose of 
tacrolimus should be adjusted as necessary.

HIV Protease inhibitors
As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase 
plasma levels of these antiretroviral agents. Following co-administration of posaconazole oral 
suspension (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects 
Cmax and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), 
respectively. Following co-administration of posaconazole oral suspension (400 mg twice daily) with 
atazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects Cmax and AUC of 
atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. The 
addition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associated 
with increases in plasma bilirubin levels. Frequent monitoring for adverse reactions and toxicity 
related to antiretroviral agents that are substrates of CYP3A4 is recommended during co-
administration with posaconazole.

Midazolam and other benzodiazepines metabolised by CYP3A4
In a study in healthy volunteers posaconazole oral suspension (200 mg once daily for 10 days) 
increased the exposure (AUC) of intravenous midazolam (0.05 mg/kg) by 83 %. In another study in 
healthy volunteers, repeat dose administration of posaconazole oral suspension (200 mg twice daily 
for 7 days) increased the Cmax and AUC of intravenous midazolam (0.4 mg single dose) by an average 
of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole oral suspension 400 mg twice 
daily for 7 days increased the intravenous midazolam Cmax and AUC by 1.6 and 6.2-fold (range 1.6 to 
7.6-fold), respectively. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg 
single oral dose) by 2.2 and 4.5-fold, respectively. In addition, posaconazole oral suspension (200 mg 
or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 8-
10 hours during co-administration.
Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered 
when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by 
CYP3A4 (e.g. midazolam, triazolam, alprazolam) (see section 4.4).

Calcium channel blockers metabolised through CYP3A4 (e.g. diltiazem, verapamil, nifedipine, 
nisoldipine)
Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is 
recommended during co-administration with posaconazole. Dose adjustment of calcium channel 
blockers may be required.

Digoxin
Administration of other azoles has been associated with increases in digoxin levels. Therefore, 
posaconazole may increase plasma concentration of digoxin and digoxin levels need to be monitored 
when initiating or discontinuing posaconazole treatment.

 



46

Sulfonylureas
Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered 
with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.

Paediatric population
Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy
There is insufficient information on the use of posaconazole in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Women of childbearing potential have to use effective contraception during treatment. Posaconazole 
must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential 
risk to the foetus.

Breast-feeding
Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of 
posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on 
initiation of treatment with posaconazole.

Fertility
Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (2.8 times the exposure 
achieved from a 300 mg intravenous dose in human) or female rats at a dose up to 45 mg/kg (3.4 times
the exposure from a 300 mg intravenous dose in patients). There is no clinical experience assessing 
the impact of posaconazole on fertility in humans.

4.7 Effects on ability to drive and use machines

Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with 
posaconazole use, which potentially may affect driving/operating machinery, caution needs to be 
used.

4.8 Undesirable effects

Safety data mainly derive from studies with the oral suspension.

Noxafil concentrate for solution for infusion was investigated in AML and MDS patients and those 
after HSCT with or at risk for GVHD only. Maximum duration of exposure to the concentrate for 
solution for infusion was shorter than with the oral suspension. Plasma exposure resulting from the 
solution for infusion was higher than observed with the oral suspension. A higher incidence of 
adverse reactions cannot be ruled out.

Summary of the safety profile

Posaconazole concentrate for solution for infusion safety
In initial studies of healthy volunteers, administration of a single dose of posaconazole infused over 
30 minutes via a peripheral venous catheter was associated with a 12 % incidence of infusion site 
reactions (4 % incidence of thrombophlebitis). Multiple doses of posaconazole administered via a 
peripheral venous catheter were associated with thrombophlebitis (60 % incidence). Therefore, in 
subsequent studies posaconazole was administered via central venous catheter. If a central venous 
catheter was not readily available, patients could receive a single infusion over 30 minutes via a 
peripheral venous catheter. Peripheral infusion time longer than 30 minutes, leads to a higher 
incidence of infusion site reactions and thrombophlebitis.

 



47

The safety of posaconazole concentrate for solution for infusion has been assessed in 268 patients in 
clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of 
posaconazole concentrate for solution for infusion when given as antifungal prophylaxis 
(Study 5520). Eleven patients received a single dose of 200 mg posaconazole concentrate for solution 
for infusion, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients 
received 300 mg daily dose for a median of 9 days. No safety data are available for administration 
> 28 days. Safety data in the elderly are limited.

The most frequently reported adverse reaction (>25 %) with an onset during the posaconazole 
intravenous phase of dosing with 300 mg once daily was diarrhoea (32 %).

The most common adverse reaction (>1 %) leading to discontinuation of posaconazole concentrate for 
solution for infusion 300 mg once daily was AML (1 %). 

Tabulated list of adverse reactions
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); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from 
the available data).

Table 2. Adverse reactions by body system and frequency reported in clinical trials and/or post-
marketing use*

Blood and lymphatic system 
disorders

Common: neutropenia

Uncommon: thrombocytopenia, leukopenia, anaemia, eosinophilia, 
lymphadenopathy, splenic infarction

Rare: haemolytic uraemic syndrome, thrombotic thrombocytopenic 
purpura, pancytopenia, coagulopathy, haemorrhage

Immune system disorders
Uncommon: allergic reaction

Rare: hypersensitivity reaction 

Endocrine disorders
Rare:
Not known:

adrenal insufficiency, blood gonadotropin decreased
pseudoaldosteronism

Metabolism and nutrition disorders
Common: electrolyte imbalance, anorexia, decreased appetite, 

hypokalaemia, hypomagnesaemia
Uncommon: Hyperglycaemia, hypoglycaemia

Psychiatric disorders
Uncommon:
Rare:

abnormal dreams, confusional state, sleep disorder
psychotic disorder, depression

Nervous system disorders
Common: paresthesia, dizziness, somnolence, headache, dysgeusia

Uncommon: convulsions, neuropathy, hypoaesthesia, tremor, aphasia, 
insomnia

Rare: cerebrovascular accident, encephalopathy, peripheral 
neuropathy, syncope

Eye disorders
Uncommon: blurred vision, photophobia, visual acuity reduced 
Rare: diplopia, scotoma

Ear and labyrinth disorder
Rare: hearing impairment

 



48

Cardiac disorders
Uncommon: long QT syndrome§, electrocardiogram abnormal§, 

palpitations, bradycardia, supraventricular extrasystoles, 
tachycardia

Rare: torsade de pointes, sudden death, ventricular tachycardia, 
cardio-respiratory arrest, cardiac failure, myocardial infarction

Vascular disorders
Common:
Uncommon:

hypertension
hypotension, thrombophlebitis, vasculitis

Rare: pulmonary embolism, deep vein thrombosis

Respiratory, thoracic and 
mediastinal disorders
Uncommon:

Rare:

cough, epistaxis, hiccups, nasal congestion, pleuritic pain, 
tachypnoea
pulmonary hypertension, interstitial pneumonia, pneumonitis

Gastrointestinal disorders
Very Common
Common:

nausea
vomiting, abdominal pain, diarrhoea, dyspepsia, dry mouth, 
flatulence, constipation, anorectal discomfort 

Uncommon: pancreatitis, abdominal distension, enteritis, epigastric 
discomfort, eructation, gastrooesophageal reflux disease, 
oedema mouth

Rare: gastrointestinal haemorrhage, ileus 

Hepatobiliary disorders
Common: liver function tests raised (ALT increased, AST increased, 

bilirubin increased, alkaline phosphatase increased, GGT 
increased)

Uncommon: hepatocellular damage, hepatitis, jaundice, hepatomegaly, 
cholestasis, hepatic toxicity, hepatic function abnormal 

Rare: hepatic failure, hepatitis cholestatic, hepatosplenomegaly, 
liver tenderness, asterixis 

Skin and subcutaneous tissue 
disorders
Common: rash, pruritis
Uncommon: mouth ulceration, alopecia, dermatitis, erythema, petechiae
Rare: Stevens Johnson syndrome, vesicular rash

Musculoskeletal and connective 
tissue disorders
Uncommon: back pain, neck pain, musculoskeletal pain, pain in extremity

Renal and urinary disorders 
Uncommon: acute renal failure, renal failure, blood creatinine increased 
Rare: renal tubular acidosis, interstitial nephritis 

Reproductive system and breast 
disorders
Uncommon: menstrual disorder
Rare: breast pain

General disorders and 
administration site conditions
Common: pyrexia (fever), asthenia, fatigue
Uncommon: oedema, pain, chills, malaise, chest discomfort, drug 

intolerance, feeling jittery, infusion site pain, infusion site 
phlebitis, infusion site thrombosis, mucosal inflammation

Rare: tongue oedema, face oedema

 



49

Investigations
Uncommon: altered medicine levels, blood phosphorus decreased, chest x-

ray abnormal 
* Based on adverse reactions observed with the oral suspension, gastro-resistant tablets, and concentrate for solution for 

infusion.
§ See section 4.4.

Description of selected adverse reactions
Hepatobiliary disorders
During post-marketing surveillance severe hepatic injury with fatal outcome has been reported (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

There is no experience with overdose of posaconazole concentrate for solution for infusion.

During clinical trials, patients who received posaconazole oral suspension doses up to 1,600 mg/day 
experienced no different adverse reactions from those reported with patients at the lower doses. 
Accidental overdose was noted in one patient who took posaconazole oral suspension 1,200 mg twice 
a day for 3 days. No adverse reactions were noted by the investigator.

Posaconazole is not removed by haemodialysis. There is no special treatment available in the case of 
overdose with posaconazole. Supportive care may be considered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02A 
C04.

Mechanism of action
Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential 
step in ergosterol biosynthesis.

Microbiology
Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus
species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species 
(Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, 
C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea 
pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological data 
suggest that posaconazole is active against Rhizomucor, Mucor, and Rhizopus; however the clinical 
data are currently too limited to assess the efficacy of posaconazole against these causative agents.

