Norvir

1 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 
 

1. NAME OF THE MEDICINAL PRODUCT  
 
Norvir 100 mg powder for oral suspension 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 
Each sachet of powder for oral suspension contains 100 mg of ritonavir. 
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM  
 
Powder for oral suspension. 
 
Beige/pale yellow to yellow powder. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 
infected patients (adults and children of 2 years of age and older). 
 
4.2 Posology and method of administration 
 
Ritonavir should be administered by physicians who are experienced in the treatment of HIV infection. 
 
Posology 
 
Ritonavir dosed as a pharmacokinetic enhancer 
 
When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of 
Product Characteristics for the particular protease inhibitor must be consulted. 
The following HIV-1 protease inhibitors have been approved for use with ritonavir as a 
pharmacokinetic enhancer at the noted doses.   
 
Adults 

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily. 
Atazanavir 300 mg once daily with ritonavir 100 mg once daily. 
Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily. 
Lopinavir co-formulated with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200 mg. 
Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART experienced patients. 
Initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the 
first 7 days, then saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART-
naïve patients. 
Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily.  Tipranavir with ritonavir 
should not be used in treatment-naïve patients. 

 Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment 
(ART) experienced patients.  Darunavir 800 mg once daily with ritonavir 100 mg once daily 
may be used in some ART experienced patients.  Refer to the darunavir Summary of Product 
Characteristics for further information on once daily dosing in ART experienced patients. 

 Darunavir 800 mg once daily with ritonavir 100 mg once daily in ART-naïve patients. 
 



3 
 

Children and adolescents 
Ritonavir is recommended for children 2 years of age and older.  For further dosage recommendations, 
refer to the product information of other protease inhibitors approved for co-administration with 
ritonavir. 
 
Special populations 
 
Renal impairment 
As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for use with caution as 
a pharmacokinetic enhancer in patients with renal insufficiency depending on the specific protease 
inhibitor with which it is co-administered.  However, since the renal clearance of ritonavir is 
negligible, the decrease in the total body clearance is not expected in patients with renal impairment.  
For specific dosing information in patients with renal impairment, refer to the Summary of Product 
Characteristics (SPC) of the co-administered protease inhibitor.  
 
Hepatic impairment 
Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver 
disease (see section 4.3).  In the absence of pharmacokinetic studies in patients with stable severe 
hepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised when 
ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-administered PI may 
occur.  Specific recommendations for use of ritonavir as a pharmacokinetic enhancer in patients with 
hepatic impairment are dependent on the protease inhibitor with which it is co-administered.  The SPC 
of the co-administered PI should be reviewed for specific dosing information in this patient 
population.  
 
Ritonavir dosed as an antiretroviral agent 
 
Adults 
The recommended dose of Norvir powder for oral suspension is 600 mg (six sachets) twice daily by 
mouth and should be given with food.  
 
Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance.  
Treatment should be initiated at 300 mg (three sachets) twice daily for a period of three days and 
increased by 100 mg (one sachet) twice daily increments up to 600 mg twice daily over a period of no 
longer than 14 days.  Patients should not remain on 300 mg twice daily for more than 3 days. 
 
Refer to Method of Administration section below and section 6.6 for details on preparing doses. 
 
Children and adolescents (2 years of age and above) 
The recommended dosage of Norvir powder for suspension in children is 350 mg/m² by mouth twice 
daily and should not exceed 600 mg twice daily.  Norvir should be started at 250 mg/m² and increased 
at 2 to 3 day intervals by 50 mg/m² twice daily.   

Paediatric dosage guidelines for Norvir powder for oral suspension (prepared as 
100 mg/10 ml)*† 

Body Surface 
Area (m2) 

Twice Daily Dose 
250 mg/m2 

Twice Daily Dose 
300 mg/m2 

Twice Daily Dose 
350 mg/m2 

0.25 6.4 ml (62.5 mg) 7.6 ml (76 mg) 8.8 ml (88 mg) 
0.50 12.6 ml (126 mg) 15.0 ml (150 mg) 17.6 ml (176 mg) 
0.75 18.8 ml (188 mg) 22.6 ml (226 mg) 26.4 ml (262.5 mg) 
1.00 25.0 ml (250 mg) 30.0 ml (300 mg) 35.0 ml (350 mg) 
1.25 31.4 ml (312.5 mg) 37.6 ml (376 mg) 43.8 ml (438mg) 
1.50 37.6 ml (376 mg) 45.0 ml (450 mg) 52.6 ml (526 mg) 

*When mixed with 9.4 ml of liquid the concentration of the suspension is 10 mg/ml.  
 
†In some instances, the volumes and/or doses have been adjusted to ensure the recommended final dose and 
dosing volume.  
 



4 
 

Body surface area can be calculated with the following equation:  BSA (m2) = √(Height (cm) X Weight (kg) / 
3600) 
 
To calculate the volume to be administered (in ml) for intermediate body surface areas not included in 
the above table, the body surface area should be multiplied by a factor of: 25 for a dose of 250 mg/m²; 
30 for 300 mg/m²; and 35 for 350 mg/m².  
 
Refer to Method of Administration section below and section 6.6 for details on preparing doses. 
 
Special populations 
 
Elderly 
Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section 
5.2). 
 
Renal impairment 
Currently, there are no data specific to this patient population and therefore specific dosage 
recommendations cannot be made.  The renal clearance of ritonavir is negligible; therefore, a decrease 
in the total body clearance is not expected in patients with renal impairment.  Because ritonavir is 
highly protein bound it is unlikely that it will be significantly removed by haemodialysis or peritoneal 
dialysis. 
 
Hepatic impairment 
Ritonavir is principally metabolised and eliminated by the liver.  Pharmacokinetic data indicate that no 
dose adjustment is necessary in patients with mild to moderate hepatic impairment (see section 5.2).  
Ritonavir must not be given to patients with severe hepatic impairment (see section 4.3).   
 
Paediatric population 
The safety and efficacy of Norvir in children aged below 2 years has 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 
Norvir powder for oral suspension is administered orally, poured on soft food (apple sauce or vanilla 
pudding) or mixed with liquid (water, chocolate milk, or infant formula).  For details on preparation 
and administration of the Norvir powder for oral suspension, see section 6.6.  Any mixing outside the 
recommendations is the responsibility of the health care professional or the user.  
 
Norvir powder for oral suspension should be taken with food.  The bitter aftertaste of Norvir powder 
for oral suspension may be lessened if peanut butter, hazelnut chocolate spread, or black currant syrup 
are taken immediately after dose administration. 
 
The prescribed dose of Norvir powder for oral suspension can be administered via a feeding tube after 
being mixed with water as detailed in section 6.6.  Follow the instructions for the feeding tube to 
administer the medicine. 
 
4.3  Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.   
 
When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the Summary of Product 
Characteristics of the co-administered protease inhibitor for contraindications. 
 
Ritonavir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients 
with decompensated liver disease. 
 



5 
 

In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and 
CYP2D6- mediated biotransformations.  The following medicines are contraindicated when used with 
ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to 
inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the 
co-administered medicinal product and risk of clinically significant adverse effects. 
 
The enzyme-modulating effect of ritonavir may be dose dependent.  For some products, 
contraindications may be more relevant when ritonavir is used as an antiretroviral agent than when 
ritonavir is used as a pharmacokinetic enhancer (e.g. rifabutin and voriconazole): 
 

Medicinal Product 
Class 

Medicinal Products 
within Class 

Rationale 

Concomitant medicinal product levels increased or decreased 

α1-Adrenoreceptor 
Antagonist 

Alfuzosin Increased plasma concentrations of alfuzosin 
which may lead to severe hypotension (see 
section 4.5). 

Analgesics Pethidine, piroxicam, 
propoxyphne 

Increased plasma concentrations of 
norpethidine, piroxicam and propoxyphene.  
Thereby, increasing the risk of serious 
respiratory depression or haematologic 
abnormalities, or other serious adverse effects 
from these agents. 

Antianginal Ranolazine Increased plasma concentrations of ranolazine 
which may increase the potential for serious 
and/or life-threatening reactions (see section 
4.5). 

Anticancer Neratinib Increased plasma concentrations of neratinib 
which may increase the potential for serious 
and/or life-threatening reactions including 
hepatotoxicity (see section 4.5). 

Venetoclax Increased plasma concentrations of venetoclax. 
Increased risk of tumor lysis syndrome at the 
dose initiation and during the dose-titration 
phase (see section 4.5). 

Antiarrhythmics Amiodarone, bepridil, 
dronedarone, 
encainide, flecanide, 
propafenone, quinidine 
 

Increased plasma concentrations of amiodarone, 
bepridil, dronedarone, encainide, flecanide, 
propafenone, quinidine.  Thereby, increasing 
the risk of arrhythmias or other serious adverse 
reactions from these agents. 

Antibiotic Fusidic Acid Increased plasma concentrations of fusidic acid 
and ritonavir. 

Antifungal Voriconazole Concomitant use of ritonavir (400 mg twice 
daily and more) and voriconazole is 
contraindicated due to a reduction in 
voriconazole plasma concentrations and 
possible loss of effect (see section 4.5). 

Anti-gout Colchicine Potential for serious and/or life-threatening 
reactions in patients with renal and/or hepatic 
impairment (see sections 4.4 and 4.5). 

Antihistamines Astemizole, 
terfenadine 

Increased plasma concentrations of astemizole 
and terfenadine.  Thereby, increasing the risk of 
serious arrhythmias from these agents. 



6 
 

Antimycobacterial Rifabutin Concomitant use of ritonavir (500 mg twice 
daily) dosed as an antiretroviral agent and 
rifabutin due to an increase of rifabutin serum 
concentrations and risk of adverse events 
including uveitis (see section 4.4).  
Recommendations regarding use of ritonavir 
dosed as a pharmacokinetic enhancer with 
rifabutin are noted in section 4.5.   

Antipsychotics/ 
Neuroleptics 

Lurasidone Increased plasma concentrations of lurasidone 
which may increase the potential for serious 
and/or life-threatening reactions (see section 
4.5). 

Clozapine, pimozide Increased plasma concentrations of clozapine 
and pimozide.  Thereby, increasing the risk of 
serious haematologic abnormalities, or other 
serious adverse effects from these agents. 

 Quetiapine Increased plasma concentrations of quetiapine 
which may lead to coma.  The concomitant 
administration with quetiapine is 
contraindicated (see section 4.5). 

Ergot Derivatives Dihydroergotamine, 
ergonovine, 
ergotamine, 
methylergonovine 

Increased plasma concentrations of ergot 
derivatives leading to acute ergot toxicity, 
including vasospasm and ischaemia. 

GI motility agent Cisapride Increased plasma concentrations of cisapride.  
Thereby, increasing the risk of serious 
arrhythmias from this agent. 

Lipid-modifying agents 
 
HMG Co-A Reductase 
Inhibitors 

Lovastatin, simvastatin Increased plasma concentrations of lovastatin 
and simvastatin; thereby, increasing the risk of 
myopathy including rhabdomyolysis (see 
section 4.5). 
 

Microsomal 
triglyceride transfer 
protein (MTTP) 
inhibitor 

Lomitapide Increased plasma concentrations of lomitapide 
(see section 4.5). 

PDE5 inhibitors Avanafil Increased plasma concentrations of avanafil 
(see section 4.4. and 4.5). 

 Sildenafil  Contraindicated when used for the treatment of 
pulmonary arterial hypertension (PAH) only.  
Increased plasma concentrations of sildenafil.  
Thereby, increasing the potential for sildenafil-
associated adverse events (which include 
hypotension and syncope).  See section 4.4 and 
section 4.5 for co-administration of sildenafil in 
patients with erectile dysfunction. 

 Vardenafil Increased plasma concentrations of vardenafil 
(see section 4.4. and 4.5). 

Sedatives/hypnotics Clorazepate, diazepam, 
estazolam, flurazepam, 
oral midazolam and 
triazolam 

Increased plasma concentrations of clorazepate, 
diazepam, estazolam, flurazepam, oral 
midazolam and triazolam.  Thereby, increasing 
the risk of extreme sedation and respiratory 
depression from these agents.  (For caution on 
parenterally administered midazolam, see 
section 4.5). 



7 
 

 

Ritonavir medicinal product level decreased 

Herbal Preparation St. John’s wort Herbal preparations containing St John’s wort 
(Hypericum perforatum) due to the risk of 
decreased plasma concentrations and reduced 
clinical effects of ritonavir (see section 4.5). 

 
4.4  Special warnings and precautions for use 
 
Ritonavir is not a cure for HIV-1 infection or AIDS.  Patients receiving ritonavir or any other 
antiretroviral therapy may continue to develop opportunistic infections and other complications of 
HIV-1 infection.  
 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent transmission 
should be taken in accordance with national guidelines. 
 
When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings and 
precautions relevant to that particular PI should be considered, therefore the Summary of Product 
Characteristics for the particular PI must be consulted. 
 
Ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer   
 
Patients with chronic diarrhoea or malabsorption 
Extra monitoring is recommended when diarrhoea occurs.  The relatively high frequency of diarrhoea 
during treatment with ritonavir may compromise the absorption and efficacy (due to decreased 
compliance) of ritonavir or other concurrent medicinal products.  Serious persistent vomiting and/or 
diarrhoea associated with ritonavir use might also compromise renal function.  It is advisable to 
monitor renal function in patients with renal function impairment. 
 
Haemophilia 
There have been reports of increased bleeding, including spontaneous skin haematomas and 
haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors.  In some 
patients additional factor VIII was given.  In more than a half of the reported cases, treatment with 
protease inhibitors was continued or reintroduced if treatment had been discontinued.  A causal 
relationship has been evoked, although the mechanism of action has not been elucidated.  
Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding. 
 
Weight and metabolic parameters:  
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose, reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
Pancreatitis 
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or 
abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of 
pancreatitis should occur.  Patients who exhibit these signs or symptoms should be evaluated and 
Norvir therapy should be discontinued if a diagnosis of pancreatitis is made (see section 4.8). 
 



8 
 

Immune Reconstitution Inflammatory Syndrome 
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic 
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms.  Typically, 
such reactions have been observed within the first few weeks or months of initiation of CART.  
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, 
and Pneumocystis jiroveci pneumonia.  Any inflammatory symptoms should be evaluated and 
treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reconstitution; however, the reported time to onset is more variable and 
can occur many months after initiation of treatment. 
 
Liver disease 
Ritonavir should not be given to patients with decompensated liver disease (see section 4.2).  Patients 
with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased 
risk for severe and potentially fatal hepatic adverse reactions.  In case of concomitant antiviral therapy 
for hepatitis B or C, please refer to the relevant product information for these medicinal products. 
 
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy and should be 
monitored according to standard practice.  If there is evidence of worsening liver disease in such 
patients, interruption or discontinuation of treatment must be considered. 
 
Renal disease 
Since the renal clearance of ritonavir is negligible, the decrease in the total body clearance is not 
expected in patients with renal impairment (see also section 4.2). 
 
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy 
(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate (DF) 
in clinical practice (see section 4.8). 
 
Medication error 
Special attention should be given to the accurate calculation of the dose of Norvir, transcription of the 
medication order, dispensing information and dosing instructions to minimise the risk for medication 
errors and underdose.  This is especially important for infants and young children. 
 
Osteonecrosis 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported in patients with advanced HIV-disease and/or long-term exposure to combination 
antiretroviral therapy (CART).  Patients should be advised to seek medical advice if they experience 
joint aches and pain, joint stiffness or difficulty in movement. 
 
PR interval prolongation 
Ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some 
healthy adult subjects.  Rare reports of 2nd or 3rd degree atrioventricular block in patients with 
underlying structural heart disease and pre-existing conduction system abnormalities or in patients 
receiving medicinal products known to prolong the PR interval (such as verapamil or atazanavir) have 
been reported in patients receiving ritonavir.  Norvir should be used with caution in such patients (see 
section 5.1). 
 



9 
 

Interactions with other medicinal products 
 
Ritonavir dosed as an antiretroviral agent 
 
The following warnings and precautions should be considered when ritonavir is used as an 
antiretroviral agent.  When ritonavir is used as a pharmacokinetic enhancer at the 100 mg and 200 mg 
level it cannot be assumed that the following warnings and precautions will also apply.  When 
ritonavir is used as a pharmacokinetic enhancer, full details on the warnings and precautions relevant 
to that particular PI must be considered, therefore the Summary of Product Characteristics, section 4.4, 
for the particular PI must be consulted to determine if the information below is applicable. 
 
PDE5 inhibitors 
Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile 
dysfunction in patients receiving ritonavir.  Co-administration of ritonavir with these medicinal 
products is expected to substantially increase their concentrations and may result in associated adverse 
reactions such as hypotension and prolonged erection (see section 4.5).  Concomitant use of avanafil 
or vardenafil with ritonavir is contraindicated (see section 4.3).  Concomitant use of sildenafil with 
ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3). 
 
HMG-CoA reductase inhibitors 
The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for 
metabolism, thus concomitant use of ritonavir with simvastatin or lovastatin is not recommended due 
to an increased risk of myopathy including rhabdomyolysis.  Caution must also be exercised and 
reduced doses should be considered if ritonavir is used concurrently with atorvastatin, which is 
metabolised to a lesser extent by CYP3A.  While rosuvastatin elimination is not dependent on 
CYP3A, an elevation of rosuvastatin exposure has been reported with ritonavir co-administration.  The 
mechanism of this interaction is not clear, but may be the result of transporter inhibition.  When used 
with ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent, the lowest doses of 
atorvastatin or rosuvastatin should be administered.  The metabolism of pravastatin and fluvastatin is 
not dependent of CYP3A, and interactions are not expected with ritonavir.  If treatment with an HMG-
CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5). 
 
Colchicine 
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A like ritonavir (see sections 4.3 and 4.5). 
 
Digoxin 
Particular caution should be used when prescribing ritonavir in patients taking digoxin since 
co-administration of ritonavir with digoxin is expected to increase digoxin levels.  The increased 
digoxin levels may lessen over time (see section 4.5). 
 
In patients who are already taking digoxin when ritonavir is introduced, the digoxin dose should be 
reduced to one-half of the patients’ normal dose and patient need to be followed more closely than 
usual for several weeks after initiating co-administration of ritonavir and digoxin. 
 
In patients who are already taking ritonavir when digoxin is introduced, digoxin should be introduced 
more gradually than usual.  Digoxin levels should be monitored more intensively than usual during 
this period, with dose adjustments made, as necessary, based on clinical, electrocardiographic and 
digoxin level findings.  
 
Ethinyl estradiol 
Barrier or other non-hormonal methods of contraception should be considered when administering 
ritonavir at therapeutic or low doses as ritonavir is likely to reduce the effect and change the uterine 
bleeding profile when co-administered with estradiol-containing contraceptives. 
 



10 
 

Glucocorticoids 
Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 
is not recommended unless the potential benefit of treatment outweighs the risk of systemic 
corticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section 4.5). 
 
Trazodone 
Particular caution should be used when prescribing ritonavir in patients using trazodone.  Trazodone is 
a CYP3A4 substrate and co-administration of ritonavir is expected to increase trazodone levels.  
Adverse reactions of nausea, dizziness, hypotension and syncope have been observed in single dose 
interaction studies in healthy volunteers (see section 4.5) 
 
Rivaroxaban 
It is not recommended to use ritonavir in patients receiving rivaroxaban, due to the risk of increased 
bleeding (see section 4.5). 
 
Riociguat 
The concomitant use of ritonavir is not recommended due to potential increase in riociguat exposure 
(see section 4.5). 
 
Vorapaxar 
The concomitant use of ritonavir is not recommended due to potential increase in vorapaxar exposure 
(see section 4.5). 
 
Bedaquiline 
Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could 
potentially increase the risk of bedaquiline-related adverse reactions.  Therefore, combination of 
bedaquiline with ritonavir should be avoided.  However, if the benefit outweighs the risk, co-
administration of bedaquiline with ritonavir must be done with caution.  More frequent 
electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and 
refer to the bedaquiline Summary of Product Characteristics). 
 
Delamanid  
Co-administration of delamanid with a strong inhibitor of CYP3A (ritonavir) may increase exposure to 
delamanid metabolite, which has been associated with QTc prolongation.  Therefore, if 
co-administration of delamanid with ritonavir is considered necessary, very frequent ECG monitoring 
throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the 
delamanid Summary of Product Characteristics).  
 
Ritonavir dosed as a pharmacokinetic enhancer 
The interaction profiles of HIV-protease inhibitors, co-administered with low dose ritonavir, are 
dependent on the specific co-administered protease inhibitor.  
 
For a description of the mechanisms and potential mechanisms contributing to the interaction profile 
of the PIs, see section 4.5.  Please also review the Summary of Product Characteristics for the 
particular boosted PI. 
 
Saquinavir 
Doses of ritonavir higher than 100 mg twice daily should not be used.  Higher doses of ritonavir have 
been shown to be associated with an increased incidence of adverse reactions.  Co-administration of 
saquinavir and ritonavir has led to severe adverse reactions, mainly diabetic ketoacidosis and liver 
disorders, especially in patients with pre-existing liver disease.   
 
Saquinavir/ritonavir should not be given together with rifampicin, due to the risk of severe 
hepatotoxicity (presenting as increased hepatic transaminases) if the three medicines are given 
together (see section 4.5). 
 



11 
 

Tipranavir 
Co-administration of tipranavir with 200 mg of ritonavir has been associated with reports of clinical 
hepatitis and hepatic decompensation including some fatalities.  Extra vigilance is warranted in 
patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of 
hepatotoxicity.  
 
Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy 
profile of the combination. 
  
Fosamprenavir 
Co-administration of fosamprenavir with ritonavir in doses greater than 100 mg twice daily has not 
been clinically evaluated.  The use of higher ritonavir doses might alter the safety profile of the 
combination and therefore is not recommended. 
 
Atazanavir 
Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has not been 
clinically evaluated.  The use of higher ritonavir doses may alter the safety profile of atazanavir 
(cardiac effects, hyperbilirubinemia) and therefore is not recommended.  Only when atazanavir with 
ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200mg once daily could be 
considered.  In this instance, close clinical monitoring is warranted.  Refer to the Summary of Product 
Characteristics for atazanavir for further details. 
 
4.5  Interaction with other medicinal products and other forms of interaction 
 
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent 
 
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation 
with the following ranked order: CYP3A4 > CYP2D6.  Co-administration of ritonavir and medicinal 
products primarily metabolised by CYP3A may result in increased plasma concentrations of the other 
medicinal product, which could increase or prolong its therapeutic and adverse effects.  For selected 
medicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over 
time.  Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter.  The 
inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease 
over time (e.g. digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal 
products” below).  Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products 
metabolised by these pathways, and may result in decreased systemic exposure to such medicinal 
products, which could decease or shorten their therapeutic effect.   
 
Important information regarding medicinal product interactions when ritonavir is used as a 
pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the 
co-administered protease inhibitor. 
 
Medicinal products that affect ritonavir levels 
 
Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing 
St John’s wort (Hypericum perforatum).  This is due to the induction of medicinal product 
metabolising enzymes by St John’s wort.  Herbal preparations containing St John’s wort must not be 
used in combination with ritonavir.  If a patient is already taking St John’s wort, St John’s wort should 
be stopped and if possible check viral levels.  Ritonavir levels may increase on stopping St John’s 
wort.  The dose of ritonavir may need adjusting.  The inducing effect may persist for at least 2 weeks 
after cessation of treatment with St John’s wort (see section 4.3).   
 
Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. 
delavirdine, efavirenz, phenytoin and rifampicin).  These interactions are noted in the medicinal 
product interaction tables below. 
 



12 
 

Medicinal product that are affected by the use of ritonavir 
 
Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease 
inhibitors and other non-antiretroviral medicinal products are listed in the tables below.  This list is not 
intended to be inclusive or comprehensive.  Individual SmPCs should be consulted. 
 

Medicinal Product Interactions – Ritonavir with Protease Inhibitors 
Co-

administered 
Medicinal 
Product 

Dose of Co-administered 
Medicinal Product (mg) 

Dose of NORVIR 
(mg) 

Medicinal 
Product 
Assessed 

AUC Cmin 

Amprenavir 600 q12h 100 q12h Amprenavir1 ↑ 64% ↑ 5 fold 
 Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition.  Clinical 

trials confirmed the safety and efficacy of 600 mg amprenavir twice daily with ritonavir 100 mg 
twice daily.  For further information, physicians should refer to the Summary of Product 
Characteristics for amprenavir. 

Atazanavir 300 q24h 100 q24h Atazanavir ↑ 86% ↑ 11 fold 
   Atazanavir2 ↑ 2 fold ↑ 3-7 fold 
 Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition.  Clinical 

trials confirmed the safety and efficacy of 300 mg atazanavir once daily with ritonavir 100 mg 
once daily in treatment experienced patients.  For further information, physicians should refer to 
the Summary of Product Characteristics for atazanavir. 

Darunavir 600, single  100 q12h Darunavir ↑ 14 fold  
 Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition.  Darunavir 

must be given with ritonavir to ensure its therapeutic effect.  Ritonavir doses higher than 
100 mg twice daily have not been studied with darunavir.  For further information, refer to the 
Summary of Product Characteristics for darunavir. 

Fosamprenavir 700 q12h 100 q12h Amprenavir ↑ 2.4 fold ↑ 11 fold 
 Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4 

inhibition.  Fosamprenavir must be given with ritonavir to ensure its therapeutic effect.  Clinical 
trials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir 
100 mg twice daily.  Ritonavir doses higher than 100 mg twice daily have not been studied with 
fosamprenavir.  For further information, physicians should refer to the Summary of Product 
Characteristics for fosamprenavir. 

Indinavir 800 q12h 100 q12h Indinavir3 ↑ 178% ND 
   Ritonavir ↑ 72% ND 
 400 q12h 400 q12h Indinavir3 ↔ ↑ 4 fold  
   Ritonavir ↔ ↔ 
 Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition.  Appropriate 

doses for this combination, with respect to efficacy and safety, have not been established.  
Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses 
higher than 100 mg twice daily.  In cases of co-administration of ritonavir (100 mg twice daily) 
and indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may be 
increased.   

