Delavirdine

Pronunciation

(de la VIR deen)

U.S. Brand Names

Rescriptor®

Synonyms

U-90152S

Generic Available

Canadian Brand Names

Rescriptor®

Use

Treatment of HIV-1 infection in combination with at least two additional antiretroviral agents

Pregnancy Risk Factor

Pregnancy Implications

It is not known if delavirdine crosses the human placenta. Delavirdine was shown to be teratogenic in some animal studies. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to delavirdine or any component of the formulation; concurrent use of alprazolam, cisapride, ergot alkaloids, midazolam, pimozide, or triazolam

Warnings/Precautions

Avoid use with benzodiazepines, cisapride, clarithromycin, dapsone, enzyme-inducing anticonvulsants (carbamazepine, phenytoin, phenobarbital, rifampin, rifabutin, or St John's wort); may lead to loss of efficacy or development of resistance. Concurrent use of lovastatin or simvastatin should be avoided (use caution with other statins). Use caution with amphetamines, antacids, antiarrhythmics, benzodiazepines (alprazolam, midazolam, and triazolam are contraindicated), clarithromycin, dihydropyridine, calcium channel blockers, dapsone, immunosuppressants, methadone, oral contraceptives, or sildenafil.

Use with caution in patients with hepatic or renal dysfunction; due to rapid emergence of resistance, delavirdine should not be used as monotherapy; cross-resistance may be conferred to other non-nucleoside reverse transcriptase inhibitors, although potential for cross-resistance with protease inhibitors is low. Long-term effects of delavirdine are not known. Safety and efficacy have not been established in children. Rash, which occurs frequently, may require discontinuation of therapy; usually occurs within 1-3 weeks and lasts <2 weeks. Most patients may resume therapy following a treatment interruption.

Adverse Reactions

>10%: Dermatologic: Rash (3.2% required discontinuation)

1% to 10%:

Central nervous system: Headache, fatigue

Dermatologic: Pruritus

Gastrointestinal: Nausea, diarrhea, vomiting

Metabolic: Increased ALT (SGPT), increased AST (SGOT)

<1%: Abnormal coordination, ethanol intolerance, allergic reaction, alopecia, anemia, angioedema, bradycardia, calculi of kidney, chest pain, confusion, dermal leukocytoblastic vasculitis, desquamation, dyspnea, ecchymosis, edema, eosinophilia, epistaxis, erythema multiforme, granulocytosis, hallucination, hematuria, hemospermia, hyperkalemia, hyperuricemia, hypocalcemia, hyponatremia, hypophosphatemia, increased lipase, increased serum alkaline phosphatase, increased serum creatine phosphokinase, increased serum creatinine, kidney pain, malaise, myalgia, neck rigidity, neuropathy, neutropenia, nonspecific hepatitis, nystagmus, palpitation, pancytopenia, paralysis, paranoid symptoms, postural hypotension, proteinuria, Stevens-Johnson syndrome, syncope, tachycardia, thrombocytopenia, vasodilation, vertigo, vesiculobullous rash

Postmarketing and/or case reports: Hepatic failure, hemolytic anemia, rhabdomyolysis, acute renal failure

Overdosage/Toxicology

Reports of human overdose with delavirdine are not available. GI decontamination and supportive measures are recommended. Dialysis is unlikely to be of benefit in removing this drug since it is extensively metabolized by the liver and is highly protein bound.