Resistance
Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle 
mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


50

Epidemiological Cut-off (ECOFF) values for Aspergillus spp.
The ECOFF values for posaconazole, which distinguish the wild type population from isolates with 
acquired resistance, have been determined by EUCAST methodology.

EUCAST ECOFF values:
 Aspergillus flavus: 0.5 mg/L
 Aspergillus fumigatus: 0.25 mg/L
 Aspergillus nidulans: 0.5 mg/L
 Aspergillus niger: 0.5 mg/L
 Aspergillus terreus: 0.25 mg/L

There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do 
not equate to clinical breakpoints.

Breakpoints
EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:
 Candida albicans: S ≤0.06 mg/L, R >0.06 mg/L
 Candida tropicalis: S ≤0.06 mg/L, R >0.06 mg/L
 Candida parapsilosis: S ≤0.06 mg/L, R >0.06 mg/L

There are currently insufficient data to set clinical breakpoints for other Candida species.

Combination with other antifungal agents
The use of combination antifungal therapies should not decrease the efficacy of either posaconazole 
or the other therapies; however, there is currently no clinical evidence that combination therapy will 
provide an added benefit.

Clinical experience

Summary of posaconazole concentrate for solution for infusion bridging study
Study 5520 was a non-comparative multi-center study performed to evaluate the pharmacokinetic 
properties, safety, and tolerability of posaconazole concentrate for solution for infusion. 

Study 5520 enrolled a total of 279 subjects, including 268 receiving at least one dose of posaconazole 
concentrate for solution for infusion. Cohort 0 was designed to evaluate the tolerability of a single 
dose of posaconazole concentrate for solution for infusion when administered via a central line. 
The subject population for Cohorts 1 and 2 included subjects with AML or MDS who had recently 
received chemotherapy and had developed or were anticipated to develop significant neutropenia. 
Two different dosing groups were evaluated in Cohorts 1 and 2: 200 mg twice daily on Day 1, 
followed by 200 mg once daily thereafter (Cohort 1) and 300 mg twice daily on Day 1, followed by 
300 mg once daily thereafter (Cohort 2).

The subject population in Cohort 3 included: 1) patients with AML or MDS who had recently 
received chemotherapy and had developed or were anticipated to develop significant neutropenia, or 
2) patients who had undergone a HSCT and were receiving immunosuppressive therapy for 
prevention or treatment of GVHD. These types of patients had been previously studied in a pivotal 
controlled trial of posaconazole oral suspension. Based on the pharmacokinetics and safety results of 
Cohorts 1 and 2, all subjects in Cohort 3 received 300 mg twice daily on Day 1, followed by 300 mg 
once daily thereafter.

The total subject population had a mean age of 51 years (range = 18-82 years), 95 % were White, the 
major ethnicity was not Hispanic or Latino (92 %), and 55 % were male. The study treated 155 
(65 %) subjects with AML or MDS, and 82 (35 %) subjects with HSCT, as the primary diseases at 
study entry.

 



51

Serial pharmacokinetic samples were collected on Day 1 and at steady-state on Day 14 for all Cohort 
1 and 2 subjects and on Day 10 for a subset of Cohort 3 subjects. This serial pharmacokinetic analysis 
demonstrated that 94 % of the subjects treated with the 300 mg once daily dose attained steady state 
Cav between 500-2500 ng/mL [Cav was the average concentration of posaconazole at steady state, 
calculated as AUC/dosing interval (24 hours).]. This exposure was selected based on 
pharmacokinetic/pharmacodymanic considerations with posaconazole oral suspension. Subjects who 
received 300 mg once daily achieved a mean Cav at steady state of 1500 ng/mL.

Summary of posaconazole oral suspension studies

Invasive aspergillosis
Oral posaconazole suspension 800 mg/day in divided doses was evaluated for the treatment of 
invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal 
formulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-
comparative salvage therapy trial. Clinical outcomes were compared with those in an external control 
group derived from a retrospective review of medical records. The external control group included 
86 patients treated with available therapy (as above) mostly at the same time and at the same sites as 
the patients treated with posaconazole. Most of the cases of aspergillosis were considered to be 
refractory to prior therapy in both the posaconazole group (88 %) and in the external control group 
(79 %).

As shown in Table 3, a successful response (complete or partial resolution) at the end of treatment 
was seen in 42 % of posaconazole-treated patients compared to 26 % of the external group. However, 
this was not a prospective, randomised controlled study and so all comparisons with the external 
control group should be viewed with caution.

Table 3. Overall efficacy of posaconazole oral suspension at the end of treatment for invasive 
aspergillosis in comparison to an external control group

Posaconazole oral 
suspension

External control group

Overall Response 45/107 (42 %) 22/86 (26 %)
Success by Species

All mycologically confirmed
Aspergillus spp.3 34/76 (45 %) 19/74 (26 %)
A. fumigatus 12/29 (41 %) 12/34 (35 %)
A. flavus 10/19 (53 %) 3/16 (19 %)
A. terreus 4/14 (29 %) 2/13 (15 %)
A. niger 3/5 (60 %) 2/7 (29 %)

Fusarium spp.
11 of 24 patients who had proven or probable fusariosis were successfully treated with posaconazole 
oral suspension 800 mg/day in divided doses for a median of 124 days and up to 212 days. Among 
eighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole, 
seven patients were classed as responders.

Chromoblastomycosis/Mycetoma
9 of 11 patients were successfully treated with posaconazole oral suspension 800 mg/day in divided 
doses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosis 
due to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.

Coccidioidomycosis
11 of 16 patients were successfully treated (at the end of treatment complete or partial resolution of 
signs and symptoms present at baseline) with posaconazole oral suspension 800 mg/day in divided 
doses for a median of 296 days and up to 460 days.

                                                     
3 Includes other less common species or species unknown

 



52

Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899)
Two randomised, controlled prophylaxis studies were conducted among patients at high risk for 
developing invasive fungal infections.

Study 316 was a randomised, double-blind trial of posaconazole oral suspension (200 mg three times 
a day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell 
transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the 
incidence of proven/probable IFIs at 16 weeks post-randomisation as determined by an independent, 
blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs 
during the on-treatment period (first dose to last dose of study medicinal product + 7 days). The 
majority (377/600, [63 %]) of patients included had Acute Grade 2 or 3 or chronic extensive 
(195/600, [32.5 %]) GVHD at study start. The mean duration of therapy was 80 days for posaconazole 
and 77 days for fluconazole.

Study 1899 was a randomised, evaluator-blinded study of posaconazole oral suspension (200 mg three 
times a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg 
twice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acute 
myelogenous leukaemia or myelodysplastic syndromes. The primary efficacy endpoint was the
incidence of proven/probable IFIs as determined by an independent, blinded external expert panel 
during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs 
at 100 days post-randomisation. New diagnosis of acute myelogenous leukaemia was the most 
common underlying condition (435/602, [72 %]). The mean duration of therapy was 29 days for 
posaconazole and 25 days for fluconazole/itraconazole.

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 4
and 5 for results from both studies. There were fewer breakthrough Aspergillus infections in patients 
receiving posaconazole prophylaxis when compared to control patients.

Table 4. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study Posaconazole oral 
suspension

Controla P-Value

Proportion (%) of patients with proven/probable IFIs

On-treatment periodb

1899d 7/304 (2) 25/298 (8) 0.0009

316e 7/291 (2) 22/288 (8) 0.0038

Fixed-time periodc

1899d 14/304 (5) 33/298 (11) 0.0031

316 d 16/301 (5) 27/299 (9) 0.0740

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the 

period from first dose to last dose of study medicinal product plus 7 days.
c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the 

baseline day to 111 days post-baseline.
d: All randomised 
e: All treated 

 



53

Table 5. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study Posaconazole oral suspension Controla

Proportion (%) of patients with proven/probable Aspergillosis

On-treatment periodb

1899d 2/304 (1) 20/298 (7)

316e 3/291 (1) 17/288 (6)

Fixed-time periodc

1899d 4/304 (1) 26/298 (9)

316 d 7/301 (2) 21/299 (7)
FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the 

period from first dose to last dose of study medicinal product plus 7 days.
c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the 

baseline day to 111 days post-baseline.
d: All randomised 
e: All treated 

In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed 
[POS 49/304 (16 %) vs. FLU/ITZ 67/298 (22 %) p= 0.048]. Based on Kaplan-Meier estimates, the 
probability of survival up to day 100 after randomisation, was significantly higher for posaconazole 
recipients; this survival benefit was demonstrated when the analysis considered all causes of death 
(P= 0.0354) as well as IFI-related deaths (P = 0.0209).

In Study 316, overall mortality was similar (POS, 25 %; FLU, 28 %); however, the proportion of IFI-
related deaths was significantly lower in the POS group (4/301) compared with the FLU 
group (12/299; P= 0.0413).

Paediatric population
There is no paediatric experience for posaconazole concentrate for solution for infusion.

Sixteen patients 8-17 years of age were treated with posaconazole oral suspension 800 mg/day in a 
study for invasive fungal infections. Based on the available data in 16 of these paediatric patients, the 
safety profile appears to be similar to patients ≥ 18 years of age.

Additionally, twelve patients 13-17 years of age received posaconazole oral suspension 600 mg/day 
for prophylaxis of invasive fungal infections (Studies 316 and 1899). The safety profile in these 
patients < 18 years of age appears similar to the safety profile observed in adults. Based on 
pharmacokinetic data in 10 of these paediatric patients, the pharmacokinetic profile appears to be 
similar to patients ≥ 18 years of age.

Safety and efficacy in paediatric patients below the age of 18 years have not been established.

Electrocardiogram evaluation
Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during 
administration of posaconazole oral suspension (400 mg twice daily with high fat meals) from 
173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the 
mean QTc (Fridericia) interval from baseline were observed.

5.2 Pharmacokinetic properties

Pharmacokinetic / Pharmacodynamic relationships
A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical 
outcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It is 

 



54

particularly important to try to ensure that maximal plasma levels are achieved in patients infected 
with Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens).