Nelfinavir 1250 q12h  100 q12h Nelfinavir ↑ 20to39% ND 
 750, single 500 q12h Nelfinavir ↑ 152% ND 
   Ritonavir ↔ ↔ 
 Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition.  Appropriate 

doses for this combination, with respect to efficacy and safety, have not been established.  
Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses 
higher than 100 mg twice daily. 

Saquinavir 1000 q12h 100 q12h Saquinavir4 ↑ 15-fold ↑ 5-fold 
   Ritonavir ↔ ↔ 
 400 q12h  400 q12h  Saquinavir4 ↑ 17-fold  ND 
   Ritonavir ↔ ↔ 
 Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition.  Saquinavir 

should only be given in combination with ritonavir.  Ritonavir 100 mg twice daily with 
saquinavir 1000 mg twice daily provides saquinavir systemic exposure over 24 hours similar to 
or greater than those achieved with saquinavir 1200 mg three times daily without ritonavir.    
 

In a clinical study investigating the interaction of rifampicin 600 mg once daily and saquinavir 
1000 mg with ritonavir 100 mg twice daily in healthy volunteers, severe hepatocellular toxicity 



13 
 

with transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days of 
co-administration was noted.  Due to the risk of severe hepatoxicity, saquinavir/ritonavir should 
not be given together with rifampicin. 
 

For further information, physicians should refer to the Summary of Product Characteristics for 
saquinavir. 

Tipranavir 500 q12h 200 q12h Tipranavir ↑ 11 fold ↑ 29 fold 
   Ritonavir ↓ 40% ND 
 Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition.  Tipranavir 

must be given with low dose ritonavir to ensure its therapeutic effect.  Doses of ritonavir less 
than 200 mg twice daily should not be used with tipranavir as they might alter the efficacy of the 
combination.  For further information, physicians should refer to the Summary of Product 
Characteristics for tipranavir. 

 ND: Not determined. 
1. Based on cross-study comparison to 1200 mg amprenavir twice daily alone. 
2. Based on cross-study comparison to 400 mg atazanavir once daily alone. 
3. Based on cross-study comparison to 800 mg indinavir three times daily alone. 
4. Based on cross-study comparison to 600 mg saquinavir three times daily alone. 

 
Medicinal product interactions – Ritonavir with antiretroviral agents other than protease 
inhibitors 
Co-
administered 
Medicinal 
Product 

Dose of Co-
administered 
Medicinal 
Product 
(mg) 

Dose of 
NORVIR (mg) 

Medicinal Product  
Assessed 

AUC Cmin 

Didanosine 200 q12h 600 q12h 2 h 
later 

Didanosine ↓ 13%   ↔ 

 As ritonavir is recommended to be taken with food and didanosine should be taken on an empty 
stomach, dosing should be separated by 2.5 h.  Dose alterations should not be necessary. 

Delavirdine 400 q8h 600 q12h Delavirdine1 ↔ ↔ 
   Ritonavir ↑ 50% ↑ 75% 
 Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to be 

affected by ritonavir.  When used in combination with delavirdine, dose reduction of ritonavir 
may be considered. 

Efavirenz 600 q24h 500 q12h Efavirenz ↑ 21%  
   Ritonavir ↑ 17%  
 A higher frequency of adverse reactions (e.g., dizziness, nausea, paraesthesia) and laboratory 

abnormalities (elevated liver enzymes) have been observed when efavirenz is co-administered 
with ritonavir dosed as an antiretroviral agent. 

Maraviroc 100 q12h 100 q12h Maraviroc ↑161% ↑28% 
 Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition.  Maraviroc 

may be given with ritonavir to increase the maraviroc exposure.  For further information, refer to 
the Summary of Product Characteristics for maraviroc. 

Nevirapine 200 q12h 600 q12h Nevirapine ↔ ↔ 
   Ritonavir ↔ ↔ 
 Co-administration of ritonavir with nevirapine does not lead to clinically relevant changes in the 

pharmacokinetics of either nevirapine or ritonavir. 
Raltegravir 400 single  100 q12h Raltegravir ↓ 16% ↓ 1% 
 Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir levels 
Zidovudine 200 q8h 300 q6h Zidovudine ↓ 25%  ND 
 Ritonavir may induce the glucuronidation of zidovudine, resulting in slightly decreased levels of 

zidovudine.  Dose alterations should not be necessary. 
 ND: Not determined 

1.  Based on parallel group comparison. 
 



14 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Alpha1-Adrenoreceptor 
Antagonist 

 

Alfuzosin Ritonavir co-administration is likely to result in increased plasma 
concentrations of alfuzosin and is therefore contraindicated (see 
section 4.3).   
 

Amphetamine Derivatives  

Amphetamine  Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 
and as a result is expected to increase concentrations of amphetamine 
and its derivatives.  Careful monitoring of therapeutic and adverse 
effects is recommended when these medicines are concomitantly 
administered with antiretroviral doses of ritonavir (see section 4.4). 
 

Analgesics 
 

Buprenorphine 16 q24h 100 q12h ↑ 57% ↑ 77% 
Norbuprenorphine   ↑ 33% ↑ 108% 
Glucuronide metabolites   ↔ ↔ 
 The increases of plasma levels of buprenorphine and its active 

metabolite did not lead to clinically significant pharmacodynamic 
changes in a population of opioid tolerant patients.  Adjustment to the 
dose of buprenorphine or ritonavir may therefore not be necessary 
when the two are dosed together.  When ritonavir is used in 
combination with another protease inhibitor and buprenorphine, the 
SPC of the co-administered protease inhibitor should be reviewed for 
specific dosing information. 
 

Pethidine, piroxicam, propoxyphene Ritonavir co-administration is likely to result in increased plasma 
concentrations of pethidine, piroxicam, and propoxyphene and is 
therefore contraindicated (see section 4.3). 
 

Fentanyl Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of fentanyl.  Careful monitoring of therapeutic 
and adverse effects (including respiratory depression) is 
recommended when fentanyl is concomitantly administered with 
ritonavir. 
 

Methadone1 5, single dose  500 q12h,  ↓ 36%  ↓ 38%  
 Increased methadone dose may be necessary when concomitantly 

administered with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer due to induction of glucuronidation.  Dose 
adjustment should be considered based on the patient’s clinical 
response to methadone therapy.   
 

Morphine Morphine levels may be decreased due to induction of 
glucuronidation by co-administered ritonavir dosed as an 
antiretroviral agent or as a pharmacokinetic enhancer. 
 



15 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Antianginal 
 

Ranolazine Due to CYP3A inhibition by ritonavir, concentrations of ranolazine 
are expected to increase.  The concomitant administration with 
ranolazine is contraindicated (see section 4.3). 

Antiarrthymics 
 

Amiodarone, bepridil, dronedarone, 
encainide, flecainide, propafenone, 
quinidine 

Ritonavir co-administration is likely to result in increased plasma 
concentrations of amiodarone, bepridil, dronedarone, encainide, 
flecainide, propafenone, and quinidine and is therefore 
contraindicated (see section 4.3). 
 

Digoxin 0.5 single IV dose 300 q12h, 3 days  ↑ 86% ND 
 0.4 single oral  

dose 
200 q12h, 13 days ↑ 22% ↔ 

 This interaction may be due to modification of P-glycoprotein 
mediated digoxin efflux by ritonavir dosed as an antriretroviral agent 
or as a pharmacokinetic enhancer.  Increased digoxin levels observed 
in patients receiving ritonavir may lessen over time as induction 
develops (see section 4.4).   
 

Antiasthmatic 
 

Theophylline1 3 mg/kg q8h 500 q12h  ↓ 43%  ↓ 32%  
 An increased dose of theophylline may be required when 

co-administered with ritonavir, due to induction of CYP1A2. 
 

Anticancer agents and kinase 
inhibitors 

 

Afatinib 20 mg, single 
dose 
40 mg, single 
dose 
40 mg, single 
dose 

200 
q12h/1h 
before 
200 q12h/ 
co-
administered 
200 q12h/6h 
after 

↑ 48%  
 
↑ 19% 
 
↑ 11% 

↑ 39%  
 
↑ 4% 
 
↑ 5% 

Serum concentrations may be increased due to Breast Cancer 
Resistance Protein (BCRP) and acute P-gp inhibition by ritonavir.  
The extent of increase in AUC and Cmax depends on the timing of 
ritonavir administration.  Caution should be exercised in 
administering afatinib with Norvir (refer to the afatinib SmPC).  
Monitor for ADRs related to afatinib. 
 

Abemaciclib Serum concentrations may be increased due to CYP3A4 inhibition by 
ritonavir. 
 
Co-administration of abemaciclib and Norvir should be avoided.  If 
this co-administration is judged unavoidable, refer to the abemaciclib 
SmPC for dosage adjustment recommendations.  Monitor for ADRs 
related to abemaciclib. 
 



16 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Apalutamide Apalutamide is a moderate to strong CYP3A4 inducer and this may 
lead to a decreased exposure of ritonavir and potential loss of 
virologic response.  In addition, serum concentrations may be 
increased when co-administered with ritonavir resulting in the 
potential for serious adverse events including seizure.   
 
Concomitant use of ritonavir with apalutamide is not recommended. 
 

Ceritinib Serum concentrations may be increased due to CYP3A and P-gp 
inhibition by ritonavir.  Caution should be exercised in administering 
ceritinib with Norvir.  Refer to the ceritinib SmPC for dosage 
adjustment recommendations.  Monitor for ADRs related to ceritinib. 
 

Dasatinib, nilotinib, vincristine, vinblastine Serum concentrations may be increased when co-administered with 
ritonavir resulting in the potential for increased incidence of adverse 
events. 
 

Encorafenib Serum concentrations may be increased when co-administered with 
ritonavir which may increase the risk of toxicity, including the risk of 
serious adverse events such as QT interval prolongation.  
Co-administration of encorafenib and ritonavir should be avoided.  If 
the benefit is considered to outweigh the risk and ritonavir must be 
used, patients should be carefully monitored for safety. 
  

Fostamatinib 
 

Co-administration of fostamatinib with ritonavir may increase 
fostamatinib metabolite R406 exposure resulting in dose-related 
adverse events such as hepatotoxicity, neutropenia, hypertension, or 
diarrhoea.  Refer to the fostamatinib SmPC for dose reduction 
recommendations if such events occur. 
 

Ibrutinib Serum concentrations of ibrutinib may be increased due to CYP3A 
inhibition by ritonavir, resulting in increased risk for toxicity 
including risk of tumor lysis syndrome.  Co-administration of 
ibrutinib and ritonavir should be avoided.  If the benefit is considered 
to outweigh the risk and ritonavir must be used, reduce the ibrutinib 
dose to 140 mg and monitor patient closely for toxicity. 
 

Neratinib Serum concentrations may be increased due to CYP3A4 inhibition by 
ritonavir. 
 
Concomitant use of neratinib with Norvir is contraindicated due to 
serious and/or life-threatening potential reactions including 
hepatotoxicity (see section 4.3). 
 

Venetoclax Serum concentrations may be increased due to CYP3A inhibition by 
ritonavir, resulting in increased risk of tumor lysis syndrome at the 
dose initiation and during the ramp-up phase (see section 4.3 and 
refer to the venetoclax SmPC). 
 
For patients who have completed the ramp-up phase and are on a 
steady daily dose of venetoclax, reduce the venetoclax dose by at 
least 75% when used with strong CYP3A inhibitors (refer to the 
venetoclax SmPC for dosing instructions). 



17 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Anticoagulants 
 

Rivaroxaban 10, single dose 600 q12h ↑ 153% ↑ 55% 
 Inhibition of CYP3A and P-gp lead to increased plasma levels and 

pharmacodynamic effects of rivaroxaban which may lead to an 
increased bleeding risk.  Therefore, the use of ritonavir is not 
recommended in patients receiving rivaroxaban. 
 

Vorapaxar Serum concentrations may be increased due to CYP3A inhibition by 
ritonavir.  The co-administration of vorapaxar with Norvir is not 
recommended (see section 4.4 and refer to the vorapaxar SmPC). 
 

Warfarin 
S-Warfarin  
R-Warfarin 

5, single dose  400 q12h   
↑ 9%  
↓ 33%  

 
↓ 9%  
↔  

 Induction of CYP1A2 and CYP2C9 lead to decreased levels of R-
warfarin while little pharmacokinetic effect is noted on S- warfarin 
when co-administered with ritonavir.  Decreased R-warfarin levels 
may lead to reduced anticoagulation, therefore it is recommended that 
anticoagulation parameters are monitored when warfarin is co-
administered with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer. 
 

Anticonvulsants 
 

Carbamazepine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of carbamazepine.  Careful monitoring of 
therapeutic and adverse effects is recommended when carbamazepine 
is concomitantly administered with ritonavir. 
 

Divalproex, lamotrigine, phenytoin Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent induces oxidation by CYP2C9 and glucuronidation and as a 
result is expected to decrease the plasma concentrations of 
anticonvulsants.  Careful monitoring of serum levels or therapeutic 
effects is recommended when these medicines are concomitantly 
administered with ritonavir.  Phenytoin may decrease serum levels of 
ritonavir. 
 

Antidepressants 
 

Amitriptyline, fluoxetine, imipramine, 
nortriptyline, paroxetine, sertraline 

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 
and as a result is expected to increase concentrations of imipramine, 
amitriptyline, nortriptyline, fluoxetine, paroxetine or sertraline.  
Careful monitoring of therapeutic and adverse effects is 
recommended when these medicines are concomitantly administered 
with antiretroviral doses of ritonavir (see section 4.4). 
 

Desipramine 100, single oral dose 500 q12h ↑ 145% ↑ 22% 
 The AUC and Cmax of the 2-hydroxy metabolite were decreased 15 

and 67%, respectively.  Dosage reduction of desipramine is 
recommended when co-administered with ritonavir dosed as an 
antiretroviral agent. 
 



18 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Trazodone 50, single dose  200 q12h  ↑ 2.4-fold ↑ 34% 
 An increase in the incidence in trazodone-related adverse reactions 

was noted when co-administered with ritonavir dosed as an 
antiretroviral agent or as a pharmacokinetic enhancer.  If trazodone is 
co-administered with ritonavir, the combination should be used with 
caution, initiating trazodone at the lowest dosage and monitoring for 
clinical response and tolerability. 
 

Anti-gout treatments 
 

Colchicine Concentrations of colchicine are expected to increase when 
coadministered with ritonavir. 
Life-threatening and fatal drug interactions have been reported in 
patients treated with colchicine and ritonavir (CYP3A4 and P-gp 
inhibition) in patients with renal and/or hepatic impairment (see 
sections 4.3 and 4.4).  Refer to the colchicine prescribing information. 

Antihistamines 
 

Astemizole, terfenadine Ritonavir co-administration is likely to result in increased plasma 
concentrations of astemizole and terfenadine and is therefore 
contraindicated (see section 4.3). 
 

Fexofenadine Ritonavir may modify P-glycoprotein mediated fexofenadine efflux 
when dosed as an antriretroviral agent or as a pharmacokinetic 
enhancer resulting in increased concentrations of fexofenadine.  
Increased fexofenadine levels may lessen over time as induction 
develops. 
 

Loratadine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A and as a result is expected to increase the 
plasma concentrations of loratadine.  Careful monitoring of 
therapeutic and adverse effects is recommended when loratidine is 
concomitantly administered with ritonavir. 
 

Anti-infectives 
 

Fusidic Acid Ritonavir co-administration is likely to result in increased plasma 
concentrations of both fusidic acid and ritonavir and is therefore 
contraindicated (see section 4.3). 
 

Rifabutin1 
 
25-O-desacetyl rifabutin metabolite  

150 daily  500 q12h,  ↑ 4-fold  
 
↑ 38-fold  

↑ 2.5-fold  
 
↑ 16-fold 

 Due to the large increase in rifabutin AUC, the concomitant use of 
rifabutin with ritonavir dosed as an antiretroviral agent is 
contraindicated (see section 4.3).  The reduction of the rifabutin 
dose to 150 mg 3 times per week may be indicated for select PIs 
when co-administered with ritonavir as a pharmacokinetic enhancer.  
The Summary of Product Characteristics of the co-administered 
protease inhibitor should be consulted for specific recommendations.  
Consideration should be given to official guidance on the appropriate 
treatment of tuberculosis in HIV-infected patients.   
 



19 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Rifampicin Although rifampicin may induce metabolism of ritonavir, limited data 
indicate that when high doses of ritonavir (600 mg twice daily) is 
co-administered with rifampicin, the additional inducing effect of 
rifampicin (next to that of ritonavir itself) is small and may have no 
clinical relevant effect on ritonavir levels in high-dose ritonavir 
therapy.  The effect of ritonavir on rifampicin is not known. 
 

Voriconazole 200 q12h 400 q12h  ↓ 82% ↓ 66% 
 200 q12h 100 q12h ↓ 39% ↓ 24% 
 Concomitant use of ritonavir dosed as an antiretroviral agent and 

voriconazole is contraindicated due to reduction in voriconazole 
concentrations (see section 4.3).  Co-administration of voriconazole 
and ritonavir dosed as a pharmacokinetic enhancer should be avoided, 
unless an assessment of the benefit/risk to the patient justifies the use 
of voriconazole. 
 

Atovaquone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent induces glucuronidation and as a result is expected to decrease 
the plasma concentrations of atovaquone.  Careful monitoring of 
serum levels or therapeutic effects is recommended when atovaquone 
is concomitantly administered with ritonavir. 
 

Bedaquiline  
 

No interaction study is available with ritonavir only.  In an interaction 
study of single-dose bedaquiline and multiple dose 
lopinavir/ritonavir, the AUC of bedaquiline was increased by 22%.  
This increase is likely due to ritonavir and a more pronounced effect 
may be observed during prolonged co-administration.  Due to the risk 
of bedaquiline related adverse events, co-administration should be 
avoided.  If the benefit outweighs the risk, co-administration of 
bedaquiline with ritonavir must be done with caution.  More frequent 
electrocardiogram monitoring and monitoring of transaminases is 
recommended (see section 4.4 and refer to the bedaquiline Summary 
of Product Characteristics). 
 

Clarithromycin 
 
14-OH clarithromycin metabolite  

500 q12h  200 q8h ↑ 77%  
 
↓ 100%  

↑ 31%  
 
↓ 99%  

 Due to the large therapeutic window of clarithromycin no dose 
reduction should be necessary in patients with normal renal function.  
Clarithromycin doses greater than 1 g per day should not be 
co-administered with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer.  For patients with renal impairment, a 
clarithromycin dose reduction should be considered: for patients with 
creatinine clearance of 30 to 60 ml/min the dose should be reduced by 
50%, for patients with creatinine clearance less than 30 ml/min the 
dose should be reduced by 75%. 
 

Delamanid No interaction study is available with ritonavir only.  In a healthy 
volunteer drug interaction study of delamanid 100 mg twice daily and 
lopinavir/ritonavir 400/100 mg twice daily for 14 days, the exposure 
of the delamanid metabolite DM-6705 was 30% increased.  Due to 
the risk of QTc prolongation associated with DM-6705, if 
co-administration of delamanid with ritonavir is considered 
necessary, very frequent ECG monitoring throughout the full 
delamanid treatment period is recommended (see section 4.4 and 
refer to the delamanid Summary of Product Characteristics). 
 



20 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Erythromycin, itraconazole Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of erythromycin and itraconazole.  Careful 
monitoring of therapeutic and adverse effects is recommended when 
erythromycin or itraconazole is used concomitantly administered with 
ritonavir. 
 

Ketoconazole 200 daily 500 q12h ↑ 3.4-fold  ↑ 55%  
 Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole.  

Due to an increased incidence of gastrointestinal and hepatic adverse 
reactions, a dose reduction of ketoconazole should be considered 
when co-administered with ritonavir dosed as an antiretroviral agent 
or as a pharmacokinetic enhancer. 
 

Sulfamethoxazole/Trimethoprim2 800/160, single 
dose  

500 q12h  ↓ 20% / ↑ 20% ↔ 

 Dose alteration of sulfamethoxazole/trimethoprim during concomitant 
ritonavir therapy should not be necessary. 
 

Antipsychotics/Neuroleptics 
 

Clozapine, pimozide Ritonavir co-administration is likely to result in increased plasma 
concentrations of clozapine or pimozide and is therefore 
contraindicated (see section 4.3). 
 

Haloperidol, risperidone, thioridazine 
 

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 
and as a result is expected to increase concentrations of haloperidol, 
risperidone and thioridazine.  Careful monitoring of therapeutic and 
adverse effects is recommended when these medicines are 
concomitantly administered with antiretroviral doses of ritonavir. 
 

Lurasidone Due to CYP3A inhibition by ritonavir, concentrations of lurasidone 
are expected to increase.  The concomitant administration with 
lurasidone is contraindicated (see section 4.3). 

  
Quetiapine Due to CYP3A inhibition by ritonavir, concentrations of quetiapine 

are expected to increase.  Concomitant administration of Norvir and 
quetiapine is contraindicated as it may increase quetiapine-related 
toxicity (see section 4.3). 
 

β2-agonist (long acting)  

Salmeterol Ritonavir inhibits CYP3A4 and as a result a pronounced increase in 
the plasma concentrations of salmeterol is expected.  Therefore 
concomitant use is not recommended. 
 

Calcium channel antagonists 
 

Amlodipine, diltiazem, nifedipine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of calcium channel antagonists.  Careful 
monitoring of therapeutic and adverse effects is recommended when 
these medicines are concomitantly administered with ritonavir. 
 



21 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Endothelin antagonists 
 

Bosentan Co-administration of bosentan and ritonavir may increase steady state bosentan maximum concentrations (Cmax) and area under the curve 
(AUC) 
 

Riociguat Serum concentrations may be increased due to CYP3A and P-gp inhibition by ritonavir.  The co-administration of riociguat with 
Norvir is not recommended (see section 4.4 and refer to riociguat 
SmPC). 
 

Ergot Derivatives 
 

Dihydroergotamine, ergonovine, 
ergotamine, methylergonovine 

Ritonavir co-administration is likely to result in increased plasma 
concentrations of ergot derivatives and is therefore contraindicated 
(see section 4.3). 
 

GI motility agent 
 

Cisapride Ritonavir co-administration is likely to result in increased plasma 
concentrations of cisapride and is therefore contraindicated (see 
section 4.3). 
 

HCV Direct Acting Antiviral  
Glecaprevir/pibrentasvir Serum concentrations may be increased due to P-glycoprotein, BCRP 

and OATP1B inhibition by ritonavir. 
 
Concomitant administration of glecaprevir/pibrentasvir and Norvir is 
not recommended due to an increased risk of ALT elevations 
associated with increased glecaprevir exposure. 
 

HCV Protease Inhibitor  
Simeprevir 200 qd 100 q12h ↑ 7.2-fold ↑ 4.7-fold 
 Ritonavir increases plasma concentrations of simeprevir as a result of 

CYP3A4 inhibition.  It is not recommended to co-administer ritonavir 
with simeprevir. 
 



22 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

HMG Co-A Reductase Inhibitors 
 

Atorvastatin, Fluvastatin, Lovastatin, 
Pravastatin, Rosuvastatin, Simvastatin 

HMG-CoA reductase inhibitors which are highly dependent on 
CYP3A metabolism, such as lovastatin and simvastatin, are expected 
to have markedly increased plasma concentrations when co-
administered with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer.  Since increased concentrations of 
lovastatin and simvastatin  may predispose patients to myopathies, 
including rhabdomyolysis, the combination of these medicinal 
products with ritonavir is contraindicated (see section 4.3).  
Atorvastatin is less dependent on CYP3A for metabolism.  While 
rosuvastatin elimination is not dependent on CYP3A, an elevation of 
rosuvastatin exposure has been reported with ritonavir co-
administration.  The mechanism of this interaction is not clear, but 
may be the result of transporter inhibition.  When used with ritonavir 
dosed as a pharmacokinetic enhancer or as an antiretroviral agent, the 
lowest possible doses of atorvastatin or rosuvastatin should be 
administered.  The metabolism of pravastatin and fluvastatin is not 
dependent on CYP3A, and interactions are not expected with 
ritonavir.  If treatment with an HMG-CoA reductase inhibitor is 
indicated, pravastatin or fluvastatin is recommended. 
 

Hormonal contraceptive 
 

Ethinyl estradiol 50 µg, single 
dose  

500 q12h ↓ 40%  ↓ 32%  

 Due to reductions in ethinyl estradiol concentrations, barrier or other 
non-hormonal methods of contraception should be considered with 
concomitant ritonavir use when dosed as an antiretroviral agent or as 
a pharmacokinetic enhancer.  Ritonavir is likely to change the uterine 
bleeding profile and reduce the effectiveness of estradiol-containing 
contraceptives (see section 4.4). 
 

Immunosupressants 
 

Cyclosporine, tacrolimus, everolimus Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of cyclosporine, tacrolimus or everolimus.  
Careful monitoring of therapeutic and adverse effects is 
recommended when these medicines are concomitantly administered 
with ritonavir. 
 

Lipid-modifying agents 
 

Lomitapide CYP3A4 inhibitors increase the exposure of lomitapide, with strong 
inhibitors increasing exposure approximately 27-fold.  Due to 
CYP3A inhibition by ritonavir, concentrations of lomitapide are 
expected to increase.  Concomitant use of Norvir with lomitapide is 
contraindicated (see prescribing information for lomitapide) (see 
section 4.3). 
 

Phosphodiesterase (PDE5) 
inhibitors 

 

Avanafil 50, single dose 600 q12h ↑ 13-fold ↑ 2.4-fold 



23 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

 Concomitant use of avanafil with ritonavir is contraindicated (see 
section 4.3). 
 

Sildenafil 100, single dose  500 q12h ↑ 11-fold ↑ 4-fold 
 Concomitant use of sildenafil for the treatment of erectile 

dysfunction, with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer should be used with caution and in no 
instance should sildenafil doses exceed 25 mg in 48 hours (see also 
section 4.4).  Concomitant use of sildenafil with ritonavir is 
contraindicated in pulmonary arterial hypertension patients (see 
section 4.3). 
 

Tadalafil 20, single dose  200 q12h  ↑ 124% ↔ 
 The concomitant use of tadalafil for the treatment of erectile 

dysfunction with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer should be with caution at reduced doses of 
no more than 10 mg tadalafil every 72 hours with increased 
monitoring for adverse reactions (see section 4.4). 
 
