Ritonavir

Pronunciation

Pronunciation: rit-OH-na-vir
Class: Protease inhibitor

Trade Names

Norvir
- Capsules, softgel 100 mg
- Solution, oral 80 mg/mL
- Tablets 100 mg

Norvir SEC (Canada)

Pharmacology

Inhibits HIV protease, rendering the enzyme incapable of processing the gag-pol polyprotein precursor, which leads to production of noninfectious immature HIV particles.

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Pharmacokinetics

Absorption

T max after administration of the oral solution is 2 h (fasting) or 4 h (nonfasting). Under nonfasting conditions, the oral solution and tablet C max decreased 23% and the extent of absorption of the oral solution decreased 7%. C max is approximately 11.2 mcg/mL.

Distribution

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

Metabolism

Liver via CYP3A, 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 (approximately 11.3% with approximately 3.5% excreted as unchanged drug) and feces (approximately 86.4% with 33.8% as unchanged drug). The half-life is 3 to 5 h. Systemic Cl is approximately 8.8 L/h (multiple dose) and approximately 4.6 L/h (single dose). Renal Cl is less than 0.1 L/h.

Special Populations

Renal Function Impairment

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

Hepatic Function Impairment

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

Elderly

Pharmacokinetics have not been studied in older patients.

Children

Steady-state oral Cl for children was about 1.5 to 1.7 times faster. In children younger than 2 years of age, trough concentrations were lower than those obtained in adults; AUC and C min were approximately 16% and 60% lower, respectively, than in adults.

Gender

Pharmacokinetic studies show no differences between men and women.

Race

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, bepridil, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), flecainide, lovastatin, oral midazolam, pimozide, propafenone, quinidine, St. John's wort, sildenafil ( Revatio ) only when used for the treatment of pulmonary arterial hypertension, simvastatin, triazolam, or voriconazole.

Dosage and Administration

Adults

PO 600 mg twice daily. Dosage titration may reduce adverse reactions; start with 300 mg twice daily and increase at 2- to 3-day intervals by 100 mg twice daily (max, 600 mg twice daily).

Children older than 1 mo of age

PO Start with 250 mg/m 2 twice daily and increase dosage at 2- to 3-day intervals by 50 mg/m 2 twice daily up to the highest tolerated dose (max, 600 mg twice daily). Usual maintenance dosage is 350 to 400 mg/m 2 twice daily.

In Combination With Protease Inhibitors
Adults

PO Decrease ritonavir dosage when given with atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir.

General Advice

  • Administer with meals.
  • Use in combination with other antiretrovirals.
  • Swallow tablets whole; do not chew, break, or crush.
  • Shake the oral solution well before measuring and administering.
  • When possible, use a calibrated dosing syringe when administering the oral solution to children.
  • Oral solution may be mixed with chocolate milk, Ensure, or Advera within 1 h of dosing.
  • When initiating combination regimens with ritonavir and reverse transcriptase inhibitors, GI tolerance may improve by initiating ritonavir alone and subsequently adding reverse transcriptase inhibitors before completing 2 wk of ritonavir monotherapy.

Storage/Stability

Capsules

Store at 36° to 46°F until dispensed. Refrigeration 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.

Solution

Store at 68° to 77°F. Do not refrigerate. Store and dispense in original container. Avoid exposure to excessive heat.

Tablets

Store at 59° to 86°F. Dispense in original container or equivalent (60 mL or less). Exposure of this product to high humidity outside the original or equivalent for longer than 2 weeks is not recommended.

Drug Interactions

Aldesleukin, azole antifungal agents (ie, fluconazole, itraconazole, ketoconazole), cyclosporine, delavirdine, fluoxetine

Ritonavir plasma concentrations may be elevated, increasing the risk of adverse reactions. Adjust the ritonavir dose as needed.

Alprazolam, atovaquone, methadone, olanzapine, pravastatin, theophylline, zidovudine

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

Anticonvulsants (ie, carbamazepine, clonazepam, ethosuximide)

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

Anticonvulsants (ie, divalproex, lamotrigine, phenytoin)

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

Antidepressants (eg, bupropion, nefazodone, SSRIs [eg, fluoxetine], trazodone, tricyclic antidepressants [eg, desipramine]), aripiprazole, atorvastatin, azole antifungal agents (ie, itraconazole, ketoconazole), benzodiazepines (eg, clorazepate, diazepam, estazolam, flurazepam, midazolam), beta-blockers (eg, metoprolol, timolol), buspirone, calcium channel blockers (eg, amlodipine, diltiazem, nifedipine, verapamil), cyclosporine, digoxin, disopyramide, dronabinol, eszopiclone, lidocaine (systemic), maraviroc, methamphetamine, mexiletine, phenothiazines (eg, perphenazine, thioridazine), protease inhibitors (eg, atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir), quetiapine, quinine, risperidone, rosuvastatin, sirolimus, steroids (eg, dexamethasone, fluticasone, prednisone), tacrolimus, vinblastine, vincristine, zolpidem

Plasma levels may be elevated by ritonavir, increasing the risk of adverse reactions; careful monitoring and/or dosage adjustment are warranted. Oral midazolam is contraindicated in patients receiving ritonavir; however, coadminister parenteral midazolam in a setting that ensures close medical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

Carbamazepine, efavirenz, mefloquine, nevirapine, rifampin, rifapentine

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

Clarithromycin

Plasma levels of both drugs may be increased. In patients with CrCl 30 to 60 mL/min, reduce clarithromycin dose by 50%; decrease by 75% in patients with CrCl less than 30 mL/min.