Drug Interactions

Substrate of CYP2D6 (minor), 3A4 (major); Inhibits CYP1A2 (weak), 2C8/9 (strong), 2C19 (strong), 2D6 (strong), 3A4 (strong)

Increased plasma concentrations of delavirdine: Clarithromycin, ketoconazole, fluoxetine

Decreased plasma concentrations of delavirdine: Amprenavir, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, didanosine, saquinavir, dexamethasone

Decreased absorption of delavirdine: Antacids, histamine-2 receptor antagonists, didanosine, proton pump inhibitors (omeprazole, lansoprazole)

Delavirdine increases plasma concentrations of: Indinavir, saquinavir, clarithromycin, dapsone, rifabutin, ergot derivatives, alprazolam, midazolam, triazolam, dihydropyridines, cisapride, quinidine, warfarin, antiarrhythmics, nonsedating antihistamines, sedative-hypnotics, calcium channel blockers, amprenavir, amphetamines, bepridil, sildenafil, pimozide, amiodarone, flecainide, propafenone, methadone, HMG-CoA reductase inhibitors

Delavirdine decreases plasma concentrations of: Didanosine

CYP2C8/9 substrates: Delavirdine may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

CYP2C19 substrates: Delavirdine may increase the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline.

CYP2D6 substrates: Delavirdine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Delavirdine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of delavirdine. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 substrates: Delavirdine may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, cyclosporine, mirtazapine, nateglinide, nefazodone, sildenafil (and other PDE-5 inhibitors), tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam, triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Delavirdine serum concentration may be decreased by St John's wort; avoid concurrent use.

Mechanism of Action

Delavirdine binds directly to reverse transcriptase, blocking RNA-dependent and DNA-dependent DNA polymerase activities

Pharmacodynamics/Kinetics

Absorption: Rapid

Distribution: Low concentration in saliva and semen; CSF 0.4% concurrent plasma concentration

Protein binding: ~98%, primarily albumin

Metabolism: Hepatic via CYP3A4 and 2D6 ( Note: May reduce CYP3A activity and inhibit its own metabolism.)

Bioavailability: 85%

Half-life elimination: 2-11 hours

Time to peak, plasma: 1 hour

Excretion: Urine (51%, <5% as unchanged drug); feces (44%); nonlinear kinetics exhibited

Dosage

Adults: Oral: 400 mg 3 times/day

Administration

Patients with achlorhydria should take the drug with an acidic beverage; antacids and delavirdine should be separated by 1 hour

Monitoring Parameters

Liver function tests if administered with saquinavir

Dietary Considerations

May be taken without regard to food.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug is not a cure for HIV, nor has it been found to reduce transmission of HIV. Take as directed, with or without food. Do not take antacids within 1 hour of delavirdine. Mix 4 tablets in 3-5 oz of water, allow to stand a few minutes, and stir; drink immediately. May cause nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help - consult prescriber if nausea or vomiting persists). Report mouth sores; skin rash or irritation; muscle weakness or tremors; easy bruising or bleeding, fever or chills; CNS changes (eg, hallucinations, confusion, dizziness, altered coordination); swelling of face, lips, or tongue; yellowing of eyes or skin; or dark urine or pale stools. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Additional Information

Potential compliance problems, frequency of administration, and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause sedation

Mental Health: Effects on Psychiatric Treatment

Fluoxetine may increase plasma concentrations of delavirdine; carbamazepine and phenobarbital may decrease plasma concentrations of delavirdine; delavirdine may increase concentrations of alprazolam, midazolam, and triazolam

Dosage Forms

Tablet, as mesylate: 100 mg, 200 mg

Extemporaneously Prepared

A dispersion of delavirdine may be prepared by adding 4 tablets to at least 3 oz of water; allow to stand for a few minutes and stir until uniform dispersion; drink immediately; rinse glass and mouth following ingestion to ensure total dose administered

References

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents, Panel on Clinical Practices for Treatment of HIV Infection," February 5, 2001. Available at: http://www.aidsinfo.nih.gov. Accessed February 14, 2001.

Havlir DV and Lange JM, "New Antiretrovirals and New Combinations," AIDS , 1998, 12(Suppl A):165-74.

Hilts AE and Fish DN, "Dosage Adjustment of Antiretroviral Agents in Patients With Organ Dysfunction," Am J Health Syst Pharm , 1998, 55:2528-33.

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.

International Brand Names

Rescriptor® (AR, AU, CA, MX)

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