Ritonavir

Trade Names:
Norvir
- Capsules, soft gelatin 100 mg
- Solution, oral 80 mg/mL

Pharmacology

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Inhibits HIV protease, the enzyme required to form functional proteins in HIV-infected cells.

Pharmacokinetics

Absorption

Well absorbed. T _max is 2 h (fasting) or 4 h (nonfasting). Under nonfasting conditions, the oral solution's peak concentration is decreased 23% and the extent of absorption is decreased 7%. C _max is 11.2 mcg/mL.

Distribution

Vd is 0.41 L/kg. Protein binding is 98% to 99%, mainly albumin and alpha-1 acid glycoprotein.

Metabolism

Liver via CYP3A is the major isoform involved in metabolism; CYP2D6 also contributes. Five metabolites have been identified. The major metabolite is isopropylthiazole oxidation metabolite (M-2), which has antiviral activity similar to that of the parent drug.

Elimination

Eliminated in the urine (3.5% excreted as unchanged drug) and feces (33.8% as unchanged drug). The t _½ is 3 to 5 h. Systemic Cl is 8.8 L/h (multiple dose) and 4.6 L/h (single dose). Renal Cl is less than 0.1 L/h.

Special Populations

Pharmacokinetics have not been studied in patients with renal function impairment; however, a decrease in renal Cl is not expected.

Potential for lower ritonavir concentration in moderate hepatic function impairment. Not studied in severe impairment. No dosage adjustment required for mild to moderate impairment.

Pharmacokinetics have not been studied in older patients.

Steady-state oral Cl for children was about 1.5 times faster. Pediatric trough concentrations were lower than those obtained in adults; AUC and C _min in children younger than 2 yr of age were approximately 16% and 60% lower, respectively, than in adults.

Pharmacokinetic studies show no differences between men and women.

Pharmacokinetic differences have not been identified.

Indications and Usage

Treatment of HIV infection in combination with other antiretroviral agents.

Contraindications

Hypersensitivity to product; concomitant therapy with alfuzosin, amiodarone, astemizole, bepridil, cisapride, conivaptan, ergot derivatives, flecainide, midazolam, pimozide, propafenone, quinidine, ranolazine, terfenadine, triazolam, or voriconazole.

Dosage and Administration

PO 600 mg twice daily. If adverse reactions occur, relief may be provided by dose titration: 300 mg twice daily and increased at 2- to 3-day intervals by 100 mg twice daily.

PO Start at 250 mg/m ² twice daily and increase dose at 2- to 3-day intervals by 50 mg/m ² twice daily (max, 600 mg twice daily).

PO When ritonavir is used in combination with saquinavir, reduce the saquinavir dosage to 400 mg twice daily. The combination is better tolerated when patients receive ritonavir 400 mg twice daily.

General Advice

• When possible, use a calibrated dosing syringe when administering the dose to children.
• Take with meals.

Storage/Stability

Store soft gelatin capsules in the refrigerator at 36° to 46°F until dispensed. Refrigeration of soft gelatin capsules by the patient is recommended but not required if used within 30 days and stored below 77°F. Protect from light. Avoid exposure to excessive heat. Store oral solution at 68° to 77°F. Do not refrigerate. Shake well before each use. Store and dispense in original container. Avoid exposure to excessive heat. Keep cap tightly closed.

Drug Interactions

Use with caution. Plasma levels may be elevated by ritonavir; adjust dose as needed.

Use with caution. Plasma levels may be reduced by ritonavir; adjust dose as needed.

Plasma levels may be elevated by ritonavir, increasing the risk of adverse reactions; careful monitoring and/or dosage adjustment are warranted.

Plasma levels may be reduced by ritonavir, decreasing the efficacy; adjust dose as needed.

Separate administration times by 2.5 h to avoid formulation incompatibilities.

Because ritonavir formulations contain alcohol, a disulfiram-like reaction can occur.

Coadministration with ritonavir is contraindicated.

Ritonavir plasma levels may be decreased, resulting in a loss of virologic response.

Plasma levels may be reduced by ritonavir, decreasing the efficacy. Consider alternative methods of contraception.

Risk of myopathy, including rhabdomyolysis, may be increased.

Indinavir plasma levels may be elevated; however, appropriate dose when coadministered with ritonavir has not been established.

Meperidine plasma levels may be decreased while levels of the active metabolite, normeperidine, may be increased; coadministration is not recommended.

Dose reduction of these agents may be needed with ritonavir administration.

Delavirdine plasma levels may be elevated; however, the appropriate dose when coadministered with ritonavir has not been established.

Saquinavir plasma levels may be elevated, increasing the risk of adverse reactions.

May lead to loss of ritonavir virologic response and possible resistance to ritonavir or the class of protease inhibitors.

Warfarin plasma levels may be decreased; INR monitoring is recommended.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Syncope, vasodilation (2%); cerebral ischemia, cerebral venous thrombosis, CV disorder, hypertension, hypotension, migraine, MI, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, vasospasm (less than 2%); orthostatic hypotension (postmarketing).

CNS

Asthenia (15%); circumoral paresthesia (7%); headache, peripheral paresthesia (6%); dizziness (4%); insomnia, paresthesia, somnolence (3%); anxiety, depression, malaise (2%); abnormal dreams, abnormal gait, agitation, amnesia, aphasia, ataxia, coma, convulsion, decreased libido, dementia, depersonalization, diplopia, emotional lability, euphoria, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, manic reaction, nervousness, neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral neuropathy, peripheral sensory neuropathy, personality disorder, sleep disorder, speech disorder, stupor, subdural hematoma, tonic-clonic seizures, tremor, urinary retention, vertigo, vestibular disorder (less than 2%); seizures (postmarketing).

