ALERT: Find out about medicines that should NOT be taken with RESCRIPTOR. This statement is included on the product†s bottle label.

Because delavirdine may inhibit the metabolism of many different drugs (eg, antiarrhythmics, calcium channel blockers, sedative hypnotics, and others), serious and/or life threatening drug interactions could result from inappropriate coadministration of some drugs with delavirdine. In addition, some drugs may markedly reduce delavirdine plasma concentrations, resulting in suboptimal antiviral activity and subsequent emergence of drug resistance. All prescribers should become familiar with the following tables in this package insert: Table 5, Drugs That Are Contraindicated With RESCRIPTOR; Table 6, Drugs That Should Not Be Co-administered With RESCRIPTOR; and Table 7, Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction. Additional details on drug interactions can be found in Tables 1 and 2 under the CLINICAL PHARMACOLOGY section.

CONCOMITANT USE OF LOVASTATIN OR SIMVASTATIN WITH RESCRIPTOR IS NOT RECOMMENDED. CAUTION SHOULD BE EXERCISED IF RESCRIPTOR IS USED CONCURRENTLY WITH OTHER HMG-COA REDUCTASE INHIBITORS THAT ARE ALSO METABOLIZED BY THE CYP3A4 PATHWAY (EG, ATORVASTATIN OR CERIVASTATIN). THE RISK OF MYOPATHY INCLUDING RHABDOMYOLYSIS MAY BE INCREASED WHEN RESCRIPTOR IS USED IN COMBINATION WITH THESE DRUGS.

Particular caution should be used when prescribing sildenafil in patients receiving RESCRIPTOR. Coadministration of sildenafil with RESCRIPTOR is expected to substantially increase sildenafil concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes, and priapism (see PRECAUTIONS, DRUG INTERACTIONS and Information for Patients, and the complete prescribing information for sildenafil).

CONCOMITANT USE OF ST. JOHN†S WORT (HYPERICUM PERFORATUM) OR ST. JOHN†S WORT CONTAINING PRODUCTS AND RESCRIPTOR IS NOT RECOMMENDED. COADMINISTRATION OF ST. JOHN†S WORT WITH NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS), INCLUDING RESCRIPTOR, IS EXPECTED TO SUBSTANTIALLY DECREASE NNRTI CONCENTRATIONS AND MAY RESULT IN SUB-OPTIMAL LEVELS OF RESCRIPTOR AND LEAD TO LOSS OF VIROLOGIC RESPONSE AND POSSIBLE RESISTANCE TO RESCRIPTOR OR TO THE CLASS OF NNRTIS.

General: Delavirdine is metabolized primarily by the liver. Therefore, caution should be exercised when administering RESCRIPTOR Tablets to patients with impaired hepatic function.

Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RESCRIPTOR. During the initial phase of the combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Resistance/Cross-Resistance: Non-nucleoside reverse transcriptase inhibitors, when used alone or in combination, may confer cross-resistance to other non-nucleoside reverse transcriptase inhibitors.

Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Skin Rash: Severe rash, including rare cases of erythema multiforme and Stevens-Johnson syndrome, has been reported in patients receiving RESCRIPTOR. Erythema multiforme and Stevens-Johnson syndrome were rarely seen in clinical trials and resolved after withdrawal of RESCRIPTOR. Any patient experiencing severe rash or rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis, swelling, and muscle or joint aches should discontinue RESCRIPTOR and consult a physician. Two cases of Stevens-Johnson syndrome have been reported through postmarketing surveillance out of a total of 339 surveillance reports.

In Studies 21 Part II and 13C (see DESCRIPTION OF CLINICAL STUDIES), rash (including maculopapular rash) was reported in more patients who were treated with RESCRIPTOR 400 mg tid (35% and 32%, respectively) than in those who were not treated with RESCRIPTOR (21% and 16%, respectively). The highest intensity of rash reported in these studies was severe (grade 3), which was observed in approximately 4% of patients treated with RESCRIPTOR in each study and in none of the patients who were not treated with RESCRIPTOR. Also in Studies 21 Part II and 13C, discontinuations due to rash were reported in more patients who received RESCRIPTOR 400 mg tid (3% and 4%, respectively) than in those who did not receive RESCRIPTOR (0% and 1%, respectively). In most cases, the duration of the rash was less than two weeks and did not require dose reduction or discontinuation of RESCRIPTOR. Most patients were able to resume therapy after rechallenge with RESCRIPTOR following a treatment interruption due to rash. The distribution of the rash was mainly on the upper body and proximal arms, with decreasing intensity of the lesions on the neck and face, and progressively less on the rest of the trunk and limbs. Occurrence of a delavirdine-associated rash after one month is uncommon. Symptomatic relief has been obtained using diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.

