ritonavir
Norvir

Available forms
Available by prescription only
Capsules: 100 mg
Oral solution: 80 mg/ml

Indications and dosages
 Treatment of HIV infection when antiretroviral therapy is warranted. Adults: 600 mg P.O. b.i.d. with meals. If nausea occurs, this schedule may provide some relief: 300 mg b.i.d., increased at 2- to 3-day intervals by 100 mg b.i.d., up to 600 mg b.i.d.
Children age 2 and older: 400 mg/m² P.O. b.i.d. with other antiretrovirals. To minimize nausea, initially 250 mg/m² b.i.d. May increase by 50 mg/m² b.i.d. at 2- to 3-day intervals.

Pharmacodynamics
Antiviral action: Ritonavir is an HIV protease inhibitor. HIV protease is an enzyme required for proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV. Ritonavir binds to the protease active site and inhibits activity of the enzyme. This inhibition prevents cleavage of viral polyproteins, resulting in formation of immature noninfectious viral particles.

Pharmacokinetics
Absorption: Absorbed better when taken with food; absolute bioavailability hasn’t been determined.
Distribution: 98% to 99% bound to plasma proteins.
Metabolism: Metabolized in the liver; P-450 3A (CYP3A) is the major isoform involved in ritonavir metabolism.
Excretion: Primarily excreted in feces, although a small amount has been found in urine. Half-life is 3 to 5 hours.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or its components. Use cautiously in patients with hepatic insufficiency.

Interactions
Drug-drug. Agents that increase CYP3A activity, such as carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, and rifampin: Increases ritonavir clearance, resulting in decreased ritonavir plasma levels. Monitor patient closely; monitor anticonvulsant drug levels. May reduce rifabutin dose if needed.
Alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, and zolpidem: May cause extreme sedation and respiratory depression when used together. Don’t give these drugs with ritonavir.
Alprazolam, methadone: Decreases levels of these drugs. Use together cautiously.
Amiodarone, bepridil, bupropion, clozapine, encainide, flecainide, meperidine, piroxicam, propafenone, propoxyphene, quinidine, rifabutin: Significantly increases plasma levels of these drugs, thus increasing the patient’s risk of arrhythmias, hematologic abnormalities, seizures, or other potentially serious adverse effects. Don’t administer together.
Amprenavir: Increases the area under the curve of amprenavir. Limited data suggest adjusting the dose of amprenavir to 600 to 1,200 mg b.i.d. and ritonavir to 100 to 200 mg b.i.d.
Clarithromycin: Increases clarithromycin levels. Patients with impaired renal function receiving drug with ritonavir require a 50% reduction in clarithromycin dosage if creatinine clearance is 30 to 60 ml/minute and a 75% reduction if it’s below 30 ml/minute.
Delavirdine, nevirapine: Alters plasma ritonavir levels. No dosage adjustment is needed.
Desipramine: Increases overall serum levels of desipramine. May require dosage adjustment.
Disopyramide: May cause cardiac and neurologic events. Use together with caution.
Disulfiram, other drugs that produce disulfiram-like reactions, such as metronidazole: Increases risk of disulfiram-like reactions. Ritonavir formulations contain alcohol that can produce reactions when used with these drugs. Monitor patient.
Efavirenz: Increases plasma levels of both drugs. Maintain dose at 600 mg b.i.d., or may reduce dose of ritonavir to 500 mg b.i.d. if intolerance occurs.
Ethinyl estradiol: Decreases ethinyl estradiol plasma levels. Advise patient to use an alternative or additional method of contraception.
Glucuronosyltransferases, including oral anticoagulants or immunosuppressants: Causes loss of therapeutic effects from directly glucuronidated agents. May need dosage alteration of these agents; monitor drug levels and drug effects. A dosage reduction greater than 50% may be required for those agents extensively metabolized by CYP3A.
HMG-CoA reductase inhibitors: Significantly increases statin levels, causing myopathy. Avoid use together.
Hormonal contraceptives: Decreases overall serum levels of the contraceptive. May require increasing the dosage of the contraceptive or advising alternative contraceptive measures.
Ketoconazole: Increases ritonavir level. Use together cautiously and monitor patient carefully.
Ketoconazole, sildenafil: Increases levels of these drugs. Use together cautiously. Don’t exceed 25 mg of sildenafil in a 48-hour period.
Nelfinavir: Increases plasma nelfinavir levels. Adjust dosage by giving ritonavir 400 mg b.i.d. and nelfinavir 500 to 750 mg b.i.d.
Saquinavir: Increases plasma saquinavir levels. Adjust dosage by giving saquinavir 400 mg b.i.d. and ritonavir 400 mg b.i.d.
Theophylline: Decreases overall serum theophylline levels. Increased dosage may be required.
Drug-herb. St. John’s wort: Substantially reduces blood levels of drug that may cause loss of therapeutic effects. Discourage use together.
Drug-food. Any food: Increases absorption. Give drug with food.
Drug-lifestyle. Smoking: Decreases serum ritonavir levels. Discourage smoking.

Adverse reactions
CNS: asthenia, headache, circumoral paresthesia, dizziness, insomnia, paresthesia, peripheral paresthesia, somnolence, thinking abnormality, generalized tonic-clonic seizure, depression, fever.
CV: vasodilation.
EENT: pharyngitis.
GI: taste perversion, abdominal pain, anorexia, constipation, diarrhea, nausea, vomiting, dyspepsia, flatulence.
Hematologic: thrombocytopenia.
Musculoskeletal: myalgia.
Skin: sweating.

Effects on lab test results
• May increase ALT, AST, alkaline phosphatase, GGT, bilirubin, glucose, triglyceride, serum lipid, potassium, CK, and uric acid levels.
• May increase PT and INR. May decrease hemoglobin, hematocrit, and WBC, platelet, neutrophil, and eosinophil counts.

Overdose and treatment
Information is limited to one patient who reported paresthesia, which resolved after the dosage was decreased.
 Treatment consists of general supportive measures. Emesis or gastric lavage may be used as well as activated charcoal. Dialysis probably isn’t helpful.

Special considerations
• Drug may be given alone or with nucleoside analogues.
• GI tolerance may be improved in patients taking ritonavir and nucleosides by starting ritonavir alone and adding nucleosides before completing 2 weeks of ritonavir monotherapy.
• Monitor patient’s response to drug therapy.
• Measure plasma HIV-1 RNA levels and CD4+ T-cell counts to determine disease progression and detect need to modify therapy.
Breast-feeding patients
• It isn’t known if ritonavir appears in breast milk. However, to prevent transmission of infection, HIV-positive women shouldn’t breast-feed.
Pediatric patients
• Safety and efficacy in children younger than age 2 haven’t been established.

Patient education
• Inform patient that drug doesn’t cure HIV infection and that he may continue to develop opportunistic infections and other complications related to HIV infection.
• Explain that drug doesn’t reduce the risk of transmitting HIV to others through sexual contact or blood contamination.
• Caution patient not to adjust dosage or stop drug without medical approval.
• Tell patient that he may improve taste of oral solution by mixing with chocolate milk, Ensure, or Advera within 1 hour of dosing.
• Tell patient that if a dose is missed, he should take the next dose as soon as possible. However, if a dose is skipped, he shouldn’t double the next dose.
• Advise patient to report use of other drugs, including OTC drugs, because of possible drug interactions.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use