Abbott Laboratories Ireland Limited

Norvir 80 mg/ml oral solution

Each ml of oral solution contains 80 mg of ritonavir.

Excipients:

Alcohol (43% v/v)

Polyoxyl 35 Castor Oil

Sunset Yellow (E110)

For a full list of excipients, see section 6.1.

Oral solution

The solution is a practically clear, orange solution for oral administration.

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).

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

Norvir solution is administered orally and should preferably be ingested with food.

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.

Adult use:

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

Lopinavirco-formulated with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200mg.

Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily

Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily

Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment (ART) experienced patients

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

Paediatric use: 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. Norvir is not recommended in children below 2 years of age due to lack of data on safety and efficacy.

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

Adult use: The recommended dosage of Norvir solution is 600 mg (7.5 ml) twice daily by mouth.

Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance. Treatment should be initiated at 300 mg (3.75 ml) twice daily for a period of three days and increased by 100 mg (1.25 ml) 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.

Paediatric use (2 years of age and above): the recommended dosage of Norvir solution in children is 350 mg/m^² by mouth twice daily and should not exceed 600 mg twice daily. Norvir should be started at 250 mg/m^² and increased at 2 to 3 day intervals by 50 mg/m^² twice daily. When possible, dose should be administered using a calibrated dosing syringe.

Paediatric Dosage Guidelines

* Body surface area can be calculated with the following equation

BSA (m^²) ⁼ √(Height (cm) X Weight (kg) / 3600)

Doses for intermediate body surface areas not included in the above table can be calculated using the following equations:

To calculate the volume to be administered (in ml) the body surface area should be multiplied by a factor of: 3.1 for a dose of 250 mg/m^²; 3.8 for one of 300 mg/m^²; and by 4.4 for 350 mg/m^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 should not be given to patients with severe hepatic impairment (see section 4.3).

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

The bitter taste of Norvir solution may be lessened if mixed with chocolate milk.

Hypersensitivity to the active substance or to any of the excipients.

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.

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 (eg rifabutin and voriconazole):

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.

Patients should be advised that current antiretroviral therapy has not been proven to prevent the risk of transmission of HIV to others through blood or sexual contact. Appropriate precautions should continue to be used.

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.

Diabetes mellitus and hyperglycaemia: New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia.

Lipodystrophy: Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicinal product related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

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 Reactivation 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.

Liver disease: Ritonavir should not be given to patients with decompensated liver disease. For patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation 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. For specific dosing information in patients with renal impairment, refer to the Summary of Product Characteristics (SPC) of the co-administered protease inhibitor. See also section 4.2.

Ritonavir oral solution contains castor oil polyoxyl which may cause stomach upset and diarrhoea. Ritonavir oral solution also contains the azo-colouring agent sunset yellow (E110) which may cause allergic reactions.

Ritonavir oral solution contains alcohol (43% v/v), ie up to 258 mg per maximum dose of 600 mg, equivalent to 65 ml beer, 27 ml wine per dose. Each 100 mg dose contains up to 43 mg alcohol and each 200 mg dose contains 86 mg alcohol. Therefore concomitant administration of Norvir with disulfiram or medicines with disulfiram-like reactions (eg metronidazole) should be avoided. Also to be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy.

Osteonecrosis: Although the etiology 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 2^nd or 3^rd 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, tadalafil or vardenafil 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 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).

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.

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)

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-administered 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 Reyataz Summary of Product Characteristics for further details.

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 Norvir 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 select medicinal products (eg 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 (eg 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, stop St John's wort 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 (eg 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.

Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine or nefazadone. 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 SmPC 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%).

A limited number (> 800) of pregnant women were exposed to ritonavir during pregnancy; a very limited number (< 300) 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 limited 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 5.3). The use of Norvir may be considered in pregnancy only when the benefits outweigh the risk to the foetus.

Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and safe method of contraception should be used during treatment.

It is not known whether this medicine is excreted in human milk. Milk excretion has not been measured in the animal studies, however a study in rats showed some effects on offspring development during lactation which are compatible with excretion of ritonavir in milk in that species. HIV infected women should not breast-feed their infants under any circumstances to avoid transmission of HIV.

No studies on the effects on the ability to drive and use machines have been performed. As somnolence and dizziness are known undesirable effects, this should be taken into account when driving or using machinery.

Norvir oral solution contains alcohol (43%).

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

In the original clinical studies (Phase II/III), adverse reactions with possible, probable or unknown relationship to ritonavir were reported in 2% of 1033 patients.

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 a frequency not known were identified via post-marketing surveillance

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.

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (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 (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).

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).

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.

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.

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 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 Therapeutic indications.

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.

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 (T_max) 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.

¹ Values expressed as geometric means. Note: ritonavir was dosed after a meal for all listed regimens.

Effects of food on oral absorption:

Ingestion of ritonavir with food results in higher ritonavir exposure than ingestion in the fasted state.

Distribution:

The apparent volume of distribution (V_B/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 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.

Metabolism:

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 C_max 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/m^² twice daily to 400 mg/m^² twice daily. Ritonavir concentrations obtained after 350 to 400 mg/m^² twice daily in paediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m^²) 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 (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.

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.

Norvir oral solution contains:

alcohol,

purified water,

polyoxyl 35 castor oil,

propylene glycol,

anhydrous citric acid,

saccharin sodium,

peppermint oil,

creamy caramel flavour,

sunset yellow E110.

Norvir should not be diluted with water.

6 months

Store below 25°C and use within the expiry date shown on the bottle. Do not refrigerate or freeze.

Avoid exposure to excessive heat. Keep the bottle tightly closed.

Norvir oral solution is supplied in amber coloured multiple-dose polyethylene terephthalate (PET) bottles in a 90 ml size.

Two pack sizes are available for Norvir oral solution:

• 1 bottle of 90 ml (90 ml) plus one 7.5 ml dosing syringe.

• 5 bottles of 90 ml (450 ml) plus five 7.5 ml dosing syringes.

The 7.5 ml dosing syringe has graduations from 0.8 ml to 7.5 ml.

Not all pack sizes may be marketed.

Shake well before each use. If, after shaking, particles or precipitate can be seen in the solution, the patient should take the next dose and see their doctor about a fresh supply.

The dosage cup or oral syringe should be cleaned immediately with hot water and dish soap after use. When cleaned immediately, drug residue is removed. The device must be dry prior to use

Abbott Laboratories Limited

Abbott House,

Vanwall Business Park,

Vanwall Road,

Maidenhead,

Berkshire,

SL6 4XE

United Kingdom

EU/1/96/016/001

EU/1/96/016/008

Date of first authorisation: 26 August 1996

Date of latest renewal: 26 August 2006

22 December 2011