Distribution
Following administration of 300 mg posaconazole concentrate for solution for infusion over 
90 minutes, mean peak plasma concentration at the end of infusion was 3280 ng/mL (74 % CV). 
Posaconazole exhibits dose proportional pharmacokinetics after single and multiple dosing in the 
therapeutic dose range (200-300 mg). Posaconazole has a distribution volume of 261 L, indicating 
extravascular distribution.

Posaconazole is highly protein bound (> 98 %), predominantly to serum albumin.

Biotransformation
Posaconazole does not have any major circulating metabolites. Of the circulating metabolites, the 
majority are glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450 
mediated) metabolites observed. The excreted metabolites in urine and faeces account for 
approximately 17 % of the administered radiolabelled dose of posaconazole oral suspension.

Elimination
Posaconazole, after administration of 300 mg of posaconazole concentrate for solution for infusion, is 
slowly eliminated with a mean half-life (t½) of 27 hours and a mean clearance of 7.3 L/hr. After 
administration of 14C-posaconazole as oral suspension, radioactivity was predominantly recovered in 
the faeces (77 % of the radiolabelled dose) with the major component being parent compound (66 % 
of the radiolabelled dose). Renal clearance is a minor elimination pathway, with 14 % of the 
radiolabelled dose excreted in urine (< 0.2 % of the radiolabelled dose is parent compound). Steady-
state plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice daily 
loading dose at Day 1).

Posaconazole plasma concentrations following administration of posaconazole concentrate for 
solution for infusion single dose increased in a greater than dose proportional manner over the range 
of 50-200 mg; by comparison, dose-dependent increases were observed over a range of 200-300 mg.

Pharmacokinetics in special populations
Children (< 18 years)
There is no paediatric experience with posaconazole concentrate for solution for infusion (see 
sections 4.2 and 5.3).

Gender
The pharmacokinetics of posaconazole concentration for solution for infusion are comparable in men 
and women.

Elderly
The pharmacokinetics of posaconazole concentrate for solution for infusion are comparable in young 
and elderly subjects. No overall differences in safety were observed between the geriatric patients and 
younger patients; therefore, no dosage adjustment is recommended for geriatric patients.

Race
There is insufficient data among different races with posaconazole concentrate for solution for 
infusion.

There was a slight decrease (16 %) in the AUC and Cmax of posaconazole oral suspension in Black 
subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the 
Black and Caucasian subjects was similar.

 



55

Weight
Pharmacokinetic modelling with an oral tablet formulation suggests that patients weighing greater 
than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for 
breakthrough fungal infections in patients weighing more than 120 kg. Patients with a low body 
weight (< 60 kg) are more likely to experience higher plasma concentrations of posaconazole and 
should be closely monitored for adverse events.

Renal impairment 
Following single-dose administration of posaconazole oral suspension, there was no effect of mild 
and moderate renal impairment (n=18, Cl cr ≥ 20 mL/min/1.73 m

2) on posaconazole pharmacokinetics; 
therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Cl cr
< 20 mL/min/1.73 m2), the AUC of posaconazole was highly variable [> 96 % CV (coefficient of 
variance)] compared to other renal groups [< 40 % CV]. However, as posaconazole is not 
significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of 
posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed 
by haemodialysis. Due to the variability in exposure, patients with severe renal impairment should be 
monitored closely for breakthrough fungal infections (see section 4.2).

Similar recommendations apply to posaconazole concentrate for solution for infusion; however, a 
specific study has not been conducted with posaconazole concentrate for solution for infusion.

Hepatic impairment
After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh 
Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six per 
group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with 
normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that 
there is a larger increase in unbound posaconazole exposure than the observed 60 % increase in total 
AUC. The elimination half-life (t1/2) was prolonged from approximately 27 hours up to ~43 hours in 
respective groups. No dose adjustment is recommended for patients with mild to severe hepatic 
impairment but caution is advised due to the potential for higher plasma exposure.

Similar recommendations apply to posaconazole concentrate for solution for infusion; however, a 
specific study has not been conducted with posaconazole concentrate for solution for infusion.

5.3 Preclinical safety data

As observed with other azole antifungal agents, effects related to inhibition of steroid hormone 
synthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effects 
were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained 
at therapeutic doses in humans. 

Neuronal phospholipidosis occurred in dogs dosed for  3 months at lower systemic exposures than 
those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one 
year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observed 
on the central or peripheral nervous systems at systemic exposures greater than those achieved 
therapeutically.

Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the 
2-year study in rats. These findings are not necessarily indicative of a potential for functional changes 
in humans.

No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety 
pharmacology study in monkeys at maximal plasma concentrations 8.9-fold greater than the 
concentrations obtained at therapeutic doses in humans with 300 mg intravenous infusion 
administration. Echocardiography revealed no indication of cardiac decompensation in a repeat dose 
safety pharmacology study in rats at a systemic exposure 2.2-fold greater than that achieved 

 



56

therapeutically. Increased systolic and arterial blood pressures (up to 29 mm-Hg) were seen in rats 
and monkeys at systemic exposures 2.2-fold and 8.9-fold greater, respectively, than those achieved 
with the human therapeutic doses.

A non-dose related incidence of thrombus/emboli in the lung was seen in the 1 month repeated dose 
study in the monkey. The clinical significance of this finding is unknown.

Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower 
than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and 
malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal 
viability. In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at 
therapeutic doses. As observed with other azole antifungal agents, these effects on reproduction were 
considered to be due to a treatment-related effect on steroidogenesis.

Posaconazole was not genotoxic in in vitro and in vivo studies. Carcinogenicity studies did not reveal 
special hazards for humans.

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed 
from 2-8 weeks of age) an increase in the incidence of brain ventricle enlargement was observed in 
treated animals as compared with concurrent control animals. No difference in the incidence of brain 
ventricle enlargement between control and treated animals was observed following the subsequent 
5-month treatment-free period. There were no neurologic, behavioural or developmental abnormalities 
in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole 
administration to juvenile dogs (4 days to 9 months of age). The clinical significance of this finding is 
unknown; therefore, the use of posaconazole concentrate for solution for infusion to patients under 
18 years of age is not recommended (see section 4.2).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Betadex Sulfobutyl Ether Sodium (SBECD)
Disodium edetate 
Hydrochloric acid [for pH adjustment]
Sodium hydroxide [for pH adjustment]
Water for injections

6.2 Incompatibilities

Noxafil must not be diluted with:
Lactated Ringer’s solution
5 % dextrose with Lactated Ringer’s solution
4.2 % sodium bicarbonate

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

6.3 Shelf life

3 years

From a microbiological point of view, once admixed, the product should be used immediately. If not 
used immediately, the solution can be stored up to 24 hours refrigerated 2°C-8°C. This medicinal 
product is for single use only.

 



57

6.4 Special precautions for storage

Store in a refrigerator at 2°C-8°C. 

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I glass vial closed with bromobutyl rubber stopper and aluminium seal containing 16.7 mL of 
solution.
Pack size: 1 vial

6.6 Special precautions for disposal and other handling

Administration instructions for Noxafil concentrate for solution for infusion

 Equilibrate the refrigerated vial of Noxafil to room temperature.
 Aseptically transfer 16.7 mL of posaconazole to an intravenous bag (or bottle) containing a 

compatible admixture diluent (see below for list of diluents) using the volume ranging from 
150 mL to 283 mL depending on the final concentration to be achieved (not less than 1 mg/mL 
and not greater than 2 mg/mL).

 Administer via a central venous line, including a central venous catheter or peripherally 
inserted central catheter (PICC) by slow intravenous infusion over approximately 90 minutes.
Noxafil concentrate for solution for infusion should not be given by bolus administration.

 If a central venous catheter is not available, a single infusion may be administered through a 
peripheral venous catheter with a volume to achieve a dilution of approximately 2 mg/mL. 
When administered through a peripheral venous catheter, the infusion should be administered 
over approximately 30 minutes.
Note: In clinical trials, multiple peripheral infusions given through the same vein resulted 
in infusion site reactions (see section 4.8).

 Noxafil is for single use.

The following medicinal products can be infused at the same time through the same intravenous line 
(or cannula) as Noxafil concentrate for solution for infusion:

Amikacin sulfate
Caspofungin
Ciprofloxacin
Daptomycin
Dobutamine hydrochloride
Famotidine
Filgrastim
Gentamicin sulfate
Hydromorphone hydrochloride
Levofloxacin
Lorazepam
Meropenem
Micafungin
Morphine sulphate
Norepinephrine bitartrate
Potassium chloride
Vancomycin hydrochloride

Any products not listed in the table above should not be coadministered with Noxafil through the 
same intravenous line (or cannula).

 



58

Noxafil concentrate for solution for infusion should be inspected visually for particulate matter prior 
to administration. The solution of Noxafil ranges from colourless to pale yellow. Variations of colour 
within this range do not affect the quality of the product.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

Noxafil must not be diluted with:
Lactated Ringer’s solution
5 % dextrose with Lactated Ringer’s solution
4.2 % sodium bicarbonate

This medicinal product must not be mixed with other medicinal products except those mentioned 
below:

5 % dextrose in water
0.9 % sodium chloride
0.45 % sodium chloride
5 % dextrose and 0.45 % sodium chloride
5 % dextrose and 0.9 % sodium chloride
5 % dextrose and 20 mEq KCl

7. MARKETING AUTHORISATION HOLDER

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

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/320/004 1 vial

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2005
Date of latest renewal: 25 October 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.

 



59

ANNEX II

A. MANUFACTURERS 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

 



60

A MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Cenexi HSC, 2, rue Louis Pasteur; 14200 Hérouville St Clair, France

Schering-Plough Labo N.V., Industriepark 30, Zone A, BE-2220 Heist-op-den-Berg, Belgium

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

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 (PSURs)

The requirements for submission of PSURs 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 marketing authorisation holder (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.

 



61

ANNEX III

LABELLING AND PACKAGE LEAFLET

 



62

A. LABELLING

 



63

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Noxafil 40 mg/mL oral suspension
posaconazole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each mL of oral suspension contains 40 mg of posaconazole.