When tadalafil is used concurrently with ritonavir in patients with 
pulmonary arterial hypertension, refer to the tadalafil Summary of 
Product Characteristics. 
 

Vardenafil 5, single dose 600 q12h ↑ 49-fold ↑ 13-fold 
 Concomitant use of vardenafil with ritonavir is contraindicated (see 

section 4.3). 
 

Sedatives/hynoptics 
 

Clorazepate, diazepam, estazolam, 
flurazepam, oral and parenteral midazolam  

Ritonavir co-administration is likely to result in increased plasma 
concentrations of clorazepate, diazepam, estazolam and flurazepam 
and is therefore contraindicated (see section 4.3).  
Midazolam is extensively metabolised by CYP3A4.  
Co-administration with Norvir may cause a large increase in the 
concentration of this benzodiazepine.  No medicinal product 
interaction study has been performed for the co-administration of 
Norvir with benzodiazepines.  Based on data for other CYP3A4 
inhibitors, plasma concentrations of midazolam are expected to be 
significantly higher when midazolam is given orally.  Therefore, 
Norvir should not be co-administered with orally administered 
midazolam (see section 4.3), whereas caution should be used with 
co-administration of Norvir and parenteral midazolam.  Data from 
concomitant use of parenteral midazolam with other protease 
inhibitors suggest a possible 3 – 4 fold increase in midazolam plasma 
levels.  If Norvir is co-administered with parenteral midazolam, it 
should be done in an intensive care unit (ICU) or similar setting 
which ensures close clinical monitoring and appropriate medical 
management in case of respiratory depression and/or prolonged 
sedation.  Dosage adjustment for midazolam should be considered, 
especially if more than a single dose of midazolam is administered. 
 

Triazolam 0.125, single 
dose 

200, 4 doses ↑ > 20 fold ↑ 87% 

 Ritonavir co-administration is likely to result in increased plasma 
concentrations of triazolam and is therefore contraindicated (see 
section 4.3). 
 



24 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Pethidine  
 
Norpethidine metabolite  

50, oral single 
dose  

500 q12h ↓ 62%  
 
↑ 47%  

↓ 59%  
 
↑ 87%  

 The use of pethidine and ritonavir is contraindicated due to the 
increased concentrations of the metabolite, norpethidine, which has 
both analgesic and CNS stimulant activity.  Elevated norpethidine 
concentrations may increase the risk of CNS effects (e.g., seizures), 
see section 4.3. 
 

Alprazolam 1, single dose  200 q12h, 2 
days 

↑ 2.5 fold ↔ 

  500 q12h, 10 
days 

↓ 12%  ↓ 16%  

 Alprazolam metabolism was inhibited following the introduction of 
ritonavir.  After ritonavir use for 10 days, no inhibitory effect of 
ritonavir was observed.  Caution is warranted during the first several 
days when alprazolam is co-administered with ritonavir dosed as an 
antiretroviral agent or as a pharmacokinetic enhancer, before 
induction of alprazolam metabolism develops. 
 

Buspirone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A and as a result is expected to increase the 
plasma concentrations of buspirone.  Careful monitoring of 
therapeutic and adverse effects is recommended when buspirone 
concomitantly administered with ritonavir. 
 

Sleeping agent  

Zolpidem 5  200, 4 doses ↑ 28% ↑ 22% 
 Zolpidem and ritonavir may be co-administered with careful 

monitoring for excessive sedative effects. 
 

Smoke cessation  

Bupropion 150  100 q12h ↓ 22% ↓ 21% 
 150  600 q12h ↓ 66% ↓ 62% 
 Bupropion is primarily metabolised by CYP2B6.  Concurrent 

administration of bupropion with repeated doses of ritonavir is 
expected to decrease bupropion levels.  These effects are thought to 
represent induction of bupropion metabolism.  However, because 
ritonavir has also been shown to inhibit CYP2B6 in vitro, the 
recommended dose of bupropion should not be exceeded.  In contrast 
to long-term administration of ritonavir, there was no significant 
interaction with bupropion after short-term administration of low 
doses of ritonavir (200 mg twice daily for 2 days), suggesting 
reductions in bupropion concentrations may have onset several days 
after initiation of ritonavir co-administration. 
 

Steroids  

Inhaled, injectable or intranasal fluticasone 
propionate, budesonide, triamcinolone 

Systemic corticosteroid effects including Cushing's syndrome and 
adrenal suppression (plasma cortisol levels were noted to be 
decreased 86% in the above study) have been reported in patients 
receiving ritonavir and inhaled or intranasal fluticasone propionate; 
similar effects could also occur with other corticosteroids metabolised 
by CYP3A e.g., budesonide and triamcinolone.  Consequently, 
concomitant administration of ritonavir dosed as an antiretroviral 
agent or as a pharmacokinetic enhancer and these glucocorticoids is 



25 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

not recommended unless the potential benefit of treatment outweighs 
the risk of systemic corticosteroid effects (see section 4.4).  A dose 
reduction of the glucocorticoid should be considered with close 
monitoring of local and systemic effects or a switch to a 
glucocorticoid, which is not a substrate for CYP3A4 (e.g., 
beclomethasone).  Moreover, in case of withdrawal of glucocorticoids 
progressive dose reduction may be required over a longer period.    
  

Dexamethasone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A and as a result is expected to increase the 
plasma concentrations of dexamethasone.  Careful monitoring of 
therapeutic and adverse effects is recommended when dexamethasone 
is concomitantly administered with ritonavir.   
 

Prednisolone 20 200 q12h ↑ 28% ↑ 9% 
 Careful monitoring of therapeutic and adverse effects is 

recommended when prednisolone is concomitantly administered with 
ritonavir.  The AUC of the metabolite prednisolone increased by 37 
and 28% after 4 and 14 days ritonavir, respectively. 
 

Thyroid hormone replacement 
therapy 

 

Levothyroxine Post-marketing cases have been reported indicating a potential 
interaction between ritonavir containing products and levothyroxine.  
Thyroid-stimulating hormone (TSH) should be monitored in patients 
treated with levothyroxine at least the first month after starting and/or 
ending ritonavir treatment. 

 ND: Not determined 
1. Based on a parallel group comparison 
2. Sulfamethoxazole was co-administered with trimethoprim.  

 
Cardiac and neurologic events have been reported when ritonavir has been co-administered with 
disopyramide, mexiletine or nefazodone.  The possibility of medicinal product interaction cannot be 
excluded. 
 
In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of 
increased therapeutic and toxic effects due to protein binding displacement of concomitant medicinal 
products should be considered. 
 
Ritonavir dosed as a pharmacokinetic enhancer 
 
Important information regarding medicinal product interactions when ritonavir is used a 
pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the co-
administered protease inhibitor.  
 
Proton pump inhibitors and H2-receptor antagonists 
Proton pump inhibitors and H2-receptor antagonists (e.g. omeprazole or ranitidine) may reduce 
concentrations for co-administered protease inhibitors.  For specific information regarding the impact 
of co-administration of acid reducing agents, refer to the Summary of Product Characteristics of the 
co-administered protease inhibitor.  Based on interaction studies with the ritonavir boosted protease 
inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does 
not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of 
exposure (about 6 - 18%). 



26 
 

 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of 
these, 2800 live births were exposed during the first trimester.  These data largely refer to exposures 
where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower 
doses as a pharmacokinetic enhancer for other PIs.  These data indicate no increase in the rate of birth 
defects compared to rates observed in population-based birth defect surveillance systems.  Animal data 
have shown reproductive toxicity (see section 5.3).  Norvir can be used during pregnancy if clinically 
needed. 
 
Ritonavir adversely interacts with oral contraceptives (OCs).  Therefore, an alternative, effective and 
safe method of contraception should be used during treatment. 
 
Breastfeeding 
Limited published data reports that ritonavir is present in human milk. 
 
There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on 
milk production.  Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) 
developing viral resistance (in HIV-postive infants) and (3) serious adverse reactions in a breastfed 
infant,  HIV infected women should not breast feed their infants under any circumstances if they are 
receiving Norvir. 
 
Fertility  
No human data on the effect of ritonavir on fertility are available.  Animal studies do not indicate 
harmful effects of ritonavir on fertility (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.   Dizziness is a 
known undesirable effect that should be taken into account when driving or using machinery. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Ritonavir dosed as a pharmacokinetic enhancer 
 
Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on 
the specific co-administered PI.  For information on adverse reactions refer to the SPC of the specific 
co-administered PI. 
 
Ritonavir dosed as an antiretroviral agent 
 
Adverse reactions from clinical trials and post-marketing experience in adult patients 
 
The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in 
combination with other antiretroviral drugs were gastrointestinal (including diarrhoea, nausea, 
vomiting, abdominal pain (upper and lower)), neurological disturbances (including paraesthesia and 
oral paraesthesia) and fatigue/asthenia. 
 
Tabulated list of adverse reactions 
 
The following adverse reactions of moderate to severe intensity with possible or probable relationship 
to ritonavir have been reported.  Within each frequency grouping, undesirable effects are presented in 
order of decreasing seriousness: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon 



27 
 

(≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from the 
available data). 
 
Events noted as having a frequency not known were identified via post-marketing surveillance 
 

Adverse reactions in clinical studies and post-marketing in adult patients 

System Order Class Frequency Adverse reaction 

Blood and lymphatic system 
disorders 

Common 
 

Decreased white blood cells, decreased 
haemoglobin, decreased neutrophils, 
increased eosinophils, thrombocytopenia 
 

Uncommon Increased neutrophils  
 

Immune system disorders Common Hypersensitivity, including urticaria and 
face oedema. 
 

 Rare Anaphylaxis 
 

Metabolism and nutrition 
disorders 

Common Hypercholesterolaemia, 
hypertriglyceridaemia, gout, oedema and 
peripheral oedema, dehydration (usually 
associated with gastrointestinal symptoms) 

 Uncommon Diabetes mellitus 
 

 Rare Hyperglycaemia 
Nervous system disorders Very common 

 
Dysgeusia, oral and peripheral paraesthesia, 
headache, dizziness, peripheral neuropathy 
 

Common Insomnia, anxiety, confusion, disturbance in 
attention, syncope, seizure 

Eye disorders Common Blurred vision 

Cardiac disorders Uncommon Myocardial infarction 

Vascular disorders Common Hypertension, hypotension including 
orthostatic hypotension, peripheral coldness 

   
Respiratory, thoracic and 
mediastinal disorders 
 

Very common Pharyngitis, oropharyngeal pain, cough  

Gastrointestinal disorders Very common 
 

Abdominal pain (upper and lower), nausea, 
diarrhoea (including severe with electrolyte 
imbalance), vomiting, dyspepsia 
 

Common Anorexia, flatulence, mouth ulcer, 
gastrointestinal haemorrhage, 
gastroesophageal reflux disease, pancreatitis 
 

Hepatobiliary disorders Common Hepatitis (including increased AST, ALT, 
GGT), blood bilirubin increased (including 
jaundice) 
 

Skin and subcutaneous tissue 
disorders 
 

Very common Pruritus, rash (including erythematous and 
maculopapular) 



28 
 

Adverse reactions in clinical studies and post-marketing in adult patients 

System Order Class Frequency Adverse reaction 

 Common 
 

Acne 

 Rare Stevens Johnson syndrome, toxic epidermal 
necrolysis (TEN) 

Musculosketal and connective 
tissue disorders 

Very common 
 

Arthralgia and back pain 
 

Common Myositis, rhabdomyolysis, myalgia, 
myopathy/CPK increased 
 

Renal and urinary disorders Common Increased urination, renal impairment (e.g. 
oliguria, elevated creatinine) 
 

 Uncommon 
 

Not known 

Acute renal failure 
 
Nephrolithiasis 

Reproductive system and breast 
disorders 

Common Menorrhagia 

General disorders and 
administration site conditions 

Very common 
 

Fatigue including asthenia, flushing, feeling 
hot 
 

Common Fever, weight loss 
 

Investigations Common 
 

Increased amylase, decreased free and total 
thyroxine  
 

Uncommon Increased glucose, increased magnesium, 
increased alkaline phosphatase 

 
Description of selected adverse reactions 
 
Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and 
jaundice have occurred in patients receiving ritonavir alone or in combination with other 
antiretrovirals. 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4). 
 
In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and can occur many months 
after initiation of treatment (see section 4.4). 
 
Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed 
hypertriglyceridaemia.  In some cases fatalities have been observed.  Patients with advanced HIV 
disease may be at risk of elevated triglycerides and pancreatitis (see section 4.4). 
 
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).  
The frequency of this is unknown (see section 4.4). 
 



29 
 

Paediatric populations 
 
The safety profile of Norvir in children 2 years of age and older is similar to that seen in adults. 
 
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 
 
Symptoms 
Human experience of acute overdose with ritonavir is limited.  One patient in clinical trials took 
ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was 
decreased.  A case of renal failure with eosinophilia has been reported. 
 
The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea 
and tremors. 
 
Management 
There is no specific antidote for overdose with ritonavir.  Treatment of overdose with ritonavir should 
consist of general supportive measures including monitoring of vital signs and observation of the 
clinical status of the patient.  Due to the solubility characteristics and possibility of transintestinal 
elimination, it is proposed that management of overdose could entail gastric lavage and administration 
of activated charcoal.  Since ritonavir is extensively metabolised by the liver and is highly protein 
bound, dialysis is unlikely to be beneficial in significant removal of the medicine.   
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmaco-therapeutic group: antiviral for systemic use, protease inhibitors ATC code: J05AE03 
 
Ritonavir dosed as a pharmacokinetic enhancer 
 
Pharmacokinetic enhancement by ritonavir is based on ritonavir’s activity as a potent inhibitor of 
CYP3A- mediated metabolism.  The degree of enhancement is related to the metabolic pathway of the 
co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the 
metabolism of ritonavir.  Maximal inhibition of metabolism of the co-administered protease inhibitor 
is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on 
the co-administered protease inhibitor.  For additional information on the effect of ritonavir on 
co-administered protease inhibitor metabolism, see section 4.5 and refer to the Summary of Product 
Characteristics of the particular co-administered PIs. 
 
Ritonavir dosed as an antiretroviral agent 
 
Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases.  
Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein 
precursor which leads to the production of HIV particles with immature morphology that are unable to 
initiate new rounds of infection.  Ritonavir has selective affinity for the HIV protease and has little 
inhibitory activity against human aspartyl proteases. 
 
Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a study 
with clinical endpoints.  However, due to ritonavir’s metabolic inhibitory properties its use as a 

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


30 
 

pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical 
practice (see section 4.2).  
 
Effects on the Electrocardiogram   
 
QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) 
controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3.  The 
maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 
400 mg twice daily ritonavir.  The Day 3 ritonavir exposure was approximately 1.5 fold higher than 
that observed with the 600 mg twice daily dose at steady state.  No subject experienced an increase in 
QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant 
threshold of 500 msec. 
 
Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study 
on Day 3.  The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12 
hour interval post dose.  Maximum PR interval was 252 msec and no second or third degree heart 
block was observed (see section 4.4). 
 
Resistance 
 
Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with 
therapeutic doses of ritonavir.  
  
Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations 
V82A/F/T/S and I84V.  Accumulation of other mutations in the protease gene (including at positions 
20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance.  In general, as mutations 
associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to 
cross-resistance.  The Summary of Product Characteristics of other protease inhibitors or official 
continuous updates should be consulted for specific information regarding protease mutations 
associated with reduced response to these agents. 
   
Clinical pharmacodynamic data 
 
The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of 
disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving 
HIV-1 infected patients.  The following studies are the most important. 
 
Adult Use 
 
A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients 
extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/µl showed 
a reduction in mortality and AIDS defining events.  The mean average change from baseline over 16 
weeks for HIV RNA levels was -0.79 log10 (maximum mean decrease: 1.29 log10) in the ritonavir 
group versus-0.01 log10 in the control group.  The most frequently used nucleosides in this study were 
zidovudine, stavudine, didanosine and zalcitabine.  
 
In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/µl) 
without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced 
viral load in plasma and increased CD4 count.  The mean average change from baseline over 48 weeks 
for HIV RNA levels was -0.88 log10 in the ritonavir group versus -0.66 log10 in the ritonavir + 
zidovudine group versus -0.42 log10 in the zidovudine group. 
 
The continuation of ritonavir therapy should be evaluated by viral load because of the possibility of 
the emergence of resistance as described under section 4.1. 
 



31 
 

Paediatric Use 
 
In an open label trial completed in 1998 in HIV infected, clinically stable children there was a 
significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir, 
zidovudine and lamivudine) following 48 weeks treatment. 
 
In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age 
4 weeks to 2 years received ritonavir 350 or 450 mg/m2 every 12 hours co-administered with 
zidovudine 160 mg/m2 every 8 hours and lamivudine 4 mg/kg every 12 hours.  In intent to treat 
analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at 
Week 16 and 104, respectively.  Response was similar in both dosing regimens and across patient age.   
 
In a study completed in 2000, 76 HIV-1 infected children aged 6 months to 12 years who were 
protease inhibitor naive and naive to lamivudine and/or stavudine received ritonavir 350 or 450 mg/m2 
every 12 hours co-administered with lamivudine and stavudine.  In intent to treat analyses, 50% and 
57% of patients in the 350 and 450 mg/m2 dose groups, respectively, achieved reduction in plasma 
HIV-1 RNA to ≤ 400 copies/ml at Week 48. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute 
bioavailability has not been determined.  The pharmacokinetics of ritonavir during multiple dose 
regimens were studied in non-fasting HIV-infected adult volunteers.  Upon multiple dosing, ritonavir 
accumulation is slightly less than predicted from a single dose due to a time and dose-related increase 
in apparent clearance (Cl/F).  Trough concentrations of ritonavir decrease over time, possibly due to 
enzyme induction, but appeared to stabilise by the end of 2 weeks.  The time to maximum 
concentration (Tmax) remained constant at approximately 4 hours with increasing dose.  Renal 
clearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range. 
 
The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shown 
in the table below. 
 

Ritonavir Dosing Regimen 
 100 mg   once 

daily 
100 mg twice 

daily1 
200 mg once 

daily 
200 mg twice 

daily 
600 mg twice 

daily 
Cmax (µg/ml) 0.84 ± 0.39 0.89 3.4 ± 1.3 4.5 ± 1.3 11.2 ± 3.6 
Ctrough (µg/ml) 0.08 ± 0.04 0.22 0.16 ± 0.10 0.6 ± 0.2 3.7 ± 2.6 
AUC12 or 24 
(µg•h/ml) 

6.6 ± 2.4 6.2 20.0 ± 5.6 21.92 ± 6.48 77.5 ± 31.5 

t½ (h) ~5 ~5 ~4 ~8 ~3 to 5 
Cl/F (L/h) 17.2 ± 6.6 16.1 10.8 ± 3.1 10.0 ± 3.2 8.8 ± 3.2 

1 Values expressed as geometric means.  Note: ritonavir was dosed after a meal for all listed regimens. 
 
Effects of food on oral absorption 
 
Administration of a single 100 mg dose of ritonavir powder for oral suspension with a moderate fat 
meal (617 kcal, 29% calories from fat) was associated with a mean decrease of 23 and 39% in 
ritonavir AUCinf and Cmax  respectively, relative to fasting conditions. Administration with a high fat 
meal (917 kcal, 60% calories from fat) was associated with a mean decrease of 32 and 49% in 
ritonavir AUCinf and Cmax respectively, relative to fasting conditions. 
 
Distribution 
The apparent volume of distribution (VB/F) of ritonavir is approximately 20 - 40 l after a single 
600 mg dose.  The protein binding of ritonavir in human plasma is approximately 98 - 99% and is 



32 
 

constant over the concentration range of 1.0 – 100 µg/ml.  Ritonavir binds to both human alpha 1-acid 
glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities. 
 
Tissue distribution studies with 14C-labelled ritonavir in rats showed the liver, adrenals, pancreas, 
kidneys and thyroid to have the highest concentrations of ritonavir.  Tissue to plasma ratios of 
approximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues.  
Ritonavir penetrates minimally into the brain. 
 
Biotransformation 
Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily 
by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform.  Animal studies as well 
as in vitro experiments with human hepatic microsomes indicated that ritonavir primarily underwent 
oxidative metabolism.  Four ritonavir metabolites have been identified in man.  The isopropylthiazole 
oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent 
compound.  However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent 
compound.   
 
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease 
inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence 
the pharmacokinetics of ritonavir (see section 4.5).   
 
Elimination 
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was 
primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, 
part of which is expected to be unabsorbed ritonavir.  In these studies renal elimination was not found 
to be a major route of elimination of ritonavir.  This was consistent with the observations in animal 
studies. 
 
Special populations 
 
No clinically significant differences in AUC or Cmax were noted between males and females.  
Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weight 
or lean body mass.  Ritonavir plasma exposures in patients 50 – 70 years of age when dosed 100 mg in 
combination with lopinavir or at higher doses in the absence of other protease inhibitors is similar to 
that observed in younger adults. 
 
Patients with impaired liver function 
After multiple dosing of ritonavir to healthy volunteers (500 mg twice daily) and subjects with mild to 
moderate hepatic impairment (Child Pugh Class A and B, 400 mg twice daily) exposure to ritonavir 
after dose normalisation was not significantly different between the two groups.   
 
Patients with impaired renal function 
Ritonavir pharmacokinetic parameters have not been studied in patients with renal impairment.  
However, since the renal clearance of ritonavir is negligible, no changes in the total body clearance are 
expected in patients with renal impairment.   
 
Paediatric patients 
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children above 2 
years of age receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily.  Ritonavir 
concentrations obtained after 350 to 400 mg/m² twice daily in paediatric patients were comparable to 
those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily.  Across dose 
groups, ritonavir oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in paediatric 
patients above 2 years of age than in adult subjects. 
 
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than 
2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily.  Ritonavir concentrations in 
this study were highly variable and somewhat lower than those obtained in adults receiving 600 mg 



33 
 

(approximately 330 mg/m²) twice daily.  Across dose groups, ritonavir oral clearance (CL/F/m2) 
declined with age with median values of 9.0 L/h/m2 in children less than 3 months of age, 7.8 L/h/m2 
in children between 3 and 6 months of age and 4.4 L/h/m2 in children between 6 and 24 months of age. 
 
5.3 Preclinical safety data 
 
Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid 
gland and kidney.  Hepatic changes involved hepatocellular, biliary and phagocytic elements and were 
accompanied by increases in hepatic enzymes.  Hyperplasia of the retinal pigment epithelium (RPE) 
and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have 
not been seen in dogs.  Ultrastructural evidence suggests that these retinal changes may be secondary 
to phospholipidosis.  However, clinical trials revealed no evidence of medicinal product-induced 
ocular changes in humans.  All thyroid changes were reversible upon discontinuation of ritonavir.  
Clinical investigation in humans has revealed no clinically significant alteration in thyroid function 
tests.  Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted 
in rats and are felt to be attributable to species-specific spontaneous disease.  Furthermore, no 
clinically significant renal abnormalities were noted in clinical trials. 
 
Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and 
ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a 
maternally toxic dosage.  Developmental toxicity in rabbits (embryolethality, decreased litter size and 
decreased foetal weights) occurred at a maternally toxic dosage. 
 
Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays 
including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse 
lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human 
lymphocytes. 
 
Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential 
specific for these species, but are regarded as of no relevance for humans. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Copovidone 
Sorbitan laurate  
Silica, colloidal anhydrous  
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
36 months. 
Following mixing with food or liquid as described in section 4.2: consume within 2 hours.  
 
6.4 Special precautions for storage 
 
Store below 30°C. 
 



34 
 

6.5 Nature and contents of container 
 
Polyethylene/aluminium/polyethylene terephthalate foil sachet.  30 sachets per carton.  Packaged with 
a mixing cup and two 10 ml calibrated oral dosing syringes.  
 
6.6 Special precautions for disposal and other handling 
 
For details on preparation and administration of Norvir powder for oral suspension, refer the patient or 
care giver to the Package Leaflet, section 3. 
 
Administering with food 
• The entire contents of each sachet is to be poured over a small amount of soft food (e.g. apple 

sauce or vanilla pudding). All of the mixed soft food must be administered within 2 hours.  
 
Administering with liquid 
The entire contents of each sachet should be suspended in 9.4 ml of liquid (water, chocolate milk, or 
infant formula) giving a final concentration of 10 mg per ml. The patient/caregiver is to be instructed 
to follow the directions below:  
• The oral dosing syringe and mixing cup should be washed in warm water and dish soap, then 

rinsed and allowed to air dry prior to first use.  
• Draw up 9.4 ml of liquid using the provided oral dosing syringe, remove the bubbles, and 

transfer the liquid to the mixing cup. All measuring should be done in ml using the syringe.  
• Pour the entire contents of 1 sachet (100 mg) into the mixing cup.  
• Close the lid and shake hard for at least 90 seconds until all the lumps have dissolved. 
• Let the liquid stand for 10 minutes in order for most of the bubbles to disappear. 
• Use the provided oral dosing syringe to measure and administer the prescribed ml volume (see 

section 4.2). Be sure to remove the bubbles prior to dose administration. 
• Once the powder is mixed, the prepared suspension should be used within 2 hours. 
• Discard any mixture remaining in the mixing cup.  
• The oral dosing syringe and mixing cup should be cleaned immediately with warm water and 

dish soap after use.  
• If the syringe breaks or becomes hard to use, the syringe should be thrown away and the new 

one used. 
 

 
7.  MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/016/009 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  26 August 1996 
Date of latest renewal:  26 August 2006 
 
 



35 
 

10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 

http://www.ema.europa.eu/


36 
 

1. NAME OF THE MEDICINAL PRODUCT  
 
Norvir 100 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 
Each film-coated tablet contains 100 mg ritonavir.  
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM  
 
Film-coated tablet. 
 
White, oval, debossed with [Abbott logo] and “NK”.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 
infected patients (adults and children of 2 years of age and older). 
 
4.2 Posology and method of administration 
 
Ritonavir should be administered by physicians who are experienced in the treatment of HIV infection. 
 
Ritonavir film-coated tablets are administered orally and should be ingested with food (see section 
5.2). 
 
