RITONAVIR

Ritonavir should be prescribed by physicians who are experienced in the treatment of HIV infection. Posology When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of Product Characteristics 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 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 Summary of Product Characteristics 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 product information of other Protease Inhibitors approved for co-administration with ritonavir. Special populations 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.

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 Adults The 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.

Children and adolescents (2 years of age and above) The recommended dosage of Ritonavir in children is 350 mg/m2 by mouth twice daily and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg/m2 and increased at 2 to 3 day intervals by 50 mg/m2 twice daily.

Ritonavir is not recommended in children below 2 years of age due to lack of data on safety and efficacy. 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. 2). 3). Paediatric population The safety and efficacy of Ritonavir in children aged below 2 years has not been established. 2 but no recommendation on a posology can be made.

2). Ritonavir film-coated tablets should be swallowed whole and not chewed, broken or crushed.

Summary of the safety profile Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on the specific coadministered PI. For information on adverse reactions refer to the SPC 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 diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia) 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); Very rare (<1/10,000); Not known (cannot be established from the available data).

Events noted as having frequency not known were identified via post-marketing surveillance. g. oliguria, elevated creatinine) Uncommon Acute renal failure Renal and urinary disorders Not known Nephrolithiasis Reproductive system and breast disorders Common Menorrhagia Very common Fatigue including asthenia, flushing, feeling hot General disorders and administration site conditions Common Fever, weight loss Common Increased amylase, decreased free and total thyroxin Investigations Uncommon Increased glucose, increased magnesium, increased alkaline phosphatase Description of selected adverse reactions Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretrovirals.

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. 4). Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia.

In some cases fatalities have been observed. 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).

4). Paediatric populations The safety profile of Ritonavir 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. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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. 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.

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 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.

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. 2). 8). Osteonecrosis Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART).

Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement. PR interval prolongation Ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects.

Rare reports of 2nd or 3rd degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving medicinal products known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving ritonavir.

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 […]

1. Ritonavir should not be given to patients with decompensated liver disease. In vitro and in vivo studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and CYP2D6- mediated biotransformations. 5). Analgesics Pethidine, propoxyphene Increased plasma concentrations of norpethidine, and propoxyphene.

Thereby, increasing the risk of serious respiratory depression or haematologic abnormalities, or other serious adverse effects from these agents. 5). 5). Venetoclax Increased plasma concentrations of venetoclax. 5). Antiarrhythmics Amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine Increased plasma concentrations of amiodarone, bepridil, dronedarone, encainide, flecainide, propafenone, quinidine.

Thereby, increasing the risk of arrhythmias or other serious adverse effects from these agents. Antibiotic Fusidic Acid Increased plasma concentrations of fusidic acid and ritonavir. 5). Antihistamines Astemizole, terfenadine Increased plasma concentrations of astemizole and terfenadine.

Thereby, increasing the risk of serious arrhythmias from these agents. 5). 5). Clozapine, pimozide Increased plasma concentrations of clozapine and pimozide. Thereby, increasing the risk of serious haematologic abnormalities, or other serious adverse effects from these agents.

Antipsychotics/ Neuroleptics Quetiapine Increased plasma concentrations of quetiapine which may lead to coma. 5). Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Increased plasma concentrations of ergot derivatives leading to acute ergot toxicity, including vasospasm and ischaemia.

GI motility agent Cisapride Increased plasma concentrations of cisapride. Thereby, increasing the risk of serious arrhythmias from this agent. 5). 5). 4. 5). Sildenafil Contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) only.

Increased plasma concentrations of sildenafil. Thereby, increasing the potential for sildenafil-associated adverse events (which include hypotension and syncope). 5 for co-administration of sildenafil in patients with erectile dysfunction.

4. 5). Sedatives/hypnotics Clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam Increased plasma concentrations of clorazepate, diazepam, estazolam, flurazepam, oral midazolam and triazolam. Thereby, increasing the risk of extreme sedation and respiratory depression from these agents.

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