Ritonavir

Drug Name: Ritonavir

Indication: 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.

Drug Category: Anti-HIV Agents; HIV Protease Inhibitors; ATC:J05AE03

Brand Names/Synonyms: Abbott 84538; Kaletra; Norvir; Norvir Sec; Ritonavir; Ritonavir [Usan]

Dosage Forms: CAPSULE (100 mg); SOLUTION (80 mg/mL of ritonavir)

Absorption: The absolute bioavailability of ritonavir has not been determined.

Interactions: DrugBank: Interactions for Ritonavir

Interactions for Ritonavir:

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.

Chemical IUPAC Name: 1,3-thiazol-5-ylmethyl [3-hydroxy-5-[3-methyl-2-[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino-butanoyl]amino-1,6-diphenyl-hexan-2-yl]aminoformate

Chemical Formula: C37H48N6O5S2

Half Life: 3-5 hours

Drug Type: Approved Drug

# Accession No: APRD00312

CAS Registry Number: 155213-67-5

Ritonavir resources

DRUG INFO
Ritonavir

Interactions for Ritonavir:

Post-Marketing Experience with Drugs Listed in Table 4

Ritonavir resources

DRUG INFO Ritonavir

Interactions for Ritonavir:

Post-Marketing Experience with Drugs Listed in Table 4

DRUG INFO
Ritonavir