Norvir
Norvir - General Information
An HIV protease inhibitor that works by interfering with the reproductive cycle of HIV. [PubChem]
Pharmacology of Norvir
Norvir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Norvir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.
Norvir for patients
Norvir Interactions
Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo (Table 2). Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (>3-fold) when co-administered with ritonavir. Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A as well as other enzymes, including glucuronosyl transferase, CYP1A2, and possibly CYP2C9.
Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed both in CONTRAINDICATIONS Table 3 and under Contraindicated Drugs in Table 4.
Those drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY, Table 2. The clinical recommendations based on the results of these studies are listed in Table 4 Established Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies.
A systematic review of over 200 medications prescribed to HIV-infected patients was performed to identify potential drug interactions with ritonavir. 2 There are a number of agents in which CYP3A or CYP2D6 partially contribute to the metabolism of the agent. In these cases, the magnitude of the interaction and therapeutic consequences cannot be predicted with any certainty.
When co-administering ritonavir with calcium channel blockers, immunosuppressants, some HMG-CoA reductase inhibitors, some steroids, or other substrates of CYP3A, or most antidepressants, certain antiarrhythmics, and some narcotic analgesics which are partially mediated by CYP2D6 metabolism, it is possible that substantial increases in concentrations of these other agents may occur, possibly requiring a dosage reduction (>50%); examples are listed in Table 4 Predicted Drug Interactions: Use With Caution, Dose Decrease May be Needed.
When co-administering ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations.
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DRUGS THAT ARE CONTRAINDICATED WITH
NORVIR USE |
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Drug Class
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Drugs Within Class That Are
CONTRAINDICATED With NORVIR |
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Antiarrhythmics
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amiodarone, bepridil, flecainide, propafenone, quinidine
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Antihistamines
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astemizole, terfenadine
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Antimigraine
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dihydroergotamine, ergotamine
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Sedative/hypnotics
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midazolam, triazolam
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GI motility agent
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cisapride
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Neuroleptic
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pimozide
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Drug Name
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Effect
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Clinical Comment
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Clarithromycin
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up clarithromycin
concentration |
For patients with renal impairment the following dosage adjustments should be considered:
· For patients with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. · For patients with CL CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
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Desipramine
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up desipramine concentration
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Dosage reduction and concentration monitoring of desipramine is recommended
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Didanosine
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Dosing of didanosine and ritonavir should be separated by 2.5 hours to avoid formulation incompatibility
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Disulfiram/Metronidazole
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Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole)
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Indinavir
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up indinavir concentration
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Appropriate doses for this combination, with respect to efficacy and safety, have not been established
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Ketoconazole
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up ketoconazole concentration
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High doses of ketoconazole (>200 mg/day) are not recommended
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Meperidine
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down meperidine concentration/
up normeperidine concentration (metabolite) |
Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures)
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Methadone
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down methadone concentration
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Dosage increase of methadone may be considered
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Oral Contraceptives
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down ethinyl estradiol
concentration |
Dosage increase or alternate contraceptive measures should be considered
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Rifabutin
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up rifabutin and rifabutin
metabolite concentration |
Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg/day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary
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Rifampin
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down ritonavir concentration
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Alternate antimycobacterial agents such as rifabutin should be considered
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Saquinavir
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up saquinavir concentration
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When used in combination therapy for up to 24 weeks, doses of 400 mg b.i.d. of ritonavir and saquinavir were better tolerated than the higher doses of the combination. Saquinavir plasma concentrations achieved with Invirase® (saquinavir mesylate) (400 mg b.i.d.) and ritonavir (400 mg b.i.d.) are similar to those achieved with Fortovaseô (saquinavir) (400 mg b.i.d.) and ritonavir (400 mg b.i.d.)
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Sildenafil
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up sildenafil concentration
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Sildenafil should not exceed a maximum single dose of
25 mg in a 48-hour period in patients receiving concomitant ritonavir therapy |
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Theophylline
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down theophylline concentration
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Increased dosage of theophylline may be required; therapeutic monitoring should be considered
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Predicted Drug Interactions: Use With Caution, Dose
Decrease of Coadministered Drug May Be Needed |
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| Examples of Drugs in Which Plasma Concentrations May Be Increased By Co-Administration With NORVIR |
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Drug Class
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Examples of Drugs
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Analgesics, narcotic
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tramadol, propoxyphene
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Antiarrhythmics
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disopyramide, lidocaine, mexilitine
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Anticonvulsants
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carbamazepine, clonazepam, ethosuximide
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Antidepressants
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bupropion, nefazodone, selective serotonin reuptake inhibitors (SSRIs), tricyclics
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Antiemetics
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dronabinol
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Antiparasitics
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quinine
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(beta)-blockers
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metoprolol, timolol
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Calcium channel blockers
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diltiazem, nifedipine, verapamil
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Hypolipidemics, HMG CoA reductase inhibitors 1
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atorvastatin, cerivastatin, lovastatin, simvastatin
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Immunosuppressants
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cyclosporine, tacrolimus
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Neuroleptics
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perphenazine, risperidone, thioridazine
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Sedative/hypnotics
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clorazepate, diazepam, estazolam, flurazepam, zolpidem
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Steroids
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dexamethasone, prednisone
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Stimulants
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methamphetamine
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1 Coadministration with lovastatin and simvastatin is not recommended.
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Predicted Drug Interactions: Use With Caution, Dose Increase of Coadministered Drug May Be Needed
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Examples of Drugs in Which Plasma Concentrations
May Be Decreased By Co-Administration With NORVIR |
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Anticoagulants
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warfarin
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Anticonvulsants
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phenytoin, divalproex, lamotrigine
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Antiparasitics
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atovaquone
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Post-Marketing Experience with Drugs Listed in Table 4
Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.
Norvir Contraindications
Ritonavir is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients. Ritonavir should not be administered concurrently with the drugs listed in the list below because competition for primarily CYP3A by ritonavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression. Postmarketing reports indicate that co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities.DRUGS THAT ARE CONTRAINDICATED WITH RITONAVIR USE:Antiarrhythmics: amiodarone, bepridil, flecainide, propafenone, quinidineAntihistamines: astemizole, terfenadineAntimigraine: dihydroergotamine, ergotamineSedative/hypnotics: midazolam, triazolamGI motility agent: cisapride Neuroleptic: pimozide
Additional information about Norvir
Norvir Indication: Indicated in combination with other antiretroviral agents for the treatment of HIV-infection.
Mechanism Of Action: Norvir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.
Drug Interactions: Not Available
Food Interactions: Take with food.
Avoid St.John's Wort.
Generic Name: Ritonavir
Synonyms: Abbott 84538
Drug Category: Anti-HIV Agents; HIV Protease Inhibitors
Drug Type: Small Molecule; Approved
Other Brand Names containing Ritonavir: Norvir; Norvir Sec;
Absorption: The absolute bioavailability of ritonavir has not been determined.
Toxicity (Overdose): Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.
Protein Binding: 98-99%
Biotransformation: Hepatic. Five metabolites have been identified. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of ritonavir, however, plasma concentrations are low. The cytochrome P450 enzymes CYP3A and CYP2D6 are primarily involved in the metabolism of ritonavir.
Half Life: 3-5 hours
Dosage Forms of Norvir: Solution Oral
Capsule Oral
Chemical IUPAC Name: 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-di(phenyl)hexan-2-yl]carbamate
Chemical Formula: C37H48N6O5S2
Ritonavir on Wikipedia: https://en.wikipedia.org/wiki/Ritonavir
Organisms Affected: Human Immunodeficiency Virus