3. LIST OF EXCIPIENTS

Contains also liquid glucose.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

One bottle of 105 mL of oral suspension.
Measuring spoon

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Shake well before use.
Read the package leaflet before use.
Oral 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

Noxafil oral suspension and tablets are NOT interchangeable.

8. EXPIRY DATE

EXP 
Any product remaining four weeks after opening the bottle should be discarded.

 



64

9. SPECIAL STORAGE CONDITIONS

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Any unused product or waste material should be disposed of in accordance with local requirements.

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/1/05/320/001 

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Noxafil

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN

 



65

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

BOTTLE LABEL

1. NAME OF THE MEDICINAL PRODUCT

Noxafil 40 mg/mL oral suspension
posaconazole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each ml of oral suspension contains 40 mg of posaconazole.

3. LIST OF EXCIPIENTS

Contains also liquid glucose.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

105 mL
oral suspension

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Shake well before use.
Read the package leaflet before use.
Oral 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 
Any product remaining four weeks after opening the bottle should be discarded.

 



66

9. SPECIAL STORAGE CONDITIONS

Do not freeze.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

Any unused product or waste material should be disposed of in accordance with local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/05/320/001 

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

 



67

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Noxafil 100 mg gastro-resistant tablets
posaconazole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each gastro-resistant tablet contains 100 mg of posaconazole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

24 gastro-resistant tablets
96 gastro-resistant tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral 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

Noxafil oral suspension and tablets are NOT interchangeable.

8. EXPIRY DATE

EXP 

9. SPECIAL STORAGE CONDITIONS

 



68

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/1/05/320/002 24 tablets
EU/1/05/320/003 96 tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

noxafil tablets

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN

 



69

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Noxafil 100 mg gastro-resistant tablets
posaconazole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

MSD

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

 



70

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Noxafil 300 mg concentrate for solution for infusion 
posaconazole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 300 mg of posaconazole.
Each mL contains 18 mg of posaconazole.

3. LIST OF EXCIPIENTS

Excipients: Betadex Sulfobutyl Ether Sodium (SBECD), disodium edetate, hydrochloric acid and 
sodium hydroxide (for pH adjustment), water for injections.
Contains sodium. See package leaflet for information.

4. PHARMACEUTICAL FORM AND CONTENTS

Concentrate for solution for infusion
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Intravenous use after dilution.
Single use vial.

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

 



71

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.

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/1/05/320/004 1 vial

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN

 



72

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Noxafil 300 mg sterile concentrate
posaconazole
Intravenous use after dilution

2. METHOD OF ADMINISTRATION

See leaflet

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6. OTHER

 



73

B. PACKAGE LEAFLET

 



74

Package leaflet: Information for the user

Noxafil 40 mg/mL oral suspension
posaconazole

Read all of this leaflet carefully before you start taking 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 Noxafil is and what it is used for
2. What you need to know before you take Noxafil
3. How to take Noxafil
4. Possible side effects
5. How to store Noxafil
6. Contents of the pack and other information

1. What Noxafil is and what it is used for

Noxafil contains a medicine called posaconazole. This belongs to a group of medicines called 
“antifungals”. It is used to prevent and treat many different fungal infections.

This medicine works by killing or stopping the growth of some types of fungi that can cause 
infections. 

Noxafil can be used in adults to treat the following types of fungal infections when other antifungal 
medicines have not worked or you have had to stop taking them:
 infections caused by fungi of the Aspergillus family that have not improved during treatment 

with the anti-fungal medicines amphotericin B or itraconazole or when these medicines have 
had to be stopped;

 infections caused by fungi of the Fusarium family that have not improved during treatment with 
amphotericin B or when amphotericin B has had to be stopped;

 infections caused by fungi that cause the conditions known as “chromoblastomycosis” and 
“mycetoma” that have not improved during treatment with itraconazole or when itraconazole 
has had to be stopped;

 infections caused by a fungus called Coccidioides that have not improved during treatment with 
one or more of amphotericin B, itraconazole or fluconazole or when these medicines have had 
to be stopped.

 Infections in the mouth or throat area (known as “thrush”) caused by fungi called Candida, 
which were not previously treated.

This medicine can also be used to prevent fungal infections in adults who are at high risk of getting a 
fungal infection, such as:
 patients who have a weak immune system due to having chemotherapy for “acute myelogenous 

leukemia” (AML) or “myelodysplastic syndromes” (MDS) 
 patients having “high-dose immunosuppressive therapy” after “hematopoietic stem cell 

transplant” (HSCT).

 



75

2. What you need to know before you take Noxafil

Do not take Noxafil
 if you are allergic to posaconazole or any of the other ingredients of this medicine (listed in 

section 6).
 if you are taking: terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, any 

medicines that contain “ergot alkaloids” such as ergotamine or dihydroergotamine, or a “statin” 
such as simvastatin, atorvastatin or lovastatin.

Do not take Noxafil if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Noxafil.

See “Other medicines and Noxafil” below for more information including information on other 
medicines which may interact with Noxafil.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Noxafil if you: 
 have had an allergic reaction to another antifungal medicine such as ketoconazole, fluconazole, 

itraconazole or voriconazole. 
 have or have ever had liver problems. You may need to have blood tests while you are taking 

this medicine.
 develop severe diarrhoea or vomiting, as these conditions may limit the effectiveness of this 

medicine.
 have an abnormal heart rhythm tracing (ECG) that shows a problem called long QTc interval
 have a weakness of the heart muscle or heart failure
 have a very slow heartbeat
 have heart rhythm disturbance
 have any problem with potassium, magnesium or calcium levels in your blood
 are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer).

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking Noxafil.

If you develop severe diarrhoea or vomiting (being sick) while taking Noxafil, talk to your doctor, 
pharmacist or nurse straight away, as this may stop it from working properly. See Section 4 for more 
information.

Children
Noxafil should not be used in children (17 years of age and younger).

Other medicines and Noxafil
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.

 



76

Do not take Noxafil if you are taking any of the following:
 terfenadine (used to treat allergies)
 astemizole (used to treat allergies)
 cisapride (used to treat stomach problems)
 pimozide (used to treat symptoms of Tourette's and mental illness) 
 halofantrine (used to treat malaria)
 quinidine (used to treat abnormal heart rhythms).
Noxafil can increase the amount of these medicines in the blood which may lead to very serious 
changes to your heart rhythm.
 any medicines that contain “ergot alkaloids” such as ergotamine or dihydroergotamine used to 

treat migraines. Noxafil can increase the amount of these medicines in the blood which may 
lead to a severe decrease in blood flow to your fingers or toes and could cause damage to them.

 a “statin” such as simvastatin, atorvastatin or lovastatin used to treat high cholesterol.

Do not take Noxafil if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking this medicine.

Other medicines
Look at the list of medicines given above that must not be taken while you are taking Noxafil. In 
addition to the medicines named above there are other medicines that carry a risk of rhythm problems 
that may be greater when they are taken with Noxafil. Please make sure you tell your doctor about all 
the medicines you are taking (prescribed or non-prescribed).

Certain medicines may increase the risk of side effects of Noxafil by increasing the amount of Noxafil 
in the blood. 

The following medicines may decrease the effectiveness of Noxafil by decreasing the amount of 
Noxafil in the blood:
 rifabutin and rifampicin (used to treat certain infections). If you are already taking rifabutin, you 

will need a blood test and you will need to look out for some possible side effects of rifabutin.
 some medicines used to treat or prevent fits including; phenytoin, carbamazepine, phenobarbital 

or primidone).
 efavirenz and fosamprenavir used to treat HIV infection.
 medicines used to decrease stomach acid such as cimetidine and ranitidine or omeprazole and 

similar medicines that are called proton pump inhibitors.

Noxafil may possibly increase the risk of side effects of some other medicines by increasing the 
amount of these medicines in the blood. These medicines include:
 vincristine, vinblastine and other “vinca alkaloids” (used to treat cancer)
 ciclosporin (used during or after transplant surgery)
 tacrolimus and sirolimus (used during or after transplant surgery)
 rifabutin (used to treat certain infections)
 medicines used to treat HIV called protease inhibitors (including lopinavir and atazanavir, 

which are given with ritonavir) 
 midazolam, triazolam, alprazolam or other “benzodiazepines” (used as sedatives or muscle 

relaxants)
 diltiazem, verapamil, nifedipine, nisoldipine or other “calcium channel blockers” (used to treat 

high blood pressure)
 digoxin (used to treat heart failure)
 Glipizide or other “sulfonylureas” (used to treat high blood sugar).

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking 
Noxafil.

 



77

Noxafil with food and drink
To improve absorption of posaconazole, whenever possible it should be taken during or immediately 
after food or a nutritional drink (see section 3 “How to take Noxafil”). There is no information on the 
effect of alcohol on posaconazole.

Pregnancy and breast-feeding
Tell your doctor if you are or think you are pregnant before you start to take Noxafil.
Do not take Noxafil if you are pregnant unless you are told to by your doctor. 
If you are a woman who could become pregnant you should use effective contraception while you are 
taking this medicine. If you become pregnant while you are taking Noxafil, contact your doctor 
straight away.

Do not breast-feed while taking Noxafil. This is because small amounts may pass into breast milk. 

Driving and using machines
You may feel dizzy, sleepy, or have blurred vision while taking Noxafil, which may affect your ability 
to drive or use tools or machines. If this happens, do not drive or use any tools or machines and 
contact your doctor. 

Noxafil contains glucose
Noxafil contains approximately 1.75 g of glucose per 5 mL of suspension. You should not take this 
medicine if you have a condition called glucose-galactose malabsorption and should take note of this 
amount of glucose if you need to watch your sugar intake for any reason.

3. How to take Noxafil

Do not switch between taking Noxafil tablets and Noxafil oral suspension without talking to your 
doctor or pharmacist because it may result in a lack of efficacy or an increased risk of adverse 
reactions.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. Your doctor will monitor your response and condition to determine 
how long Noxafil needs to be given and whether any change is needed to your daily dose. 