Norvir film-coated tablets should be swallowed whole and not chewed, broken or crushed. 
 
Posology 
 
Ritonavir dosed as a pharmacokinetic enhancer  
 
When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary 
of Product Characteristics for the particular protease inhibitor must be consulted. 
 
The following HIV-1 protease inhibitors have been approved for use with ritonavir as a 
pharmacokinetic enhancer at the noted doses.   
 
Adults 

Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily. 
Atazanavir 300 mg once daily with ritonavir 100 mg once daily. 
Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily. 
Lopinavir co-formulated with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200 mg. 
Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART experienced patients. 
Initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the 
first 7 days, then saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART-
naïve patients. 
Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily.  Tipranavir with ritonavir 
should not be used in treatment-naïve patients. 



37 
 

 Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment. 
(ART) experienced patients.  Darunavir 800 mg once daily with ritonavir 100 mg once daily 
may be used in some ART experienced patients. Refer to the darunavir Summary of Product 
Characteristics for further information on once daily dosing in ART experienced patients. 

 Darunavir 800 mg once daily with ritonavir 100 mg once daily in ART-naïve patients. 
 

Children and adolescents 
Ritonavir is recommended for children 2 years of age and older.  For further dosage recommendations, 
refer to the product information of other Protease Inhibitors approved for co-administration with 
ritonavir.   
 
Special populations 
 
Renal impairment 
As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for use with caution as 
a pharmacokinetic enhancer in patients with renal insufficiency depending on the specific protease 
inhibitor with which it is co-administered.  However, since the renal clearance of ritonavir is 
negligible, the decrease in the total body clearance is not expected in patients with renal impairment.  
For specific dosing information in patients with renal impairment, refer to the Summary of Product 
Characteristics (SPC) of the co-administered protease inhibitor.  
 
Hepatic impairment 
Ritonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver 
disease, (see section 4.3).  In the absence of pharmacokinetic studies in patients with stable severe 
hepatic impairment (Child Pugh Grade C) without decompensation, caution should be exercised when 
ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-administered PI may 
occur.  Specific recommendations for use of ritonavir as a pharmacokinetic enhancer in patients with 
hepatic impairment are dependent on the protease inhibitor with which it is co-administered.  The SPC 
of the co-administered PI should be reviewed for specific dosing information in this patient 
population.  
 
Ritonavir dosed as an antiretroviral agent 
 
Adults 
The recommended dose of Norvir film-coated tablets is 600 mg (6 tablets) twice daily (total of 
1200 mg per day) by mouth. 
 
Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance.  
Treatment should be initiated at 300 mg (3 tablets) twice daily for a period of three days and increased 
by 100 mg (1 tablet) twice daily increments up to 600 mg twice daily over a period of no longer than 
14 days.  Patients should not remain on 300 mg twice daily for more than 3 days. 
 
Children and adolescents (2 years of age and above) 
The recommended dosage of Norvir in children is 350 mg/m² by mouth twice daily and should not 
exceed 600 mg twice daily.  Norvir should be started at 250 mg/m² and increased at 2 to 3 day 
intervals by 50 mg/m² twice daily (please refer to the Norvir 100 mg powder for oral suspension 
Summary of Product Characteristics). 
 
For older children it may be feasible to substitute tablets for the maintenance dose of the powder for 
oral suspension.  
 



38 
 

Dosage conversion from powder for oral suspension to tablets for children 
 

Powder for oral suspension dose Tablet dose 
176 mg (17.6 ml) twice daily 200 mg in the morning and 200 mg in the 

evening 
262.5 mg (26.4 ml) twice daily 300 mg in the morning and 300 mg in the 

evening 
350 mg (35.0 ml) twice daily 400 mg in the morning and 300 mg in the 

evening  
438 mg (43.8 ml) twice daily 500 mg in the morning and 400 mg in the 

evening 
526 mg (52.6 ml) twice daily 500 mg in the morning and 500 mg in the 

evening 
 
Norvir is not recommended in children below 2 years of age due to lack of data on safety and efficacy. 
 
Special populations 
 
Elderly 
Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section 
5.2). 
 
Renal impairment 
Currently, there are no data specific to this patient population and therefore specific dosage 
recommendations cannot be made.  The renal clearance of ritonavir is negligible therefore; a decrease 
in the total body clearance is not expected in patients with renal impairment.  Because ritonavir is 
highly protein bound it is unlikely that it will be significantly removed by haemodialysis or peritoneal 
dialysis. 
 
Hepatic impairment 
Ritonavir is principally metabolised and eliminated by the liver.  Pharmacokinetic data indicate that no 
dose adjustment is necessary in patients with mild to moderate hepatic impairment (see section 5.2).  
Ritonavir must not be given to patients with severe hepatic impairment (see section 4.3).   
 
Paediatric population 
The safety and efficacy of Norvir in childred aged below 2 years has not been established. Currently 
available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be 
made. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.   
 
When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the Summary of Product 
Characteristics of the co-administered protease inhibitor for contraindications. 
 
Ritonavir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients 
with decompensated liver disease.  
 
In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and 
CYP2D6- mediated biotransformations.  The following medicines are contraindicated when used with 
ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to 
inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the 
co-administered medicinal product and risk of clinically significant adverse effects. 
 



39 
 

The enzyme-modulating effect of ritonavir may be dose dependent.  For some products, 
contraindications may be more relevant when ritonavir is used as an antiretroviral agent than when 
ritonavir is used as a pharmacokinetic enhancer (e.g. rifabutin and voriconazole): 
 

Medicinal Product 
Class 

Medicinal Products 
within Class 

Rationale 

Concomitant medicinal product levels increased or decreased 

α1-Adrenoreceptor 
Antagonist 

Alfuzosin Increased plasma concentrations of alfuzosin 
which may lead to severe hypotension (see 
section 4.5). 

Analgesics Pethidine, piroxicam, 
propoxyphne 

Increased plasma concentrations of 
norpethidine, piroxicam and propoxyphene.  
Thereby, increasing the risk of serious 
respiratory depression or haematologic 
abnormalities, or other serious adverse effects 
from these agents. 

Antianginal Ranolazine Increased plasma concentrations of ranolazine 
which may increase the potential for serious 
and/or life-threatening reactions (see section 
4.5). 

Anticancer Neratinib Increased plasma concentrations of neratinib 
which may increase the potential for serious 
and/or life-threatening reactions including 
hepatotoxicity (see section 4.5). 

Venetoclax Increased plasma concentrations of venetoclax. 
Increased risk of tumor lysis syndrome at the 
dose initiation and during the dose-titration 
phase (see section 4.5). 

Antiarrhythmics Amiodarone, bepridil, 
dronedarone, 
encainide, flecainide, 
propafenone, quinidine 
 

Increased plasma concentrations of amiodarone, 
bepridil, dronedarone, encainide, flecainide, 
propafenone, quinidine.  Thereby, increasing 
the risk of arrhythmias or other serious adverse 
effects from these agents. 

Antibiotic Fusidic Acid Increased plasma concentrations of fusidic acid 
and ritonavir. 

Antifungal Voriconazole Concomitant use of ritonavir (400 mg twice 
daily and more) and voriconazole is 
contraindicated due to a reduction in 
voriconazole plasma concentrations and 
possible loss of effect (see section 4.5). 

Antihistamines Astemizole, 
terfenadine 

Increased plasma concentrations of astemizole 
and terfenadine.  Thereby, increasing the risk of 
serious arrhythmias from these agents. 

Anti-gout Colchicine Potential for serious and/or life-threatening 
reactions in patients with renal and/or hepatic 
impairment (see sections 4.4 and 4.5). 

Antimycobacterial Rifabutin Concomitant use of ritonavir (500 mg twice 
daily) dosed as an antiretroviral agent and 
rifabutin due to an increase of rifabutin serum 
concentrations and risk of adverse reactions 
including uveitis (see section 4.4).  
Recommendations regarding use of ritonavir 
dosed as a pharmacokinetic enhancer with 
rifabutin are noted in section 4.5.   



40 
 

Antipsychotics/ 
Neuroleptics 

Lurasidone Increased plasma concentrations of lurasidone 
which may increase the potential for serious 
and/or life-threatening reactions (see section 
4.5). 

Clozapine, pimozide Increased plasma concentrations of clozapine 
and pimozide.  Thereby, increasing the risk of 
serious haematologic abnormalities, or other 
serious adverse effects from these agents. 

Quetiapine Increased plasma concentrations of quetiapine 
which may lead to coma.  The concomitant 
administration with quetiapine is 
contraindicated (see section 4.5). 

Ergot Derivatives Dihydroergotamine, 
ergonovine, 
ergotamine, 
methylergonovine 

Increased plasma concentrations of ergot 
derivatives leading to acute ergot toxicity, 
including vasospasm and ischaemia. 

GI motility agent Cisapride Increased plasma concentrations of cisapride.  
Thereby, increasing the risk of serious 
arrhythmias from this agent. 

Lipid-modifying agents 
 
HMG Co-A Reductase 
Inhibitors 

Lovastatin, simvastatin Increased plasma concentrations of lovastatin 
and simvastatin; thereby, increasing the risk of 
myopathy including rhabdomyolysis (see 
section 4.5). 
 

Microsomal 
triglyceride transfer 
protein (MTTP) 
inhibitor 

Lomitapide Increased plasma concentrations of lomitapide 
(see section 4.5). 

PDE5 inhibitor Avanafil Increased plasma concentrations of avanafil 
(see section 4.4. and 4.5). 

Sildenafil  Contraindicated when used for the treatment of 
pulmonary arterial hypertension (PAH) only.  
Increased plasma concentrations of sildenafil.  
Thereby, increasing the potential for sildenafil-
associated adverse events (which include 
hypotension and syncope).  See section 4.4 and 
section 4.5 for co-administration of sildenafil in 
patients with erectile dysfunction. 

Vardenafil Increased plasma concentrations of vardenafil 
(see section 4.4. and 4.5). 

Sedatives/hypnotics Clorazepate, diazepam, 
estazolam, flurazepam, 
oral midazolam and 
triazolam 

Increased plasma concentrations of clorazepate, 
diazepam, estazolam, flurazepam, oral 
midazolam and triazolam.  Thereby, increasing 
the risk of extreme sedation and respiratory 
depression from these agents.  (For caution on 
parenterally administered midazolam, see 
section 4.5.). 

Ritonavir medicinal product level decreased 

Herbal Preparation St. John’s Wort Herbal preparations containing St John’s wort 
(Hypericum perforatum) due to the risk of 
decreased plasma concentrations and reduced 
clinical effects of ritonavir (see section 4.5). 

 



41 
 

4.4 Special warnings and precautions for use 
 
Ritonavir is not a cure for HIV-1 infection or AIDS.  Patients receiving Ritonavir or any other 
antiretroviral therapy may continue to develop opportunistic infections and other complications of 
HIV-1 infection.  
 
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce 
the risk of sexual transmission, a residual risk cannot be excluded.  Precautions to prevent transmission 
should be taken in accordance with national guidelines. 
 
When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings and 
precautions relevant to that particular PI should be considered, therefore the Summary of Product 
Characteristics for the particular PI must be consulted. 
 
Ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer   
 
Patients with chronic diarrhoea or malabsorption 
Extra monitoring is recommended when diarrhoea occurs.  The relatively high frequency of diarrhoea 
during treatment with ritonavir may compromise the absorption and efficacy (due to decreased 
compliance) of ritonavir or other concurrent medicinal products.  Serious persistent vomiting and/or 
diarrhoea associated with ritonavir use might also compromise renal function.  It is advisable to 
monitor renal function in patients with renal function impairment. 
 
Haemophilia 
There have been reports of increased bleeding, including spontaneous skin haematomas and 
haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors.  In some 
patients additional factor VIII was given.  In more than a half of the reported cases, treatment with 
protease inhibitors was continued or reintroduced if treatment had been discontinued.  A causal 
relationship has been evoked, although the mechanism of action has not been elucidated.  
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. 
 
Weight and metabolic parameters:  
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose, reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
Pancreatitis 
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or 
abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of 
pancreatitis should occur.  Patients who exhibit these signs or symptoms should be evaluated and 
Norvir therapy should be discontinued if a diagnosis of pancreatitis is made (see section 4.8). 
 
Immune Reconstitution Inflammatory Syndrome 
In HIV-infected patients with severe immune deficiency at the time of institution of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic 
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms.  Typically, 
such reactions have been observed within the first few weeks or months of initiation of CART.  
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, 
and Pneumocystis jiroveci pneumonia.  Any inflammatory symptoms should be evaluated and 
treatment instituted when necessary. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reconstitution; however, the reported time to onset is more variable and 
can occur many months after initiation of treatment. 
 



42 
 

Liver disease 
Ritonavir should not be given to patients with decompensated liver disease (see section 4.2).  Patients 
with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased 
risk for severe and potentially fatal hepatic adverse reactions.  In case of concomitant antiviral therapy 
for hepatitis B or C, please refer to the relevant product information for these medicinal products. 
 
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased 
frequency of liver function abnormalities during combination antiretroviral therapy and should be 
monitored according to standard practice.  If there is evidence of worsening liver disease in such 
patients, interruption or discontinuation of treatment must be considered. 
 
Renal disease 
Since the renal clearance of ritonavir is negligible, the decrease in the total body clearance is not 
expected in patients with renal impairment (see also section 4.2). 
 
Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy 
(including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate (DF) 
in clinical practice (see section 4.8). 
 
Osteonecrosis 
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol 
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been 
reported in patients with advanced HIV-disease and/or long-term exposure to combination 
antiretroviral therapy (CART).  Patients should be advised to seek medical advice if they experience 
joint aches and pain, joint stiffness or difficulty in movement. 
 
PR interval prolongation 
Ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some 
healthy adult subjects.  Rare reports of 2nd or 3rd degree atrioventricular block in patients with 
underlying structural heart disease and pre-existing conduction system abnormalities or in patients 
receiving medicinal products known to prolong the PR interval (such as verapamil or atazanavir) have 
been reported in patients receiving ritonavir.  Norvir should be used with caution in such patients (see 
section 5.1). 
 
Interactions with other medicinal products 
 
Ritonavir dosed as an antiretroviral agent 
 
The following warnings and precautions should be considered when ritonavir is used as an 
antiretroviral agent.  When ritonavir is used as a pharmacokinetic enhancer at the 100 mg and 200 mg 
level it cannot be assumed that the following warnings and precautions will also apply.  When 
ritonavir is used as a pharmacokinetic enhancer, full details on the warnings and precautions relevant 
to that particular PI must be considered, therefore the Summary of Product Characteristics, section 4.4, 
for the particular PI must be consulted to determine if the information below is applicable. 
 
PDE5 inhibitors 
Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile 
dysfunction in patients receiving ritonavir.  Co-administration of ritonavir with these medicinal 
products is expected to substantially increase their concentrations and may result in associated adverse 
reactions such as hypotension and prolonged erection (see section 4.5).  Concomitant use of avanafil 
or vardenafil with ritonavir is contraindicated (see section 4.3).  Concomitant use of sildenafil with 
ritonavir is contraindicated in pulmonary arterial hypertension patients (see section 4.3). 
 
HMG-CoA reductase inhibitors 
The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for 
metabolism, thus concomitant use of ritonavir with simvastatin or lovastatin is not recommended due 
to an increased risk of myopathy including rhabdomyolysis.  Caution must also be exercised and 



43 
 

reduced doses should be considered if ritonavir is used concurrently with atorvastatin, which is 
metabolised to a lesser extent by CYP3A.  While rosuvastatin elimination is not dependent on 
CYP3A, an elevation of rosuvastatin exposure has been reported with ritonavir co-administration.  The 
mechanism of this interaction is not clear, but may be the result of transporter inhibition.  When used 
with ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent, the lowest doses of 
atorvastatin or rosuvastatin should be administered.  The metabolism of pravastatin and fluvastatin is 
not dependent of CYP3A, and interactions are not expected with ritonavir.  If treatment with an HMG-
CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5). 
 
Colchicine 
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A like ritonavir (see sections 4.3 and 4.5). 
 
Digoxin 
Particular caution should be used when prescribing ritonavir in patients taking digoxin since 
co-administration of ritonavir with digoxin is expected to increase digoxin levels.  The increased 
digoxin levels may lessen over time (see section 4.5). 
 
In patients who are already taking digoxin when ritonavir is introduced, the digoxin dose should be 
reduced to one-half of the patients’ normal dose and patients need to be followed more closely than 
usual for several weeks after initiating co-administration of ritonavir and digoxin. 
 
In patients who are already taking ritonavir when digoxin is introduced, digoxin should be introduced 
more gradually than usual.  Digoxin levels should be monitored more intensively than usual during 
this period, with dose adjustments made, as necessary, based on clinical, electrocardiographic and 
digoxin level findings.  
 
Ethinyl estradiol 
Barrier or other non-hormonal methods of contraception should be considered when administering 
ritonavir at therapeutic or low doses as ritonavir is likely to reduce the effect and change the uterine 
bleeding profile when co-administered with estradiol-containing contraceptives. 
 
Glucocorticoids 
Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 
is not recommended unless the potential benefit of treatment outweighs the risk of systemic 
corticosteroid effects, including Cushing’s syndrome and adrenal suppression (see section 4.5). 
 
Trazodone 
Particular caution should be used when prescribing ritonavir in patients using trazodone.  Trazodone is 
a CYP3A4 substrate and co-administration of ritonavir is expected to increase trazodone levels.  
Adverse reactions of nausea, dizziness, hypotension and syncope have been observed in single dose 
interaction studies in healthy volunteers (see section 4.5) 
 
Rivaroxaban 
It is not recommended to use ritonavir in patients receiving rivaroxaban, due to the risk of increased 
bleeding (see section 4.5). 
 
Riociguat 
The concomitant use of ritonavir is not recommended due to potential increase in riociguat exposure 
(see section 4.5). 
 
Vorapaxar 
The concomitant use of ritonavir is not recommended due to potential increase in vorapaxar exposure 
(see section 4.5). 
 



44 
 

Bedaquiline 
Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could 
potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of 
bedaquiline with ritonavir should be avoided.  However, if the benefit outweighs the risk, co-
administration of bedaquiline with ritonavir must be done with caution. More frequent 
electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and 
refer to the bedaquiline Summary of Product Characteristics). 
 
Delamanid 
Co-administration of delamanid with a strong inhibitor of CYP3A (ritonavir) may increase exposure to 
delamanid metabolite, which has been associated with QTc prolongation.  Therefore, if 
co-administration of delamanid with ritonavir is considered necessary, very frequent ECG monitoring 
throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the 
delamanid Summary of Product Characteristics).  
 
Ritonavir dosed as a pharmacokinetic enhancer 
 
The interaction profiles of HIV-protease inhibitors, co-administered with low dose ritonavir, are 
dependant on the specific co-administered protease inhibitor.  
 
For a description of the mechanisms and potential mechanisms contributing to the interaction profile 
of the PIs, see section 4.5.  Please also review the Summary of Product Characteristics for the 
particular boosted PI. 
 
Saquinavir 
Doses of ritonavir higher than 100 mg twice daily should not be used.  Higher doses of ritonavir have 
been shown to be associated with an increased incidence of adverse reactions.  Co-administration of 
saquinavir and ritonavir has led to severe adverse reactions, mainly diabetic ketoacidosis and liver 
disorders, especially in patients with pre-existing liver disease.   
 
Saquinavir/ritonavir should not be given together with rifampicin, due to the risk of severe 
hepatotoxicity (presenting as increased hepatic transaminases) if the three medicines are given 
together (see section 4.5). 
 
Tipranavir 
Co-administration of tipranavir with 200 mg of ritonavir has been associated with reports of clinical 
hepatitis and hepatic decompensation including some fatalities.  Extra vigilance is warranted in 
patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of 
hepatotoxicity.  
 
Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy 
profile of the combination.   
  
Fosamprenavir 
Co-administration of fosamprenavir with ritonavir in doses greater than 100 mg twice daily has not 
been clinically evaluated.  The use of higher ritonavir doses might alter the safety profile of the 
combination and therefore is not recommended. 
 
Atazanavir 
Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has not been 
clinically evaluated.  The use of higher ritonavir doses may alter the safety profile of atazanavir 
(cardiac effects, hyperbilirubinemia) and therefore is not recommended.  Only when atazanavir with 
ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200mg once daily could be 
considered. In this instance, close clinical monitoring is warranted.  Refer to the Summary of Product 
Characteristics for atazanavir for further details. 
 



45 
 

4.5 Interaction with other medicinal products and other forms of interaction 
 
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent 
 
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation 
with the following ranked order: CYP3A4 > CYP2D6.  Co-administration of ritonavir and medicinal 
products primarily metabolised by CYP3A may result in increased plasma concentrations of the other 
medicinal product, which could increase or prolong its therapeutic and adverse effects. For selected 
medicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over 
time.  Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter.  The 
inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease 
over time (e.g. digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal 
products” below).  Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products 
metabolised by these pathways, and may result in decreased systemic exposure to such medicinal 
products, which could decease or shorten their therapeutic effect.   
 
Important information regarding medicinal product interactions when ritonavir is used as a 
pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the 
co-administered protease inhibitor. 
 
Medicinal products that affect ritonavir levels 
 
Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing 
St John’s wort (Hypericum perforatum).  This is due to the induction of medicinal product 
metabolising enzymes by St John’s wort.  Herbal preparations containing St John’s wort must not be 
used in combination with ritonavir.  If a patient is already taking St John’s wort, St John’s wort should 
be stopped and if possible check viral levels.  Ritonavir levels may increase on stopping St John’s 
wort.  The dose of ritonavir may need adjusting.  The inducing effect may persist for at least 2 weeks 
after cessation of treatment with St John’s wort (see section 4.3).   
 
Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. 
delavirdine, efavirenz, phenytoin and rifampicin).  These interactions are noted in the medicinal 
product interaction tables below. 
 
Medicinal products that are affected by the use of ritonavir 
 
Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease 
inhibitors and other non-antiretroviral medicinal products are listed in the tables below.  This list is not 
intended to be inclusive or comprehensive.  Individual SmPCs should be consulted. 
 



46 
 

Medicinal Product Interactions – Ritonavir with Protease Inhibitors 
 

Co-
administered 

Medicinal 
Product 

Dose of Co-administered 
Medicinal Product (mg) 

Dose of NORVIR 
(mg) 

Medicinal 
Product 
Assessed 

AUC Cmin 

Amprenavir 600 q12h 100 q12h Amprenavir1 ↑ 64% ↑ 5 fold 
 Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition.  Clinical 

trials confirmed the safety and efficacy of 600 mg amprenavir twice daily with ritonavir 100 mg 
twice daily.  For further information, physicians should refer to the Summary of Product 
Characteristics for amprenavir. 

Atazanavir 300 q24h 100 q24h Atazanavir ↑ 86% ↑ 11 fold 
   Atazanavir2 ↑ 2 fold ↑ 3-7 fold 
 Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition.  Clinical 

trials confirmed the safety and efficacy of 300 mg atazanavir once daily with ritonavir 100 mg 
once daily in treatment experienced patients.  For further information, physicians should refer to 
the Summary of Product Characteristics for atazanavir. 

Darunavir 600, single 100 q12h Darunavir ↑ 14 fold  
 Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition.  Darunavir 

must be given with ritonavir to ensure its therapeutic effect.  Ritonavir doses higher than 
100 mg twice daily have not been studied with darunavir.  For further information, refer to the 
Summary of Product Characteristics for darunavir. 

Fosamprenavir 700 q12h 100 q12h Amprenavir ↑ 2.4 fold ↑ 11 fold 
 Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4 

inhibition.  Fosamprenavir must be given with ritonavir to ensure its therapeutic effect.  Clinical 
trials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir 
100 mg twice daily.  Ritonavir doses higher than 100 mg twice daily have not been studied with 
fosamprenavir.  For further information, physicians should refer to the Summary of Product 
Characteristics for fosamprenavir. 

Indinavir 800 q12h 100 q12h Indinavir3 ↑ 178% ND 
   Ritonavir ↑ 72% ND 
 400 q12h 400 q12h Indinavir3 ↔ ↑ 4 fold  
   Ritonavir ↔ ↔ 
 Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition.  Appropriate 

doses for this combination, with respect to efficacy and safety, have not been established.  
Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses 
higher than 100 mg twice daily.  In cases of co-administration of ritonavir (100 mg twice daily) 
and indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may be 
increased.   

Nelfinavir 1250 q12h  100 q12h Nelfinavir ↑ 20to39% ND 
 750, single 500 q12h Nelfinavir ↑ 152% ND 
   Ritonavir ↔ ↔ 
 Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition.  

Appropriate doses for this combination, with respect to efficacy and safety, have not been 
established.  Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved 
with doses higher than 100 mg twice daily. 



47 
 

Saquinavir 1000 q12h 100 q12h Saquinavir4 ↑ 15-fold ↑ 5-fold 
   Ritonavir ↔ ↔ 
 400 q12h  400 q12h  Saquinavir4 ↑ 17-fold  ND 
   Ritonavir ↔ ↔ 
 Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition.  Saquinavir 

should only be given in combination with ritonavir.  Ritonavir100 mg twice daily with 
saquinavir 1000 mg twice daily provides saquinavir systemic exposure over 24 hours similar to 
or greater than those achieved with saquinavir 1200 mg three times daily without ritonavir.    
 
In a clinical study investigating the interaction of rifampicin 600 mg once daily and saquinavir 
1000 mg with ritonavir 100 mg twice daily in healthy volunteers, severe hepatocellular toxicity 
with transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days of 
co-administration was noted.  Due to the risk of severe hepatoxicity, saquinavir/ritonavir should 
not be given together with rifampicin. 
 
For further information, physicians should refer to the Summary of Product Characteristics for 
saquinavir. 

Tipranavir 500 q12h 200 q12h Tipranavir ↑ 11 fold ↑ 29 fold 
   Ritonavir ↓ 40% ND 
 Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition.  Tipranavir 

must be given with low dose ritonavir to ensure its therapeutic effect.  Doses of ritonavir less 
than 200 mg twice daily should not be used with tipranavir as they might alter the efficacy of the 
combination.  For further information, physicians should refer to the Summary of Product 
Characteristics for tipranavir. 

