No

Antiretroviral Agent, Protease Inhibitor

In combination with other antiretroviral agents; treatment of HIV infection when therapy is warranted

B

Clinical effects on the fetus: Administer during pregnancy only if benefits to mother outweigh risks to the fetus

Breast-feeding/lactation: HIV-infected mothers are discouraged from breast-feeding to decrease postnatal transmission of HIV

Patients with known hypersensitivity to ritonavir or any ingredients; concurrent amiodarone, bepridil, flecainide, propafenone, quinidine, astemizole, terfenadine, dihydroergotamine, ergotamine, midazolam, triazolam, cisapride, pimozide.

Use caution in patients with hepatic insufficiency; safety and efficacy have not been established in children <16 years of age; use caution with benzodiazepines, antiarrhythmics (flecainide, encainide, bepridil, amiodarone, quinidine) and certain analgesics (meperidine, piroxicam, propoxyphene). Use with HMG CoA-reductase inhibitors (lovastatin, simvastatin, atorvastatin, cerivastatin) not recommended.

Protease inhibitors cause dyslipidemia which includes elevated cholesterol and triglycerides and a redistribution of body fat centrally to cause "protease paunch", buffalo hump, facial atrophy, and breast enlargement. These agents also cause hyperglycemia.

Gastrointestinal: Diarrhea, nausea, vomiting, taste perversion

Endocrine & metabolic: Increased triglycerides

Hematologic: Anemia, decreased WBCs

Hepatic: Increased GGT

Neuromuscular & skeletal: Weakness

1% to 10%:

Cardiovascular: Vasodilation

Central nervous system: Fever, headache, malaise, dizziness, insomnia, somnolence, thinking abnormally

Dermatologic: Rash

Endocrine & metabolic: Hyperlipidemia, increased uric acid, increased glucose

Gastrointestinal: Abdominal pain, anorexia, constipation, dyspepsia, flatulence, local throat irritation

Hematologic: Neutropenia, eosinophilia, neutrophilia, prolonged PT, leukocytosis

Hepatic: Increased LFTs

Neuromuscular & skeletal: Increased CPK, myalgia, paresthesia

Respiratory: Pharyngitis

Miscellaneous: Diaphoresis, increased potassium, increased calcium,

Human experience is limited; there is no specific antidote for overdose with ritonavir. Dialysis is unlikely to be beneficial in significant removal of the drug. Charcoal or gastric lavage may be useful to remove unabsorbed drug.

CYP1A2, 2A6, 2C9, 2C19, 2E1, and 3A3/4 enzyme substrate, CYP2D6 enzyme substrate (minor); CYP1A2 enzyme inducer; CYP2A6, 2C9, 1A2, 2C19, 2D6, 2E1, and 3A3/4 inhibitor

Amprenavir AUC is increased by ritonavir

Antiarrhythmics (aminodarone, bepridil, flecainide, propafenone, quinidine) toxicity may be greatly increased - concurrent use of ritonavir is contraindicated

Astemizole and terfenadine - cardiac toxicity (arrhythmia) is increased - concurrent use is contraindicated

Benzodiazepines (clorazepate, diazepam, estazolam, flurazepam midazolam, triazolam) toxicity may be increased - concurrent use of midazolam and triazolam is specifically contraindicated

Cisapride toxicity (arrhythmia) may be increased by ritonavir - concurrent use is contraindicated

Clarithromycin serum concentrations are increased by ritonavir

Desipramine (and possibly other TCA's) serum levels may be increased by ritonavir, requiring dosage adjustment)

Ergot alkaloids (dihydroergotamine, ergotamine) toxicity is increased by ritonavir - concurrent use is contraindicated

HMG CoA reductase inhibitors (atorvastatin, cerivastatin, lovastatin, simvastatin) serum concentrations may be increased by ritonavir, increasing the risk of myopathy/rhabdomyolysis

Indinavir serum concentrations are increased by ritonavir

Ketoconazole serum concentrations are increased by ritonavir

Meperidine: serum concentrations of metabolite (normeperidine) are increased by ritonavir, which may increase the risk of CNS toxicity

Pimozide toxicity is significantly increased by ritonavir - concurrent use is contraindicated

Rifabutin and rifabutin metabolite serum concentrations may be increased by ritonavir; reduce rifabutin dose to 150 mg every other day

Sildenafil serum concentrations may be increased by ritonavir-do not exceed maximum 25mg in a 48 hour period.

