Rescriptor

delavirdine mesylate

Dosage Form: tablet
Rescriptor®

brand of delavirdine mesylate tablets

Rescriptor Description

Rescriptor Tablets contain delavirdine mesylate, a synthetic non-nucleoside reverse transcriptase inhibitor (NNRTI) of the human immunodeficiency virus type 1 (HIV-1). The chemical name of delavirdine mesylate is piperazine, 1-[3-[(1-methyl-ethyl)amino]-2- pyridinyl]-4-[[5-[(methylsulfonyl)amino]-1H-indol-2-yl]carbonyl]-, monomethanesulfonate. Its molecular formula is C22H28N6O3S•CH4O3S, and its moleculardweight is 552.68. The structural formula is:

Delavirdine mesylate is an odorless white-to-tan crystalline powder. The aqueous solubility of delavirdine free base at 23°C is 2,942 mcg/mL at pH 1.0, 295 mcg/mL at pH 2.0, and 0.81 mcg/mL at pH 7.4.

Each Rescriptor Tablet, for oral administration, contains 100 or 200 mg of delavirdine mesylate (henceforth referred to as delavirdine). Inactive ingredients consist of carnauba wax, colloidal silicon dioxide, croscarmellose sodium, lactose, magnesium stearate, and microcrystalline cellulose. In addition, the 100-mg tablet contains Opadry White YS-1-7000-E and the 200-mg tablet contains hypromellose, Opadry White YS-1-18202-A, and Pharmaceutical Ink Black.

MICROBIOLOGY

Mechanism of Action

Delavirdine is an NNRTI of HIV-1. Delavirdine binds directly to reverse transcriptase (RT) and blocks RNA-dependent and DNA-dependent DNA polymerase activities. Delavirdine does not compete with template:primer or deoxynucleoside triphosphates. HIV-2 RT and human cellular DNA polymerases α, γ, or δ are not inhibited by delavirdine. In addition, HIV-1 group O, a group of highly divergent strains that are uncommon in North America, may not be inhibited by delavirdine.

In Vitro HIV-1 Susceptibility: In vitro anti-HIV-1 activity of delavirdine was assessed by infecting cell lines of lymphoblastic and monocytic origin and peripheral blood lymphocytes with laboratory and clinical isolates of HIV-1. IC50 and IC90 values (50% and 90% inhibitory concentrations) for laboratory isolates (n = 5) ranged from 0.005 to 0.030 μM and 0.04 to 0.10 μM, respectively. Mean IC50 of clinical isolates (n = 74) was 0.038 μM (range: 0.001 to 0.69 μM); 73 of 74 clinical isolates had an IC50 ≤0.18 μM. The IC90 of 24 of these clinical isolates ranged from 0.05 to 0.10 μM. In drug combination studies of delavirdine with zidovudine, didanosine, zalcitabine, lamivudine, interferon-α, and protease inhibitors, additive to synergistic anti–HIV-1 activity was observed in cell culture. The relationship between the in vitro susceptibility of HIV-1 RT inhibitors and the inhibition of HIV replication in humans has not been established.

Drug Resistance: Phenotypic analyses of isolates from patients treated with Rescriptor as monotherapy showed a 50- to 500-fold reduced susceptibility in 14 of 15 patients by Week 8 of therapy. Genotypic analysis of HIV-1 isolates from patients receiving Rescriptor plus zidovudine combination therapy (n = 79) showed resistance-conferring mutations in all isolates by Week 24 of therapy. In patients treated with Rescriptor, the mutations in RT occurred predominantly at amino acid positions 103 and less frequently at positions 181 and 236. In a separate study, an average of 86-fold increase in the zidovudine susceptibility of patient isolates (n = 24) was observed after 24 weeks of combination therapy with Rescriptor and zidovudine. The clinical relevance of the phenotypic and the genotypic changes associated with therapy with Rescriptor has not been established.

