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Delavirdine Mesylate

Class: HIV Nonnucleoside Reverse Transcriptase Inhibitors
- Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: 1-[3-[(1-Methylethyl)amino]-2-pyridinyl]-4-[[5-[(methylsulfonyl)amino]-1H-indol-2-yl]carbonyl]-piperazinemonomethanesulfonate
Molecular Formula: C22H28N6O3S•CH4 O3S
CAS Number: 147221-93-0
Brands: Rescriptor

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).

Uses for Delavirdine Mesylate

Treatment of HIV Infection

Treatment of HIV-1 infection in adults; usually used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).

Experts state delavirdine not recommended for initial treatment regimens in antiretroviral-naive adults because of inferior virologic efficacy and inconvenient dosing regimen.

Data insufficient comparing delavirdine regimens to the preferred 3-drug regimens for initial treatment in antiretroviral-naive adults; consider that the proportion of clinical study patients responding to regimen of delavirdine and 2 NRTIs with sustained plasma HIV-1 levels <400 copies/mL over 1 year has been relatively low.

Delavirdine Mesylate Dosage and Administration

Administration

Oral Administration

Administer orally 3 times daily with or without food.

For patients unable to swallow tablets, 100-mg tablets may be administered as slurry or dispersion in water. To prepare dispersion containing 400 mg, place four 100-mg tablets in a glass containing ≥90 mL of water, let stand for a few minutes, then stir until a uniform dispersion occurs. Consume dispersion promptly; rinse glass with more water and swallow the rinse.

The 200-mg tablets are not readily dispersed in water and should be swallowed intact.

Patients with achlorhydria should take delavirdine with an acidic beverage (e.g., orange or cranberry juice).

Dosage

Available as delavirdine mesylate; dosage expressed in terms of delavirdine mesylate.

Pediatric Patients

Treatment of HIV Infection
Oral

Adolescents ≥16 years of age: 400 mg 3 times daily.

Adults

Treatment of HIV Infection
Oral

400 mg 3 times daily.

Special Populations

Hepatic Impairment

Data insufficient to make dosage recommendation for patients with hepatic impairment; use with caution.

Renal Impairment

Dosage adjustments not needed.

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Delavirdine Mesylate

Contraindications

  • Known hypersensitivity to delavirdine or any ingredient in the formulation.

  • Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alprazolam, cisapride, ergot alkaloids, midazolam, pimozide, triazolam). (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Interactions

Concomitant use with certain drugs not recommended (e.g., lovastatin, simvastatin, rifampin, rifabutin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) or requires particular caution (sildenafil). (See Specific Drugs under Interactions.)

Sensitivity Reactions

Dermatologic Reactions

Severe rash, erythema multiforme, Stevens-Johnson syndrome reported; these severe reactions resolved after drug discontinued.

Patients experiencing severe rash or rash accompanied by fever, blistering, oral lesions, conjunctivitis, swelling, or muscle or joint aches should discontinue delavirdine and seek medical assistance.

Mild rash also reported. Rash usually occurs during first month of therapy, mainly on upper body and proximal arms with decreasing intensity of lesions on neck and face and progressively less on rest of trunk and limbs.

Rash usually resolves in <2 weeks and generally does not require dosage reduction or contraindicate use of the drug. If delavirdine therapy is interrupted because of rash, most patients are able to resume therapy with the drug.

Mild or moderate rash can be treated with diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.

General Precautions

HIV Resistance

Possibility of HIV resistant to delavirdine and possible cross-resistance to other NNRTIs.

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance reported in patients receiving antiretroviral therapy. Mechanisms and long-term consequences unknown; causal relationship not established.

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in the setting of immune reconstitution; time to onset is variable and can occur many months after initiation of antiretroviral therapy.

Specific Populations

Pregnancy

Category C.

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Lactation

Distributed into milk in rats; not known whether distributed into human milk.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy not established in children <16 years of age.

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Extensively metabolized in liver; use with caution in those with hepatic impairment.

Common Adverse Effects

Rash, asthenia/fatigue, nausea.

Interactions for Delavirdine Mesylate

Metabolized by CYP3A and CYP2D6.

Inhibits CYP3A and, to a lesser extent, 2C9, 2D6, and 2C19.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A; possible alteration in metabolism of delavirdine and/or other drug.