Dermatologic

Rash (4%); sweating (3%); acne, contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum, onychomycosis, pruritus, psoriasis, pustular rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, urticaria, vesiculobullous rash (less than 2%).

EENT

Pharyngitis, throat irritation (3%); abnormal electro-oculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, ear pain, eye disorder, eye pain, hearing impairment, increased cerumen, iritis, parosmia, photophobia, taste loss, tinnitus, uveitis, visual field defect, vitreous disorder (less than 2%).

Endocrine

Adrenal cortex insufficiency, diabetes mellitus (less than 2%).

GI

Nausea (30%); diarrhea (23%); vomiting (17%); taste perversion (11%); anorexia (8%); dyspepsia (6%); flatulence (2%); abnormal stools, bloody diarrhea, cheilitis, colitis, dry mouth, dysphagia, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis, GI disorder, GI hemorrhage, gingivitis, ileus, melena, mouth ulcer, pancreatitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, tenesmus, thirst, tongue edema, ulcerative colitis (less than 2%).

Genitourinary

Abnormal kidney function, acute kidney failure, breast pain, cystitis, dysuria, hematuria, impotence, kidney calculus, kidney failure, kidney pain, menorrhagia, penis disorder, polyuria, urethritis, urinary frequency, UTI, vaginitis (less than 2%); renal function impairment (postmarketing).

Hematologic-Lymphatic

Neutropenia (9%); hyperamylasemia (7%); thrombocytopenia (5%); anemia (4%); acute myeloblastic leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, thrombocytopenia (less than 2%); hemophilia A or B, increased bleeding (postmarketing).

Hepatic

Cholestatic jaundice, hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, liver damage (less than 2%).

Lab Tests

Elevated cholesterol (45%); decreased WBC (37%); triglycerides more than 800 mg/dL (34%); elevated gamma-glutamyltransferase (20%); decreased RBC (19%); decreased Hct (17%); elevated CPK (12%); elevated AST (10%); elevated ALT (9%); decreased neutrophils (6%); elevated uric acid, decreased Hgb (4%).

Metabolic

Albuminuria, alcohol intolerance, avitaminosis, dehydration, edema, enzymatic abnormality, glycosuria, gout, hypercholesterolemia, increased BUN, peripheral edema, xanthomatosis (less than 2%); redistribution of body fat (postmarketing).

Metabolic-Nutritional

Weight loss (2%).

Musculoskeletal

Arthralgia, myalgia (2%); arthritis, arthrosis, back pain, bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps, muscle cramps, muscle weakness, myositis, neck pain, neck rigidity, twitching (less than 2%).

Respiratory

Asthma, bronchitis, dyspnea, epistaxis, hiccup, hypoventilation, increased cough, interstitial pneumonia, larynx edema, lung disorder, rhinitis, sinusitis (less than 2%).

Miscellaneous

Abdominal pain (8%); fever (5%); pain (2%); accidental injury, allergic reaction, altered hormone level, cachexia, chest pain, chills, enlarged abdomen, facial edema, facial pain, flu syndrome, hypothermia, pelvic pain, photosensitivity reaction, substernal chest pain (less than 2%); dehydration usually with GI symptoms and sometimes resulting in hypotension, syncope, or renal function impairment (postmarketing).

Precautions

Pregnancy

Category B .

Lactation

Undetermined. HIV-infected mothers should not breast-feed their infants.

Children

Not recommended for children younger than 1 mo of age.

Hepatic Function

Use caution. Increased hepatic transaminase levels (5 × ULN), hepatitis, and jaundice have been reported. Ritonavir concentration may be lower.

Allergic reactions

Mild skin eruptions, urticaria, bronchospasm, angioedema, anaphylaxis, and Stevens-Johnson syndrome have been reported.

Cross-resistance

Varying degrees of cross-resistance among protease inhibitors have been observed; continued administration following loss of viral suppression may increase likelihood of cross-resistance to other protease inhibitors.

Diabetes mellitus

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia may occur.

Fat redistribution

Redistribution/accumulation of body fat observed in patients receiving antiretroviral therapy.

Hemophilia

There have been reports of increased bleeding, including skin hematomas and hemarthrosis in patients with hemophilia type A and B.

Immune reconstitution syndrome

Has been reported in patients receiving combination antiretroviral therapy.

Lipid elevations

Substantial increases in total triglycerides and cholesterol can occur.

Pancreatitis

Major toxicity; may be fatal. Consider if patient develops abdominal pain, nausea, vomiting, or lab test abnormalities.

Overdosage

Symptoms

Paresthesia, renal failure with eosinophilia.

Patient Information

• Advise patient to read the patient information material before using product the first time and with each refill.
• Advise patient to take ritonavir with food.
• Advise patient to take medication exactly as prescribed.
• Warn patient not to alter the dose or discontinue the medication without consulting health care provider.
• If a dose is missed, instruct patient to take the next dose as soon as possible. If a dose is skipped, do not double the next dose.
• Inform patient that this medication is not a cure for HIV infection and secondary illnesses associated with the disease may continue to be acquired.
• Emphasize to patient, family, and significant others that this medication does not reduce the risk of transmitting HIV to others through sexual contact or blood contamination.
• Inform patient to report symptoms associated with paresthesia (eg, sensations of burning, prickling, numbness) to health care provider for a possible reduction in dosage.
• Inform patient to report any other serious adverse reactions to health care provider.
• Explain that the long-term effects of this medication are not known at this time.

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