The table below shows the recommended dose and length of treatment which depend on the type of 
infection that you have and may be individually adapted for you by your doctor. Do not adapt your 
dose yourself before consulting your doctor or change your treatment regime.

Whenever possible you should take posaconazole during or immediately after food or a nutritional 
drink.

Indication Recommended dose and length of treatment
Treatment of refractory Fungal 
Infections (Invasive aspergillosis,
Fusariosis,
Chromoblastomycosis/Mycetoma, 
Coccidioidomycosis)

The recommended dose is 200 mg (one 5 mL spoonful) taken 
four times daily.
Alternatively, if recommended by your doctor, you may take 
400 mg (two 5 mL spoonfuls) twice a day provided that you are 
able to take both doses during or after food or a nutritional 
drink. 

First time treatment of Thrush On the first day of treatment take 200 mg (one 5 mL spoonful) 
once. After the first day, take 100 mg (2.5 mL) once a day.

Prevention of serious Fungal 
Infections

Take 200 mg (one 5 mL spoonful) three times a day.

 



78

If you take more Noxafil than you should
If you are concerned that you may have taken too much, contact your doctor or healthcare 
professional immediately.

If you forget to take Noxafil
If you have missed a dose, take it as soon as you remember and then carry on as before. However, if it 
is almost time for your next dose, take your dose when it is due. Do not take a double dose to make up 
for a forgotten dose. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects
Tell your doctor, pharmacist or nurse straight away if you notice any of the following serious 
side effects – you may need urgent medical treatment:
 nausea or vomit (feeling or being sick), diarrhoea
 signs of liver problems - these include yellowing of your skin or whites of the eyes, unusually 

dark urine or pale faeces, feeling sick for no reason, stomach problems, loss of appetite or 
unusual tiredness or weakness, an increase in liver enzymes shown up in blood tests

 allergic reaction

Other side effects
Tell your doctor, pharmacist or nurse if you notice any of the following side effects:

Common: the following may affect up to 1 in 10 people
 a change in the salt level in your blood shown in blood tests - signs include feeling confused or 

weak
 abnormal skin sensations, such as numbness, tingling, itching, creeping, pricking or burning
 headache
 low potassium levels – shown up in blood tests
 low magnesium levels – shown up in blood tests
 high blood pressure
 loss of appetite, stomach pain or upset stomach, passing wind, dry mouth, changes in your taste
 heartburn (a burning sensation in the chest rising up to the throat)
 low levels of “neutrophils” a type of white blood cell (neutropenia) –this can make you more 

likely to get infections and be shown up in blood tests
 fever
 feeling weak, dizzy, tired or sleepy
 rash
 itching
 constipation
 rectal discomfort

Uncommon: the following may affect up to 1 in 100 people
 anaemia - signs include headaches, feeling tired or dizzy, being short of breath or looking pale 

and a low level of haemoglobin shown up in blood tests
 low level of platelets (thrombocytopenia) shown in blood tests – this may lead to bleeding
 low level of “leukocytes” a type of white blood cell (leukopenia) shown in blood tests – this 

can make you more likely to get infections 

 



79

 high level of “eosinophils” a type of white blood cell (eosinophilia) – this can happen if you 
have inflammation

 inflammation of the blood vessels 
 heart rhythm problems 
 fits (convulsions) 
 nerve damage (neuropathy)
 abnormal heart rhythm – shown up on a heart trace (ECG), palpitations, slow or fast heartbeat, 

high or low blood pressure
 low blood pressure
 inflammation of the pancreas (pancreatitis) – this may cause severe stomach pain
 oxygen supply to the spleen is interrupted (splenic infarction) - this may cause severe stomach 

pain
 severe kidney problems – signs include passing more or less urine, that is a different colour 

than usual 
 high blood levels of creatinine – shown in blood tests
 cough, hiccups
 nose bleeds
 severe sharp chest pain when breathing in (pleurritic pain)
 swelling of lymph glands (lymphadenopathy)
 reduced feeling of sensitivity especially on the skin
 tremor
 high or low blood sugar levels
 blurred vision, sensitivity to light
 hair loss (alopecia)
 mouth ulcers
 shivering, feeling generally unwell
 pain, back or neck pain, pain in arms or legs
 water retention (oedema)
 menstrual problems (abnormal vaginal bleeding)
 inability to sleep (insomnia)
 being completely or partially unable to talk 
 swelling of the mouth 
 abnormal dreams, or difficulty sleeping
 problems with co-ordination or balance
 mucosal inflammation
 stuffy nose
 difficulty breathing
 chest discomfort
 feeling bloated
 mild to severe nausea, vomiting, cramps and diarrhoea, usually caused by a virus, stomach pain
 belching
 feeling jittery

Rare: the following may affect up to 1 in 1,000 people
 pneumonia – signs include feeling short of breath and producing discoloured phlegm
 high blood pressure in the blood vessels in the lungs (pulmonary hypertension) this can cause 

serious damage to your lungs and heart
 blood problems such as unusual blood clotting or prolonged bleeding
 severe allergic reactions, including widespread blistering rash and skin peeling
 mental problems such as hearing voices or seeing things that are not there 
 fainting
 having problems thinking or talking, having jerking movements, especially in your hands that 

you cannot control

 



80

 stroke – signs include pain, weakness, numbness, or tingling in the limbs
 having a blind or dark spot in your field of vision
 heart failure or heart attack which could lead to the heart stopping beating and death, heart 

rhythm problems, with sudden death
 blood clots in your legs (deep vein thrombosis) – signs include intense pain or swelling of the 

legs
 blood clots in your lungs (pulmonary embolism) – signs include feeling short of breath or pain 

while breathing
 bleeding into your stomach or gut – signs include vomiting blood or passing blood in your stool
 a blockage in your gut (intestinal obstruction) especially in the “ileum”. The blockage will 

prevent the contents of your intestine from passing through to the lower bowel signs include 
feeling bloated, vomiting, severe constipation, loss of appetite, and cramps

 “haemolytic uraemic syndrome” when red blood cells breakup (hemolysis) which may happen 
with or without kidney failure 

 “pancytopenia” low level of all blood cells (red and white blood cells and platelets) shown in 
blood tests

 large purple discolourations on the skin (thrombotic thrombocytopenic purpura) 
 swelling of the face or tongue
 depression
 double vision
 breast pain
 adrenal glands not working properly – this may cause weakness, tiredness, loss of appetite, skin 

discolouration
 pituitary gland not working properly – this may cause low blood levels of some hormones that 

affect the function of the male or female sex organs
 hearing problems

Not known: frequency cannot be estimated from the available data
 pseudoaldosteronism, which results in high blood pressure with a low potassium level (shown 

in blood test)
 some patients have also reported feeling confused after taking Noxafil.

Tell your doctor, pharmacist or nurse if you notice any of the side effects listed above.

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 help provide more information on the 
safety of this medicine.

5. How to store Noxafil

 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 label. The expiry date 

refers to the last day of that month.
 Do not freeze.
 If you have any suspension left in a bottle more than four weeks after it was first opened, you 

should not use this medicine. Please return the bottle containing any leftover suspension to your 
pharmacist.

 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.

 

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81

6. Contents of the pack and other information

What Noxafil contains

- The active substance in Noxafil is posaconazole. Each millilitre of oral suspension contains 
40 milligrams of posaconazole.

- The other ingredients in the suspension are polysorbate 80, simeticone, sodium benzoate 
(E211), sodium citrate dihydrate, citric acid monohydrate, glycerol, xanthan gum, liquid 
glucose, titanium dioxide (E171), artificial cherry flavour containing benzyl alcohol and 
propylene glycol, and purified water.

What Noxafil looks like and contents of the pack

Noxafil is a white, cherry flavoured, 105 mL oral suspension packaged in amber glass bottles. A 
measuring spoon is provided with each bottle for measuring 2.5 and 5 mL doses of the oral
suspension.

Marketing Authorisation Holder and Manufacturer

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

Manufacturer
Cenexi HSC
2, rue Louis Pasteur
F-14200 Hérouville St Clair
France

For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel : +32 (0)2 776 62 11
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)2 776 62 11
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 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 44 82 4000
dkmail@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel.: 8007 4433 (+356 99917558)
malta_info@merck.com

 



82

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

Ελλάδα
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 21 446 5700
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.: + 40 21 529 2900
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 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: + 371-67364224
msd_lv@merck.com

United Kingdom
Merck Sharp & Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

 



83

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.

 



84

Package leaflet: Information for the user

Noxafil 100 mg gastro-resistant tablets
posaconazole

Read all of this leaflet carefully before you start taking 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 Noxafil is and what it is used for
2. What you need to know before you take Noxafil
3. How to take Noxafil
4. Possible side effects
5. How to store Noxafil
6. Contents of the pack and other information

1. What Noxafil is and what it is used for

Noxafil contains a medicine called posaconazole. This belongs to a group of medicines called 
“antifungals”. It is used to prevent and treat many different fungal infections.

This medicine works by killing or stopping the growth of some types of fungi that can cause 
infections. 

Noxafil can be used in adults to treat the following types of fungal infections when other antifungal 
medicines have not worked or you have had to stop taking them:
 infections caused by fungi of the Aspergillus family that have not improved during treatment 

with the anti-fungal medicines amphotericin B or itraconazole or when these medicines have 
had to be stopped;

 infections caused by fungi of the Fusarium family that have not improved during treatment with 
amphotericin B or when amphotericin B has had to be stopped;

 infections caused by fungi that cause the conditions known as “chromoblastomycosis” and 
“mycetoma” that have not improved during treatment with itraconazole or when itraconazole 
has had to be stopped;

 infections caused by a fungus called Coccidioides that have not improved during treatment with 
one or more of amphotericin B, itraconazole or fluconazole or when these medicines have had 
to be stopped.