Carcinogenesis, Mutagenesis and Impairment of Fertility:Delavirdine was negative in a battery of genetic toxicology tests which included an Ames assay, an in vitro rat hepatocyte unscheduled DNA synthesis assay, an in vitro chromosome aberration assay in human peripheral lymphocytes, an in vitro mutation assay in Chinese hamster ovary cells, and an in vivo micronucleus test in mice.

Lifetime carcinogenicity studies were conducted in rats at doses of 10, 32 and 100 mg/kg/day and in mice at doses of 62.5, 250 and 500 mg/kg/day for males and 62.5, 125 and 250 mg/kg/day for females. In rats, delavirdine was noncarcinogenic at maximally tolerated doses that produced exposures (AUC) up to 12 (male rats) and 9 (female rats) times human exposure at the recommended clinical dose. In mice, delavirdine produced significant increases in the incidence of hepatocellular adenoma/adenocarcinoma in both males and females, hepatocellular adenoma in females, and mesenchymal urinary bladder tumors in males. The systemic drug exposures (AUC) in female mice were 0.5- to 3-fold and in male mice 0.2- to 4-fold of those in humans at the recommended clinical dose. Given the lack of genotoxic activity of delavirdine, the relevance of urinary bladder and hepatocellular neoplasm in delavirdine-treated mice to humans is not known.

Delavirdine at doses of 20, 100, and 200 mg/kg/day did not cause impairment of fertility in rats when males were treated for 70 days and females were treated for 14 days prior to mating.

Pregnancy: Pregnancy Category C: Delavirdine has been shown to be teratogenic in rats. Delavirdine caused ventricular septal defects in rats at doses of 50, 100, and 200 mg/kg/day when administered during the period of organogenesis. The lowest dose of delavirdine that caused malformations produced systemic exposures in pregnant rats equal to or lower than the expected human exposure to RESCRIPTOR (C_min 15 mM) at the recommended dose. Exposure in rats approximately 5-fold higher than the expected human exposure resulted in marked maternal toxicity, embryotoxicity, fetal developmental delay, and reduced pup survival. Additionally, reduced pup survival on postpartum day 0 occurred at an exposure (mean C_min) approximately equal to the expected human exposure.

Delavirdine was excreted in the milk of lactating rats at a concentration three to five times that of rat plasma.

Delavirdine at doses of 200 and 400 mg/kg/day administered during the period of organogenesis caused maternal toxicity, embryotoxicity and abortions in rabbits. The lowest dose of delavirdine that resulted in these toxic effects produced systemic exposures in pregnant rabbits approximately 6-fold higher than the expected human exposure to RESCRIPTOR (C_min 15 mM) at the recommended dose.

The no-observed-adverse-effect dose in the pregnant rabbit was 100 mg/kg/day. Various malformations were observed at this dose, but the incidence of such malformations was not statistically significantly different from those observed in the control group. Systemic exposures in pregnant rabbits at a dose of 100 mg/kg/day were lower than those expected in humans at the recommended clinical dose. Malformations were not apparent at 200 and 400 mg/kg/day; however, only a limited number of fetuses were available for examination as a result of maternal and embryo death.

No adequate and well-controlled studies in pregnant women have been conducted. RESCRIPTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Of 9 pregnancies reported in premarketing clinical studies and postmarketing experience, a total of 10 infants were born (including 1 set of twins). Eight of the infants were born healthy. One infant was born HIV-positive but was otherwise healthy and with no congenital abnormalities detected, and 1 infant was born prematurely (34 to 35 weeks) with a small muscular ventricular septal defect that spontaneously resolved. The patient received approximately six weeks of treatment with delavirdine and zidovudine early in the course of the pregnancy.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to RESCRIPTOR and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

Because of both the potential for HIV transmission and any possible adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving RESCRIPTOR.

Pediatric Use: Safety and effectiveness of delavirdine in combination with other antiretroviral agents have not been established in HIV-1†infected individuals younger than 16 years of age.

GERIATRIC USE: CLINICAL STUDIES OF RESCRIPTOR DID NOT INCLUDE SUFFICIENT NUMBERS OF SUBJECTS AGED 65 AND OVER TO DETERMINE WHETHER THEY RESPOND DIFFERENTLY FROM YOUNGER SUBJECTS. IN GENERAL, CAUTION SHOULD BE TAKEN WHEN DOSING RESCRIPTOR IN ELDERLY PATIENTS DUE TO THE GREATER FREQUENCY OF DECREASED HEPATIC, RENAL OR CARDIAC FUNCTION AND OF CONCOMITANT DISEASE OR OTHER DRUG THERAPY.

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