Colchicine

Colchicine plasma concentrations may be elevated, increasing the risk of toxicity. Coadministration of colchicine and ritonavir is contraindicated in patients with hepatic or renal impairment. In patients with healthy renal and hepatic function, coadminister ritonavir and colchicine with caution, using a maximum colchicine dosage of 0.3 mg twice daily. Carefully monitor for colchicine-related adverse reactions.

Deferasirox

Plasma concentrations and pharmacologic effects of deferasirox may be decreased by ritonavir. Avoid coadministration of deferasirox and ritonavir. If concurrent use cannot be avoided, consider a starting dosage of deferasirox 30 mg/kg/day. Adjust the deferasirox dose further according to serum ferritin concentrations and clinical response.

Disulfiram, metronidazole

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

Drugs that are highly dependent on CYP3A for Cl, have a narrow therapeutic index, or that may result in a potentially serious adverse reaction because of the expected magnitude of an interaction (eg, alfuzosin, amiodarone, bepridil, bosentan, cisapride, conivaptan, dihydroergotamine, dronedarone, eplerenone, ergonovine, ergotamine, flecainide, lovastatin, methylergonovine, midazolam oral, pimozide, propafenone, quinidine, ranolazine, sildenafil [for the treatment of pulmonary arterial hypertension], simvastatin, St. John's wort [Hypericum perforatum], triazolam, voriconazole [with doses of ritonavir 400 mg every 12 hours or more])

Coadministration with ritonavir is contraindicated.

Ethinyl estradiol

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

Food

When the oral solution was given under nonfasting conditions, peak ritonavir concentrations and extent of absorption decreased relative to fasting conditions. Extent of absorption of ritonavir from the capsule was higher when given with a meal relative to fasting conditions. It is recommended that ritonavir be taken with meals, if possible.

Grapefruit juice

Grapefruit juice may increase the plasma concentrations and pharmacologic effects of ritonavir. If grapefruit juice cannot be avoided, close clinical monitoring is indicated. Adjust the ritonavir dose accordingly.

Iloperidone

Plasma concentrations and pharmacologic effects of iloperidone may be increased by ritonavir. Reduce the dose of iloperidone by one-half when coadministered with ritonavir. If ritonavir is discontinued, increase the dose of iloperidone to the original dose.

Indinavir

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

Ixabepilone, nilotinib

Plasma concentrations may be elevated by ritonavir, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration with ritonavir.

Levothyroxine

Thyroxine serum concentrations may be increased or decreased, resulting in hyperthyroidism or hypothyroidism. Monitor patients when starting or stopping ritonavir. Adjust the levothyroxine dose as needed.

Meperidine

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

Muscarinic receptor antagonists (eg, darifenacin, fesoterodine, solifenacin, tolterodine)

Muscarinic receptor antagonist plasma concentrations may be increased by ritonavir. When ritonavir is coadministered, the dosage of darifenacin should not exceed 7.5 mg daily, the dosage of solifenacin should not exceed 5 mg daily, the dosage of tolterodine should not exceed 2 mg daily, and the dosage of fesoterodine should not exceed 4 mg daily.

Opioid analgesics (eg, alfentanil, buprenorphine, fentanyl, propoxyphene, sufentanil, tramadol)

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

Phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil)

Coadministration of ritonavir and sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension. For erectile dysfunction, use concomitantly with caution and with increased monitoring for adverse reactions. The phosphodiesterase type 5 inhibitors inhibitor dosage should not exceed the following: sildenafil 25 mg within 48 h; tadalafil 10 mg every 72 h; vardenafil 2.5 mg every 72 h.

Rifabutin

Plasma concentrations of rifabutin and its metabolite may be elevated. Reduce the rifabutin dose by at least 75%.

Salmeterol

Pharmacologic effects of salmeterol may be increased by ritonavir, increasing the risk of CV toxicity (eg, QT prolongation). Coadministration is not recommended.

Selective 5-HT 1 receptor agonists (eg, eletriptan)

Ritonavir may increase plasma concentrations and pharmacologic effects of these agents. It is recommended that eletriptan not be given within 72 h of ritonavir.