Cross-Resistance: Rescriptor may confer cross-resistance to other NNRTIs when used alone or in combination. Mutations at positions 103 and/or 181 have been found in resistant virus during treatment with Rescriptor and other NNRTIs. These mutations have been associated with cross-resistance among NNRTIs in vitro.

Rescriptor - Clinical Pharmacology

Pharmacokinetics

Absorption and Bioavailability: Delavirdine is rapidly absorbed following oral administration, with peak plasma concentrations occurring at approximately 1 hour. Following administration of delavirdine 400 mg 3 times daily (n = 67, HIV-1–infected patients), the mean ±SD steady-state peak plasma concentration (Cmax) was 35 ± 20 μM (range: 2 to 100 μM), systemic exposure (AUC) was 180 ± 100 μM•hr (range: 5 to 515 μM•hr), and trough concentration (Cmin) was 15 ± 10 μM (range: 0.1 to 45 μM). The single-dose bioavailability of delavirdine tablets relative to an oral solution was 85% ± 25% (n = 16, non-HIV–infected subjects). The single-dose bioavailability of delavirdine tablets (100-mg strength) was increased by approximately 20% when a slurry of drug was prepared by allowing delavirdine tablets to disintegrate in water before administration (n = 16, non-HIV–infected subjects). The bioavailability of the 200-mg strength delavirdine tablets has not been evaluated when administered as a slurry because they are not readily dispersed in water (see DOSAGE AND ADMINISTRATION).

Delavirdine may be administered with or without food. In a multiple-dose, crossover study, delavirdine was administered every 8 hours with food or every 8 hours, 1 hour before or 2 hours after a meal (n = 13, HIV-1–infected patients). Patients remained on their typical diet throughout the study; meal content was not standardized. When multiple doses of delavirdine were administered with food, geometric mean Cmax was reduced by approximately 25%, but AUC and Cmin were not altered.

Distribution: Delavirdine is extensively bound (approximately 98%) to plasma proteins, primarily albumin. The percentage of delavirdine that is protein-bound is constant over a delavirdine concentration range of 0.5 to 196 μM. In 5 HIV-1–infected patients whose total daily dose of delavirdine ranged from 600 to 1,200 mg, cerebrospinal fluid concentrations of delavirdine averaged 0.4% ± 0.07% of the corresponding plasma delavirdine concentrations; this represents about 20% of the fraction not bound to plasma proteins. Steady-state delavirdine concentrations in saliva (n = 5, HIV-1–infected patients who received delavirdine 400 mg 3 times daily) and semen (n = 5 healthy volunteers who received delavirdine 300 mg 3 times daily) were about 6% and 2%, respectively, of the corresponding plasma delavirdine concentrations collected at the end of a dosing interval.

Metabolism and Elimination: Delavirdine is extensively converted to several inactive metabolites. Delavirdine is primarily metabolized by cytochrome P450 3A (CYP3A), but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. Delavirdine exhibits nonlinear steady-state elimination pharmacokinetics, with apparent oral clearance decreasing by about 22-fold as the total daily dose of delavirdine increases from 60 to 1,200 mg/day. In a study of 14C-delavirdine in 6 healthy volunteers who received multiple doses of delavirdine tablets 300 mg 3 times daily, approximately 44% of the radiolabeled dose was recovered in feces, and approximately 51% of the dose was excreted in urine. Less than 5% of the dose was recovered unchanged in urine. The parent plasma half-life of delavirdine increases with dose; mean half-life following 400 mg 3 times daily is 5.8 hours, with a range of 2 to 11 hours.

  In vitro and in vivo studies have shown that delavirdine reduces CYP3A activity and inhibits its own metabolism. In vitro studies have also shown that delavirdine reduces CYP2C9, CYP2D6, and CYP2C19 activity. Inhibition of hepatic CYP3A activity by delavirdine is reversible within 1 week after discontinuation of drug.

Special Populations

Hepatic or Renal Impairment: The pharmacokinetics of delavirdine in patients with hepatic or renal impairment have not been investigated (see PRECAUTIONS).

