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Active ingredient: Ritonavir - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Anti-HIV Agents
  • HIV Protease Inhibitors

Dosage Forms

  • Capsule (100 mg)
  • Solution (80 mg/mL of ritonavir)

Brands / Synonyms

Abbott 84538; Kaletra; Norvir; Norvir Sec; Ritonavir [Usan]

Indications

Indicated in combination with other antiretroviral agents for the treatment of HIV-infection.

Pharmacology

Ritonavir 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. Ritonavir 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.

Mechanism of Action

Ritonavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.

Absorption

The absolute bioavailability of ritonavir has not been determined.

Toxicity

Human experience of acute overdose with NORVIR is limited. One patient in clinical trials took NORVIR 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.

Biotrnasformation / Drug Metabolism

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.

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

Drug 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.

 

Table 4
Drug Interactions With NORVIR
CONTRAINDICATED DRUGS
(Same as Table 3)
DRUGS THAT ARE CONTRAINDICATED WITH
NORVIR USE
Drug Class
Drugs Within Class That Are
CONTRAINDICATED With NORVIR
Antiarrhythmics
amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines
astemizole, terfenadine
Antimigraine
dihydroergotamine, ergotamine
Sedative/hypnotics
midazolam, triazolam
GI motility agent
cisapride
Neuroleptic
pimozide

 

Established Drug Interactions: Alteration in Dose or
Regimen  Recommended Based
on Drug Interaction Studies
Drug Name
Effect
Clinical Comment
Clarithromycin
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.
Desipramine
up desipramine concentration
Dosage reduction and concentration monitoring of desipramine is recommended
Didanosine
 
Dosing of didanosine and ritonavir should be separated by 2.5 hours to avoid formulation incompatibility
Disulfiram/Metronidazole
 
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)
Indinavir
up indinavir concentration
Appropriate doses for this combination, with respect to efficacy and safety, have not been established
Ketoconazole
up ketoconazole concentration
High doses of ketoconazole (>200 mg/day) are not recommended
Meperidine
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)
Methadone
down methadone concentration
Dosage increase of methadone may be considered
Oral Contraceptives
down ethinyl estradiol
 concentration
Dosage increase or alternate contraceptive measures should be considered
Rifabutin
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
Rifampin
down ritonavir concentration
Alternate antimycobacterial agents such as rifabutin should be considered
Saquinavir
up saquinavir concentration
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.)
Sildenafil
up sildenafil concentration
Sildenafil should not exceed a maximum single dose of
25 mg in a 48-hour period in patients receiving concomitant ritonavir therapy
Theophylline
down theophylline concentration
Increased dosage of theophylline may be required; therapeutic monitoring should be considered

 

Predicted Drug Interactions: Use With Caution, Dose
Decrease of Coadministered Drug May Be Needed
Examples of Drugs in Which Plasma Concentrations May Be Increased
By Co-Administration With NORVIR
Drug Class
Examples of Drugs
Analgesics, narcotic
tramadol, propoxyphene
Antiarrhythmics
disopyramide, lidocaine, mexilitine
Anticonvulsants
carbamazepine, clonazepam, ethosuximide
Antidepressants
bupropion, nefazodone, selective serotonin reuptake inhibitors (SSRIs), tricyclics
Antiemetics
dronabinol
Antiparasitics
quinine
(beta)-blockers
metoprolol, timolol
Calcium channel blockers
diltiazem, nifedipine, verapamil
Hypolipidemics, HMG CoA reductase inhibitors 1
atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants
cyclosporine, tacrolimus
Neuroleptics
perphenazine, risperidone, thioridazine
Sedative/hypnotics
clorazepate, diazepam, estazolam, flurazepam, zolpidem
Steroids
dexamethasone, prednisone
Stimulants
methamphetamine
1 Coadministration with lovastatin and simvastatin is not recommended.
Predicted Drug Interactions: Use With Caution, Dose Increase of Coadministered Drug May Be Needed
Examples of Drugs in Which Plasma Concentrations
May Be Decreased By Co-Administration
With NORVIR
Anticoagulants
warfarin
Anticonvulsants
phenytoin, divalproex, lamotrigine
Antiparasitics
atovaquone

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.

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