Tyrosine kinase receptor inhibitors (eg, dasatinib)

Ritonavir may elevate plasma concentrations of these agents, increasing the pharmacologic effects and risk of adverse reactions. Closely monitor the clinical response of the patient. Adjust the dose of tyrosine kinase receptor inhibitor as needed.

Voriconazole

Voriconazole levels may be decreased when coadministered with ritonavir, leading to a loss of antifungal response. Therefore, coadministration of voriconazole with ritonavir doses of 400 mg every 12 h or more is contraindicated. Avoid coadministration of voriconazole and ritonavir 100 mg.

Warfarin

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

Adverse Reactions

Cardiovascular

Syncope, vasodilation (2%); cerebral ischemia, cerebral venous thrombosis, CV disorder, hypertension, hypotension, MI, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, vasospasm (less than 2%); first-, second-, or third-degree heart block, orthostatic hypotension, right bundle branch block (postmarketing).

CNS

Asthenia (15%); circumoral paresthesia, headache (7%); 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, emotional lability, euphoria, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, manic reaction, migraine, 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, vertigo, vestibular disorder (less than 2%); abnormal thinking, confusion (1%); 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, diplopia, ear pain, extraocular palsy, 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%); abdominal pain, anorexia (8%); dyspepsia (6%); flatulence (2%); abdomen enlarged, 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, pelvic pain, penis disorder, polyuria, urethritis, urinary frequency, urinary retention, UTI, vaginitis (less than 2%); renal 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%); increased bleeding in patients with hemophilia A or B (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 GGT (20%); decreased RBC (19%); decreased Hct (17%); triglycerides more than 1,500 mg/dL (13%); elevated CPK (12%); elevated AST (10%); elevated ALT (9%); decreased neutrophils (6%); decreased Hgb, elevated uric acid (4%).

Metabolic-Nutritional

Weight loss (2%); albuminuria, alcohol intolerance, altered hormone level, avitaminosis, cachexia, dehydration, edema, enzymatic abnormality, facial edema, glycosuria, gout, hypercholesterolemia, increased BUN, peripheral edema, xanthomatosis (less than 2%); redistribution/accumulation of body fat (postmarketing).

Musculoskeletal

Arthralgia, myalgia (2%); arthritis, arthrosis, back pain, bone disorder, bone pain, 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

Fever (5%); pain (2%); accidental injury, allergic reaction, chest pain, chills, 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 impairment (postmarketing).

Precautions

Warnings

Coadministration of ritonavir with sedative hypnotics, antiarrhythmic agents, or ergot derivatives may result in serious and/or life-threatening adverse reactions (eg, cardiac arrhythmias, prolonged or increased sedation, respiratory depression).


Monitor

Because ritonavir can increase triglycerides, cholesterol, AST, ALT, GGT, CPK, and uric acid concentrations, perform appropriate lab testing prior to initiating therapy and periodically during therapy or if any clinical signs/symptoms occur during therapy. Monitor blood glucose closely. Consider increased ALT/AST monitoring in patients with hepatitis B or C, especially during the first 3 mo of ritonavir therapy.


Pregnancy

Category B .

Lactation

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

Children

Safety and efficacy not established in children younger than 1 mo of age.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Hypersensitivity

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

Hepatic Function

Not recommended in severe hepatic impairment. Use caution in patients with preexisting liver diseases, liver enzyme abnormalities, or hepatitis.

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.

CV disorders

Ritonavir may prolong the PR interval. Use with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, or cardiomyopathies.

Diabetes mellitus/hyperglycemia

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

Fat redistribution/accumulation

Redistribution/accumulation of body fat has been 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.

Hepatic effects

Hepatic transaminase elevations exceeding 5 × ULN, hepatitis, and jaundice have occurred.

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.
  • Review list of medications that must not be taken with ritonavir because of risk of very serious reactions.
  • Advise patient to take ritonavir with food.
  • Advise patient or caregiver to use measuring cup, dosing spoon, or oral syringe to measure prescribed dose of oral solution.
  • Warn patient not to alter the dose or discontinue the medication without consulting health care provider.
  • Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
  • 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. Appropriate precautions must still be followed.
  • 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.
  • Caution patient taking sildenafil, tadalafil, or vardenafil of increased risk of sildenafil-, tadalafil-, or vardenafil-induced adverse reactions (eg, low BP, sustained erection, visual changes). Instruct patients to promptly report any symptoms to health care provider. Caution patient that an erection lasting longer than 4 h requires immediate medical help to prevent permanent damage to the penis.
  • Advise patient that ritonavir may produce ECG changes (eg, PR prolongation) and to report symptoms such as dizziness, light-headedness, abnormal heart rhythm, and loss of consciousness to health care provider.
  • Advise women using estrogen-based hormonal contraceptive to use additional or alternative nonhormonal contraceptive measures while taking this medication.
  • Advise HIV-infected mothers not to breast-feed infants to avoid risk of HIV transmission to the infant.

Copyright © 2009 Wolters Kluwer Health.

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