Age: The pharmacokinetics of delavirdine have not been adequately studied in patients aged <16 years or >65 years.

Gender: Data from population pharmacokinetics suggest that the plasma concentrations of delavirdine tend to be higher in females than in males. However, this difference is not considered to be clinically significant.

Race: No significant differences in the mean trough delavirdine concentrations were observed between different racial or ethnic groups.

Drug Interactions

(See also PRECAUTIONS: Drug Interactions.)

Specific drug interaction studies were performed with delavirdine and a number of drugs. Table 1 summarizes the effects of delavirdine on the geometric mean AUC, Cmax, and Cmin of coadministered drugs. Table 2 shows the effects of coadministered drugs on the geometric mean AUC, Cmax, and Cmin of delavirdine.

For information regarding clinical recommendations, see  CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions. 

Table 1. Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Delavirdine

Coadministered Drug	Dose of Coadministered Drug	Dose of Rescriptor	n	% Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)
				Cmax	AUC	Cmin
HIV-Protease Inhibitors
Indinavir	400 mg t.i.d. for 7 days	400 mg t.i.d. for 7 days	28	↓36a (↓52 to ↓14)	↔ a	↑118 a (↑16 to ↑312)
	600 mg t.i.d. for 7 days	400 mg t.i.d. for 7 days	28	↔	↑53 a (↑7 to ↑120)	↑298 a (↑104 to ↑678)
Nelfinavirb	750 mg t.i.d. for 14 days	400 mg t.i.d. for 7 days	12	↑88 (↑66-↑113)	↑107 (↑83-↑135)	↑136 (↑103-↑175)
Saquinavir	Soft gel capsule 1,000 mg t.i.d. for 28 days	400 mg t.i.d. for 28 days	20	↑98c (↑4 to ↑277)	↑121c (↑14 to ↑340)	↑199c (↑37 to ↑553)
Nucleoside Reverse Transcriptase Inhibitors
Didanosine (buffered tablets)	125 or 250 mg b.i.d. for 28 days	400 mg t.i.d. for 28 days	9	↓20d (↓44 to ↑15)	↓21d (↓40 to ↑5)	-
Zidovudine	200 mg t.i.d. for >38 days	100 mg q.i.d. to 400 mg t.i.d. for 8 to 10 days	34	↔	↔	-
Anti-infective Agents
Clarithromycin	500 mg b.i.d. for 15 days	300 mg t.i.d. for 30 days	6	-	↑100	-
Rifabutin	300 mg q.d. for 15 to 99 days	400 to 1,000 mg t.i.d. for 45 to 129 days	5	↑128 (↑71 to ↑203)	↑230 (↑119 to ↑396)	↑452 (↑246 to ↑781)

↑ Indicates increase.

↓ Indicates decrease.

↔ Indicates no significant change.

a Relative to indinavir 800 mg t.i.d. without Rescriptor.

b Plasma concentrations of the nelfinavir active metabolite (nelfinavir hydroxy-t-butylamide) were significantly reduced by delavirdine, which is more than compensated for by increased nelfinavir concentration.

c Saquinavir soft gel capsule 1,000 mg t.i.d. plus Rescriptor 400 mg t.i.d. relative to saquinavir soft gel capsule 1,200 mg t.i.d. without Rescriptor.

d Rescriptor taken with didanosine (buffered tablets) relative to doses of Rescriptor and didanosine (buffered tablets) separated by at least 1 hour.

- Indicates no data available.

