Delavirdine Mesylate

Class: Nonnucleoside 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; nonnucleoside reverse transcriptase inhibitor (NNRTI).^{1 200}

Uses for Delavirdine Mesylate

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.¹

Not recommended for initial antiretroviral regimens (less supportive data and less potent virologic activity than other NNRTIs, inconvenient dosing).²⁰⁰

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Consider the following before initiating in antiretroviral-naive patients: Data insufficient comparing delavirdine regimens to the preferred 3-drug regimens;¹ portion of clinical study patients responding to regimen of delavirdine and 2 nucleoside reverse transcriptase inhibitors (NRTIs) with sustained plasma HIV-1 levels <400 copies/mL over 1 year has been relatively low.¹

Delavirdine Mesylate Dosage and Administration

Administration

Oral Administration

Administer orally with or without food.¹

For patients unable to swallow tablets, 100-mg tablets may be administered as slurry or dispersion in water.¹ 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.^{1 6} Dispersion should be consumed promptly; rinse glass with more water and swallow the rinse.¹

The 200-mg tablets are not readily dispersed in water^{1 33} and should be swallowed intact.¹

Patients with achlorhydria should take delavirdine with an acidic beverage (e.g., orange or cranberry juice).¹

Dosage

Available as delavirdine mesylate; dosage expressed in terms of delavirdine mesylate.¹

Pediatric Patients

Treatment of HIV Infection

Oral

Adolescents ≥16 years of age: 400 mg 3 times daily.¹

Adults

Treatment of HIV Infection

Oral

400 mg 3 times daily.¹

Special Populations

Hepatic Impairment

Data insufficient to make dosage recommendation for patients with hepatic impairment;²⁰⁰ use with caution.^{1 200}

Renal Impairment

Dosage adjustments not needed.²⁰⁰

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Delavirdine Mesylate

Contraindications

• Known hypersensitivity to delavirdine or any ingredient in the formulation.¹

• 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).¹ (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).¹ (See Specific Drugs under Interactions.)

Sensitivity Reactions

Dermatologic Reactions

Severe rash, erythema multiforme, Stevens-Johnson syndrome reported; these severe reactions resolved after drug discontinued.¹

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.¹

Mild rash also reported.¹ 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.¹

Rash usually resolves in <2 weeks and generally does not require dosage reduction or contraindicate use of the drug.¹ If delavirdine therapy is interrupted because of rash, most patients are able to resume therapy with the drug.¹

Mild or moderate rash can be treated with diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.¹

General Precautions

HIV Resistance

Possibility of HIV resistant to delavirdine and possible cross-resistance to other NNRTIs.¹

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.¹

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 jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.¹

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.¹

Specific Populations

Pregnancy

Category C.¹

Antiretroviral Pregnancy Registry at 800-258-4263 or .^{1 202}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.^{1 202}

Pediatric Use

Safety and efficacy not established in children <16 years of age.¹

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.¹

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Hepatic Impairment

Extensively metabolized in liver; use with caution in those with hepatic impairment.¹

Common Adverse Effects

Rash, asthenia/fatigue, nausea.¹

Interactions for Delavirdine Mesylate

Metabolized by CYP3A and CYP2D6.¹

Inhibits CYP3A and, to a lesser extent, CYP2C9, CYP2D6, CYP2C19.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A;¹ possible alteration in metabolism of delavirdine and/or other drug.¹

Specific Drugs

Delavirdine Mesylate Pharmacokinetics

Absorption

Bioavailability

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

Bioavailability of delavirdine tablets is 85% relative to that of an oral solution of the drug.¹ Bioavailability of 100-mg tablets is increased by approximately 20% when allowed to disintegrate in water and administered as a slurry.¹

Food

Food does not have an appreciable effect on plasma concentrations or AUC.¹

Distribution

Extent

Not fully characterized.¹

Distributed into CSF in low concentrations.¹

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

98%.¹

Elimination

Metabolism

Metabolized by CYP3A and CYP2D6.¹

Elimination Route

Excreted in feces (44%) and urine (51%).¹

Half-life

5.8 hours.¹

Stability

Storage

Oral

Tablets

20–25°C in tight container; protect from high humidity.¹

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.^{1 6 7 8 10 11 12 214}

• Active against HIV-1; inactive against HIV-2.^{1 8 31}

• Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.^{1 6 7 8 10 11 12 15}

• HIV-1 with reduced susceptibility to delavirdine have been selected in vitro and have emerged during therapy with the drug.^{1 6 8 19 31}

• Strains of HIV-1 resistant to delavirdine may be cross-resistant to some other NNRTIs.^{1 6 7}

• Cross-resistance between delavirdine and NRTIs unlikely since the drugs bind at difference sites on reverse transcriptase and have different mechanisms of action.^{1 15} Cross-resistance between delavirdine and HIV protease inhibitors (PIs) unlikely since the drugs have different target enzymes and mechanisms of action.¹

Advice to Patients

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.¹ Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.¹

• Importance of using in conjunction with other antiretrovirals—not for monotherapy.¹

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.¹

• 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.²⁰⁰ 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.^{1 200}

• Importance of reading patient information provided by the manufacturer.¹

• Importance of patients with achlorhydria taking delavirdine with an acidic beverage.¹

• If a dose is missed, the next dose should be taken as soon as possible.¹ If a dose is skipped, do not take a double dose to make up for the missed dose.¹

• 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.¹

• Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.¹

• 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.¹

• 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.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Advise HIV-infected women not to breast-feed.¹

• Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Rescriptor 200MG Tablets (VIIV HEALTHCARE): 30/$59.99 or 90/$170.98