This medicine can also be used to prevent fungal infections in adults who are at high risk of getting a 
fungal infection, such as:
 patients who have a weak immune system due to having chemotherapy for “acute myelogenous 

leukemia” (AML) or “myelodysplastic syndromes” (MDS) 
 patients having “high-dose immunosuppressive therapy” after “hematopoietic stem cell 

transplant” (HSCT).

 



85

2. What you need to know before you take Noxafil

Do not take Noxafil
 if you are allergic to posaconazole or any of the other ingredients of this medicine (listed in 

section 6).
 if you are taking: terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, any 

medicines that contain “ergot alkaloids” such as ergotamine or dihydroergotamine, or a “statin” 
such as simvastatin, atorvastatin or lovastatin.

Do not take Noxafil if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Noxafil.

See “Other medicines and Noxafil” below for more information including information on other 
medicines which may interact with Noxafil.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Noxafil if you: 
 have had an allergic reaction to another antifungal medicine such as ketoconazole, fluconazole, 

itraconazole or voriconazole. 
 have or have ever had liver problems. You may need to have blood tests while you are taking 

this medicine.
 develop severe diarrhoea or vomiting, as these conditions may limit the effectiveness of this 

medicine.
 have an abnormal heart rhythm tracing (ECG) that shows a problem called long QTc interval
 have a weakness of the heart muscle or heart failure
 have a very slow heartbeat
 have heart rhythm disturbance
 have any problem with potassium, magnesium or calcium levels in your blood
 are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer).

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
taking Noxafil.

If you develop severe diarrhoea or vomiting (being sick) while taking Noxafil, talk to your doctor, 
pharmacist or nurse straight away, as this may stop it from working properly. See Section 4 for more 
information.

Children
Noxafil should not be used in children (17 years of age and younger).

Other medicines and Noxafil

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.

 



86

Do not take Noxafil if you are taking any of the following:
 terfenadine (used to treat allergies)
 astemizole (used to treat allergies)
 cisapride (used to treat stomach problems)
 pimozide (used to treat symptoms of Tourette's and mental illness) 
 halofantrine (used to treat malaria)
 quinidine (used to treat abnormal heart rhythms).
Noxafil can increase the amount of these medicines in the blood which may lead to very serious 
changes to your heart rhythm.
 any medicines that contain “ergot alkaloids” such as ergotamine or dihydroergotamine used to 

treat migraines. Noxafil can increase the amount of these medicines in the blood which may 
lead to a severe decrease in blood flow to your fingers or toes and could cause damage to them.

 a “statin” such as simvastatin, atorvastatin or lovastatin used to treat high cholesterol.

Do not take Noxafil if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking this medicine.

Other medicines
Look at the list of medicines given above that must not be taken while you are taking Noxafil. In 
addition to the medicines named above there are other medicines that carry a risk of rhythm problems 
that may be greater when they are taken with Noxafil. Please make sure you tell your doctor about all
the medicines you are taking (prescribed or non-prescribed).

Certain medicines may increase the risk of side effects of Noxafil by increasing the amount of Noxafil 
in the blood. 

The following medicines may decrease the effectiveness of Noxafil by decreasing the amount of 
Noxafil in the blood:
 rifabutin and rifampicin (used to treat certain infections). If you are already taking rifabutin, you 

will need a blood test and you will need to look out for some possible side effects of rifabutin.
 some medicines used to treat or prevent fits including; phenytoin, carbamazepine, phenobarbital 

or primidone).
 efavirenz and fosamprenavir used to treat HIV infection.

Noxafil may possibly increase the risk of side effects of some other medicines by increasing the 
amount of these medicines in the blood. These medicines include:
 vincristine, vinblastine and other “vinca alkaloids” (used to treat cancer)
 ciclosporin (used during or after transplant surgery)
 tacrolimus and sirolimus (used during or after transplant surgery)
 rifabutin (used to treat certain infections)
 medicines used to treat HIV called protease inhibitors (including lopinavir and atazanavir, 

which are given with ritonavir) 
 midazolam, triazolam, alprazolam or other “benzodiazepines” (used as sedatives or muscle 

relaxants)
 diltiazem, verapamil, nifedipine, nisoldipine or other “calcium channel blockers” (used to treat 

high blood pressure)
 digoxin (used to treat heart failure)
 Glipizide or other “sulfonylureas” (used to treat high blood sugar).

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking 
Noxafil.

Pregnancy and breast-feeding
Tell your doctor if you are or think you are pregnant before you start to take Noxafil.
Do not take Noxafil if you are pregnant unless you are told to by your doctor. 

 



87

If you are a woman who could become pregnant you should use effective contraception while you are 
taking this medicine. If you become pregnant while you are taking Noxafil, contact your doctor 
straight away.

Do not breast-feed while taking Noxafil. This is because small amounts may pass into breast milk. 

Driving and using machines
You may feel dizzy, sleepy, or have blurred vision while taking Noxafil, which may affect your ability 
to drive or use tools or machines. If this happens, do not drive or use any tools or machines and 
contact your doctor.

3. How to take Noxafil

Do not switch between taking Noxafil tablets and Noxafil oral suspension without talking to your 
doctor or pharmacist because it may result in a lack of efficacy or an increased risk of adverse 
reactions.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 

How much to take
The usual dose is 300 mg (three 100 mg tablets) twice a day on the first day, then 300 mg (three 
100 mg tablets) once a day, thereafter.

The length of treatment may depend on the type of infection that you have and may be individually 
adapted for you by your doctor. Do not adapt your dose yourself before consulting your doctor or 
change your treatment regimen.

Taking this medicine
 Swallow the tablet whole with some water.
 Do not crush, chew, break or dissolve the tablet.
 Tablets may be taken with or without food.

If you take more Noxafil than you should
If you think that you may have taken too much Noxafil, talk to a doctor or go to the hospital straight 
away.

If you forget to take Noxafil
 If you forget a dose, take it as soon as you remember it. 
 However, if it is almost time for your next dose, skip the missed dose and go back to your 

regular schedule. 
 Do not take a double dose to make up for a forgotten dose. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

Serious side effects
Tell your doctor, pharmacist or nurse straight away if you notice any of the following serious 
side effects – you may need urgent medical treatment:
 nausea or vomit (feeling or being sick), diarrhoea

 



88

 signs of liver problems - these include yellowing of your skin or whites of the eyes, unusually 
dark urine or pale faeces, feeling sick for no reason, stomach problems, loss of appetite or 
unusual tiredness or weakness, an increase in liver enzymes shown up in blood tests

 allergic reaction

Other side effects
Tell your doctor, pharmacist or nurse if you notice any of the following side effects:

Common: the following may affect up to 1 in 10 people
 a change in the salt level in your blood shown in blood tests - signs include feeling confused or 

weak
 abnormal skin sensations, such as numbness, tingling, itching, creeping, pricking or burning
 headache
 low potassium levels – shown up in blood tests
 low magnesium levels – shown up in blood tests
 high blood pressure
 loss of appetite, stomach pain or upset stomach, passing wind, dry mouth, changes in your taste
 heartburn (a burning sensation in the chest rising up to the throat)
 low levels of “neutrophils” a type of white blood cell (neutropenia) –this can make you more 

likely to get infections and be shown up in blood tests
 fever
 feeling weak, dizzy, tired or sleepy
 rash
 itching
 constipation
 rectal discomfort

Uncommon: the following may affect up to 1 in 100 people
 anaemia - signs include headaches, feeling tired or dizzy, being short of breath or looking pale 

and a low level of haemoglobin shown up in blood tests
 low level of platelets (thrombocytopenia) shown in blood tests – this may lead to bleeding
 low level of “leukocytes” a type of white blood cell (leukopenia) shown in blood tests – this 

can make you more likely to get infections 
 high level of “eosinophils” a type of white blood cell (eosinophilia) – this can happen if you 

have inflammation
 inflammation of the blood vessels 
 heart rhythm problems 
 fits (convulsions) 
 nerve damage (neuropathy)
 abnormal heart rhythm – shown up on a heart trace (ECG), palpitations, slow or fast heartbeat, 

high or low blood pressure
 low blood pressure
 inflammation of the pancreas (pancreatitis) – this may cause severe stomach pain
 oxygen supply to the spleen is interrupted (splenic infarction) - this may cause severe stomach 

pain
 severe kidney problems – signs include passing more or less urine, that is a different colour 

than usual 
 high blood levels of creatinine – shown in blood tests
 cough, hiccups
 nose bleeds
 severe sharp chest pain when breathing in (pleurritic pain)
 swelling of lymph glands (lymphadenopathy)
 reduced feeling of sensitivity especially on the skin
 tremor

 



89

 high or low blood sugar levels
 blurred vision, sensitivity to light
 hair loss (alopecia)
 mouth ulcers
 shivering, feeling generally unwell
 pain, back or neck pain, pain in arms or legs
 water retention (oedema)
 menstrual problems (abnormal vaginal bleeding)
 inability to sleep (insomnia)
 being completely or partially unable to talk 
 swelling of the mouth 
 abnormal dreams, or difficulty sleeping
 problems with co-ordination or balance
 mucosal inflammation
 stuffy nose
 difficulty breathing
 chest discomfort
 feeling bloated
 mild to severe nausea, vomiting, cramps and diarrhoea, usually caused by a virus, stomach pain
 belching
 feeling jittery

Rare: the following may affect up to 1 in 1,000 people
 pneumonia – signs include feeling short of breath and producing discoloured phlegm
 high blood pressure in the blood vessels in the lungs (pulmonary hypertension) this can cause 

serious damage to your lungs and heart
 blood problems such as unusual blood clotting or prolonged bleeding
 severe allergic reactions, including widespread blistering rash and skin peeling
 mental problems such as hearing voices or seeing things that are not there 
 fainting
 having problems thinking or talking, having jerking movements, especially in your hands that 

you cannot control
 stroke – signs include pain, weakness, numbness, or tingling in the limbs
 having a blind or dark spot in your field of vision
 heart failure or heart attack which could lead to the heart stopping beating and death, heart 

rhythm problems, with sudden death
 blood clots in your legs (deep vein thrombosis) – signs include intense pain or swelling of the 

legs 
 blood clots in your lungs (pulmonary embolism) – signs include feeling short of breath or pain 

while breathing
 bleeding into your stomach or gut – signs include vomiting blood or passing blood in your stool 
 a blockage in your gut (intestinal obstruction) especially in the “ileum”. The blockage will 

prevent the contents of your intestine from passing through to the lower bowel signs include 
feeling bloated, vomiting, severe constipation, loss of appetite, and cramps

 “haemolytic uraemic syndrome” when red blood cells breakup (hemolysis) which may happen 
with or without kidney failure 

 “pancytopenia” low level of all blood cells (red and white blood cells and platelets) shown in 
blood tests

 large purple discolourations on the skin (thrombotic thrombocytopenic purpura) 
 swelling of the face or tongue
 depression
 double vision
 breast pain

 



90

 adrenal glands not working properly – this may cause weakness, tiredness, loss of appetite, skin
discolouration

 pituitary gland not working properly – this may cause low blood levels of some hormones that 
affect the function of the male or female sex organs

 hearing problems

Not known: frequency cannot be estimated from the available data
 pseudoaldosteronism, which results in high blood pressure with a low potassium level (shown 

in blood test)
 some patients have also reported feeling confused after taking Noxafil.