Ritonavir may also increase the serum concentrations of the following drugs--dose decrease may be needed: amprenavir, bupropion, carbamazepine, clonazepam, clorazepate, cyclosporin, dexamethasone, diltiazem, disopyramide, dronabinol, ethosuximide, fluoxetine (and other SSRI's), lidocaine, methamphetamine, metoprolol, mexilitine, nifedipine, nefazodone, perphenazine, prednisone, propoxyphene, quinine, risperidone, tacrolimus, tramadol, thioridazine, timolol, verapamil, zolpidem

Decreased effect:

Ethinyl estradiol serum concentrations may be decreased (may also decrease effectiveness of combo products)

Methadone serum concentrations are decreased by ritonavir

Theophylline serum concentrations may be decreased by ritonavir

In addition, ritonavir may decrease the serum concentrations of the following drugs--dose increase may be needed: atovaquone, divalproex, lamotrigine, phenytoin, warfarin

Store both capsules and oral solution in refrigerator (36°F to 46°F; 2°C to 80°C); may be left out at room temperature if used within 30 days

Ritonavir inhibits HIV protease and renders the enzyme incapable of processing of polyprotein precursor which leads to production of noninfectious immature HIV particles

Absorption: Variable, with or without food

Distribution: High concentrations are produced in serum and lymph nodes

Protein binding: 98% to 99%

Metabolism: Hepatic; 5 metabolites, low concentration of an active metabolite achieved in plasma (oxidative); see Drug Interactions

Half-life: 3-5 hours

Elimination: Renal clearance is negligible

Oral:

Adults: 600 mg twice daily; dose escalation tends to avoid nausea that many patients experience upon initiation of full dosing. Escalate the dose as follows: 300 mg twice daily for 1 day, 400 mg twice daily for 2 days, 500 mg twice daily for 1 day, then 600 mg twice daily. Ritonavir may be better tolerated when used in combination with other antiretrovirals by initiating the drug alone and subsequently adding the second agent within 2 weeks.

If used in combination with saquinavir, dose is 400 mg twice daily

Dosing adjustment in renal impairment: None necessary

Dosing adjustment in hepatic impairment: Not determined; caution advised with severe impairment

Triglycerides, cholesterol, LFTs, CPK, uric acid, basic HIV monitoring, viral load, and CD4 count, glucose

May cause confusion

Contraindicated with bupropion, clozapine, pimozide, most benzodiazepines, and zolpidem; may use temazepam or lorazepam

No information available to require special precautions

No effects or complications reported

Take with food. Mix liquid formulation with chocolate milk or liquid nutritional supplement. You may experience headache or confusion; if these persist notify prescriber. Diarrhea may be moderate to severe. Notify prescriber if problematic. Report swelling, numbness of tongue, mouth, lips, unresolved vomiting, fever, chills, or extreme fatigue. Breast-feeding precautions: Do not breast-feed while taking this drug.

Capsule: 100 mg

Solution: 80 mg/mL (240 mL)

Danner SA, Carr A, Leonard JM, et al, "A Short-Term Study of the Safety, Pharmacokinetics, and Efficacy of Ritonavir, an Inhibitor of HIV-1 Protease. European-Australian Collaborative Ritonavir Study Group," N Engl J Med, 1995, 333(23):1528-33.

Deeks SG, Smith M, Holodniy M, et al, "HIV-1 Protease Inhibitors. A Review for Clinicians," JAMA, 1997, 277(2):145-53.

Hilts AE and Fish DN, "Dosage Adjustment of Antiretroviral Agents in Patients With Organ Dysfunction," Am J Health Syst Pharm, 1998, 55:2528-33.

Hsu A, Granneman GR, Cao G, et al, "Pharmacokinetic Interactions Between Two Human Immunodeficiency Virus Protease Inhibitors, Ritonavir and Saquinavir," Clin Pharmacol Ther, 1998, 63(4):453-64.

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Kaul DR, Cinti SK, Carver PL, et al, "HIV Protease Inhibitors: Advances in Therapy and Adverse Reactions, Including Metabolic Complications," Pharmacotherapy, 1999, 19(3):281-98.

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Mueller BU, Zuckerman J, Nelson J, et al, "A Phase I/II Study of the Protease Inhibitor Ritonavir (ABT-538) in Children With HIV Infection," Int Conf AIDS, 1996, 11:37.

Rana KZ and Dudley MN, "Human Immunodeficiency Virus Protease Inhibitors," Pharmacotherapy, 1999, 19(1):35-59.

Rhone SA, Hogg RS, Yip B, et al, "The Antiviral Effect of Ritonavir and Saquinavir in Combination Amongst HIV Infected Adults: Results From a Community-Based Study," AIDS, 1998, 12(6):619-24.

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection," April 1999, http://www.hivatis.org.