Norvir 100 mg powder for oral suspension

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).

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

Posology

Ritonavir is no longer recommended in clinical practice at the antiretroviral dose of 1 200 mg (600 mg twice daily).

Ritonavir's use as a pharmacokinetic enhancer of other protease inhibitors is the prevalent use in clinical practice. Ritonavir's Product Information has been updated to reflect its common use as a pharmacokinetic enhancer of concomitantly administered antiviral agents. Previous information that was generated when used as an antiretroviral agent is retained as this is still considered clinically relevant.

Ritonavir dosed as a pharmacokinetic enhancer

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.

 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). For specific dosing information for the co-administered protease inhibitor in elderly patients, refer to the SmPC of the co‑administered protease inhibitor.

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 SmPC 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 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.

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

When ritonavir is used as a pharmacokinetic enhancer of other protease inhibitors, consult the SmPC of the co‑administered protease inhibitor for contraindications.

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:

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.

Ritonavir dosed as a pharmacokinetic enhancer

Patients with chronic diarrhoea or malabsorption

Extra monitoring is recommended when diarrhoea occurs. The relatively high frequency of diarrhoea during treatment with ritonavir may compromise the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medicinal products. Serious persistent vomiting and/or diarrhoea associated with ritonavir use might also compromise renal function. It is advisable to monitor renal function in patients with renal function impairment.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than a half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should, therefore, be made aware of the possibility of increased bleeding.

Weight and metabolic parameters:

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Pancreatitis

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Norvir therapy should be discontinued if a diagnosis of pancreatitis is made (see section 4.8).

Immune Reconstitution Inflammatory Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to 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).

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.

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 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 a pharmacokinetic enhancer with HIV-protease inhibitors

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.

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 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 estradiol-containing contraceptives.

Glucocorticoids

Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5).

Trazodone

Particular caution should be used when prescribing ritonavir in patients using trazodone. Trazodone is a CYP3A4 substrate and co-administration of ritonavir is expected to increase trazodone levels. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed in single dose interaction studies in healthy volunteers (see section 4.5).

Rivaroxaban

It is not recommended to use ritonavir in patients receiving rivaroxaban, due to the risk of increased bleeding (see section 4.5).

Riociguat

The concomitant use of ritonavir is not recommended due to potential increase in riociguat exposure (see section 4.5).

Vorapaxar

The concomitant use of ritonavir is not recommended due to potential increase in vorapaxar exposure (see section 4.5).

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).

Ritonavir dosed as a pharmacokinetic enhancer

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.

Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine or nefazodone. The possibility of medicinal product interaction cannot be excluded.

In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of increased therapeutic and toxic effects due to protein binding displacement of concomitant medicinal products should be considered.

Ritonavir dosed as a pharmacokinetic enhancer

Important information regarding medicinal product interactions when ritonavir is used a pharmacokinetic enhancer is also contained in the SmPC of the co-administered protease inhibitor.

Proton pump inhibitors and H₂-receptor antagonists

Proton pump inhibitors and H₂-receptor antagonists (e.g. omeprazole or ranitidine) may reduce concentrations for co‑administered protease inhibitors. For specific information regarding the impact of co‑administration of acid reducing agents, refer to the Summary of Product Characteristics of the co-administered protease inhibitor. Based on interaction studies with the ritonavir boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure (about 6 - 18%).

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 breastfeed 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.

Summary of the safety profile

Ritonavir dosed as a pharmacokinetic enhancer

Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific co-administered 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

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 Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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.

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 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.

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). The current SmPC reflects use only as a pharmacokinetic enhancer.

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 SmPC 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

Ritonavir was initially developed and approved with a maximal daily dose of 1 200 mg daily as a standalone antiretroviral agent. Current treatment guidelines recommend use of ritonavir as a pharmacokinetic enhancer of other protease inhibitors at lower daily doses, and is most commonly used at doses of 100 to 200 mg/day. The SmPCs of the co-administered protease inhibitors describe the clinical development for ritonavir's use as a pharmacokinetic enhancer.

Paediatric Population

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 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 (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.

The PK interaction between Norvir and indinavir was evaluated in 5 groups of healthy adult volunteers in a randomized, multiple-dose, open-label study. At steady state, Norvir increased plasma indinavir concentrations with area under the curve (AUC) increased up to 475% and maximum concentration (C_max) increased up to 110%.

In a study to evaluate the PK interaction between Norvir and saquinavir in healthy volunteers in 6 groups of a single-dose crossover study, co-administration of Norvir and saquinavir resulted in a > 50-fold increase in the AUC and a 22-fold increase in the C_max of saquinavir.

Effects of food on oral absorption

Administration of a single 100 mg dose of ritonavir powder for oral suspension with a moderate fat meal (617 kcal, 29% calories from fat) was associated with a mean decrease of 23 and 39% in ritonavir AUC_inf and C_max respectively, relative to fasting conditions. Administration with a high fat meal (917 kcal, 60% calories from fat) was associated with a mean decrease of 32 and 49% in ritonavir AUC_inf and C_max respectively, relative to fasting conditions.

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.

Biotransformation

Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform. Animal studies as well as in vitro experiments with human hepatic microsomes indicated that ritonavir primarily underwent oxidative metabolism. Four ritonavir metabolites have been identified in man. The isopropylthiazole oxidation metabolite (M‑2) is the major metabolite and has antiviral activity similar to that of parent compound. However, the AUC of the M‑2 metabolite was approximately 3% of the AUC of parent compound.

Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence the pharmacokinetics of ritonavir (see section 4.5).

Elimination

Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool, part of which is expected to be unabsorbed ritonavir. In these studies renal elimination was not found to be a major route of elimination of ritonavir. This was consistent with the observations in animal studies.

Special populations

No clinically significant differences in AUC or 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 of ritonavir 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.

Copovidone

Sorbitan laurate

Silica, colloidal anhydrous

Not applicable.

18 months.

Following mixing with food or liquid as described in section 4.2: consume within 2 hours.

Store below 30°C.

Polyethylene/aluminium/polyethylene terephthalate foil sachet. 30 sachets per carton. Packaged with a mixing cup and two 10 ml calibrated oral dosing syringes.

For details on preparation and administration of Norvir powder for oral suspension, refer the patient or care giver to the Package Leaflet, section 3.

Administering with food

• The entire contents of each sachet is to be poured over a small amount of soft food (e.g. apple sauce or vanilla pudding). All of the mixed soft food must be administered within 2 hours.

Administering with liquid

The entire contents of each sachet should be suspended in 9.4 ml of liquid (water, chocolate milk, or infant formula) giving a final concentration of 10 mg per ml. The patient/caregiver is to be instructed to follow the directions below:

• The oral dosing syringe and mixing cup should be washed in warm water and dish soap, then rinsed and allowed to air dry prior to first use.

• Draw up 9.4 ml of liquid using the provided oral dosing syringe, remove the bubbles, and transfer the liquid to the mixing cup. All measuring should be done in ml using the syringe.

• Pour the entire contents of 1 sachet (100 mg) into the mixing cup.

• Close the lid and shake hard for at least 90 seconds until all the lumps have dissolved.

• Let the liquid stand for 10 minutes in order for most of the bubbles to disappear.

• Use the provided oral dosing syringe to measure and administer the prescribed ml volume (see section 4.2). Be sure to remove the bubbles prior to dose administration.

• Once the powder is mixed, the prepared suspension should be used within 2 hours.

• Discard any mixture remaining in the mixing cup.

• The oral dosing syringe and mixing cup should be cleaned immediately with warm water and dish soap after use.

• If the syringe breaks or becomes hard to use, the syringe should be thrown away and the new one used.