Ritonavir is a selective, competitive, reversible inhibitor of HIV protease. By interfering with the formation of essential proteins and enzymes, ritonavir blocks the maturation of the virus and causes formation of nonfunctional, immature, noninfectious virions. Ritonavir targets the HIV replication cycle after translation and before assembly. Thus, the drug is also active in chronically HIV infected cells. Ritonavir is well absorbed following oral administration, with peak plasma concentrations (Cmax) attained within 2 to 4 hours. Ritonavir is 98% to 99% bound to plasma proteins. The plasma half-life of ritonavir in adults averages 3 to 5 hours. The drug is metabolized in the liver. Ritonavir is eliminated through the urine and feces, five metabolites have been identified in urine and feces. Indication: Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. Contraindications: Ritonavir is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients. Ritonavir should not be administered concurrently with the drugs listed in Table 1 because competition for primarily CYP3A by ritonavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression. It is reported that co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities.
Table 1: Drugs that are contraindicated with ritonavir use:
|Drug Class||Drugs within class that are contraindicated with ritonavir|
|GI motility agent||Cisapride|
|Alpha1-adrenoreceptor antagonist||Alfuzosin HCL|
|Antiarrhythmics||Amiodarone, bepridil, flecainide, propafenone, quinidine|
|Ergot derivatives||Dihydroergotamine, ergotamine, ergonovine, methylergonovine|
Ritonavir tablets are for oral administration. It is recommended that Ritonavir be taken with meals if possible. The effects of antacids on the absorption of ritonavir have not been studied.
Note: When used to boost protease inhibitors, lower doses of ritonvair are recommended depending upon the protease inhibitor to be boosted and as per prevalent guidelines.
The recommended dosage of ritonavir is 600 mg twice daily by mouth. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. Concomitant Therapy: If saquinavir and ritonavir are used in combination, the dosage of saquinavir should be reduced to 400 mg twice daily. The optimum dosage of Ritonavir (400 mg or 600 mg twice daily), in combination with saquinavir, has not been determined; however, the combination regimen is better tolerated in patients who receive Ritonavir 400 mg twice daily. General dosing guidelines: Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued. In addition, patients initiating combination regimens with ritonavir and nucleosides may improve gastrointestinal tolerance by initiating ritonavir alone and subsequently adding nucleosides before completing two weeks of ritonavir monotherapy.
Drug And Food Interactions: The boosting effect of ritonavir on other PIs has led to its increased use as a pharmacoenhancer to help raise and maintain the plasma concentrations of other PIs. Drug interactions may occur when ritonavir is coadministered with a wide variety of other drugs, mostly due to pharmacokinetic interactions. Ritonavir is metabolized by isoforms of the cytochrome P450 (CYP450) enzyme system. When it is administered with other drugs that are extensively metabolized by these isoenzymes, competition for the isoenzymes may result in decreased metabolism and elevated plasma concentration of these drugs. Concomitant use of delavirdine and ritonavir may increase area under the plasma concentration-time curve (AUC), Cmax, and Cmin of ritonavir. Appropriate doses of this combination with respect to safety and efficacy have not been established. Concomitant use of ritonavir with didanosine, methadone, or theophylline may result in decreased concentrations of the second drug; dosage adjustment may be required. Concomitant use of ritonavir with either clarithromycin, desipramine, ketoconazole, or rifabutin may result in increased concentrations of the second drug; dosage adjustment may be required. Concomitant use of ethinyl estradiol-containing oral or patch contraceptives with ritonavir may result in significant reductions of mean Cmax and AUC. Alternate methods of contraception should be considered for patients who are currently taking ritonavir. A decrease in ritonavir dose may be needed when concurrently taken with certain sedatives and hypnotics, including buspirone, clorazepate, diazepam, estazolam, flurazepam, and zolpidem. Concurrent use of these sedatives with ritonavir increases the plasma concentrations of the sedative. Particular caution should be used when prescribing sildenafil with patients receiving ritonavir. Coadministration of these two drugs is expected to substantially increase sildenafil concentrations (as much as an 11-fold increase in AUC) and may result in an increase in sildenafil-associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. The starting dose should not exceed 25 mg in a 48-hour period in patients concurrently receiving ritonavir. Tadalafil and vardenafil should also be prescribed with caution to patients receiving ritonavir, with increased monitoring for adverse effects. No more than 10 mg tadalafil or 2.5 mg vardenafil every 72 hours should be prescribed. Use of ritonavir with disulfiram may result in a disulfiram reaction due to ethanol content in ritonavir soft gelatin capsule and oral solution formulations; concomitant use of ritonavir and metronidazole may result in a similar disulfiram-like reaction. Concurrent use of reduced doses of ritonavir with either indinavir or saquinavir may result in increased Cmin of the second drug. Concomitant use of ritonavir and meperidine may result in increased risk for central nervous system stimulation (e.g., seizures), due to increased concentrations of meperidine's metabolite, normeperidine. Concurrent use of rifampin and ritonavir may result in decreased ritonavir concentrations and virologic response; an alternative mycobacterial is recommended. Ritonavir is a potent CYP450 inducer and CYP3A4 inhibitor and substrate. Ritonavir 400 mg given every 12 hours for 9 days decreased the steady state Cmax and AUC of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Coadministration of voriconazole with ritonavir (400 mg every 12 hours) is contraindicated because ritonavir at this dosage significantly decreases plasma voriconazole concentrations in healthy subjects. In vitro drug metabolism studies suggest a potential for drug interactions when trazodone is given with CYP3A4 inhibitors. Ritonavir, a potent CYP3A4 inhibitor, increased the Cmax, AUC, and elimination half-life, and decreased the clearance of trazodone after administration of ritonavir twice daily for 2 days.
Category B. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ritonavir is administered to a nursing woman. However, it is advised that HIV-infected women do not breast-feed to avoid postnatal transmission of HIV to a child who may not be infected.
The safety and pharmacokinetic profile of ritonavir in paediatric patients below the age of 2 years have not been established. In HIV-infected patients aged 2 to 16 years, the adverse event profile appears to be similar to that for adult patients.
The most frequently reported adverse effects of ritonavir include asthenia, nausea, diarrhea, vomiting, anorexia, abdominal pain, taste perversion, and circumoral and peripheral paresthesias. Less common adverse effects include fever, headache, malaise, vasodilation, constipation, dyspepsia, flatulence, local throat irritation, myalgia, dizziness, insomnia, somnolence, abnormal thinking, pharyngitis, rash, sweating, increase in creatine phosphokinase, and hyperlipidemia. One of the more serious adverse effects of ritonavir is potentially fatal pancreatitis. Patients with signs or symptoms of pancreatitis, including nausea, vomiting, abdominal pain, and increased serum lipase or amylase concentrations, should be evaluated and ritonavir therapy discontinued if a diagnosis of pancreatitis is made. Immune reconstitution syndrome has been reported in HIV infected patients treated with combination antiretroviral therapy, including ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Other serious adverse effects include body fat redistribution and accumulation, increased bleeding in patients with hemophilia type A or B, hyperglycemia, hyperlipidemia, new-onset diabetes mellitus, and exacerbation of existing diabetes mellitus.
Store in a cool, dry and dark place.