Tell your doctor, pharmacist or nurse if you notice any of the side effects listed above.

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 help provide more information on the 
safety of this medicine.

5. How to store Noxafil

 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 blister after EXP. The 

expiry date refers to the last day of that month.
 This medicine does not require any special storage conditions. 
 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 Noxafil contains
The active substance in Noxafil is posaconazole. Each tablet contains 100 mg of posaconazole.

The other ingredients are: hypromellose acetate succinate; cellulose, microcrystalline; 
hydroxypropylcellulose (E463); silica dental type; croscarmellose sodium; magnesium stearate, 
polyvinyl alcohol, macrogol 3350 , titanium dioxide (E171), talc, iron oxide yellow (E172).

What Noxafil looks like and contents of the pack

Noxafil gastro-resistant tablets are yellow-coated and capsule-shaped, debossed “100” on one side 
packaged in a blister in cartons of 24 (2x12) or 96 (8x12) tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

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

 

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91

Manufacturer
SP Labo N.V.
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel : +32 (0)2 776 62 11
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)2 776 62 11
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 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 44 82 4000
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

Ελλάδα
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 21 446 5700
inform_pt@merck.com

 



92

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.: + 40 21 529 2900
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 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: + 371-67364224
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 medicinal product is available on the European Medicines Agency web 
site: http://www.ema.europa.eu.

 



93

Package leaflet: Information for the user

Noxafil 300 mg concentrate for solution for infusion
posaconazole

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 Noxafil is and what it is used for
2. What you need to know before you use Noxafil
3. How to use Noxafil
4. Possible side effects
5. How to store Noxafil
6. Contents of the pack and other information

1. What Noxafil is and what it is used for

Noxafil contains a medicine called posaconazole. This belongs to a group of medicines called 
“antifungals”. Noxafil is used to prevent and treat many different fungal infections.

Noxafil works by killing or stopping the growth of some types of fungi that can cause infections. 

Noxafil can be used in adults to treat the following types of fungal infections when other antifungal 
medicines have not worked or you have had to stop taking them:
 infections caused by fungi of the Aspergillus family that have not improved during treatment 

with the anti-fungal medicines amphotericin B or itraconazole or when these medicines have 
had to be stopped;

 infections caused by fungi of the Fusarium family that have not improved during treatment with 
amphotericin B or when amphotericin B has had to be stopped;

 infections caused by fungi that cause the conditions known as “chromoblastomycosis” and 
“mycetoma” that have not improved during treatment with itraconazole or when itraconazole 
has had to be stopped;

 infections caused by a fungus called Coccidioides. that have not improved during treatment 
with one or more of amphotericin B, itraconazole or fluconazole or when these medicines have 
had to be stopped.

Noxafil can also be used to prevent fungal infections in adults who are at high risk of getting a fungal 
infection, such as:
 patients who have a weak immune system due to having chemotherapy for “acute myelogenous 

leukemia” (AML) or “myelodysplastic syndromes” (MDS) 
 patients having “high-dose immunosuppressive therapy” after “hematopoietic stem cell 

transplant” (HSCT).

 



94

2. What you need to know before you use Noxafil

Do not use Noxafil
 if you are allergic to posaconazole or any of the other ingredients of this medicine (listed in 

section 6).
 if you are taking: terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, any 

medicines that contain “ergot alkaloids” such as ergotamine or dihydroergotamine, or a “statin” 
such as simvastatin, atorvastatin or lovastatin.

Do not use Noxafil if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Noxafil.

See “Other medicines and Noxafil” below for information on other medicines which may interact 
with Noxafil.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking Noxafil if you: 
 have had an allergic reaction to another antifungal medicine such as ketoconazole, fluconazole, 

itraconazole or voriconazole. 
 have or have ever had liver problems. You may need to have blood tests while you are taking 

Noxafil.
 have an abnormal heart rhythm tracing (ECG) that shows a problem called long QTc interval
 have a weakness of the heart muscle or heart failure
 have a very slow heartbeat
 have heart rhythm disturbance
 have any problem with potassium, magnesium or calcium levels in your blood
 are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer).

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before 
using Noxafil.

Children 
Noxafil should not be used in children (17 years of age and younger).

Other medicines and Noxafil
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.

Do not take Noxafil if you are taking any of the following:
 terfenadine (used to treat allergies)
 astemizole (used to treat allergies)
 cisapride (used to treat stomach problems)
 pimozide (used to treat symptoms of Tourette's disorder)
 halofantrine (used to treat malaria)
 quinidine (used to treat abnormal heart rhythms).
Noxafil can increase the amount of these medicines in the blood which may lead to very serious 
changes to your heart rhythm.
 any medicines that contain “ergot alkaloids” such as ergotamine or dihydroergotamine used to 

treat migraines. Noxafil can increase the amount of these medicines in the blood which may 
lead to a severe decrease in blood flow to your fingers or toes and could cause damage to them.

 a “statin” such as simvastatin, atorvastatin or lovastatin used to treat high cholesterol.

Do not take Noxafil if any of the above apply to you. If you are not sure, talk to your doctor or 
pharmacist before taking Noxafil.

 



95

Other medicines
Look at the list of medicines given above that must not be taken while you are taking Noxafil. In 
addition to the medicines named above there are other medicines that carry a risk of rhythm problems 
that may be greater when they are taken with posaconazole. Please make sure you tell your doctor 
about all the medicines you are taking (prescribed or non-prescribed).

Certain medicines may increase the risk of side effects of Noxafil by increasing the amount of Noxafil 
in the blood.

The following medicines may decrease the effectiveness of Noxafil by decreasing the amount of 
Noxafil in the blood:
 rifabutin and rifampicin (used to treat certain infections). If you are already taking rifabutin, 

you will need a blood test and you will need to look out for some possible side effects of 
rifabutin.

 some medicines used to treat or prevent fits including: phenytoin, carbamazepine, phenobarbital 
or primidone.

 efavirenz and fosamprenavir used to treat HIV infection.

Noxafil may possibly increase the risk of side effects of some other medicines by increasing the 
amount of these medicines in the blood. These medicines include:
 vincristine, vinblastine and other “vinca alkaloids” (used to treat cancer)
 ciclosporin (used during or after transplant surgery)
 tacrolimus and sirolimus (used during or after transplant surgery)
 rifabutin (used to treat certain infections)
 medicines used to treat HIV called protease inhibitors (including lopinavir and atazanavir, 

which are given with ritonavir)
 midazolam, triazolam, alprazolam or other “benzodiazepines” (used as sedatives or muscle 

relaxants)
 diltiazem, verapamil, nifedipine, nisoldipine or other “calcium channel blockers” (used to treat 

high blood pressure)
 digoxin (used to treat heart failure)
 Glipizide or other “sulfonylureas” (used to treat high blood sugar)

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking 
Noxafil.

Pregnancy and breast-feeding
Tell your doctor if you are or think you are pregnant before you start to take Noxafil.
Do not use Noxafil if you are pregnant unless you are told to by your doctor.
If you are a woman who could become pregnant you should use effective contraception while you are 
using Noxafil. If you become pregnant while you are using Noxafil, contact your doctor straight away.

Do not breast-feed while using Noxafil. This is because small amounts may pass into breast milk.

Driving and using machines
You may feel dizzy, sleepy, or have blurred vision while taking Noxafil, which may affect your ability 
to drive or use tools or machines. If this happens, do not drive or use any tools or machines and 
contact your doctor.

Noxafil contains sodium
This medicinal product contains 462 mg (20 mmol) sodium per dose. This should be taken into 
consideration by patients on a controlled sodium diet.

 



96

3. How to use Noxafil

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.

The recommended dose is 300 mg twice a day on the first day, then 300 mg once a day, thereafter.

Noxafil concentrate for solution for infusion will be diluted to the correct concentration by your 
pharmacist or nurse.

Noxafil concentrate for solution for infusion will always be prepared and given to you by a healthcare 
professional.
You will be given Noxafil:
 through a plastic tube placed in your vein (intravenous infusion)
 usually over 90 minutes

The length of treatment may depend on the type of infection that you have or the length of time your 
immune system is not working properly and may be individually adapted for you by your doctor. Do 
not adapt your dose yourself before consulting your doctor or change your treatment regimen.

If a dose of Noxafil has been forgotten
As you will be given this medicine under close medical supervision, it is unlikely that a dose would be 
missed. However, tell your doctor or pharmacist if you think that a dose has been forgotten.

