ritonavir: prescribing information – dosing, contraindications, interactions, side effects

Ritonavir is indicated as a pharmacokinetic enhancer of co-administered protease inhibitors as part of antiretroviral combination therapy in human immunodeficiency virus-1 (HIV-1) infected patients (adults and children of 2 years of age and older) (see sections 4.2, 4.4, 5.1, 5.2).

Ritonavir should be prescribed by physicians who are experienced in the treatment of HIV infection.

Posology

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of Product Characteristics (SmPC) 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
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.
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 SmPC 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 SmPC of other protease inhibitors approved for co-administration with ritonavir.

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 for ritonavir is necessary for elderly patients (see section 5.2).

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, a decrease in the total body clearance of ritonavir is not expected in patients with renal impairment.

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 protease inhibitor 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 SmPC of the co-administered protease inhibitor should be reviewed for specific dosing information in this patient population.

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.

Ritonavir should be prescribed 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

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of Product Characteristics (SmPC) 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
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.
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 SmPC 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 SmPC of other protease inhibitors approved for co-administration with ritonavir.

Special populations

Elderly
Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see section 5.2).

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, a decrease in the total body clearance of ritonavir is not expected in patients with renal impairment.

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 protease inhibitor 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 SmPC of the co-administered protease inhibitor should be reviewed for specific dosing information in this patient population.

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.

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

Ritonavir should not be given 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 enzyme-modulating effect of ritonavir may be dose dependent (see section 5.1). 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:

Medicinal Product
Class
Medicinal Products within Class
Rationale
Concomitant medicinal product levels increased or decreased
1-Adrenoreceptor
Antagonist
Alfuzosin
Increased plasma concentrations of alfuzosin which may lead to severe hypotension (see section 4.5).
Analgesics
Pethidine, propoxyphene
Increased plasma concentrations of norpethidine 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.
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.
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).

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).

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

Ritonavir should not be given 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 enzyme-modulating effect of ritonavir may be dose dependent (see section 5.1). 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:

Medicinal Product
Class
Medicinal Products within Class
Rationale
Concomitant medicinal product levels increased or decreased
1-Adrenoreceptor
Antagonist
Alfuzosin
Increased plasma concentrations of alfuzosin which may lead to severe hypotension (see section 4.5).

Analgesics
Pethidine, propoxyphene
Increased plasma concentrations of norpethidine 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.
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).
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).

Summary of the safety profile

Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific co-administered protease inhibitor. For information on adverse reactions refer to the SmPC of the specific co-administered protease inhibitor.

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 (≥ 1/1 000 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

Adverse reactions in clinical studies and post-marketing in adult patients
System Order Class
Frequency
Adverse reaction
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)

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).

Paediatric population

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.

Summary of the safety profile

Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific co-administered protease inhibitor. For information on adverse reactions refer to the SmPC of the specific co-administered protease inhibitor.

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 (≥ 1/1 000 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

Hepatobiliary disorders
Common

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

Adverse reactions in clinical studies and post-marketing in adult patients
System Order Class
Frequency
Adverse reaction
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 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).

Paediatric population

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.

General

Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors. Full details on the warnings and precautions relevant to that particular protease inhibitor should be considered, therefore the SmPC for the particular protease inhibitor must be consulted.

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. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Patients with coexisting conditions

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 asymptomatic 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, a decrease in the total body clearance of ritonavir 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. Ritonavir should be used with caution in such patients (see section 5.1).

Interactions with other medicinal products

HIV-protease inhibitors co-administered with ritonavir

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 protease inhibitors, see section 4.5. Please also review the SmPC for the particular boosted protease inhibitor.

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 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted. Refer to the SmPC for atazanavir for further details.

Other non-antiretroviral medicinal products co-administered with Ritonavir

The following warnings and precautions should be considered if 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 protease inhibitor must be considered, therefore the SmPC, section 4.4, for the particular protease inhibitor 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 oestradiol
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 oestradiol-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).

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 SmPC).

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 SmPC).

Medication error

Special attention should be given to the accurate calculation of the dose of ritonavir, 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.