Specific Drugs

Drug

Interaction

Comments

Amphetamines

Possible increased amphetamine concentrations

Use with caution

Antacids, aluminum- or magnesium-containing

Decreased delavirdine concentrations

Take delavirdine at least 1 hour before or after antacids

Antiarrhythmic agents (amiodarone, flecainide, systemic lidocaine, propafenone, quinidine)

Possible increased concentrations of antiarrhythmic agent; potential for serious or life-threatening effects (e.g., cardiac arrhythmias) with certain agents

Use concomitantly with caution; monitor plasma concentrations of antiarrhythmic agent

Anticoagulants, oral

Possible increased warfarin concentrations

Monitor INR; adjust warfarin dosage accordingly

Anticonvulsants (carbamazepine, phenytoin, phenobarbital)

Decreased delavirdine concentrations; possible loss of virologic response and development of resistance to the antiretroviral and other NNRTIs

Do not use concomitantly with delavirdine

Antifungals, azoles (fluconazole, ketoconazole, voriconazole)

Fluconazole: Pharmacokinetic interaction not clinically important

Ketoconazole: Increased delavirdine concentrations

Voriconazole: Increased voriconazole concentrations

Voriconazole: Monitor frequently for voriconazole adverse effects

Antimycobacterials (rifabutin, rifampin, rifapentine)

Rifabutin: Decreased delavirdine AUC; increased rifabutin AUC

Rifampin: Decreased delavirdine AUC

Possible loss of virologic response and increased risk of delavirdine or NNRTI resistance

Concomitant use with rifabutin, rifampin, or rifapentine not recommended

Atazanavir

No in vitro evidence of antagonistic antiretroviral effects

Benzodiazepines (alprazolam, midazolam, triazolam)

Potential for serious and/or life-threatening adverse effects such as prolonged or increased sedation or respiratory depression

Concomitant use contraindicated

Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, isradipine, nifedipine, nimodipine, nisoldipine, verapamil)

Possible increased concentrations of calcium-channel blocking agent

Use concomitantly with caution; clinical monitoring recommended

Cisapride

Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)

Concomitant use contraindicated

Co-trimoxazole

Interaction unlikely

Corticosteroids (dexamethasone, fluticasone)

Dexamethasone: Possible decreased delavirdine concentrations

Dexamethasone: Use with caution; delavirdine may be less effective

Fluticasone (orally inhaled, intranasal): Possible increased fluticasone concentrations

Fluticasone (orally inhaled, intranasal): Use concomitantly with caution; consider alternative to fluticasone, especially when long-term corticosteroid therapy is anticipated

Darunavir

No in vitro evidence of antagonistic antiretroviral effects

Didanosine

Decreased delavirdine concentrations if given at same time as buffered didanosine preparations; clinically important pharmacokinetic interaction not observed when buffered didanosine administered 1 hour after delavirdine

In vitro evidence of additive to synergistic antiretroviral effects

Administer buffered didanosine (pediatric oral solution admixed with antacid) at least 1 hour before or after delavirdine

Efavirenz

Do not use concomitantly

Emtricitabine

In vitro evidence of additive or synergistic antiretroviral effects

Ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine)

Concomitant use contraindicated

Estrogens/Progestins

Hormonal contraceptives: Possible increased concentrations of ethinyl estradiol

Clinical importance unknown

Etravirine

Possible increased etravirine concentrations

Do not use concomitantly

Fluoxetine

Increased delavirdine trough concentrations

Fosamprenavir

Studies using amprenavir (active metabolite of fosamprenavir) indicate increased amprenavir concentrations and AUC and possible decreased delavirdine concentrations and AUC; possible decreased antiretroviral efficacy and increased risk of antiretroviral resistance

In vitro evidence of synergistic antiretroviral effects

Fosamprenavir (with or without low-dose ritonavir): Concomitant use contraindicated

Histamine H2-receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine)

Possible decreased GI absorption of delavirdine

Long-term concomitant use not recommended

HMG-CoA reductase inhibitors (statins)

Atorvastatin, fluvastatin, lovastatin, simvastatin: Possible increased concentrations of the antilipemic agents; increased risk of myopathy and/or rhabdomyolysis

Atorvastatin: Use lowest possible atorvastatin dosage; consider using pravastatin instead

Fluvastatin: Use lowest possible fluvastatin dosage; consider using pravastatin instead

Lovastatin: Do not use concomitantly

Simvastatin: Do not use concomitantly

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Potential for increased concentrations of cyclosporine, sirolimus, or tacrolimus

Monitor plasma concentrations of immunosuppressive agent

Indinavir

Delavirdine inhibits indinavir metabolism and may increase indinavir concentrations and AUC; no effect on delavirdine pharmacokinetics

Use reduced indinavir dosage of 600 mg every 8 hours with usual delavirdine dosage (400 mg 3 times daily)

Lamivudine

In vitro evidence of additive or synergistic antiretroviral effects

Lopinavir/ritonavir

Possible increased lopinavir concentrations

Appropriate dosages for concomitant use with respect to safety and efficacy not established

Macrolides (clarithromycin)