 ND: Not determined. 
1.  Based on cross-study comparison to 1200 mg amprenavir twice daily alone. 
2.  Based on cross-study comparison to 400 mg atazanavir once daily alone. 
3.  Based on cross-study comparison to 800 mg indinavir three times daily alone. 
4.  Based on cross-stud y comparison to 600 mg saquinavir three times daily alone. 

 
Medicinal product interactions – Ritonavir with antiretroviral agents other than protease 

inhibitors 
 

Co-
administered 
Medicinal 
Product 

Dose of Co-
administered 
Medicinal Product 
(mg) 

Dose of NORVIR 
(mg) 

Medicinal 
Product 
Assessed 

AUC Cmin 

Didanosine 200 q12h 600 q12h 2 h later Didanosine ↓ 13%   ↔ 
 As ritonavir is recommended to be taken with food and didanosine should be taken on an empty 

stomach, dosing should be separated by 2.5 h.  Dose alterations should not be necessary. 
Delavirdine 400 q8h 600 q12h Delavirdine1 ↔ ↔ 
   Ritonavir ↑ 50% ↑ 75% 
 Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to be 

affected by ritonavir.  When used in combination with delavirdine, dose reduction of ritonavir 
may be considered. 

Efavirenz 600 q24h 500 q12h Efavirenz ↑ 21%  
   Ritonavir ↑ 17%  
 A higher frequency of adverse reactions (e.g., dizziness, nausea, paraesthesia) and laboratory 

abnormalities (elevated liver enzymes) have been observed when efavirenz is co-administered 
with ritonavir dosed as an antiretroviral agent. 

Maraviroc 100 q12h 100 q12h Maraviroc ↑ 161% ↑ 28% 
 Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition.  Maraviroc 

may be given with ritonavir to increase the maraviroc exposure.  For further information, refer to 
the Summary of Product Characteristics for maraviroc. 

Nevirapine 200 q12h 600 q12h Nevirapine ↔ ↔ 
   Ritonavir ↔ ↔ 
 Co-administration of ritonavir with nevirapine does not lead to clinically relevant changes in the 

pharmacokinetics of either nevirapine or ritonavir. 
Raltegravir 400 single  100 q12h Raltegravir ↓ 16% ↓ 1% 
 Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir levels 



48 
 

Zidovudine 200 q8h 300 q6h Zidovudine ↓ 25%  ND 
 Ritonavir may induce the glucuronidation of zidovudine, resulting in slightly decreased levels of 

zidovudine.  Dose alterations should not be necessary. 
 ND: Not determined 

1.  Based on parallel group comparison. 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Alpha1-Adrenoreceptor 
Antagonist 

 

Alfuzosin Ritonavir co-administration is likely to result in increased plasma 
concentrations of alfuzosin and is therefore contraindicated (see 
section 4.3).   
 

Amphetamine Derivatives  

Amphetamine  Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 
and as a result is expected to increase concentrations of amphetamine 
and its derivatives. Careful monitoring of therapeutic and adverse 
effects is recommended when these medicines are concomitantly 
administered with antiretroviral doses of ritonavir (see section 4.4). 
 

Analgesics 
 

Buprenorphine 16 q24h 100 q12h ↑ 57% ↑ 77% 
Norbuprenorphine   ↑ 33% ↑ 108% 
Glucuronide metabolites   ↔ ↔ 
 The increases of plasma levels of buprenorphine and its active 

metabolite did not lead to clinically significant pharmacodynamic 
changes in a population of opioid tolerant patients.  Adjustment to the 
dose of buprenorphine or ritonavir may therefore not be necessary 
when the two are dosed together.  When ritonavir is used in 
combination with another protease inhibitor and buprenorphine, the 
SPC of the co-administered protease inhibitor should be reviewed for 
specific dosing information. 
 

Pethidine, piroxicam, propoxyphene Ritonavir co-administration is likely to result in increased plasma 
concentrations of pethidine, piroxicam, and propoxyphene and is 
therefore contraindicated (see section 4.3). 
 

Fentanyl Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of fentanyl.  Careful monitoring of therapeutic 
and adverse effects (including respiratory depression) is 
recommended when fentanyl is concomitantly administered with 
ritonavir. 
 

Methadone1 5, single dose  500 q12h,  ↓ 36%  ↓ 38%  
 Increased methadone dose may be necessary when concomitantly 

administered with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer due to induction of glucuronidation. Dose 
adjustment should be considered based on the patient’s clinical 
response to methadone therapy.   
 



49 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Morphine Morphine levels may be decreased due to induction of 
glucuronidation by co-administered ritonavir dosed as an 
antiretroviral agent or as a pharmacokinetic enhancer. 
 

Antianginal 
 

Ranolazine Due to CYP3A inhibition by ritonavir, concentrations of ranolazine 
are expected to increase.  The concomitant administration with 
ranolazine is contraindicated (see section 4.3). 

Antiarrthymics 
 

Amiodarone, bepridil, dronedarone, 
encainide, flecainide, propafenone, 
quinidine 

Ritonavir co-administration is likely to result in increased plasma 
concentrations of amiodarone, bepridil, dronedarone, encainide, 
flecainide, propafenone, and quinidine and is therefore 
contraindicated (see section 4.3). 
 

Digoxin 0.5 single IV dose 300 q12h, 3 days  ↑ 86% ND 
 0.4 single oral  

dose 
200 q12h, 13 days ↑ 22% ↔ 

 This interaction may be due to modification of P-glycoprotein 
mediated digoxin efflux by ritonavir dosed as an antriretroviral agent 
or as a pharmacokinetic enhancer.  Increased digoxin levels observed 
in patients receiving ritonavir may lessen over time as induction 
develops (see section 4.4).   
 

Antiasthmatic 
 

Theophylline1 3 mg/kg q8h 500 q12h  ↓ 43%  ↓ 32%  
 An increased dose of theophyline may be required when co-

administered with ritonavir, due to induction of CYP1A2. 
 

Anticancer agents and kinase 
inhibitors 

 

Afatinib 20 mg, single 
dose 
40 mg, single 
dose 
40 mg, single 
dose 

200 
q12h/1h 
before 
200 q12h/ 
co-
administered 
200 q12h/6h 
after 

↑ 48%  
 
↑ 19% 
 
↑ 11% 

↑ 39%  
 
↑ 4% 
 
↑ 5% 

Serum concentrations may be increased due to Breast Cancer 
Resistance Protein (BCRP) and acute P-gp inhibition by ritonavir.  
The extent of increase in AUC and Cmax depends on the timing of 
ritonavir administration.  Caution should be exercised in 
administering afatinib with Norvir (refer to the afatinib SmPC).  
Monitor for ADRs related to afatinib. 
 



50 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Abemaciclib Serum concentrations may be increased due to CYP3A4 inhibition by 
ritonavir. 
 
Co-administration of abemaciclib and Norvir should be avoided.  If 
this co-administration is judged unavoidable, refer to the abemaciclib 
SmPC for dosage adjustment recommendations.  Monitor for ADRs 
related to abemaciclib. 
 

Apalutamide Apalutamide is a moderate to strong CYP3A4 inducer and this may 
lead to a decreased exposure of ritonavir and potential loss of 
virologic response.  In addition, serum concentrations may be 
increased when co-administered with ritonavir resulting in the 
potential for serious adverse events including seizure.   
 
Concomitant use of ritonavir with apalutamide is not recommended. 
 

Ceritinib Serum concentrations may be increased due to CYP3A and P-gp 
inhibition by ritonavir.  Caution should be exercised in administering 
ceritinib with Norvir.  Refer to the ceritinib SmPC for dosage 
adjustment recommendations.  Monitor for ADRs related to ceritinib. 
 

Dasatinib, nilotinib, vincristine, vinblastine Serum concentrations may be increased when co-administered with 
ritonavir resulting in the potential for increased incidence of adverse 
reactions. 
 

Encorafenib Serum concentrations may be increased when co-administered with 
ritonavir which may increase the risk of toxicity, including the risk of 
serious adverse events such as QT interval prolongation.  
Co-administration of encorafenib and ritonavir should be avoided.  If 
the benefit is considered to outweigh the risk and ritonavir must be 
used, patients should be carefully monitored for safety. 
 

Fostamatinib Co-administration of fostamatinib with ritonavir may increase 
fostamatinib metabolite R406 exposure resulting in dose-related 
adverse events such as hepatotoxicity, neutropenia, hypertension, or 
diarrhoea.  Refer to the fostamatinib SmPC for dose reduction 
recommendations if such events occur. 
 

Ibrutinib Serum concentrations of ibrutinib may be increased due to CYP3A 
inhibition by ritonavir, resulting in increased risk for toxicity 
including risk of tumor lysis syndrome.  Co-administration of 
ibrutinib and ritonavir should be avoided.  If the benefit is considered 
to outweigh the risk and ritonavir must be used, reduce the ibrutinib 
dose to 140 mg and monitor patient closely for toxicity. 
 

Neratinib Serum concentrations may be increased due to CYP3A4 inhibition by 
ritonavir. 
 
Concomitant use of neratinib with Norvir is contraindicated due to 
serious and/or life-threatening potential reactions including 
hepatotoxicity (see section 4.3). 
 



51 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Venetoclax Serum concentrations may be increased due to CYP3A inhibition by 
ritonavir, resulting in increased risk of tumor lysis syndrome at the 
dose initiation and during the ramp-up phase (see section 4.3 and 
refer to the venetoclax SmPC). 
 
For patients who have completed the ramp-up phase and are on a 
steady daily dose of venetoclax, reduce the venetoclax dose by at 
least 75% when used with strong CYP3A inhibitors (refer to the 
venetoclax SmPC for dosing instructions). 

Anticoagulants 
 

Rivaroxaban 10, single dose 600 q12h ↑ 153% ↑ 55%  
 Inhibition of CYP3A and P-gp lead to increased plasma levels and 

pharmacodynamic effects of rivaroxaban which may lead to an 
increased bleeding risk. Therefore, the use of ritonavir is not 
recommended in patients receiving rivaroxaban. 
 

Vorapaxar Serum concentrations may be increased due to CYP3A inhibition by 
ritonavir.  The co-administration of vorapaxar with Norvir is not 
recommended (see section 4.4 and refer to the vorapaxar SmPC). 
 

Warfarin 
S-Warfarin  
R-Warfarin 

5, single dose  400 q12h   
↑ 9%  
↓ 33%  

 
↓ 9%  
↔  

 Induction of CYP1A2 and CYP2C9 lead to decreased levels of R-
warfarin while little pharmacokinetic effect is noted on S- warfarin 
when co-administered with ritonavir.  Decreased R-warfarin levels 
may lead to reduced anticoagulation, therefore it is recommended that 
anticoagulation parameters are monitored when warfarin is 
co-administered with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer. 
 

Anticonvulsants 
 

Carbamazepine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of carbamazepine.  Careful monitoring of 
therapeutic and adverse effects is recommended when carbamazepine 
is concomitantly administered with ritonavir. 
 

Divalproex, lamotrigine, phenytoin Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent induces oxidation by CYP2C9 and glucuronidation and as a 
result is expected to decrease the plasma concentrations of 
anticonvulsants. Careful monitoring of serum levels or therapeutic 
effects is recommended when these medicines are concomitantly 
administered with ritonavir. Phenytoin may decrease serum levels of 
ritonavir. 
 

Antidepressants 
 

Amitriptyline, fluoxetine, imipramine, 
nortriptyline, paroxetine, sertraline 

Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 
and as a result is expected to increase concentrations of imipramine, 
amitriptyline, nortriptyline, fluoxetine, paroxetine or sertraline. 
Careful monitoring of therapeutic and adverse effects is 
recommended when these medicines are concomitantly administered 
with antiretroviral doses of ritonavir (see section 4.4). 
 



52 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Desipramine 100, single oral dose 500 q12h ↑ 145% ↑ 22% 
 The AUC and Cmax of the 2-hydroxy metabolite were decreased 15 

and 67%, respectively.  Dosage reduction of desipramine is 
recommended when co-administered with ritonavir dosed as an 
antiretroviral agent. 
 

Trazodone 50, single dose  200 q12h  ↑ 2.4-fold ↑ 34% 
 An increase in the incidence in trazodone-related adverse reactions 

was noted when co-administered with ritonavir dosed as an 
antiretroviral agent or as a pharmacokinetic enhancer.  If trazodone is 
co-administered with ritonavir, the combination should be used with 
caution, initiating trazodone at the lowest dosage and monitoring for 
clinical response and tolerability. 
 

Anti-gout treatments 
 

Colchicine Concentrations of colchicine are expected to increase when 
coadministered with ritonavir. 
Life-threatening and fatal drug interactions have been reported in 
patients treated with colchicine and ritonavir (CYP3A4 and P-gp 
inhibition) in patients with renal and/or hepatic impairment (see 
sections 4.3 and 4.4).  Refer to the colchicine prescribing information. 

Antihistamines 
 

Astemizole, terfenadine Ritonavir co-administration is likely to result in increased plasma 
concentrations of astemizole and terfenadine and is therefore 
contraindicated (see section 4.3). 
 

Fexofenadine Ritonavir may modify P-glycoprotein mediated fexofenadine efflux 
when dosed as an antriretroviral agent or as a pharmacokinetic 
enhancer resulting in increased concentrations of fexofenadine.  
Increased fexofenadine levels may lessen over time as induction 
develops. 
 

Loratadine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A and as a result is expected to increase the 
plasma concentrations of loratadine.  Careful monitoring of 
therapeutic and adverse effects is recommended when loratidine is 
concomitantly administered with ritonavir. 
 

Anti-infectives 
 

Fusidic Acid Ritonavir co-administration is likely to result in increased plasma 
concentrations of both fusidic acid and ritonavir and is therefore 
contraindicated (see section 4.3). 
 

Rifabutin1 
 
25-O-desacetyl rifabutin metabolite  

150 daily  500 q12h,  ↑ 4-fold  
 
↑ 38-fold  

↑ 2.5-fold  
 
↑ 16-fold 



53 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

 Due to the large increase in rifabutin AUC, the concomitant use of 
rifabutin with ritonavir dosed as an antiretroviral agent is 
contraindicated (see section 4.3).  The reduction of the rifabutin 
dose to 150 mg 3 times per week may be indicated for select PIs 
when co-administered with ritonavir as a pharmacokinetic enhancer.  
The Summary of Product Characteristics of the co-administered 
protease inhibitor should be consulted for specific recommendations.  
Consideration should be given to official guidance on the appropriate 
treatment of tuberculosis in HIV-infected patients.   
 

Rifampicin Although rifampicin may induce metabolism of ritonavir, limited data 
indicate that when high doses of ritonavir (600 mg twice daily) is 
co-administered with rifampicin, the additional inducing effect of 
rifampicin (next to that of ritonavir itself) is small and may have no 
clinical relevant effect on ritonavir levels in high-dose ritonavir 
therapy.  The effect of ritonavir on rifampicin is not known. 
 

Voriconazole 200 q12h 400 q12h  ↓ 82% ↓ 66% 
 200 q12h 100 q12h ↓ 39% ↓ 24% 
 Concomitant use of ritonavir dosed as an antiretroviral agent and 

voriconazole is contraindicated due to reduction in voriconazole 
concentrations (see section 4.3).  Co-administration of voriconazole 
and ritonavir dosed as a pharmacokinetic enhancer should be avoided, 
unless an assessment of the benefit/risk to the patient justifies the use 
of voriconazole. 
 

Atovaquone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent induces glucuronidation and as a result is expected to decrease 
the plasma concentrations of atovaquone. Careful monitoring of 
serum levels or therapeutic effects is recommended when atovaquone 
is concomitantly administered with ritonavir. 
 

Bedaquiline No interaction study is available with ritonavir only. In an interaction 
study of single-dose bedaquiline and multiple dose 
lopinavir/ritonavir, the AUC of bedaquiline was increased by 22%.  
This increase is likely due to ritonavir and a more pronounced effect 
may be observed during prolonged co-administration.  Due to the risk 
of bedaquiline related adverse events, co-administration should be 
avoided.  If the benefit outweighs the risk, co-administration of 
bedaquiline with ritonavir must be done with caution.  More frequent 
electrocardiogram monitoring and monitoring of transaminases is 
recommended (see section 4.4 and refer to the bedaquiline Summary 
of Product Characteristics). 
 



54 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Clarithromycin 
 
14-OH clarithromycin metabolite  

500 q12h  200 q8h ↑ 77%  
 
↓ 100%  

↑ 31%  
 
↓ 99%  

 Due to the large therapeutic window of clarithromycin no dose 
reduction should be necessary in patients with normal renal function.  
Clarithromycin doses greater than 1 g per day should not be co-
administered with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer.  For patients with renal impairment, a 
clarithromycin dose reduction should be considered: for patients with 
creatinine clearance of 30 to 60 ml/min the dose should be reduced by 
50%, for patients with creatinine clearance less than 30 ml/min the 
dose should be reduced by 75%. 
 

Delamanid No interaction study is available with ritonavir only.  In a healthy 
volunteer drug interaction study of delamanid 100 mg twice daily and 
lopinavir/ritonavir 400/100 mg twice daily for 14 days, the exposure 
of the delamanid metabolite DM-6705 was 30% increased.  Due to 
the risk of QTc prolongation associated with DM-6705, if 
co-administration of delamanid with ritonavir is considered 
necessary, very frequent ECG monitoring throughout the full 
delamanid treatment period is recommended (see section 4.4 and 
refer to the delamanid Summary of Product Characteristics). 
 

Erythromycin, itraconazole Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of erythromycin and itraconazole.  Careful 
monitoring of therapeutic and adverse effects is recommended when 
erythromycin or itraconazole is used concomitantly administered with 
ritonavir. 
 

Ketoconazole 200 daily 500 q12h ↑ 3.4-fold  ↑ 55%  
 Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole.  

Due to an increased incidence of gastrointestinal and hepatic adverse 
reactions, a dose reduction of ketoconazole should be considered 
when co-administered with ritonavir dosed as an antiretroviral agent 
or as a pharmacokinetic enhancer. 
 

Sulfamethoxazole/Trimethoprim2 800/160, single 
dose  

500 q12h  ↓ 20% / ↑ 20% ↔ 

 Dose alteration of sulfamethoxazole/trimethoprim during concomitant 
ritonavir therapy should not be necessary. 
 

Antipsychotics/Neuroleptics 
 

Clozapine, pimozide Ritonavir co-administration is likely to result in increased plasma 
concentrations of clozapine or pimozide and is therefore 
contraindicated (see section 4.3). 
 

Haloperidol, risperidone, thioridazine Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6 
and as a result is expected to increase concentrations of haloperidol, 
risperidone and thioridazine.  Careful monitoring of therapeutic and 
adverse effects is recommended when these medicines are 
concomitantly administered with antiretroviral doses of ritonavir. 
 

Lurasidone Due to CYP3A inhibition by ritonavir, concentrations of lurasidone 
are expected to increase.  The concomitant administration with 
lurasidone is contraindicated (see section 4.3). 
 



55 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Quetiapine Due to CYP3A inhibition by ritonavir, concentrations of quetiapine 
are expected to increase.  Concomitant administration of Norvir and 
quetiapine is contraindicated as it may increase quetiapine-related 
toxicity (see section 4.3). 
 

β2-agonist (long acting)  

Salmeterol Ritonavir inhibits CYP3A4 and as a result a pronounced increase in 
the plasma concentrations of salmeterol is expected.  Therefore 
concomitant use is not recommended. 
 

Calcium channel antagonists 
 

Amlodipine, diltiazem, nifedipine Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of calcium channel antagonists.  Careful 
monitoring of therapeutic and adverse effects is recommended when 
these medicines are concomitantly administered with ritonavir. 
 

Endothelin antagonists 
 

Bosentan Co-administration of bosentan and ritonavir may increase steady state 
bosentan maximum concentr ations (Cmax) and area under the curve 
(AUC). 
 

Riociguat Serum concentrations may be increased due to CYP3A and P-gp inhibition by ritonavir.  The co-administration of riociguat with 
Norvir is not recommended (see section 4.4 and refer to riociguat 
SmPC). 
 

Ergot Derivatives 
 

Dihydroergotamine, ergonovine, 
ergotamine, methylergonovine 

Ritonavir co-administration is likely to result in increased plasma 
concentrations of ergot derivatives and is therefore contraindicated 
(see section 4.3). 
 

GI motility agent 
 

Cisapride Ritonavir co-administration is likely to result in increased plasma 
concentrations of cisapride and is therefore contraindicated (see 
section 4.3). 
 

HCV Direct Acting Antiviral  
Glecaprevir/pibrentasvir Serum concentrations may be increased due to P-glycoprotein, BCRP 

and OATP1B inhibition by ritonavir. 
 
Concomitant administration of glecaprevir/pibrentasvir and Norvir is 
not recommended due to an increased risk of ALT elevations 
associated with increased glecaprevir exposure. 
 

HCV Protease Inhibitor  
Simeprevir 200 qd 100 q12h ↑ 7.2-fold ↑ 4.7-fold 



56 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

 Ritonavir increases plasma concentrations of simeprevir as a result of 
CYP3A4 inhibition.  It is not recommended to co-administer ritonavir 
with simeprevir. 
 

HMG Co-A Reductase Inhibitors 
 

Atorvastatin, Fluvastatin, Lovastatin, 
Pravstatin, Rosuvastatin, Simvastatin 

HMG-CoA reductase inhibitors which are highly dependent on 
CYP3A metabolism, such as lovastatin and simvastatin, are expected 
to have markedly increased plasma concentrations when co-
administered with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer.  Since increased concentrations of 
lovastatin and simvastatin may predispose patients to myopathies, 
including rhabdomyolysis, the combination of these medicinal 
products with ritonavir is contraindicated (see section 4.3).  
Atorvastatin is less dependent on CYP3A for metabolism.  While 
rosuvastatin elimination is not dependent on CYP3A, an elevation of 
rosuvastatin exposure has been reported with ritonavir co-
administration.  The mechanism of this interaction is not clear, but 
may be the result of transporter inhibition.  When used with ritonavir 
dosed as a pharmacokinetic enhancer or as an antiretroviral agent, the 
lowest possible doses of atorvastatin or rosuvastatin should be 
administered.  The metabolism of pravastatin and fluvastatin is not 
dependent on CYP3A, and interactions are not expected with 
ritonavir.  If treatment with an HMG-CoA reductase inhibitor is 
indicated, pravastatin or fluvastatin is recommended. 
 

Hormonal contraceptive 
 

Ethinyl estradiol 50 µg, single 
dose  

500 q12h ↓ 40%  ↓ 32%  

 Due to reductions in ethinyl estradiol concentrations, barrier or other 
non-hormonal methods of contraception should be considered with 
concomitant ritonavir use when dosed as an antiretroviral agent or as 
a pharmacokinetic enhancer.  Ritonavir is likely to change the uterine 
bleeding profile and reduce the effectiveness of estradiol-containing 
contraceptives (see section 4.4). 
 

Immunosupressants 
 

Cyclosporine, tacrolimus, everolimus Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A4 and as a result is expected to increase the 
plasma concentrations of cyclosporine, tacrolimus or everolimus.  
Careful monitoring of therapeutic and adverse effects is 
recommended when these medicines are concomitantly administered 
with ritonavir. 
 

Lipid-modifying agents 
 

Lomitapide CYP3A4 inhibitors increase the exposure of lomitapide, with strong 
inhibitors increasing exposure approximately 27-fold.  Due to 
CYP3A inhibition by ritonavir, concentrations of lomitapide are 
expected to increase.  Concomitant use of Norvir with lomitapide is 
contraindicated (see prescribing information for lomitapide) (see 
section 4.3). 
 



57 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

Phosphodiesterase (PDE5) 
inhibitors 

 

Avanafil 50, single dose 600 q12h ↑ 13-fold ↑ 2.4-fold 
Concomitant use of avanafil with ritonavir is contraindicated (see 
section 4.3). 
 

Sildenafil 100, single dose  500 q12h ↑ 11-fold ↑ 4-fold 
 Concomitant use of sildenafil for the treatment of erectile dysfunction 

with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic 
enhancer should be with caution and in no instance should sildenafil 
doses exceed 25 mg in 48 hours (see also section 4.4).  Concomitant 
use of sildenafil with ritonavir is contraindicated in pulmonary 
arterial hypertension patients (see section 4.3). 
 

Tadalafil 20, single dose  200 q12h  ↑ 124% ↔ 
 The concomitant use of tadalafil for the treatment of erectile 

dysfunction with ritonavir dosed as an antiretroviral agent or as a 
pharmacokinetic enhancer should be with caution at reduced doses of 
no more than 10 mg tadalafil every 72 hours with increased 
monitoring for adverse reactions (see section 4.4). 
 
When tadalafil is used concurrently with ritonavir in patients with 
pulmonary arterial hypertension, refer to the tadalafil Summary of 
Product Characteristics. 

Vardenafil 5, single dose 600 q12h ↑ 49-fold ↑ 13-fold 
 Concomitant use of vardenafil with ritonavir is contraindicated (see 

section 4.3). 
 

Sedatives/hypnotics 
 

Clorazepate, diazepam, estazolam, 
flurazepam, oral and parenteral midazolam  

Ritonavir co-administration is likely to result in increased plasma 
concentrations of clorazepate, diazepam, estazolam and flurazepam 
and is therefore contraindicated (see section 4.3).  
Midazolam is extensively metabolised by CYP3A4.  
Co-administration with Norvir may cause a large increase in the 
concentration of this benzodiazepine.  No medicinal product 
interaction study has been performed for the co-administration of 
Norvir with benzodiazepines.  Based on data for other CYP3A4 
inhibitors, plasma concentrations of midazolam are expected to be 
significantly higher when midazolam is given orally.  Therefore, 
Norvir should not be co-administered with orally administered 
midazolam (see section 4.3), whereas caution should be used with 
co-administration of Norvir and parenteral midazolam.  Data from 
concomitant use of parenteral midazolam with other protease 
inhibitors suggest a possible 3 – 4 fold increase in midazolam plasma 
levels.  If Norvir is co-administered with parenteral midazolam, it 
should be done in an intensive care unit (ICU) or similar setting 
which ensures close clinical monitoring and appropriate medical 
management in case of respiratory depression and/or prolonged 
sedation.  Dosage adjustment for midazolam should be considered, 
especially if more than a single dose of midazolam is administered. 
 

