ritonavir (Norvir, RTV)
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Introduction
Tradename: Norvir.
Indications
- treatment of HIV, used in connection with nucleoside analogs
Contraindications
- concurrent use of drugs which prolong the QT interval
- other drugs (see analgesics, cardiac agents, allergy medications, ergot alkaloids, antimicrobial agents, & psychotropic agents below)
Dosage
- adults: 600 mg PO BID
- children:
- take with food
- copius fluids
- intolerance
- stop until resolution of symptoms
- restart with escalating dose over 7-10 days
- do NOT use suboptimal dose
Tabs: 100 mg.
Storage
- must be protected from heat & moisture
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]
elimination via liver
Monitor
- liver function tests (serum AST, serum ALT, serum GGT) baseline & periodically periodically[7]
- signs of infection
Adverse effects
- not common (1-10%)
- nausea/vomiting, diarrhea, taste disturbance, circumoral & peripheral paresthesias, weakness
- uncommon (< 1%)
- headache, confusion,
- hyperlipidemia, elevated serum triglycerides & serum cholesterol
- switching to cobicistat may improve serum triglycerides[11]
- abnormal liver function tests
- other
- lipodystrophy syndrome
- central visceral redistribution of fat
- wasting of extremities
- hyperlipidemia
- insulin resistance
- prolongation of the QT interval
- anorexia
- abdominal pain
- nephrolithiasis
- lipodystrophy syndrome
- drug adverse effects of antiretroviral protease inhibitors
- drug adverse effects of antiretroviral agents
Drug interactions
- many:
- inhibitor of cyt P450 3A4, cyt P450 2D6 & cyt P450 2C
- weak substrate of cyt P450 2D6 & cyt P450 3A4
- drugs which prolong the QT interval
- 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]
- expected increased plasma levels of:
- benzodiazepines & other sedative/hypnotics, i.e.
- alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zoldipem
- lorazepam & oxazepam undergo hepatic conjugation & should be OK with ritonavir
- abrupt withdrawal of glucocorticoids metabolized by cyt-P450 3A4 including inhaled glucocorticoids fluticasone & budesonide can result in adrenal insufficiency - (no abdominal hyperpigmentation)[13]
- analgesics
- meperidine, piroxicam, propoxyphene
- acetaminophen, aspirin & oxycodone & suggested alternatives
- cardiac agents
- allergy medications
- astemizole, terfenadine
- loratadine is OK
- ergot alkaloids
- gastrointestinal agents:
- antimicrobial agents:
- rifabutin
- clarithromycin & ethambutol are suggested alternatives
- azole antifungal agents
- psychotropic agents
- bupropion, clozapine, pimozide, alprazolam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam, zoldipem
- temazepam, lorazepam & desipramine are OK
- HIV agents
- 20 fold increase in saquinavir
- 25% decrease in zidovudine (AZT); no dose adjustment
- 13% decrease in didanosine (ddI); no dose adjustment
- fluoxetine (Prozac) in combination may result in serotonin syndrome
- drug interaction(s) of fluticasone with HIV1 protease inhibitors
- drug interaction(s) of antiretroviral protease inhibitor in combination with ritonavir
- drug interaction(s) of boceprevir in combination with ritonavir & Kaletra
- drug interaction(s) of boceprevir in combination with ritonavir & darunavir
- drug interaction(s) of boceprevir in combination with ritonavir & atazanavir
- drug interaction(s) of saquinavir with ritonavir
- drug interaction(s) of statins with antiviral protease inhibitors
- drug interaction(s) of antibiotics with warfarin
- drug interaction(s) of eplerenone with ritonavir
Laboratory
Mechanism of action
- resistance may develop: cross-resistance with indinavir & possibly nelfinavir
- antiretroviral booster
- inhibits metabolism of antiretroviral agents metabolized by cyt P450 3A4
More general terms
Additional terms
- 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
Component of
- Paxlovid (nirmatrelvir/ritonavir)
- nirmatrelvir/ritonavir
- dasabuvir/ombitasvir/paritaprevir/ritonavir (Viekira XR)
- ombitasvir/paritaprevir/ritonavir (Viekira, Technivie)
- lopinavir/ritonavir (Kaletra)
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Physician's Desk Reference (PDR) 56th edition, Medical Economics, 2002
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Medical Knowledge Self Assessment Program (MKSAP) 11, 17 American College of Physicians, Philadelphia 1998, 2015
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ Department of Veterans Affairs, VA National Formulary
- ↑ 7.0 7.1 Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260704&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 8.0 8.1 FDA MedWatch 10/21/2010 Invirase (saquinavir): Label Change - Risk of Abnormal Heart Rhythm http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm230449.htm
- ↑ 9.0 9.1 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) - ↑ 10.0 10.1 Prescriber's Letter 21(6): 2014 Oral Meds to Keep in Original Containers Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=300622&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 11.0 11.1 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
- ↑ 12.0 12.1 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: https://www.ncbi.nlm.nih.gov/pubmed/35567754 PMCID: PMC9348462 Free PMC article
- ↑ 13.0 13.1 NEJM Knowledge+ Complex Medical Care