No change in delavirdine pharmacokinetic; increased clarithromycin AUC

Dosage adjustments not needed in patients with normal renal function; reduce clarithromycin dosage by 50% in patients with Clcr 30–60 mL/minute and by 75% in patients with Clcr <30 mL/minute

Maraviroc

Possible increased maraviroc concentrations

No in vitro evidence of antagonistic antiretroviral effects

Recommended maraviroc dosage is 150 mg twice daily in patients receiving delavirdine

Methadone

Possible increased methadone concentrations

Methadone dosage may need to be reduced

Nelfinavir

Decreased delavirdine concentrations and AUC; increased nelfinavir concentrations and AUC

In vitro evidence of synergistic antiretroviral effects

Appropriate dosages for concomitant use with respect to safety and efficacy not established

Nevirapine

Do not use concomitantly

Pimozide

Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)

Concomitant use contraindicated

Proton-pump inhibitors (omeprazole, lansoprazole)

Possible decreased GI absorption of delavirdine

Long-term concomitant use not recommended

Quinupristin and dalfopristin

Possible increased delavirdine concentrations

Raltegravir

In vitro evidence of additive to synergistic antiretroviral effects

Rilpivirine

Possible increased rilpivirine concentrations

Do not use concomitantly

Ritonavir

Increased ritonavir concentrations

Appropriate dosages for concomitant use with respect to safety, efficacy, and pharmacokinetics not established

Saquinavir

Increased saquinavir concentrations and AUC; no clinically important effect on delavirdine concentrations

Ritonavir-boosted saquinavir: Concomitant use not evaluated

Appropriate dosages for concomitant use with respect to safety, efficacy, and pharmacokinetics not established

Simeprevir

Possible increased simeprevir concentrations

Concomitant use not recommended

St. John’s wort (Hypericum perforatum)

Possible loss of virologic response and increased risk of delavirdine or NNRTI resistance

Do not use concomitantly

Sildenafil

Possible increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)

Use caution; do not exceed 25 mg once every 48 hours

Tenofovir

No in vitro evidence of antagonistic antiretroviral effects

Tipranavir

In vitro evidence of additive antiretroviral effects

Trazodone

Possible increased trazodone concentrations

Adverse effects (nausea, dizziness, hypotension, syncope) reported with concomitant use of trazodone and other CYP3A inhibitors (e.g., ritonavir)

Use with caution; consider using decreased trazodone dosage

Zidovudine

No pharmacokinetic interaction

In vitro evidence of additive or synergistic antiretroviral effects

Delavirdine Mesylate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract; peak plasma concentrations achieved within 1 hour.

Bioavailability of delavirdine tablets is 85% relative to that of an oral solution of the drug. Bioavailability of 100-mg tablets is increased by approximately 20% when allowed to disintegrate in water and administered as a slurry.

Food

Food does not have an appreciable effect on plasma concentrations or AUC.

Distribution

Extent

Not fully characterized.

Distributed into CSF in low concentrations.

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

98%.

Elimination

Metabolism

Metabolized by CYP3A and CYP2D6.

Elimination Route

Excreted in feces (44%) and urine (51%).

Half-life

5.8 hours.

Stability

Storage

Oral

Tablets

20–25°C in tight container; protect from high humidity.

Actions and Spectrum

  • Pharmacologically related to other NNRTIs (e.g., efavirenz, etravirine, nevirapine, rilpivirine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.

  • Active against HIV-1; inactive against HIV-2.

  • Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.

  • HIV-1 with reduced susceptibility to delavirdine have been selected in vitro and have emerged during therapy with the drug.

  • Strains of HIV-1 resistant to delavirdine may be cross-resistant to some other NNRTIs.

  • Cross-resistance between delavirdine and NRTIs unlikely since the drugs bind at difference sites on reverse transcriptase and have different mechanisms of action. Cross-resistance between delavirdine and HIV protease inhibitors (PIs) unlikely since the drugs have different target enzymes and mechanisms of action.

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.

  • Importance of reading patient information provided by the manufacturer.

  • Importance of patients with achlorhydria taking delavirdine with an acidic beverage.

  • If a dose is missed, the next dose should be taken as soon as possible. If a dose is skipped, do not take a double dose to make up for the missed dose.

  • Importance of discontinuing delavirdine and consulting a clinician if severe rash or rash accompanied by fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches occurs.

  • Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products (e.g., St. John’s wort), and any concomitant illnesses.

  • Advise patients receiving PDE5 inhibitors (e.g., sildenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, visual disturbances, priapism) and that any symptoms should be promptly reported to their clinician.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.

  • Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Delavirdine Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

100 mg

Rescriptor

ViiV

200 mg

Rescriptor

ViiV

AHFS DI Essentials™. © Copyright 2020, Selected Revisions February 12, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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