Triazolam 0.125, single 
dose 

200, 4 doses ↑ > 20 fold ↑ 87% 



58 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

 Ritonavir co-administration is likely to result in increased plasma 
concentrations of triazolam and is therefore contraindicated (see 
section 4.3). 
 

Pethidine  
 
Norpethidine metabolite  

50, oral single 
dose  

500 q12h ↓ 62%  
 
↑ 47%  

↓ 59%  
 
↑ 87%  

 The use of pethidine and ritonavir is contraindicated due to the 
increased concentrations of the metabolite, norpethidine, which has 
both analgesic and CNS stimulant activity.  Elevated norpethidine 
concentrations may increase the risk of CNS effects (e.g., seizures), 
see section 4.3. 
 

Alprazolam 1, single dose  200 q12h, 2 
days 

↑ 2.5 fold ↔ 

  500 q12h, 10 
days 

↓ 12%  ↓ 16%  

 Alprazolam metabolism was inhibited following the introduction of 
ritonavir.  After ritonavir use for 10 days, no inhibitory effect of 
ritonavir was observed.  Caution is warranted during the first several 
days when alprazolam is co-administered with ritonavir dosed as an 
antiretroviral agent or as a pharmacokinetic enhancer, before 
induction of alprazolam metabolism develops. 
 

Buspirone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A and as a result is expected to increase the 
plasma concentrations of buspirone.  Careful monitoring of 
therapeutic and adverse effects is recommended when buspirone 
concomitantly administered with ritonavir. 
 

Sleeping agent  

Zolpidem 5  200, 4 doses ↑ 28% ↑ 22% 
 Zolpidem and ritonavir may be co-administered with careful 

monitoring for excessive sedative effects. 
 

Smoke cessation  

Bupropion 150  100 q12h ↓ 22% ↓ 21% 
 150  600 q12h ↓ 66% ↓ 62% 
 Bupropion is primarily metabolised by CYP2B6.  Concurrent 

administration of bupropion with repeated doses of ritonavir is 
expected to decrease bupropion levels.  These effects are thought to 
represent induction of bupropion metabolism.  However, because 
ritonavir has also been shown to inhibit CYP2B6 in vitro, the 
recommended dose of bupropion should not be exceeded.  In contrast 
to long-term administration of ritonavir, there was no significant 
interaction with bupropion after short-term administration of low 
doses of ritonavir (200 mg twice daily for 2 days), suggesting 
reductions in bupropion concentrations may have onset several days 
after initiation of ritonavir co-administration. 
 

Steroids  

Inhaled, injectable or intranasal fluticasone 
propionate, budesonide, triamcinolone 

Systemic corticosteroid effects including Cushing's syndrome and 
adrenal suppression (plasma cortisol levels were noted to be 
decreased 86% in the above study) have been reported in patients 
receiving ritonavir and inhaled or intranasal fluticasone propionate; 



59 
 

Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products 

Co-administered Medicinal Products Dose of Co-
administered 
Medicinal 
Products (mg) 

Dose of 
NORVIR 
(mg) 

Effect on Co-
administered 
Medicinal 
Products AUC  

Effect on Co-
administered 
Medicinal 
Products Cmax  

similar effects could also occur with other corticosteroids metabolised 
by CYP3A e.g., budesonide and triamcinolone.  Consequently, 
concomitant administration of ritonavir dosed as an antiretroviral 
agent or as a pharmacokinetic enhancer and these glucocorticoids is 
not recommended unless the potential benefit of treatment outweighs 
the risk of systemic corticosteroid effects (see section 4.4).  A dose 
reduction of the glucocorticoid should be considered with close 
monitoring of local and systemic effects or a switch to a 
glucocorticoid, which is not a substrate for CYP3A4 (e.g., 
beclomethasone).  Moreover, in case of withdrawal of glucocorticoids 
progressive dose reduction may be required over a longer period.     

Dexamethasone Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral 
agent inhibits CYP3A and as a result is expected to increase the 
plasma concentrations of dexamethasone.  Careful monitoring of 
therapeutic and adverse effects is recommended when dexamethasone 
is concomitantly administered with ritonavir.   
 

Prednisolone 20 200 q12h ↑ 28% ↑ 9% 
 Careful monitoring of therapeutic and adverse effects is 

recommended when prednisolone is concomitantly administered with 
ritonavir.  The AUC of the metabolite prednisolone increased by 37 
and 28% after 4 and 14 days ritonavir, respectively. 
 

Thyroid hormone replacement 
therapy 

 

Levothyroxine Post-marketing cases have been reported indicating a potential 
interaction between ritonavir containing products and levothyroxine.  
Thyroid-stimulating hormone (TSH) should be monitored in patients 
treated with levothyroxine at least the first month after starting and/or 
ending ritonavir treatment. 

 ND: Not determined 
1. Based on a parallel group comparison 
2. Sulfamethoxazole was co-administered with trimethoprim.  

 
Cardiac and neurologic events have been reported when ritonavir has been co-administered with 
disopyramide, mexiletine or nefazodone.  The possibility of medicinal product interaction cannot be 
excluded. 
 
In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of 
increased therapeutic and toxic effects due to protein binding displacement of concomitant medicinal 
products should be considered. 
 
Ritonavir dosed as a pharmacokinetic enhancer 
 
Important information regarding medicinal product interactions when ritonavir is used a 
pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the co-
administered protease inhibitor. 
 
Proton pump inhibitors and H2-receptor antagonists 
Proton pump inhibitors and H2-receptor antagonists (e.g. omeprazole or ranitidine) may reduce 
concentrations for co-administered protease inhibitors.  For specific information regarding the impact 
of co-administration of acid reducing agents, refer to the Summary of Product Characteristics of the 
co-administered protease inhibitor.  Based on interaction studies with the ritonavir boosted protease 
inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does 



60 
 

not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of 
exposure (about 6 - 18%).  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
A large amount (6100 live births) of pregnant women were exposed to ritonavir during pregnancy; of 
these, 2800 live births were exposed during the first trimester.  These data largely refer to exposures 
where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower 
doses as a pharmacokinetic enhancer for other PIs.  These data indicate no increase in the rate of birth 
defects compared to rates observed in population-based birth defect surveillance systems.  Animal data 
have shown reproductive toxicity (see section 5.3).  Norvir can be used during pregnancy if clinically 
needed. 
 
Ritonavir adversely interacts with oral contraceptives (OCs).  Therefore, an alternative, effective and 
safe method of contraception should be used during treatment. 
 
Breastfeeding 
Limited published data reports that ritonavir is present in human milk. 
 
There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on 
milk production.  Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) 
developing viral resistance (in HIV-postive infants) and (3) serious adverse reactions in a breastfed 
infant,  HIV infected women should not breast feed their infants under any circumstances if they are 
receiving Norvir.   
 
Fertility 
No human data on the effect of ritonavir on fertility are available.  Animal studies do not indicate 
harmful effects of ritonavir on fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed.  Dizziness is a 
known undesirable effect that should be taken into account when driving or using machinery. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Ritonavir dosed as a pharmacokinetic enhancer 
 
Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on 
the specific co-administered PI.  For information on adverse reactions refer to the SPC of the specific 
co-administered PI. 
 
Ritonavir dosed as an antiretroviral agent 
 
Adverse reactions from clinical trials and post-marketing experience in adult patients 
 
The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in 
combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, 
vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and 
oral paresthesia) and fatigue/asthenia. 
 



61 
 

Tabulated list of adverse reactions 
 
The following adverse reactions of moderate to severe intensity with possible or probable relationship 
to ritonavir have been reported.  Within each frequency grouping, undesirable effects are presented in 
order of decreasing seriousness: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon 
(≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from the 
available data). 
 
Events noted as having frequency not known were identified via post-marketing surveillance. 
 

Adverse reactions  in clinical studies and post-marketing in adult patients 

System Order Class Frequency Adverse reaction 

Blood and lymphatic system 
disorders 

Common 
 

Decreased white blood cells, decreased 
haemoglobin, decreased neutrophils, 
increased eosinophils, thrombocytopenia 
 

Uncommon Increased neutrophils  
 

Immune system disorders Common Hypersensitivity including urticaria, and 
face oedema 
 

 Rare Anaphylaxis 
 

Metabolism and nutrition 
disorders 

Common Hypercholesterolaemia, 
hypertriglyceridaemia, gout, oedema and 
peripheral oedema, dehydration (usually 
associated with gastrointestinal symptoms) 

 Uncommon Diabetes mellitus  
 

 Rare Hyperglycaemia 
 

Nervous system disorders Very common 
 
 

Dysgeusia, oral and peripheral paraesthesia, 
headache, dizziness, peripheral neuropathy 
 

Common Insomnia, anxiety, confusion, disturbance in 
attention, syncope, seizure 
 

Eye disorders Common Blurred vision 
 

Cardiac disorders Uncommon Myocardial infarction 
 

Vascular disorders Common Hypertension, hypotension including 
orthostatic hypotension, peripheral coldness 
 

Respiratory, thoracic and 
mediastinal disorders 
 

Very common Pharyngitis, oropharyngeal pain, cough  

Gastrointestinal disorders Very common 
 

Abdominal pain (upper and lower), nausea, 
diarrhoea (including severe with electrolyte 
imbalance), vomiting, dyspepsia 
 

Common Anorexia, flatulence, mouth ulcer, 
gastrointestinal haemorrhage, 
gastroesophageal reflux disease, pancreatitis 
 



62 
 

Hepatobiliary disorders Common 
 

Hepatitis (including increased AST, ALT, 
GGT), blood bilirubin increased (including 
jaundice) 
 

Skin and subcutaneous tissue 
disorders 

Very common Pruritus, rash (including erythematous and 
maculopapular) 
 

 
 

Common Acne 

 Rare Stevens Johnson syndrome, toxic epidermal 
necrolysis (TEN) 
 

Musculosketal and connective 
tissue disorders 

Very common 
 

Arthralgia and back pain 
 

Common Myositis, rhabdomyolysis, myalgia, 
myopathy/CPK increased 
 

Renal and urinary disorders  Common Increased urination, renal impairment (e.g. 
oliguria, elevated creatinine) 
 

 Uncommon 
 

Not known 

Acute renal failure 
 
Nephrolithiasis 

Reproductive system and breast 
disorders 
 

Common 
 

Menorrhagia 

General disorders and 
administration site conditions 

Very common 
 

Fatigue including asthenia, flushing, feeling 
hot 
 

Common Fever, weight loss 
 

Investigations Common 
 

Increased amylase, decreased free and total 
thyroxin  
 

Uncommon Increased glucose, increased magnesium, 
increased alkaline phosphatase 

 
Description of selected adverse reactions 
 
Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and 
jaundice have occurred in patients receiving ritonavir alone or in combination with other 
antiretrovirals. 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4). 
 
In HIV-infected patients with severe immune deficiency at the time of initiation of combination 
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic 
infections may arise.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and can occur many months 
after initiation of treatment (see section 4.4). 
 
Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed 
hypertriglyceridemia.  In some cases fatalities have been observed.  Patients with advanced HIV 
disease may be at risk of elevated triglycerides and pancreatitis (see section 4.4). 
 



63 
 

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk 
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).  
The frequency of this is unknown (see section 4.4). 
 
Paediatric populations 
 
The safety profile of Norvir in children 2 years of age and older is similar to that seen in adults. 
 
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 
 
Symptoms 
Human experience of acute overdose with ritonavir is limited.  One patient in clinical trials took 
ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was 
decreased.  A case of renal failure with eosinophilia has been reported. 
 
The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea 
and tremors. 
 
Management 
There is no specific antidote for overdose with ritonavir.  Treatment of overdose with ritonavir should 
consist of general supportive measures including monitoring of vital signs and observation of the 
clinical status of the patient.  Due to the solubility characteristics and possibility of transintestinal 
elimination, it is proposed that management of overdose could entail gastric lavage and administration 
of activated charcoal.  Since ritonavir is extensively metabolised by the liver and is highly protein 
bound, dialysis is unlikely to be beneficial in significant removal of the medicine.   
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors ATC code: J05AE03 
 
Ritonavir dosed as a pharmacokinetic enhancer 
 
Pharmacokinetic enhancement by ritonavir is based on ritonavir’s activity as a potent inhibitor of 
CYP3A- mediated metabolism.  The degree of enhancement is related to the metabolic pathway of the 
co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the 
metabolism of ritonavir.  Maximal inhibition of metabolism of the co-administered protease inhibitor 
is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on 
the co-administered protease inhibitor.  For additional information on the effect of ritonavir on 
co-administered protease inhibitor metabolism, see section 4.5 and refer to the Summary of Product 
Characteristics of the particular co-administered PIs. 
 
Ritonavir dosed as an antiretroviral agent  
 
Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases.  
Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein 
precursor which leads to the production of HIV particles with immature morphology that are unable to 
initiate new rounds of infection.  Ritonavir has selective affinity for the HIV protease and has little 
inhibitory activity against human aspartyl proteases. 

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


64 
 

 
Ritonavir was the first protease inhibitor (approved in 1996) for which efficacy was proven in a study 
with clinical endpoints.  However, due to ritonavir’s metabolic inhibitory properties its use as a 
pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical 
practice (see section 4.2). 
 
Effects on the Electrocardiogram   
 
QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) 
controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3.  The 
maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 
400 mg twice daily ritonavir.  The Day 3 ritonavir exposure was approximately 1.5 fold higher than 
that observed with the 600 mg twice daily dose at steady state.  No subject experienced an increase in 
QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant 
threshold of 500 msec. 
 
Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study 
on Day 3.  The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12 
hour interval post dose.  Maximum PR interval was 252 msec and no second or third degree heart 
block was observed (see section 4.4). 
 
Resistance 
 
Ritonavir-resistant isolates of HIV-1 have been selected in vitro and isolated from patients treated with 
therapeutic doses of ritonavir.   
 
Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations 
V82A/F/T/S and I84V.  Accumulation of other mutations in the protease gene (including at positions 
20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance.  In general, as mutations 
associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to 
cross-resistance.  The Summary of Product Characteristics of other protease inhibitors or official 
continuous updates should be consulted for specific information regarding protease mutations 
associated with reduced response to these agents. 
 
Clinical pharmacodynamic data 
 
The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of 
disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving 
HIV-1 infected patients.  The following studies are the most important. 
 
Adult Use 
 
A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients 
extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/µl showed 
a reduction in mortality and AIDS defining events.  The mean average change from baseline over 16 
weeks for HIV RNA levels was -0.79 log10 (maximum mean decrease: 1.29 log10) in the ritonavir 
group versus -0.01 log10 in the control group.  The most frequently used nucleosides in this study were 
zidovudine, stavudine, didanosine and zalcitabine.  
 
In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/µl) 
without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced 
viral load in plasma and increased CD4 count.  The mean average change from baseline over 48 weeks 
for HIV RNA levels was -0.88 log10 in the ritonavir group versus -0.66 log10 in the ritonavir + 
zidovudine group versus -0.42 log10 in the zidovudine group. 
 
The continuation of ritonavir therapy should be evaluated by viral load because of the possibility of 
the emergence of resistance as described under section 4.1. 



65 
 

 
Paediatric Use 
 
In an open label trial completed in 1998 in HIV infected, clinically stable children there was a 
significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir, 
zidovudine and lamivudine) following 48 weeks treatment. 
 
In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age 
4 weeks to 2 years received ritonavir 350 or 450 mg/m2 every 12 hours co-administered with 
zidovudine 160 mg/m2 every 8 hours and lamivudine 4 mg/kg every 12 hours.  In intent to treat 
analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at 
Week 16 and 104, respectively.  Response was similar in both dosing regimens and across patient age.   
 
In a study completed in 2000, 76 HIV-1 infected children aged 6 months to 12 years who were 
protease inhibitor naive and naive to lamivudine and/or stavudine received ritonavir 350 or 450 mg/m2 
every 12 hours co-administered with lamivudine and stavudine.  In intent to treat analyses, 50% and 
57% of patients in the 350 and 450 mg/m2 dose groups, respectively, achieved reduction in plasma 
HIV-1 RNA to ≤ 400 copies/ml at Week 48. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute 
bioavailability have not been determined.  The pharmacokinetics of ritonavir during multiple dose 
regimens were studied in non-fasting HIV-infected adult volunteers.  Upon multiple dosing, ritonavir 
accumulation is slightly less than predicted from a single dose due to a time and dose-related increase 
in apparent clearance (Cl/F).  Trough concentrations of ritonavir decrease over time, possibly due to 
enzyme induction, but appeared to stabilise by the end of 2 weeks.  The time to maximum 
concentration (Tmax) remained constant at approximately 4 hours with increasing dose.  Renal 
clearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range. 
 
The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shown 
in the table below.  Plasma concentrations of ritonavir after administration of a single 100 mg dose 
tablet are similar to the 100 mg soft gelatin capsule under fed conditions. 
 

Ritonavir Dosing Regimen 

 100 mg   once 
daily 

100 mg twice 
daily1 

200 mg once 
daily 

200 mg twice 
daily 

600 mg twice 
daily 

Cmax (µg/ml) 0.84 ± 0.39 0.89 3.4 ± 1.3 4.5 ± 1.3 11.2 ± 3.6 
Ctrough (µg/ml) 0.08 ± 0.04 0.22 0.16 ± 0.10 0.6 ± 0.2 3.7 ± 2.6 
AUC12 or 24 
(µg•h/ml) 

6.6 ± 2.4 6.2 20.0 ± 5.6 21.92 ± 6.48 77.5 ± 31.5 

t½ (h) ~5 ~5 ~4 ~8 ~3 to 5 
Cl/F (L/h) 17.2 ± 6.6 16.1 10.8 ± 3.1 10.0 ± 3.2 8.8 ± 3.2 

1 Values expressed as geometric means.  Note: ritonavir was dosed after a meal for all listed regimens. 
 
Effects of food on oral absorption 
Food slightly decreases the bioavailability of the Norvir tablet.  Administration of a single 100 mg 
dose of Norvir tablet with a moderate fat meal (857 kcal, 31% calories from fat) or a high fat meal 
(907 kcal, 52% calories from fat) was associated with a mean decrease of 20-23% in ritonavir AUC 
and Cmax. 
 
Distribution 
The apparent volume of distribution (VB/F) of ritonavir is approximately 20 - 40 l after a single 
600 mg dose.  The protein binding of ritonavir in human plasma is approximately 98 - 99% and is 



66 
 

constant over the concentration range of 1.0 – 100 µg/ml.  Ritonavir binds to both human alpha 1-acid 
glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities. 
 
Tissue distribution studies with 14C-labelled ritonavir in rats showed the liver, adrenals, pancreas, 
kidneys and thyroid to have the highest concentrations of ritonavir.  Tissue to plasma ratios of 
approximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues.  
Ritonavir penetrates minimally into the brain. 
 
Biotransformation 
Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily 
by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform.  Animal studies as well 
as in vitro experiments with human hepatic microsomes indicated that ritonavir primarily underwent 
oxidative metabolism.  Four ritonavir metabolites have been identified in man.  The isopropylthiazole 
oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent 
compound.  However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent 
compound.   
 
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease 
inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence 
the pharmacokinetics of ritonavir (see section 4.5).   
 
Elimination 
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was 
primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, 
part of which is expected to be unabsorbed ritonavir.  In these studies renal elimination was not found 
to be a major route of elimination of ritonavir.  This was consistent with the observations in animal 
studies. 
 
Special populations   
 
No clinically significant differences in AUC or Cmax were noted between males and females.  
Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weight 
or lean body mass.  Ritonavir plasma exposures in patients 50 – 70 years of age when dosed 100 mg in 
combination with lopinavir or at higher doses in the absence of other protease inhibitors is similar to 
that observed in younger adults. 
 
Patients with impaired liver function 
After multiple dosing of ritonavir to healthy volunteers (500 mg twice daily) and subjects with mild to 
moderate hepatic impairment (Child Pugh Class A and B, 400 mg twice daily) exposure to ritonavir 
after dose normalisation was not significantly different between the two groups.   
 
Patients with impaired renal function 
Ritonavir pharmacokinetic parameters have not been studied in patients with renal impairment.  
However, since the renal clearance of ritonavir is negligible, no changes in the total body clearance are 
expected in patients with renal impairment. 
 
Paediatric patients 
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children above 2 
years of age receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily.  Ritonavir 
concentrations obtained after 350 to 400 mg/m² twice daily in paediatric patients were comparable to 
those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily.  Across dose 
groups, ritonavir oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in paediatric 
patients above 2 years of age than in adult subjects. 
 
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than 
2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily.  Ritonavir concentrations in 
this study were highly variable and somewhat lower than those obtained in adults receiving 600 mg 



67 
 

(approximately 330 mg/m²) twice daily.  Across dose groups, ritonavir oral clearance (CL/F/m2) 
declined with age with median values of 9.0 L/h/m2 in children less than 3 months of age, 7.8 L/h/m2 
in children between 3 and 6 months of age and 4.4 L/h/m2 in children between 6 and 24 months of age. 
 
5.3 Preclinical safety data 
 
Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid 
gland and kidney.  Hepatic changes involved hepatocellular, biliary and phagocytic elements and were 
accompanied by increases in hepatic enzymes.  Hyperplasia of the retinal pigment epithelium (RPE) 
and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have 
not been seen in dogs.  Ultrastructural evidence suggests that these retinal changes may be secondary 
to phospholipidosis.  However, clinical trials revealed no evidence of medicinal product-induced 
ocular changes in humans.  All thyroid changes were reversible upon discontinuation of ritonavir.  
Clinical investigation in humans has revealed no clinically significant alteration in thyroid function 
tests.  Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted 
in rats and are felt to be attributable to species-specific spontaneous disease.  Furthermore, no 
clinically significant renal abnormalities were noted in clinical trials. 
 
Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and 
ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a 
maternally toxic dosage.  Developmental toxicity in rabbits (embryolethality, decreased litter size and 
decreased foetal weights) occurred at a maternally toxic dosage. 
 
Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays 
including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse 
lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human 
lymphocytes. 
 
Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential 
specific for these species, but are regarded as of no relevance for humans. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet: 
Copovidone 
Sorbitan laurate 
Calcium hydrogen phosphate, anhydrous 
Silica, colloidal anhydrous 
Sodium stearyl fumarate 
 
Film-coating: 
Hypromellose 
Titanium dioxide (E171) 
Macrogols  
Hydroxypropyl cellulose 
Talc 
Silica, colloidal anhydrous 
Polysorbate 80 
 
6.2 Incompatibilities 
 
Not applicable. 
 



68 
 

6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special temperature storage conditions.  Store in the 
original bottle in order to protect from moisture.  
 
6.5 Nature and contents of container 
 
Norvir tablets are supplied in white high density polyethylene (HDPE) bottles closed with 
polypropylene caps.  
  
Three pack sizes are available for Norvir tablets: 
− 1 bottle of 30 tablets  
− 1 bottle of 60 tablets 
− Multipack containing 90 (3 bottles of 30) film-coated tablets  
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/016/005-007 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  26 August 1996 
Date of latest renewal:  26 August 2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 
  



69 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) 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 

 
 



70 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 
Name and address of the manufacturer responsible for batch release 
 
Film-coated tablets and powder for oral suspension 
 
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
Powder for oral suspension only 
 
AbbVie Logistics B.V., Zuiderzeelaan 53, 8017 JV Zwolle, The Netherlands 
 
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 marketing authorisation holder (MAH) shall submit PSURs for this product in accordance with 
the requirements set out in the list of Union reference dates (EURD list) provided for under Article 
107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
• Risk management plan (RMP)  
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
 
• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
If the dates for submission of a PSUR and the update of a RMP conincide, they can be submitted at the 
same time. 
  



71 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 

  



72 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A.  LABELLING 



73 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
NORVIR POWDER FOR ORAL SUSPENSION - Carton containing 30 sachets each containing 
100mg ritonavir 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Norvir 100 mg powder for oral suspension 
ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each sachet contains 100 mg of ritonavir. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 sachets of powder for oral suspension 
Carton also contains 1 mixing cup and 2 oral dosing syringes 
 
 
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 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 30°C 
 
 
10.  SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



74 
 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/016/009 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Norvir 100 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN  



75 
 

MINIMUM PARTICULARS TO APPEAR ON SMALL PACKAGING UNITS 
 
NORVIR POWDER FOR ORAL SUSPENSION - Sachet Label Text 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Norvir 100 mg powder for oral suspension 
ritonavir 
Oral use 
 
 
2. METHOD OF ADMINISTRATION  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY UNIT 
 
100 mg 



76 
 

  
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
NORVIR FILM-COATED TABLETS - CARTON WITH BLUE BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Norvir 100 mg film-coated tablets 
ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg ritonavir. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Norvir tablets should be taken with food.  
The tablets should be swallowed whole and not chewed, broken or crushed. 
 
 
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 
 
Child resistant closure 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original bottle in order to protect from moisture. 
 
 



77 
 

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 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/016/005 
EU/1/96/016/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Norvir 100 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN  



78 
 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
NORVIR FILM-COATED TABLETS - Bottle Label Text 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Norvir 100 mg film-coated tablets 
ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg ritonavir. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
60 film-coated 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 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original bottle 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



79 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/016/005 
EU/1/96/016/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable 
 



80 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
NORVIR FILM-COATED TABLETS - Multipack containing 90 (3 bottles of 30) film-coated 
tablets with blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Norvir 100 mg film-coated tablets 
ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg ritonavir. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 90 (3 bottles of 30) film-coated tablets  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Norvir tablets should be taken with food.  
The tablets should be swallowed whole and not chewed, broken or crushed. 
 
 
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 
 
Child resistant closure 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original bottle in order to protect from moisture. 
 