When Noxafil treatment is stopped by your doctor you should not experience any effects.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects
Tell your doctor, pharmacist or nurse straight away if you notice any of the following serious 
side effects – you may need urgent medical treatment:
 nausea or vomit (feeling or being sick), diarrhoea,
 signs of liver problems, these include yellowing of your skin or whites of the eyes, unusually 

dark urine or pale faeces, feeling sick for no reason, stomach problems, loss of appetite or 
unusual tiredness or weakness, an increase in liver enzymes shown up in blood tests

 allergic reaction

Other side effects
Tell your doctor, pharmacist or nurse if you notice any of the following side effects:

Common: the following may affect up to 1 in 10 people
 a change in the salt level in your blood shown in blood tests signs include feeling confused or 

weak
 abnormal skin sensations, such as numbness, tingling, itching, creeping, pricking, or burning
 swelling, redness, and tenderness along the vein in which Noxafil was given
 headache
 low potassium levels – shown up in blood tests
 low magnesium levels – shown up in blood tests
 high blood pressure
 loss of appetite, stomach pain or upset stomach, passing wind, dry mouth, changes in your taste

 



97

 heartburn (a burning sensation in the chest rising up to the throat)
 low levels of “neutrophils” a type of white blood cell (neutropenia) – this can make you more 

likely to get infections and be shown up in blood tests
 fever
 feeling weak, dizzy, tired, or sleepy
 rash
 itching
 constipation
 rectal discomfort

Uncommon: the following may affect up to 1 in 100 people
 anaemia- signs include headaches, feeling tired or dizzy, being short of breath or looking pale 

and a low level of haemoglobin shown up in blood tests
 low level of platelets (thrombocytopenia) shown in blood tests – this may lead to bleeding
 low level of “leukocytes” a type of white blood cell (leukopenia) shown in blood tests – this 

can make you more likely to get infections 
 high level of “eosinophils” a type of white blood cell (eosinophilia) – this can happen if you 

have inflammation
 inflammation of the blood vessels
 heart rhythm problems
 fits (convulsions)
 nerve damage (neuropathy)
 abnormal heart rhythm – shown up on a heart trace (ECG), palpitations, slow or fast heartbeat, 

high or low blood pressure
 low blood pressure
 inflammation of the pancreas (pancreatitis) – this may cause severe stomach pain
 oxygen supply to the spleen is interrupted (splenic infarction) - this may cause severe stomach 

pain
 severe kidney problems – signs include passing more or less urine that is a different colour than 

usual 
 high blood levels of creatinine – shown in blood tests
 cough, hiccups
 nose bleeds
 severe sharp chest pain when breathing in (pleurritic pain)
 swelling of lymph glands (lymphadenopathy)
 reduced feeling of sensitivity especially on the skin 
 tremor
 high or low blood sugar levels 
 blurred vision, sensitivity to light
 hair loss (alopecia) 
 mouth ulcers
 shivering, feeling generally unwell
 pain, back or neck pain, pain in arms or legs
 water retention (oedema)
 menstrual problems (abnormal vaginal bleeding)
 inability to sleep (insomnia)
 being completely or partially unable to talk
 swelling of the mouth
 abnormal dreams, or difficulty sleeping
 problems with co-ordination or balance
 mucosal inflammation
 stuffy nose
 difficulty breathing

 



98

 chest discomfort
 feeling bloated
 mild to severe nausea, vomiting, cramps and diarrhoea, usually caused by a virus, stomach pain
 belching
 feeling jittery
 inflammation or pain at injection site

Rare: the following may affect up to 1 in 1,000 people
 pneumonia – signs include feeling short of breath and producing discoloured phlegm
 high blood pressure in the blood vessels in the lungs (pulmonary hypertension) this can cause 

serious damage to your lungs and heart
 blood problems such as unusual blood clotting or prolonged bleeding
 severe allergic reactions, including widespread blistering rash and skin peeling
 mental problems such as hearing voices or seeing things that are not there 
 fainting
 having problems thinking or talking, having jerking movements, especially in your hands that 

you cannot control
 stroke – signs include pain, weakness, numbness, or tingling in the limbs
 having a blind or dark spot in your field of vision
 heart failure or heart attack which could lead to the heart stopping beating and death, heart 

rhythm problems, with sudden death
 blood clots in your legs (deep vein thrombosis) – signs include intense pain or swelling of the 

legs
 blood clots in your lungs (pulmonary embolism) – signs include feeling short of breath or pain 

while breathing
 bleeding into your stomach or gut – signs include vomiting blood or passing blood in your stool
 a blockage in your gut (intestinal obstruction) especially in the “ileum”. The blockage will 

prevent the contents of your intestine from passing through to the lower bowel signs include 
feeling bloated, vomiting, severe constipation, loss of appetite, and cramps

 “haemolytic uraemic syndrome” when red blood cells breakup (hemolysis) which may happen 
with or without kidney failure

 “pancytopenia” low level of all blood cells (red and white blood cells and platelets) shown in 
blood tests

 large purple discolourations on the skin (thrombotic thrombocytopenic purpura)
 swelling of the face or tongue
 depression
 double vision
 breast pain
 adrenal glands not working properly – this may cause weakness, tiredness, loss of appetite, skin 

discolouration
 pituitary gland not working properly – this may cause low blood levels of some hormones that 

affect the function of the male or female sex organs
 hearing problems

Not known: frequency cannot be estimated from the available data
 pseudoaldosteronism, which results in high blood pressure with a low potassium level (shown 

in blood test)
 some patients have also reported feeling confused after using Noxafil.

Tell your doctor, pharmacist or nurse if you notice any of the side effects listed above.

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 

 



99

system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Noxafil

 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 label. The expiry date 

refers to the last day of that month.
 Store in a refrigerator (2C–8C).
 Once prepared, the product should be used immediately. If not used immediately, the solution 

can be stored up to 24 hours at 2°C-8°C (in a refrigerator). This medicinal product is for single 
use only and any unused solution should be discarded.

 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 Noxafil contains
The active substance is posaconazole. Each vial contains 300 mg of posaconazole.

The other ingredients are: Betadex Sulfobutyl Ether Sodium (SBECD), disodium edetate, 
hydrochloric acid (concentrated), sodium hydroxide, water for injections.

What Noxafil looks like and contents of the pack
Noxafil concentrate for solution for infusion is a clear, colourless to yellow liquid. Variations of 
colour within this range do not affect the quality of the product.

This medicine is available in a single use glass vial closed with bromobutyl rubber stopper and 
aluminium seal.

Marketing Authorisation Holder and Manufacturer

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

Manufacturer
SP Labo N.V.
Industriepark 30
B-2220 Heist-op-den-Berg
Belgium

For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder:

België/Belgique/Belgien
MSD Belgium BVBA/SPRL
Tél/Tel : +32 (0)2 776 62 11
dpoc_belux@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel. + 370 5 278 02 47
msd_lietuva@merck.com

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


100

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)2 776 62 11
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 5300
hungary_msd@merck.com

Danmark
MSD Danmark ApS
Tlf: + 45 44 82 4000
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

Ελλάδα
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 21 446 5700
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.: + 40 21 529 2900
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 5204 201
msd.slovenia@merck.com

Ísland
Vistor hf.
Sími: + 354 535 7000

Slovenská republika
Merck Sharp & Dohme, s. r. o.
Tel: +421 2 58282010
dpoc_czechslovak@merck.com

 



101

Italia
MSD Italia S.r.l. 
Tel: +39 06 361911
medicalinformation.it@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0)9 804 650
info@msd.fi

Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ.: 800 00 673 (+357 22866700)
cyprus_info@merck.com

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 77 5700488
medicinskinfo@merck.com

Latvija
SIA Merck Sharp & Dohme Latvija
Tel: + 371-67364224
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.

---------------------------------------------------------------------------------------------------------------------------

The following information is intended for healthcare professionals only:

Administration instructions for Noxafil concentrate for solution for infusion

 Equilibrate the refrigerated vial of Noxafil to room temperature.
 Aseptically transfer 16.7 mL of posaconazole to an intravenous bag (or bottle) containing a 

compatible admixture diluent (see below for list of diluents) using the volume ranging from 
150 mL to 283 mL depending on the final concentration to be achieved (not less than 1 mg/mL 
and not greater than 2 mg/mL).

 Administer via a central venous line, including a central venous catheter or peripherally 
inserted central catheter (PICC) by slow intravenous infusion over approximately 90 minutes.
Noxafil concentrate for solution for infusion should not be given by bolus administration.

 If a central venous catheter is not available, a single infusion may be administered through a 
peripheral venous catheter with a volume to achieve a dilution of approximately 2 mg/mL. 
When administered through a peripheral venous catheter, the infusion should be administered 
over approximately 30 minutes.
Note: In clinical trials, multiple peripheral infusions given through the same vein resulted 
in infusion site reactions (see section 4.8).

 Noxafil is for single use.

The following medicinal products can be infused at the same time through the same intravenous line 
(or cannula) as Noxafil concentrate for solution for infusion:

Amikacin sulfate
Caspofungin
Ciprofloxacin
Daptomycin
Dobutamine hydrochloride
Famotidine
Filgrastim
Gentamicin sulfate
Hydromorphone hydrochloride

 



102

Levofloxacin
Lorazepam
Meropenem
Micafungin
Morphine sulphate
Norepinephrine bitartrate
Potassium chloride
Vancomycin hydrochloride

Any products not listed in the table above should not be coadministered with Noxafil through the 
same intravenous line (or cannula).

The infusion solution should be inspected visually for particulate matter prior to administration. The 
solution of Noxafil ranges from colourless to pale yellow. Variations of colour within this range do 
not affect the quality of the product.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

Noxafil must not be diluted with:
Lactated Ringer’s solution
5 % dextrose with Lactated Ringer’s solution
4.2 % sodium bicarbonate

This medicinal product must not be mixed with other medicinal products except those mentioned 
below:

5 % dextrose in water
0.9 % sodium chloride
0.45 % sodium chloride
5 % dextrose and 0.45 % sodium chloride
5 % dextrose and 0.9 % sodium chloride
5 % dextrose and 20 mEq KCl

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A MANUFACTURERS 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