1. Name Of The Medicinal Product
Norvir 80 mg/ml oral solution
2. Qualitative And Quantitative Composition
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.
3. Pharmaceutical Form
Oral solution
The solution is a practically clear, orange solution for oral administration.
4. Clinical Particulars
4.1 Therapeutic Indications
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infected patients (adults and children of 2 years of age and older).
4.2 Posology And Method Of Administration
Ritonavir should be administered by physicians who are experienced in the treatment of HIV infection.
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/m² by mouth twice daily and should not exceed 600 mg twice daily. Norvir should be started at 250 mg/m² and increased at 2 to 3 day intervals by 50 mg/m² twice daily. The dose should be administered using a calibrated dosing syringe.
Paediatric Dosage Guidelines
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* Body surface area can be calculated with the following equation
BSA (m²) =√(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/m²; 3.8 for one of 300 mg/m²; and by 4.4 for 350 mg/m².
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.
4.3 Contraindications
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):
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4.4 Special Warnings And Precautions For Use
Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving ritonavir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection.
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 2nd or 3rd degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving medicinal products known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving ritonavir. Norvir should be used with caution in such patients (see section 5.1).
Interactions with other medicinal products
Ritonavir dosed as an antiretroviral agent
The following Warnings and Precautions should be considered when ritonavir is used as an antiretroviral agent. When ritonavir is used as a pharmacokinetic enhancer at the 100 mg and 200 mg level it cannot be assumed that the following warnings and precautions will also apply. When ritonavir is used as a pharmacokinetic enhancer, full details on the warnings and precautions relevant to that particular PI must be considered, therefore the Summary of Product Characteristics, section 4.4, for the particular PI must be consulted to determine if the information below is applicable.
PDE5 inhibitors: Particular caution should be used when prescribing sildenafil, 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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order: CYP3A4 > CYP2D6. Co-administration of 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 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.
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