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ritonavir (Norvir, RTV)

Tradename: Norvir. Indications: - treatment of HIV, used in connection with nucleoside analogs - acceptable for use during pregnancy [9] Contraindications: 1) concurrent use of drugs which prolong the QT interval 2) other drugs (see analgesics, cardiac agents, allergy medications, ergot alkaloids, antimicrobial agents, & psychotropic agents below) Dosage: 1) adults: 600 mg PO BID 2) children: a) start 250 mg/m2 BID b) titrate up to 400 mg/m2 BID 3) take with food 4) copius fluids 5) intolerance a) stop until resolution of symptoms b) restart with escalating dose over 7-10 days c) do NOT use suboptimal dose Tabs: 100 mg. Solution: 80 mg/mL (240 mL) Storage: - must be protected from heat & moisture - Norvir & Kaletra) can be dispensed in original container or USP equivalent container or can be stored outside of these containers for up to 2 weeks [10] Monitor: 1) liver function tests (serum AST, serum ALT, serum GGT) baseline & periodically periodically [7] 2) signs of infection Pharmacokinetics: - metabolized in the liver by CYP2D6 & CYP3A4 - ritonavir inhibits cyt P450 3A4 (inhibition significant at boosting dose of 100 mg) - inhibition of CYP3A4 is irreversible - maximal inhibition of CUP3A4 occurs within 48 hours - 80% of CYP3A4 activity resolves within 3 days of stopping ritonavir in young & elderly - individual variability noted - ritonavir is only a weak inhibitor of CYP2D6 at a boosting dose of 100 mg - ritonavir is an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, & uridine diphosphate- glucuronyltransferase (UDP-UGT) - ritonanir inhibits P-glycoprotein transporter & breast cancer resistance protein (BCRP), expressed in the intestine, leading to an increased intestinal absorption of some drugs including direct-acting oral anticoagulants - ritonavir inhibits hepatic uptake transporters organic anion transporting polypeptides (OATP-1B1 & OATP-1B3), resulting in increased plasma concentrations of drugs including statins [12] Adverse effects: 1) not common (1-10%) - nausea/vomiting, diarrhea, taste disturbance, circumoral & peripheral paresthesias, weakness 2) uncommon (< 1%) - headache, confusion, - hyperlipidemia, elevated serum triglycerides & serum cholesterol - switching to cobicistat may improve serum triglycerides [11] - abnormal liver function tests 3) other - lipodystrophy syndrome - central visceral redistribution of fat - wasting of extremities - hyperlipidemia - insulin resistance - prolongation of the QT interval - anorexia - abdominal pain - nephrolithiasis Drug interactions: 1) many: a) inhibitor of cyt P450 3A4, cyt P450 2D6 & cyt P450 2C b) weak substrate of cyt P450 2D6 & cyt P450 3A4 2) drugs which prolong the QT interval 3) increased plasma levels of: - amiodarone, bepridil, bupropion, clozapine, dihydroergotamine, encainide, ergotamine, flecainide, meperidine, pimozide, piroxicam, propafenone, simvastatin, lovastatin, propoxyphene, quinidine, rifabutin, rifampin, saquinavir, clarithromycin - ritonavir in combination with saquinavir may increase risk of torsades de pointes or complete heart block [8] 4) expected increased plasma levels of: - benzodiazepines & other sedative/hypnotics, i.e. a) alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zoldipem b) lorazepam & oxazepam undergo hepatic conjugation & should be OK with ritonavir 5) abrupt withdrawal of glucocorticoids metabolized by cyt-P450 3A4 including inhaled glucocorticoids fluticasone & budesonide can result in adrenal insufficiency - (no abdominal hyperpigmentation) [13] 6) analgesics a) meperidine, piroxicam, propoxyphene b) acetaminophen, aspirin & oxycodone & suggested alternatives 7) cardiac agents - amiodarone, encainide, flecainide, propafenone, quinidine, bepridil - simvastatin, lovastatin 8) allergy medications a) astemizole, terfenadine b) loratadine is OK 9) ergot alkaloids - ergotamine, dihydroergotamine 10) gastrointestinal agents: a) cisapride b) cimetidine 11) antimicrobial agents: a) rifabutin b) clarithromycin & ethambutol are suggested alternatives c) azole antifungal agents 12) psychotropic agents a) bupropion, clozapine, pimozide, alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zoldipem b) temazepam, lorazepam & desipramine are OK 13) HIV agents a) 20 fold increase in saquinavir b) 25% decrease in zidovudine (AZT); no dose adjustment c) 13% decrease in didanosine (ddI); no dose adjustment 14) fluoxetine (Prozac) in combination may result in serotonin syndrome Laboratory: - ritonavir in serum/plasma Mechanism of action: 1) resistance may develop: cross-resistance with indinavir & possibly nelfinavir 2) antiretroviral booster - inhibits metabolism of antiretroviral agents metabolized by cyt P450 3A4

Interactions

drug interactions drug adverse effects (more general classes)

Related

cytochrome P450 2D6 (cytochrome P450 2D, cytochrome P450 DB1, debrisoquine-4-hydroxylase, CYP2D6) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) QT interval

General

antiretroviral protease inhibitor

Properties

INHIBITS: HIV protease MISC-INFO: elimination route LIVER pregnancy-category B safety in lactation -

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Physician's Desk Reference (PDR) 56th edition, Medical Economics, 2002
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 17 American College of Physicians, Philadelphia 1998, 2015
  5. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  6. Department of Veterans Affairs, VA National Formulary
  7. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com
  8. FDA MedWatch 10/21/2010 Invirase (saquinavir): Label Change - Risk of Abnormal Heart Rhythm http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm230449.htm
  9. Zuger A Use of Antiretroviral Drugs in Pregnancy. Physician's First Watch, April 22, 2014 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. 2014. AIDSinfo. Clinical Guidelines Portal. March 28, 2014. http://aidsinfo.nih.gov/Guidelines/HTML/3/perinatal-guidelines/0 (corresponding NGC guideline withdrawn March 2016)
  10. Prescriber's Letter 21(6): 2014 Oral Meds to Keep in Original Containers Detail-Document#: 300622 (subscription needed) http://www.prescribersletter.com
  11. Echeverria P et al Significant Improvement in Triglyceride Levels After Switching From Ritonavir to Cobicistat in Suppressed HIV-1-Infected Subjects With Dyslipidaemia. Medscape: HIV Medicine. 2017;18(10):782-786 https://www.medscape.com/viewarticle/889773
  12. Marzolini C, Kuritzkes DR, Marra F Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications. Clin Pharmacol Ther. 2022 Dec;112(6):1191-1200 PMID: 35567754 PMCID: PMC9348462 Free PMC article
  13. NEJM Knowledge+ Complex Medical Care

Component-of

dasabuvir/ombitasvir/paritaprevir/ritonavir (Viekira XR) lopinavir/ritonavir (Kaletra) ombitasvir/paritaprevir/ritonavir (Viekira, Technivie) Paxlovid (nirmatrelvir/ritonavir)