 



81 
 

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 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/016/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Norvir 100 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



82 
 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
NORVIR FILM-COATED TABLETS BOTTLE LABEL TEXT – 3 BOTTLES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Norvir 100 mg film-coated tablets 
ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 100 mg ritonavir. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated 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 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original bottle 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



83 
 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/96/016/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable 
 
  



84 
 

 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B.  PACKAGE LEAFLET 
  



85 
 

Package leaflet: Information for the user 
 

Norvir 100 mg powder for oral suspension  
ritonavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you or your child. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- 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 or pharmacist.  This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
1. What Norvir is and what it is used for 
2. What you need to know before you or your child takes Norvir 
3. How to take Norvir 
4. Possible side effects 
5. How to store Norvir 
6. Contents of the pack and other information 
 
 
1. What Norvir is and what it is used for 
 
Norvir contains the active substance ritonavir.  Norvir is a protease inhibitor used to control HIV 
infection.  Norvir is used in combination with other anti-HIV medicines (antiretrovirals) to control 
your HIV infection.  Your doctor will discuss with you the best combination of medicines for you 
 
Norvir is used by children 2 years of age or older, adolescents and adults who are infected with HIV, 
the virus which causes AIDS.   
 
 
2. What you need to know before you or your child takes Norvir 
 
Do not take Norvir 
 
− if you are allergic to ritonavir or any of the other ingredients of Norvir (see section 6).  
 
− if you have severe liver disease. 
 
− if you are currently taking any of the following medicines: 

− astemizole or terfenadine (commonly used to treat allergy symptoms – these medicines 
may be available without prescription); 

− amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine (used to 
correct irregular heartbeats); 

− dihydroergotamine, ergotamine (used to treat migraine headache); 
− ergonovine, methylergonovine (used to stop excessive bleeding that may occur following 

childbirth or an abortion); 
− clorazepate, diazepam, estazolam, flurazepam, triazolam or oral (taken by mouth) 

midazolam (used to help you sleep and/or relieve anxiety); 
− clozapine, pimozide, (used to treat abnormal thoughts or feelings); 
− quetiapine (used to treat schizophrenia, bipolar disorder and major depressive disorder); 
− lurasidone (used to treat depression); 
− ranolazine (used to treat chronic chest pain [angina]); 
− pethidine, piroxicam, propoxyphene (used to relieve pain); 



86 
 

− cisapride (used to relieve certain stomach problems); 
− rifabutin (used to prevent/treat certain infections)*; 
− voriconazole (used to treat fungal infections)*; 
− simvastatin, lovastatin (used to lower blood cholesterol); 
− neratinib (used to treat breast cancer); 
− lomitapide (used to lower blood cholesterol); 
− alfuzosin (used to treat enlarged prostate gland); 
− fusidic acid (used to treat bacterial infections); 
− sildenafil if you suffer from a lung disease called pulmonary arterial hypertension that 

makes breathing difficult.  Patients without this disease may use sildenafil for impotence 
(erectile dysfunction) under their doctor’s supervision (see the section on Other 
medicines and Norvir);  

− avanafil or vardenafil (used to treat erectile dysfunction);  
− colchicine (used to treat gout) if you have kidney and/or liver problems (see the section 

on Other medicines and Norvir); 
− products containing St John’s wort (Hypericum perforatum) as this may stop Norvir from 

working properly.  St John’s wort is often used in herbal medicines that you can buy 
yourself. 

 
*   Your doctor may decide that you can take rifabutin and/or voriconazole with a booster (lower dose) 

of Norvir but a full dose of Norvir must not be taken together with these two medicines.  
 
If you are currently taking any of these medicines, ask your doctor about switching to a different 
medicine while you are taking Norvir.  
 
Also read the list of medicines under ‘Other medicines and Norvir’ for use with certain other 
medicines which require special care. 
 
Warnings and precautions 
 
Talk to your doctor before taking Norvir. 
 
Important information 
 
- If Norvir is taken in combination with other antiretroviral medicines, it is important that you 

also carefully read the leaflets that are provided with these other medicines.  There may be 
additional information in those leaflets about situations when Norvir should be avoided.  If you 
have any further questions about Norvir (ritonavir) or the other medicines prescribed, please ask 
your doctor or pharmacist. 

- Norvir is not a cure for HIV infection or AIDS. 
- People taking Norvir may still develop infections or other illnesses associated with HIV 

infection or AIDS.  It is therefore important that you remain under the supervision of your 
doctor while taking Norvir. 

− You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy.  Discuss with your physician the precautions needed to avoid infecting 
other people. 

 
Tell your doctor if you have/had: 
 
- A history of liver disease.   
- Hepatitis B or C and are being treated with a combination of antiretroviral agents, as you are at 

a greater risk of a severe and potentially life threatening reaction because of the effect on the 
liver.  Regular blood tests may be required to check your liver is working properly. 

- Haemophilia, as there have been reports of increased bleeding in patients with haemophilia who 
are taking this type of medicine (protease inhibitors).  The reason for this is not known.  You 



87 
 

may need additional medicine to help your blood clot (factor VIII), in order to control any 
bleeding. 

- Erectile dysfunction, as the medicines used to treat erectile dysfunction can cause hypotension 
and prolonged erection. 

- Diabetes, as there have been reports of worsening of or the development of diabetes (diabetes 
mellitus) in some patients taking protease inhibitors. 

- Kidney (renal) disease, since your doctor may need to check the dose of your other medicines 
(such as protease inhibitors). 

 
Tell your doctor if you experience: 
 
- Diarrhoea or vomiting that is not improving (persistent), as this may reduce how well the 

medicines you are taking work. 
- Feeling sick (nausea), vomiting or have stomach pain, because these may be signs of 

inflammation of the pancreas (pancreatitis).  Some patients taking Norvir can develop serious 
problems with their pancreas.  Tell your doctor as soon as possible if this applies to you. 

- Symptoms of infection – inform your doctor immediately.  Some patients with advanced HIV 
infection (AIDS) who then start anti-HIV treatment may develop the symptoms of infections 
they have had in the past even if they didn’t know they had had them.  It is believed that this 
happens because the body's immune response improves and helps the body to fight these 
infections. 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection.  Autoimmune disorders may occur many months after 
the start of treatment.  If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment. 

- Joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty 
moving, tell your doctor, as this may be a sign of a problem that can destroy bone 
(osteonecrosis).  Some patients taking a number of antiretroviral medicines may develop this 
disease.  

- Muscle pain, tenderness or weakness, particularly in combination with antiretroviral therapy 
including protease inhibitors and nucleoside analogues.  On rare occasions these muscle 
disorders have been serious. (See section 4. Possible side effects) 

- Dizziness, lightheadedness, fainting spells or abnormal heartbeat.  Some patients taking 
Norvir may experience changes in the electrocardiogram (ECG).  Tell your doctor if you have a 
heart defect or conduction defect. 

- If you have any other health concerns, discuss these with your doctor as soon as you can. 
 
Children and adolescents 
 
Norvir is not recommended in children below 2 years of age. 
 
Other medicines and Norvir 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription.  There are some medicines you cannot 
take at all with Norvir.  These are listed earlier in section 2, under ‘Do not take Norvir’.  There are 
some other medicines that can only be used under certain circumstances as described below. 
 
The following warnings apply when Norvir is taken as a full dose.  However, these warnings may also 
apply when Norvir is used in lower doses (a booster) with other medicines.  
 



88 
 

Tell your doctor if you are taking any of the medicines listed below, as special care should be 
taken. 
 
- Sildenafil or tadalafil for impotence (erectile dysfunction).   

The dose and/or frequency of use of these medicines may need to be reduced to avoid 
hypotension and prolonged erection.  You must not take Norvir with sildenafil if you suffer from 
pulmonary arterial hypertension (see also section 2. What you need to know before you or 
your child takes Norvir).  Tell your doctor if you are taking tadalafil for pulmonary arterial 
hypertension. 

- Colchicine (for gout) as Norvir may raise the blood levels of this medicine.  You must not take 
Norvir with colchicine if you have kidney and/or liver problems (see also ‘Do not take Norvir’ 
above). 

- Digoxin (heart medicine).  Your doctor may need to adjust the dose of digoxin and monitor you 
while you are taking digoxin and Norvir in order to avoid heart problems. 

- Hormonal contraceptives containing ethinyl oestradiol as Norvir may reduce the effectiveness 
of these medicines.  It is recommended that a condom or other non-hormonal method of 
contraception is used instead.  You may also notice irregular uterine bleeding if you are taking 
this type of hormonal contraceptive with Norvir. 

- Atorvastatin or rosuvastatin (for high cholesterol) as Norvir may raise the blood levels of 
these medicines.  Talk to your doctor before you take any cholesterol-reducing medicines with 
Norvir (see also ‘Do not take Norvir’ above). 

- Steroids (e.g. dexamethasone, fluticasone propionate, prednisolone, triamcinolone) as Norvir 
may raise the blood levels of these medicines which may lead to Cushing’s syndrome 
(development of a rounded face) and reduce production of the hormone cortisol.  Your doctor 
may wish to reduce the steroid dose or monitor your side effects more closely. 

- Trazodone (a medicine for depression) as, unwanted effects like nausea, dizziness, low blood 
pressure and fainting can occur when taken with Norvir.  

- Rifampicin and saquinavir (used for tuberculosis and HIV, respectively) as serious liver 
damage can occur when taken with Norvir. 

- Bosentan, riociguat (used for pulmonary arterial hypertension) as Norvir may increase the 
blood levels of this medicine. 

 
There are medicines that may not mix with Norvir because their effects could increase or decrease 
when taken together.  In some cases your doctor may need to perform certain tests, change the dose or 
monitor you regularly.  This is why you should tell your doctor if you are taking any medicines, 
including those you have bought yourself or herbal products, but it is especially important to mention 
these:  
 
- amphetamine or amphetamine derivatives; 
- antibiotics (e.g. erythromycin, clarithromycin);  
- anticancer treatments (e.g. abemaciclib, afatinib, apalutamide, ceritinib, encorafenib, dasatinib, 

ibrutinib, nilotinib, venetoclax, vincristine, vinblastine); 
- medicines used to treat low blood platelet count (e.g. fostamatinib); 
- anticoagulants (e.g. rivaroxaban, vorapaxar, warfarin); 
- antidepressants (e.g. amitriptyline, desipramine, fluoxetine, imipramine, nefazodone, 

nortriptyline, paroxetine, sertraline, trazodone); 
- antifungals (e.g. ketoconazole, itraconazole);  
- antihistamines (e.g. loratadine, fexofenadine);  
- antiretroviral medicines, including HIV-protease inhibitors (amprenavir, atazanavir, darunavir, 

fosamprenavir, indinavir, nelfinavir, saquinavir, tipranavir), non-nucleoside reverse transcriptase 
inhibitors (NNRTI) (delavirdine, efavirenz, nevirapine), and others (didanosine, maraviroc, 
raltegravir, zidovudine);  

- anti-tuberculosis medicine (bedaquiline and delamanid); 
- antiviral medicine used to treat chronic hepatitis C virus (HCV) infection in adults (e.g. 

glecaprevir/pibrentasvir and simeprevir); 
- anxiety medicine, buspirone;  
- asthma medicine, theophylline, salmeterol;  



89 
 

- atovaquone, a medicine used to treat a certain type of pneumonia and malaria; 
- buprenorphine, a medicine used for the treatment of chronic pain; 
- bupropion, a medicine used to help you stop smoking; 
- epilepsy medicines (e.g. carbamazepine, divalproex, lamotrigine, phenytoin); 
- heart medicines (e.g. disopyramide, mexiletine and calcium channel antagonists such as 

amlodipine, diltiazem and nifedipine);  
- immune system medicines (e.g. cyclosporine, tacrolimus, everolimus);  
- levothyroxine (used to treat thyroid problems); 
- morphine and morphine-like medicines used to treat severe pain (e.g. methadone, fentanyl); 
- sleeping pills (e.g. alprazolam, zolpidem) and also midazolam administered by injection;  
- tranquillisers (e.g. haloperidol, risperidone, thioridazine);  
- colchicine, a treatment for gout. 
 
There are some medicines you cannot take at all with Norvir.  These are listed earlier in section 2, 
under ‘Do not take Norvir’. 
 
Taking Norvir with food and drink 
 
See section 3. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a 
baby, it is very important that you ask your doctor for advice before taking this medicine. 
 
There is a large amount of information on the use of ritonavir (the active ingredient in Norvir) during 
pregnancy.  In general, pregnant mothers received ritonavir after the first three months of pregnancy at 
a lower dose (booster) along with other protease inhibitors.  Norvir did not appear to increase the 
chance of developing birth defects compared to the general population. 
 
Norvir can pass into breast milk.  To avoid transmitting the infection, mothers with HIV must not 
breast feed their babies. 
 
Driving and using machines 
 
Norvir can cause dizziness.  If you are affected do not drive or use machinery.  
 
 
3. How to take Norvir 
 
Always take this medicine exactly as your doctor or pharmacist has told you.  Check with your doctor 
or pharmacist if you are not sure.  Take this medicine one or two times a day every day with food.  
 
For doses of exactly 100 mg amounts (100, 200, 300, 400, 500, or 600 mg) pour the entire content of 
each sachet over soft food (apple sauce or vanilla pudding) or mix with a small amount of liquid 
(water, chocolate milk, or infant formula) and consume entire serving.  
 
For doses less than 100 mg amounts or doses between 100 mg amounts, the content of the entire 
sachet is to be mixed with a liquid and then dosed by the appropriate ml volume as told to you 
by your doctor using the oral dosing syringe.   
 
For administration using a feeding tube follow the instructions in section ‘How do I take the correct 
dose of Norvir powder for oral suspension mixed with liquid?’  Use water to mix the medicine and 
follow the feeding tube instructions to administer the medicine. 
 



90 
 

Recommended doses of Norvir are: 
 
• if Norvir is used to boost the effects of other anti-HIV medicines, the typical dose for adults is 1 

or 2 sachets once or twice daily.  For more detailed dose recommendations, including those for 
children, see the Package Leaflet of the anti-HIV medicines Norvir is given in combination 
with. 
 

• if your doctor prescribes a full dose, adults may be started on a dose of 3 sachets in the morning 
and 3 sachets 12 hours later, gradually increasing over a period of up to 14 days to the full dose 
of 6 sachets twice daily.  Children (2 – 12 years of age) will start with a dose smaller than this 
and continue up to the maximum allowed for their size.   

 
Your doctor will advise you on the dosage to be taken. 
 
Norvir should be taken every day to help control your HIV, no matter how much better you feel.  If a 
side effect is preventing you from taking Norvir, tell your doctor straight away.  During episodes of 
diarrhoea your doctor may decide that extra monitoring is needed. 
 
Always keep enough Norvir on hand so you don't run out.  When you travel or need to stay in the 
hospital, make sure you have enough Norvir to last until you can get a new supply. 
 
Norvir powder for oral suspension has a lingering aftertaste.  Eating peanut butter, hazelnut chocolate 
spread, or black currant syrup immediately after taking the medication may help clear the aftertaste 
from your mouth.  
 
Prepare only one dose at a time using the correct number of sachets.  When mixing the powder with 
food or liquid, be sure to take the whole dose within 2 hours.  Do not mix Norvir with anything else 
without talking to your doctor or pharmacist.   
 
How do I take the correct dose of Norvir powder for oral suspension mixed with food (full 
sachet)?  
 
Follow the instructions below: 

 

Step 1. Before mixing dose of Norvir, collect the 
following supplies: (see Figure 1). 
 
Step 2. Check prescription for number of sachets 
or call your doctor or pharmacist. 

Figure 1  

 
Step 3. Before first using the mixing cup, wash the cup in warm water and dish soap. Rinse and allow 
to air dry. 
 



91 
 

 

Step 4. Put a small serving of soft food (applesauce or 
vanilla pudding) in a cup (see Figure 2). 

Figure 2  

 

Step 5. Tear open sachet (see Figure 3). 
 

 
Figure 3 

 

 

 

Step 6. Pour ALL powder from sachet onto food (see 
Figure 4).  
 

 
Figure 4 

 

 

 

Step 7. Mix thoroughly (see Figure 5). 
 

 
Figure 5 

 

Step 8. Feed serving to patient. 



92 
 

 

Step 9. ENTIRE serving must be eaten (see Figure 6). If 
powder residue is left, add more spoonfuls of food and 
serve to patient. Use within 2 hours. 
 

 
Figure 6 
 

 

 

Step 10. Place empty sachet in rubbish. Wash and dry 
preparation area. Immediately wash the spoon and cup in 
warm water and dish soap (see Figure 7). Rinse and 
allow to air dry. 
 

 
Figure 7 

 

 
How do I take the correct dose of Norvir powder for oral suspension mixed with liquid?  
 
Follow the instructions below: 

 

Figure 1 

What you need 
 
Before mixing a dose of Norvir, collect the items 
shown in Figure 1. 
 
You may need more than 1 sachet for each dose. 
Check the prescription label on the carton or call 
your doctor or pharmacist if you are not sure. If 
you do need more than 1 sachet, repeat all the 
steps with each sachet.  

 

Using the syringe 
Before first using the dosing syringe, wash the 
syringe in warm water and dish soap. Rinse and 
allow to air dry. 
 
Reading the scale 
a. Each millilitre (ml) is shown as a number 

with a big line. 
b. Each 0.2 ml is shown as a smaller line 

between the numbers.  
 
Check the syringe before each use 
You will need to use a new syringe if: 
• you cannot clean the syringe 
• you cannot read the scale 



93 
 

• you cannot move the plunger 
• the syringe is damaged or leaking. 
 

 

Figure 2 

Step 1. Fill the syringe 
 
a. Push the plunger all the way into syringe. 
b. Place the syringe tip into the liquid. 
c. Slowly pull the plunger back to the 10 ml mark 
on the syringe (see Figure 2). 

 

 

Figure 3 

Step 2. Move any bubbles to the tip of the 
syringe 
 
a. Hold the syringe with the tip pointing up. 
b. Tap the syringe with your 
other hand. This will move any bubbles to the tip.  
c. Pull the plunger down. 
Be careful not to pull the plunger out. 
d. Tap the syringe again. This will help to break 
up the bubbles and make sure they are all at the 
tip (see Figure 3). 

 

 

Figure 4 

Step 3. Measure the liquid 
 
a. Keep the syringe pointed up. 
b. Slowly push the plunger up until the top of the 
plunger is at 9.4 ml - this will remove any bubbles 
from the syringe (see Figure 4). 

 

Figure 5 

Step 4. Empty the syringe 

a. Slowly push the plunger to empty the liquid 
from the syringe into the mixing cup (see Figure 
5). 

 

Figure 6 

Step 5. Pour the powder into the cup 
 
a. Tear open the sachet. 
b. Pour all of the powder into the mixing cup. 
c. Check if the sachet is empty. 

Be careful not to spill any powder outside of 
the mixing cup (see Figure 6). 



94 
 

 

Figure 7 

Step 6. Mix the powder and liquid 
 
a.Tightly screw on the lid and keep shaking the 
mixing cup hard for at least 90 seconds until all 
the lumps have gone. 
b. Check for any lumps of powder. If there are 
still lumps, keep shaking until they have all gone.   
c. The liquid may look cloudy - this is okay. 
d. Let the liquid stand for 10 minutes and most of 
the bubbles will disappear. 
e. You may see some small bubbles on top of the 
liquid - this is also okay (see Figure 7). 

 

Figure 8 

Step 7. Fill the syringe 
 
a. Push the plunger completely into the syringe. 
b. Place the syringe tip at the bottom of the 
mixing cup. 
c. Slowly pull the plunger back to the 10 ml mark 
- try not to pull any bubbles into the syringe (see 
Figure 8). 

 

Figure 9 

Step 8. Remove any bubbles 
 
a. Hold the syringe with the tip pointing up. 
b. Tap the syringe with your other hand. This will 
move any bubbles to the tip. 
c. Pull the plunger down. Be careful not to pull 
the plunger out. 
d. Tap the syringe again to break up the bubbles 
so they are all at the tip (see Figure 9). 
e. Slowly push the plunger until you see a small 
amount of liquid at the tip of the syringe. 
f. If there are any large air bubbles, empty the 
liquid from the syringe into the mixing cup and 
start again from Step 7. 



95 
 

 

Figure 10 

Step 9. Measure the dose 
 
a. Check the prescription label on the carton for 
the dose in ml. If you are not sure, call your 
doctor or pharmacist. 
b. Point the syringe into the mixing cup and 
slowly push the plunger to the correct ml for the 
dose (see Figure 10). 
c. If you push out too much liquid, start again 
from Step 7. Be careful not to spill the liquid 
outside of the mixing cup. 
 

 

Figure 11 

Step 10. Give the medicine to the patient 
 
a. Place the syringe tip against the inside of the 
patient’s cheek. 
b. Slowly push the plunger to give all of the dose 
(see Figure 11). 
c. Give the patient the full dose within 2 hours of 
opening the sachet. 

 

 
Step 11. (If required) 
 
If you need to use more than one sachet, repeat the 
process from the beginning. 
 

 
Step 12. After you have finished 
 
a. Place the empty sachet and any left over 
medicine from the mixing cup into a rubbish bag. 
b. Remove the plunger from the syringe. 
c. Hand wash the syringe, plunger, and mixing 
cup and lid in warm water and dish soap. Rinse 
with water and allow to air dry. Do not wash these 
in the dishwasher. 
d. Wash and dry the area used to mix the 
medicine. 

 
If you take more Norvir than you should 
 
Numbness, tingling, or a “pins and needles” sensation may occur if you take too much Norvir.  If you 
realise you have taken more Norvir than you were supposed to, contact your doctor or the Accident 
and Emergency Department of your nearest hospital straight away.  
 
If you forget to take Norvir 
 
If you miss a dose, take the missed dose as soon as possible.  If it is nearly time for the next dose, just 
take that one.  Do not take a double dose to make up for a forgotten dose. 
 



96 
 

If you stop taking Norvir 
 
Even if you feel better, do not stop taking Norvir without talking to your doctor.  Taking Norvir as 
recommended should give you the best chance of delaying resistance to the medicines. 
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
Like all medicines, Norvir can cause side effects, although not everybody gets them.  Also, the side 
effects of Norvir when used with other antiretroviral medicines are dependent on the other medicines.  
So it is important that you carefully read the side effects section of the leaflets that are provided with 
these other medicines. 
 
Very common: may affect more than 1 in 10 people 
 
• upper or lower stomach ache 

  
• vomiting  
• diarrhoea (may be severe)  
• feeling sick (nausea) 
• flushing, feeling hot  
• headache  
• dizziness 
• pain in the throat 
• cough 
• upset stomach or indigestion  

• a tingling sensation or numbness in  
the hands, feet or around the lips and 
mouth 

• feeling weak/tired 
• bad taste in the mouth 
• damage to the nerves that can cause 

weakness and pain 
• itching 
• rash 
• joint pain and back pain 

 
Common: may affect up to 1 in 10 people   
 
• allergic reactions including skin  

rashes (may be red, raised, itchy),  
severe swelling of the skin and  
other tissues 

• inability to sleep (insomnia) 
• anxiety 
• increase in cholesterol 
• increase in triglycerides 
• gout 
• stomach bleeding 
• inflammation of the liver and yellowing of 

skin or whites of the eyes 
• increase in urination 
• reduced kidney function 
• seizures (fits) 
• low levels of blood platelets 
• thirst (dehydration) 
• abnormally heavy periods 

• wind (flatulence) 
• loss of appetite 
• mouth ulcer 
• muscle aches (pain), tenderness or 

weakness 
• fever 
• weight loss 
• laboratory test results: 

changes in blood test results  
(such as blood chemistry and  
blood count) 

• confusion 
• difficulty paying attention 
• fainting 
• blurred vision 
• swelling of the hands and feet 
• high blood pressure 
• low blood pressure and feeling faint when 

getting up 
• coldness in the hands and feet 
• acne 

 



97 
 

Uncommon: may affect up to 1 in 100 people 
 
• heart attack  
• diabetes 

• kidney failure 

 
Rare: may affect up to 1 in 1,000 people 
 
• severe or life threatening skin  

reaction including blisters 
(Stevens Johnson syndrome, toxic 
epidermal necrolysis) 

• serious allergic reaction (anaphylaxis) 
• high levels of sugar in the blood 

 
Not known: frequency cannot be estimated from the available data 
 
• kidney stones 
 
Tell your doctor if you feel sick (nauseous), are vomiting, or have stomach pain, because these may be 
signs of an inflamed pancreas.  Also tell your doctor if you experience joint stiffness, aches and pains 
(especially of the hip, knee and shoulder) and difficulty moving, as this may be a sign of 
osteonecrosis.  See also section 2. What you need to know before you or your child takes Norvir. 
 
In patients with haemophilia types A and B, there have been reports of increased bleeding while taking 
this treatment or another protease inhibitor.  Should this happen to you, seek immediate advice from 
your doctor.   
 
Abnormal liver function tests, hepatitis (inflammation of the liver), and rarely jaundice, have been 
reported in patients taking Norvir.  Some people had other illnesses or were taking other medicines.  
People with liver disease or hepatitis may have worsening of liver disease.   
 
There have been reports of muscle pain, tenderness or weakness, particularly when taking medicines 
to lower cholesterol in combination with antiretroviral therapy, including protease inhibitors and 
nucleoside analogues.  On rare occasions these muscle disorders have been serious (rhabdomyolysis).  
In the event of unexplained or continual muscle pain, tenderness, weakness or cramps, stop taking the 
medicine, contact your doctor as soon as possible or go to the Accident and Emergency Department of 
your nearest hospital. 
 
Inform your doctor as soon as possible if you experience any symptoms that suggest an allergic 
reaction after taking Norvir such as rash, hives or breathing difficulties. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 
contact your doctor, pharmacist, Accident and Emergency department or if it is urgent get 
immediate medical help. 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist.  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 Norvir 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Norvir powder for oral suspension after the expiry date on the sachet and carton.  The 
expiry date refers to the last day of the month. 

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


98 
 

 
Norvir powder for oral suspension should be stored below 30°C.   
 
Do not use this medicine if you notice the powder is not beige/pale yellow to yellow. 
 
Do not throw away any medicines via wastewater.  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 Norvir contains 
 
- The active substance is ritonavir.  Each sachet of Norvir contains 100 mg ritonavir.  
- The other ingredients are copovidone; sorbitan laurate; silica, colloidal anhydrous.  
 
