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  • Norvir
    / AbbVie


    Active Ingredient
    Ritonavir 100 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    30 X 100 mg

    partial basket chart 17398 14527

    Related information


    Dosage

    Ritonavir should be administered by physicians who are experienced in the treatment of HIV infection. Ritonavir film-coated tablets are administered orally and should be ingested with food. Ritonavir film-coated tablets should be swallowed whole and not chewed, broken or crushed.
    Ritonavir dosed as a pharmacokinetic enhancer
    When Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the prescribing information 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: Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily. Atazanavir 300 mg once daily with ritonavir 100 mg once daily. Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily. Lopinavir co-formulated with ritonavir (lopinavir/ritonavir 400 mg/100 mg or 800 mg/200 mg. Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART experienced patients. Initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days, then saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART-naïve patients. Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. (tipranavir with ritonavir should not be used in treatment-naïve patients). Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment (ART) experienced patients. Darunavir 800 mg once daily with ritonavir 100 mg once daily may be used in some ART experienced patients. Refer to the darunavir SmPC for further information on once daily dosing in ART experienced patients. Darunavir 800mg once daily with ritonavir 100 mg once daily in ART-naïve patients.
    Children and adolescentsRitonavir is recommended for children 2 years of age and older. Tablets are appropriate for use in children that are able to swallow tablets.
    Renal impairmentAs 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 prescribing information of the co-administered protease inhibitor.
    Hepatic impairmentRitonavir should not be given as a pharmacokinetic enhancer to patients with decompensated liver disease. 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.
    See prescribing information for full details.
    Ritonavir dosed as an antiretroviral agent
    AdultThe recommended dose of Ritonavir film-coated tablets is 600 mg (6 tablets) twice daily (total of 1200 mg per day) by mouth. Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance. Treatment should be initiated at 300 mg (3 tablets) twice daily for a period of three days and increased by 100 mg (1 tablet) twice daily increments up to 600 mg twice daily over a period of no longer than 14 days. Patients should not remain on 300 mg twice daily for more than 3 days.
    Paediatric use:
    2 years of age and above (in children that are able to swallow tablets): the recommended dosage of the drug in children is 350 mg/m² by mouth twice daily and should not exceed 600 mg twice daily. The dosage should be started at 250 mg/m² and increased at 2 to 3 day intervals by 50 mg/m² twice daily (please note that formulations of 80 mg/ml oral solution is not registered in Israel).
    Elderly: Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients.
    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. Ritonavir must not be given to patients with severe hepatic impairment.
    Paediatric population: The safety and efficacy of Norvir in children aged below 2 years has not been established.


    Indications

    Indicated alone or in combination with other antiretroviral agents for the treatment of patients with HIV-infection when therapy is warranted based on clinical and/or immunological evidence of disease progression.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients.
    When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the prescribing information 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 (e.g. rifabutin and voriconazole).
    See prescribing information for full details.


    Special Precautions

    Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving Ritonavir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection. While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines. When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings and precautions relevant to that particular PI should be considered, therefore the prescribing information 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.
    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 Ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.
    Immune Reconstitution Inflammatory SyndromeIn HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
    Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution  however, the reported time to onset is more variable and can occur many months after initiation of treatment.
    See prescribing information for full details.


    Side Effects

    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 prescribing information of the specific co-administered PI.
    Ritonavir dosed as an antiretroviral agent: Adverse reactions from clinical trials and post-marketing experience in adult patients: The most frequently reported adverse drug reactions among patients receiving ritonavir alone or in
    combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia) and fatigue/asthenia.
    See prescribing information for full details.


    Drug interactions

    Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent: Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation with the following ranked order:
    CYP3A4 > CYP2D6. Co-administration of ritonavir and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse effects. For selected medicinal products (e.g. alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease over time (e.g. digoxin and fexofenadine). 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 prescribing information 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.
    Serum levels of ritonavir may be affected by select co-administered medicinal products (e.g. delavirdine, efavirenz, phenytoin and rifampicin). These interactions are noted in the medicinal product interaction tables below.
    Medicinal products that are affected by the use of ritonavir: Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease inhibitors and other non-antiretroviral medicinal products are listed in the tables at the attached doctor’s leaflet.
    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 prescribing information 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 coadministration of acid reducing agents, refer to the prescribing information 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%).
    See prescribing information for full details.


    Pregnancy and Lactation

    Pregnancy: 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.
    Lactation: Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-postive infants) and (3) serious adverse reactions in a breastfed infant, HIV infected women should not breast-feed their infants under any circumstances if they are receiving Norvir.
    See prescribing information for full details.


    Overdose

    Symptoms: Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was decreased. A case of renal failure with eosinophilia has been reported.
    The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea and tremors.
    Management: There is no specific antidote for overdose with ritonavir. Treatment of overdose with ritonavir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Due to the solubility characteristics and possibility of transintestinal elimination, it is proposed that management of overdose could entail gastric lavage and administration of activated charcoal. Since ritonavir is extensively metabolised by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the medicine.


    Important notes

    Effects on ability to drive and use machines: Dizziness is a
    known undesirable effect that should be taken into account when driving or using machinery.
    Storage: Store at a temperature below 30°C. Store in the original bottle in order to protect from moisture.


    Manufacturer
    AbbVie Ltd., UK
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