General

Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors. Full details on the warnings and precautions relevant to that particular protease inhibitor should be considered, therefore the SmPC for the particular protease inhibitor must be consulted.

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. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Patients with co-existing conditions

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 asymptomatic 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, a decrease in the total body clearance of ritonavir 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. Ritonavir should be used with caution in such patients (see section 5.1).

Interactions with other medicinal products

HIV-protease inhibitors co-administered with Ritonavir

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 protease inhibitors, see section 4.5. Please also review the SmPC for the particular boosted protease inhibitor.

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 200 mg once daily could be considered. In this instance, close clinical monitoring is warranted. Refer to the SmPC for atazanavir for further details.

Other non-antiretroviral medicinal products co-administered with ritonavir

The following warnings and precautions should be considered if 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 protease inhibitor must be considered, therefore the SmPC, section 4.4, for the particular protease inhibitor 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 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 oestradiol
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 oestradiol-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).

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 SmPC).

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 SmPC).

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium- free’.

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 SmPC 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. phenytoin and rifampicin). These interactions are noted in the medicinal product interaction tables below.

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
Atazanavir
300 q24h
100 q24h
Atazanavir
↑ 86%
↑ 11 fold

Atazanavir1
↑ 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 SmPC 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 SmPC 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 SmPC for fosamprenavir.
Indinavir q12h
100 q12h
Indinavir2
↑ 178%
ND

Ritonavir
↑ 72%
ND

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 q12h
100 q12h
Nelfinavir
↑
20to39%
ND

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.
Tipranavir 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 SmPC for tipranavir.

ND: Not determined.
1. Based on cross-study comparison to 400 mg atazanavir once daily alone.
2. Based on cross-study comparison to 800 mg indinavir 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 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 SmPC for maraviroc.
Raltegravir
400 single
100 q12h
Raltegravir
↓ 16%
↓ 1%

Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir levels

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 SmPC of the co-administered protease inhibitor should be reviewed for specific dosing information.

Pethidine, propoxyphene
Ritonavir co-administration is likely to result in increased plasma concentrations of norpethidine 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.

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

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 SmPC 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. 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.

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
Atazanavir
300 q24h
100 q24h
Atazanavir
↑ 86%
↑ 11 fold

Atazanavir1
↑ 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 SmPC 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 SmPC 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 SmPC for fosamprenavir.
Indinavir
800 q12h
100 q12h
Indinavir2
↑ 178%
ND

Ritonavir
↑ 72%
ND

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

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.
Tipranavir
500 q12h 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 SmPC for tipranavir.

ND: Not determined.

1. Based on cross-study comparison to 400 mg atazanavir once daily alone.
2. Based on cross-study comparison to 800 mg indinavir 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
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 SmPC for maraviroc.
Raltegravir
400 single
100 q12h
Raltegravir
↓ 16%
↓ 1%

Co-adminsitration of ritonavir and raltegravir results in a minor reduction in raltegravir levels

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 SmPC of the co-administered protease inhibitor should be reviewed for specific dosing information.

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

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
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.

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

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.

Breast-feeding
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-positive infants) and (3) serious adverse reactions in a breastfed infant, women living with HIV should not breast-feed their infants 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).

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.

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

Symptoms
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1 500 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

Pharmaco-therapeutic group: antiviral for systemic use, protease inhibitors ATC code: J05AE03

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

achieved most commonly with ritonavir doses of 100 mg to 200 mg daily, and is dependent on the co-administered protease inhibitor.

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.

For additional information on the effect of ritonavir on co-administered protease inhibitor metabolism, see section 4.5 and refer to the SmPC of the particular co-administered protease inhibitors.

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.

Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors ATC code: J05AE03

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 achieved most commonly with ritonavir doses of 100 mg to 200 mg daily, and is dependent on the co-administered protease inhibitor.

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.

For additional information on the effect of ritonavir on co-administered protease inhibitor metabolism, see section 4.5 and refer to the SmPC of the particular co-administered protease inhibitors.

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.

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
Cmax (µg/ml)

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
Cmax (µg/ml)