What Norvir looks like and contents of the pack 
 
Norvir powder for oral suspension comes in individual sachets containing 100 mg ritonavir.  
30 sachets are packed in a carton together with 1 mixing cup and 2 oral dosing syringes.  
 
Not all pack sizes may be marketed. 
 
Norvir is also supplied as a film-coated tablet containing 100 mg ritonavir. 
 
Marketing Authorisation Holder 
 
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
Manufacturers 
 
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany  
AbbVie Logistics B.V., Zuiderzeelaan 53, 8017 JV Zwolle, The Netherlands 
 
For any information about this medicine, please contact the local representative of the  
Marketing Authorisation Holder: 
 
België/Belgique/Belgien 
AbbVie SA 
Tél/Tel: +32 10  477811 

Lietuva 
AbbVie UAB  
Tel: +370 5 205 3023 
 

България 
АбВи ЕООД 
Тел.: +359 2 90 30 430 

Luxembourg/Luxemburg 
AbbVie SA 
Belgique/Belgien 
Tél/Tel: +32 10 477811 
 

Česká republika 
AbbVie s.r.o.  
Tel: +420 233 098 111 

Magyarország 
AbbVie Kft. 
Tel.: +36 1 455 8600 
 

Danmark 
AbbVie A/S 
Tlf: +45 72 30-20-28 

Malta 
V.J.Salomone Pharma Limited  
Tel: +356 22983201 
 

Deutschland 
AbbVie Deutschland GmbH & Co. KG 
Tel: 00800 222843 33 (gebührenfrei) 

Nederland 
AbbVie B.V. 
Tel: +31 (0)88 322 2843 



99 
 

Tel: +49 (0) 611 / 1720-0 
 
Eesti 
AbbVie Biopharmaceuticals GmbH Eesti filiaal  
Tel: +372 623 1011 

Norge 
AbbVie AS 
Tlf: +47 67 81 80 00 
 

Ελλάδα 
AbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε. 
Τηλ: +30 214 4165 555 

Österreich 
AbbVie GmbH  
Tel: +43 1 20589-0 
 

España 
AbbVie Spain, S.L.U.  
Tel: +34 9 1 384 0910 

Polska 
AbbVie Polska Sp. z o.o. 
Tel.: +48 22 372 78 00  
 

France 
AbbVie 
Tél: +33 (0)1 45 60 13 00 

Portugal 
AbbVie, Lda.  
Tel: +351 (0)21 1908400 
 

Hrvatska  
AbbVie d.o.o. 
Tel: +385 (0)1 5625 501 

România 
AbbVie S.R.L. 
Tel: +40 21 529 30 35 
 

Ireland 
AbbVie Limited  
Tel: +353 (0)1 4287900 

Slovenija 
AbbVie Biofarmacevtska družba d.o.o. 
Tel: +386 (1)32 08 060 

Ísland 
Vistor hf. 
Tel: +354 535 7000 

Slovenská republika 
AbbVie s.r.o. 
Tel: +421 2 5050 0777 
 

Italia 
AbbVie S.r.l.  
Tel: +39 06 928921 

Suomi/Finland 
AbbVie Oy  
Puh/Tel: +358 (0) 10 2411 200 
 

Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: +357 22 34 74 40 

Sverige 
AbbVie AB 
Tel: +46 (0)8 684 44 600 
 

Latvija 
AbbVie SIA  
Tel: +371 67605000 

United Kingdom 
AbbVie Ltd  
Tel: +44 (0)1628 561090 

 
This leaflet was last approved in {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 

http://www.ema.europa.eu/


100 
 

Package leaflet: Information for the user 
 

Norvir 100 mg film-coated tablets 
ritonavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you or your child. 
− Keep this leaflet.  You may need to read it again. 
− If you have any further questions, ask your doctor or pharmacist. 
− This medicine has been prescribed for you.  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 or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet:  
1. What Norvir is and what it is used for 
2. What you need to know before you or your child takes Norvir 
3. How to take Norvir 
4. Possible side effects 
5. How to store Norvir 
6. Contents of the pack and other information 
 
 
1. What Norvir is and what it is used for 
 
Norvir contains the active substance ritonavir.  Norvir is a protease inhibitor used to control HIV 
infection.  Norvir is used in combination with other anti-HIV medicines (antiretrovirals) to control 
your HIV infection.  Your doctor will discuss with you the best combination of medicines for you. 
 
Norvir is used by children 2 years of age or older, adolescents and adults who are infected with HIV, 
the virus which causes AIDS.   
 
 
2. What you need to know before you or your child takes Norvir 
 
Do not take Norvir 
 
− if you are allergic to ritonavir or any of the other ingredients of Norvir (see section 6).  
 
− if you have severe liver disease. 
 
− if you are currently taking any of the following medicines: 

− astemizole or terfenadine (commonly used to treat allergy symptoms – these medicines 
may be available without prescription); 

− amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine (used to 
correct irregular heartbeats); 

− dihydroergotamine, ergotamine (used to treat migraine headache); 
− ergonovine, methylergonovine (used to stop excessive bleeding that may occur following 

childbirth or an abortion); 
− clorazepate, diazepam, estazolam, flurazepam, triazolam or oral (taken by mouth) 

midazolam (used to help you sleep and/or relieve anxiety); 
− clozapine, pimozide, (used to treat abnormal thoughts or feelings);  



101 
 

− quetiapine (used to treat schizophrenia, bipolar disorder and major depressive disorder); 
− lurasidone (used to treat depression); 
− ranolazine (used to treat chronic chest pain [angina]); 
− pethidine, piroxicam, propoxyphene (used to relieve pain); 
− cisapride (used to relieve certain stomach problems); 
− rifabutin (used to prevent/treat certain infections)*; 
− voriconazole (used to treat fungal infections)*; 
− simvastatin, lovastatin (used to lower blood cholesterol); 
− neratinib (used to treat breast cancer); 
− lomitapide (used to lower blood cholesterol); 
− alfuzosin (used to treat enlarged prostate gland); 
− fusidic acid (used to treat bacterial infections); 
− sildenafil if you suffer from a lung disease called pulmonary arterial hypertension that 

makes breathing difficult.  Patients without this disease may use sildenafil for impotence 
(erectile dysfunction) under their doctor’s supervision (see the section on Other 
medicines and Norvir); 

− avanafil or vardenafil (used to treat erectile dysfunction);  
− colchicine (used to treat gout) if you have kidney and/or liver problems (see the section 

on Other medicines and Norvir); 
− products containing St John’s wort (Hypericum perforatum) as this may stop Norvir from 

working properly.  St John’s wort is often used in herbal medicines that you can buy 
yourself. 

 
*    Your doctor may decide that you can take rifabutin and/or voriconazole with a booster (lower 

dose) of Norvir but a full dose of Norvir must not be taken together with these two medicines. 
 
If you are currently taking any of these medicines, ask your doctor about switching to a different 
medicine while you are taking Norvir.  
 
Also read the list of medicines under ‘Other medicines and Norvir’ for use with certain other 
medicines which require special care. 
 
Warnings and precautions 
 
Talk to your doctor before taking Norvir. 
 
Important information 
 
− If Norvir is taken in combination with other antiretroviral medicines, it is important that you 

also carefully read the leaflets that are provided with these other medicines.  There may be 
additional information in those leaflets about situations when Norvir should be avoided.  If you 
have any further questions about Norvir (ritonavir) or the other medicines prescribed, please ask 
your doctor or pharmacist. 

− Norvir is not a cure for HIV infection or AIDS. 
− People taking Norvir may still develop infections or other illnesses associated with HIV 

infection or AIDS.  It is therefore important that you remain under the supervision of your 
doctor while taking Norvir. 

− You can still pass on HIV when taking this medicine, although the risk is lowered by effective 
antiretroviral therapy.  Discuss with your physician the precautions needed to avoid infecting 
other people. 

 



102 
 

Tell your doctor if you have/had: 
 
− A history of liver disease.   
− Hepatitis B or C and are being treated with a combination of antiretroviral agents, as you are at 

a greater risk of a severe and potentially life threatening reaction because of the effect on the 
liver.  Regular blood tests may be required to check your liver is working properly. 

− Haemophilia, as there have been reports of increased bleeding in patients with haemophilia 
who are taking this type of medicine (protease inhibitors).  The reason for this is not known.  
You may need additional medicine to help your blood clot (factor VIII), in order to control any 
bleeding. 

− Erectile dysfunction, as the medicines used to treat erectile dysfunction can cause hypotension 
and prolonged erection. 

− Diabetes, as there have been reports of worsening of or the development of diabetes (diabetes 
mellitus) in some patients taking protease inhibitors. 

− Kidney (renal) disease, since your doctor may need to check the dose of your other medicines 
(such as protease inhibitors). 

 
Tell your doctor if you experience: 
 
− Diarrhoea or vomiting that is not improving (persistent), as this may reduce how well the 

medicines you are taking work. 
− Feeling sick (nausea), vomiting or have stomach pain, because these may be signs of 

inflammation of the pancreas (pancreatitis).  Some patients taking Norvir can develop serious 
problems with their pancreas.  Tell your doctor as soon as possible if this applies to you. 

− Symptoms of infection – inform your doctor immediately.  Some patients with advanced HIV 
infection (AIDS) who then start anti-HIV treatment may develop the symptoms of infections 
they have had in the past even if they didn’t know they had had them.  It is believed that this 
happens because the body's immune response improves and helps the body to fight these 
infections. 
In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection.  Autoimmune disorders may occur many months after 
the start of treatment.  If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment. 

− Joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty 
moving, tell your doctor, as this may be a sign of a problem that can destroy bone 
(osteonecrosis).  Some patients taking a number of antiretroviral medicines may develop this 
disease.  

− Muscle pain, tenderness or weakness, particularly in combination with antiretroviral therapy 
including protease inhibitors and nucleoside analogues.  On rare occasions these muscle 
disorders have been serious. (See section 4 Possible side effects) 

- Dizziness, lightheadedness, fainting spells or abnormal heartbeat.  Some patients taking 
Norvir may experience changes in the electrocardiogram (ECG).  Tell your doctor if you have a 
heart defect or conduction defect.  

− If you have any other health concerns, discuss these with your doctor as soon as you can. 
 
Children and adolescents 
 
Norvir is not recommended in children below 2 years of age. 
 
Other medicines and Norvir 
 
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other 
medicines, including medicines obtained without a prescription.  There are some medicines you cannot 



103 
 

take at all with Norvir.  These are listed earlier in section 2, under ‘Do not take Norvir’.  There are 
some other medicines that can only be used under certain circumstances as described below.   
 
The following warnings apply when Norvir is taken as a full dose.  However, these warnings may also 
apply when Norvir is used in lower doses (a booster) with other medicines.  
 
Tell your doctor if you are taking any of the medicines listed below, as special care should be 
taken. 
 
− Sildenafil or tadalafil for impotence (erectile dysfunction).   

The dose and/or frequency of use of these medicines may need to be reduced to avoid 
hypotension and prolonged erection.  You must not take Norvir with sildenafil if you suffer 
from pulmonary arterial hypertension (see also section 2. What you need to know before you 
or your child takes Norvir).  Tell your doctor if you are taking tadalafil for pulmonary arterial 
hypertension. 

− Colchicine (for gout) as Norvir may raise the blood levels of this medicine. You must not take 
Norvir with colchicine if you have kidney and/or liver problems (see also ‘Do not take Norvir’ 
above). 

− Digoxin (heart medicine).  Your doctor may need to adjust the dose of digoxin and monitor you 
while you are taking digoxin and Norvir in order to avoid heart problems. 

− Hormonal contraceptives containing ethinyl oestradiol as Norvir may reduce the effectiveness 
of these medicines.  It is recommended that a condom or other non-hormonal method of 
contraception is used instead.  You may also notice irregular uterine bleeding if you are taking 
this type of hormonal contraceptive with Norvir. 

− Atorvastatin or rosuvastatin (for high cholesterol) as Norvir may raise the blood levels of 
these medicines.  Talk to your doctor before you take any cholesterol-reducing medicines with 
Norvir (see also ‘Do not take Norvir’ above). 

− Steroids (e.g. dexamethasone, fluticasone propionate, prednisolone, triamcinolone) as Norvir 
may raise the blood levels of these medicines which may lead to Cushing’s syndrome 
(development of a rounded face) and reduce production of the hormone cortisol.  Your doctor 
may wish to reduce the steroid dose or monitor your side effects more closely. 

− Trazodone (a medicine for depression) as, unwanted effects like nausea, dizziness, low blood 
pressure and fainting can occur when taken with Norvir.  

− Rifampicin and saquinavir (used for tuberculosis and HIV, respectively) as serious liver 
damage can occur when taken with Norvir. 

− Bosentan, riociguat (used for pulmonary arterial hypertension) as Norvir may increase the 
blood levels of this medicine. 

 
There are medicines that may not mix with Norvir because their effects could increase or decrease 
when taken together.  In some cases your doctor may need to perform certain tests, change the dose or 
monitor you regularly.  This is why you should tell your doctor if you are taking any medicines, 
including those you have bought yourself or herbal products, but it is especially important to mention 
these:  
 
− amphetamine or amphetamine derivatives; 
− antibiotics (e.g. erythromycin, clarithromycin);  
− anticancer treatments (e.g. abemaciclib; afatinib, apalutamide, ceritinib, encorafenib, dasatinib, 

ibrutinib, nilotinib, venetoclax, vincristine, vinblastine); 
− medicines used to treat low blood platelet count (e.g. fostamatinib); 
− anticoagulants (e.g. rivaroxaban, vorapaxar, warfarin); 
− antidepressants (e.g. amitriptyline, desipramine, fluoxetine, imipramine, nefazodone, 

nortriptyline, paroxetine, sertraline, trazodone); 
− antifungals (e.g. ketoconazole, itraconazole);  
− antihistamines (e.g. loratidine, fexofenadine);  
− antiretroviral medicines including HIV-protease inhibitors (amprenavir, atazanavir, darunavir, 

fosamprenavir, indinavir, nelfinavir, saquinavir, tipranavir) non-nucleoside reverse transcriptase 



104 
 

inhibitors( NNRTI) (delavirdine, efavirenz, nevirapine), and others (didanosine, maraviroc, 
raltegravir, zidovudine);  

− anti-tuberculosis medicine (bedaquiline and delamanid); 
− antiviral medicine used to treat chronic hepatitis C virus (HCV) infection in adults (e.g. 

glecaprevir/pibrentasvir and simeprevir); 
− anxiety medicine, buspirone;  
− asthma medicine, theophylline, salmeterol; 
− atovaquone, a medicine used to treat a certain type of pneumonia and malaria; 
− buprenorphine, a medicine used for the treatment of chronic pain; 
− bupropion, a medicine used to help you stop smoking; 
− epilepsy medicines (e.g. carbamazepine, divalproex, lamotrigine, phenytoin); 
− heart medicines (e.g. disopyramide, mexiletine and calcium channel antagonists such as 

amlodipine, diltiazem and nifedipine);  
− immune system (e.g. cyclosporine, tacrolimus, everolimus);  
− levothyroxine (used to treat thyroid probems); 
− morphine and morphine-like medicines used to treat severe pain (e.g. methadone, fentanyl); 
− sleeping pills (e.g. alprazolam, zolpidem) and also midazolam administered by injection;  
− tranquillisers (e.g. haloperidol, risperidone, thioridazine);  
− colchicine, a treatment for gout. 
 
There are some medicines you cannot take at all with Norvir.  These are listed earlier in section 2, 
under ‘Do not take Norvir’. 
 
Taking Norvir with food and drink 
 
Norvir tablets should be taken with food. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a 
baby, it is very important that you ask your doctor for advice before taking this medicine. 
 
There is a large amount of information on the use of ritonavir (the active ingredient in Norvir) during 
pregnancy.  In general, pregnant mothers received ritonavir after the first three months of pregnancy at 
a lower dose (booster) along with other protease inhibitors.  Norvir did not appear to increase the 
chance of developing birth defects compared to the general population. 
 
Norvir can pass into breast milk.  To avoid transmitting the infection, mothers with HIV must not 
breast feed their babies. 
 
Driving and using machines 
 
Norvir can cause dizziness.  If you are affected do not drive or use machinery.  
 
 
3. How to take Norvir 
 
Always take this medicine exactly as your doctor or pharmacist has told you.  Check with your doctor 
or pharmacist if you are not sure.  Take this medicine one or two times a day every day with food.   
 
It is important that Norvir tablets are swallowed whole and not chewed, broken or crushed. 
 
Recommended doses of Norvir are: 
 
• if Norvir is used to boost the effects of certain other anti-HIV medicines the typical dose for 

adults is 1 to 2 tablets once or twice daily.  For more detailed dose recommendations, including 



105 
 

those for children, see the Package Leaflet of the anti-HIV medicines Norvir is given in 
combination with. 

 
• if your doctor prescribes a full dose, adults may be started on a dose of 3 tablets in the morning 

and 3 tablets 12 hours later, gradually increasing over a period of up to 14 days to the full dose 
of 6 tablets twice daily (totaling 1,200mg per day).  Children (2 – 12 years of age) will start with 
a dose smaller than this and continue up to the maximum allowed for their size.   

 
Your doctor will advise you on the dosage to be taken. 
 
Norvir should be taken every day to help control your HIV, no matter how much better you feel.  If a 
side effect is preventing you from taking Norvir as directed, tell your doctor straight away.  During 
episodes of diarrhoea your doctor may decide that extra monitoring is needed. 
 
Always keep enough Norvir on hand so you don't run out.  When you travel or need to stay in the 
hospital, make sure you have enough Norvir to last until you can get a new supply. 
 
If you take more Norvir than you should 
 
Numbness, tingling, or a “pins and needles” sensation may occur if you take too much Norvir.  If you 
realise you have taken more Norvir than you were supposed to, contact your doctor or the Accident 
and Emergency Department of your nearest hospital straight away.  
 
If you forget to take Norvir 
 
If you miss a dose, take the missed dose as soon as possible.  If it is nearly time for the next dose, just 
take that one.  Do not take a double dose to make up for a forgotten dose. 
 
If you stop taking Norvir 
 
Even if you feel better, do not stop taking Norvir without talking to your doctor.  Taking Norvir as 
recommended should give you the best chance of delaying resistance to the medicines.   
 
 
4. Possible side effects 
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
Like all medicines, Norvir can cause side effects, although not everybody gets them.  Also, the side 
effects of Norvir when used with other antiretroviral medicines are dependent on the other medicines.  
So it is important that you carefully read the side effects section of the leaflets that are provided with 
these other medicines. 
 
Very common: may affect more than 1 in 10 people 
 
• upper or lower stomach ache 

  
• vomiting  
• diarrhoea (may be severe) 
• feeling sick (nausea)  
• flushing, feeling hot 
• headache 
• dizziness 
• pain in the throat 

• a tingling sensation or numbness in  
the hands, feet or around the lips and 
mouth 

• feeling weak/tired 
• bad taste in the mouth 
• damage to the nerves that can cause 

weakness and pain 
• itching 
• rash 
• joint pain and back pain 



106 
 

• cough 
• upset stomach or indigestion 

 
Common: may affect up to 1 in 10 people  
 
• allergic reactions including skin  

rashes (may be red, raised, itchy),  
severe swelling of the skin and  
other tissues 

• inability to sleep (insomnia) 
• anxiety 
• increase in cholesterol 
• increase in triglycerides 
• gout 
• stomach bleeding 
• inflammation of the liver and yellowing of 

skin or whites of the eyes 
• increase in urination 
• reduced kidney function 
• seizures (fits) 
• low levels of blood platelets 
• thirst (dehydration)  
• abnormally heavy periods 

• wind (flatulence) 
• loss of appetite 
• mouth ulcer 
• muscle aches (pain), tenderness or 

weakness 
• fever 
• weight loss 
• laboratory test results: 

changes in blood test results  
(such as blood chemistry and  
blood count) 

• confusion 
• difficulty paying attention 
• fainting 
• blurred vision 
• swelling of the hands and feet 
• high blood pressure 
• low blood pressure and feeling faint 

when getting up 
• coldness in the hands and feet 
• acne 

 
Uncommon: may affect up to 1 in 100 people  
 
• heart attack  
• diabetes 

• kidney failure  

 
Rare: may affect up to 1 in 1,000 people 
 
• severe or life threatening skin  

reaction including blisters 
(Stevens Johnson syndrome, toxic 
epidermal necrolysis) 

• serious allergic reaction (anaphylaxis) 
• high levels of sugar in the blood 

 
Not known: frequency cannot be estimated from the available data 
 
• kidney stones 
 
Tell your doctor if you feel sick (nauseous), are vomiting, or have stomach pain, because these may be 
signs of an inflamed pancreas.  Also tell your doctor if you experience joint stiffness, aches and pains 
(especially of the hip, knee and shoulder) and difficulty moving, as this may be a sign of 
osteonecrosis.  See also section 2. What you need to know before you or your child takes Norvir. 
 
In patients with haemophilia type A and B, there have been reports of increased bleeding while taking 
this treatment or another protease inhibitor.  Should this happen to you, seek immediate advice from 
your doctor.   
 
Abnormal liver function tests, hepatitis (inflammation of the liver), and rarely jaundice, have been 
reported in patients taking Norvir.  Some people had other illnesses or were taking other medicines.  
People with liver disease or hepatitis may have worsening of liver disease.   
 



107 
 

There have been reports of muscle pain, tenderness or weakness, particularly when taking medicines 
to lower cholesterol in combination with antiretroviral therapy, including protease inhibitors and 
nucleoside analogues.  On rare occasions these muscle disorders have been serious (rhabdomyolysis).  
In the event of unexplained or continual muscle pain, tenderness, weakness or cramps, stop taking the 
medicine, contact your doctor as soon as possible or go to the Accident and Emergency Department of 
your nearest hospital. 
 
Inform your doctor as soon as possible if you experience any symptoms that suggest an allergic 
reaction after taking Norvir such as rash, hives or breathing difficulties. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 
contact your doctor, pharmacist, Accident and Emergency department or if it is urgent get 
immediate medical help. 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist.  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 Norvir 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Norvir after the expiry date on the label.  The expiry date refers to the last day of that 
month. 
 
This medicinal product does not require any special temperature storage conditions.  Store in the 
original bottle in order to protect from moisture. 
 
Do not use this medicine if you notice any discolouration. 
 
Do not throw away any medicines via wastewater.  Ask your pharmacist how to throw away medicines 
you no longer use.  These measures will help the environment. 
 
 
6. Contents of the pack and other information 
 
What Norvir contains 
 
− The active substance is ritonavir.  Each film-coated tablet contains 100 mg ritonavir. 
 
− The other tablet ingredients are: copovidone, sorbitan laurate, anhydrous calcium hydrogen 

phosphate, colloidal anhydrous silica, sodium stearyl fumarate.   
 
− The tablet coating is composed of: hypromellose, titanium dioxide, macrogols, hydroxypropyl 

cellulose, talc, colloidal anhydrous silica, polysorbate 80. 
 
What Norvir looks like and contents of the pack 
 
Norvir film-coated tablets are white debossed with [Abbott logo] and the code “NK”. 
 
Three pack sizes are available for Norvir tablets:   
− 1 bottle of 30 tablets 
− 1 bottle of 60 tablets 

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


108 
 

− Multipacks comprising 3 bottles each containing 30 film-coated tablets (90 tablets) 
 
Not all pack sizes may be marketed. 
 
Norvir is also supplied as a powder for oral suspension containing 100 mg of ritonavir. 
 
Marketing Authorisation Holder  
 
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
Manufacturers 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
AbbVie SA 
Tél/Tel: +32 10  477811 

Lietuva 
AbbVie UAB  
Tel: +370 5 205 3023 
 

България 
АбВи ЕООД 
Тел.: +359 2 90 30 430 

Luxembourg/Luxemburg 
AbbVie SA 
Belgique/Belgien 
Tél/Tel: +32 10 477811 
 

Česká republika 
AbbVie s.r.o.  
Tel: +420 233 098 111 

Magyarország 
AbbVie Kft. 
Tel.: +36 1 455 8600 
 

Danmark 
AbbVie A/S 
Tlf: +45 72 30-20-28 

Malta 
V.J.Salomone Pharma Limited  
Tel: +356 22983201 
 

Deutschland 
AbbVie Deutschland GmbH & Co. KG 
Tel: 00800 222843 33 (gebührenfrei) 
Tel: +49 (0) 611 / 1720-0 
 

Nederland 
AbbVie B.V. 
Tel: +31 (0)88 322 2843 

Eesti 
AbbVie Biopharmaceuticals GmbH Eesti filiaal  
Tel: +372 623 1011 

Norge 
AbbVie AS 
Tlf: +47 67 81 80 00 
 

Ελλάδα 
AbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε. 
Τηλ: +30 214 4165 555 

Österreich 
AbbVie GmbH  
Tel: +43 1 20589-0 
 

España 
AbbVie Spain, S.L.U.  
Tel: +34 9 1 384 0910 

Polska 
AbbVie Polska Sp. z o.o. 
Tel.: +48 22 372 78 00  
 

France 
AbbVie 
Tél: +33 (0)1 45 60 13 00 

Portugal 
AbbVie, Lda.  
Tel: +351 (0)21 1908400 



109 
 

 

Hrvatska  
AbbVie d.o.o. 
Tel: +385 (0)1 5625 501 

România 
AbbVie S.R.L. 
Tel: +40 21 529 30 35 
 

Ireland 
AbbVie Limited  
Tel: +353 (0)1 4287900 

Slovenija 
AbbVie Biofarmacevtska družba d.o.o. 
Tel: +386 (1)32 08 060 
 

Ísland 
Vistor hf. 
Tel: +354 535 7000 

Slovenská republika 
AbbVie s.r.o. 
Tel: +421 2 5050 0777 
 

Italia 
AbbVie S.r.l.  
Tel: +39 06 928921 

Suomi/Finland 
AbbVie Oy  
Puh/Tel: +358 (0) 10 2411 200 
 

Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: +357 22 34 74 40 

Sverige 
AbbVie AB 
Tel: +46 (0)8 684 44 600 
 

Latvija 
AbbVie SIA  
Tel: +371 67605000 

United Kingdom 
AbbVie Ltd  
Tel: +44 (0)1628 561090 

 
This leaflet was last revised in {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) 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