Table 2. Pharmacokinetic Parameters for Delavirdine in the Presence of Coadministered Drugs

Coadministered Drug	Dose of Coadministered Drug	Dose of Rescriptor	n	% Change in Delavirdine Pharmacokinetic Parameters (90% CI)
				Cmax	AUC	Cmin
HIV-Protease Inhibitors
Indinavir	400 or 600 mg t.i.d. for 7 days	400 mg t.i.d. for 7 days	81	No apparent changes based on a comparison to historical data
Nelfinavir	750 mg t.i.d. for 7 days	400 mg t.i.d. for 14 days	7	↓27 (↓49 to ↑4)	↓31 (↓57 to ↑10)	↓33 (↓70 to ↑49)
Saquinavir	Soft gel capsule 1,000 mg t.i.d. for 28 days	400 mg t.i.d. for 7 to 28 days	23	No apparent changes based on a comparison to historical data
Nucleoside Reverse Transcriptase Inhibitors
Didanosine (buffered tablets)	125 or 200 mg b.i.d. for 28 days	400 mg t.i.d. for 28 days	9	↓32a (↓48 to↓11)	↓19 a (↓37 to ↑6)	↔a
Zidovudine	200 mg t.i.d. for ≥7 days	400 mg t.i.d. for 7 to 14 days	42	No apparent changes based on a comparison to historical data
Anti-infective Agents
Clarithromycin	500 mg b.i.d. for 15 days	300 mg t.i.d. for 30 days	6	↔	↔	↔
Fluconazole	400 mg q.d. for 15 days	300 mg t.i.d. for 30 days	8	↔	↔	↔
Ketoconazole	Various	200 to 400 mg t.i.d.	26	-	-	↑50b
Rifabutin	300 mg q.d. for 14 days	400 mg t.i.d. for 28 days	7	↓72 (↓61 to ↓80)	↓82 (↓74 to ↓88)	↓94 (↓90 to ↓96)
Rifampin	600 mg q.d. for 15 days	400 mg t.i.d. for 30 days	7	↓90 (↓94 to ↓83)	↓97 (↓98 to ↓95)	↓100
Sulfamethoxazole or Trimethoprim & Sulfamethoxazole	Various	200 to 400 mg t.i.d.	311	-	-	↔b
Other
Antacid (Maalox® TC)	20 mL	300 mg single dose	12	↓52 (↓68 to ↓29)	↓44 (↓58 to ↓27)	-
Fluoxetine	Various	200 to 400 mg t.i.d.	36	-	-	↑50b
Phenytoin, Phenobarbital, Carbamazepine	Various	300 to 400 mg t.i.d.	8	-	-	↓90b

↑ Indicates increase.

↓ Indicates decrease.

↔ Indicates no significant change.

a Rescriptor taken with didanosine (buffered tablets) relative to doses of Rescriptor and didanosine (buffered tablets) separated by at least 1 hour.

b Population pharmacokinetic data from efficacy studies.

- Indicates no data available.

Indications and Usage for Rescriptor

Rescriptor Tablets are indicated for the treatment of HIV-1 infection in combination with at least 2 other active antiretroviral agents when therapy is warranted.

The following should be considered before initiating therapy with Rescriptor in treatment-naive patients. There are insufficient data directly comparing antiretroviral regimens containing Rescriptor with currently preferred 3-drug regimens for initial treatment of HIV. In studies comparing regimens consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) (currently considered suboptimal) to Rescriptor plus 2 NRTIs, the proportion of patients receiving the regimen containing Rescriptor who achieved and sustained an HIV-1 RNA level <400 copies/mL over 1 year of therapy was relatively low (see DESCRIPTION OF CLINICAL STUDIES).

Resistant virus emerges rapidly when Rescriptor is administered as monotherapy. Therefore, Rescriptor should always be administered in combination with other antiretroviral agents.

DESCRIPTION OF CLINICAL STUDIES

For clinical Studies 21 Part II and 13C described below, efficacy was evaluated by the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL through Week 52 as measured by the Roche Amplicor® HIV-1 Monitor (standard assay). An intent-to-treat analysis was performed where only subjects who achieved confirmed suppression and sustained it through Week 52 are regarded as responders. All other subjects (including never suppressed, discontinued, and those who rebounded after initial suppression of <400 copies/mL) are considered failures at Week 52. Results of an interim analysis of efficacy conducted for studies 21 Part II and 13C by independent Data and Safety Monitoring Boards (DSMBs) revealed that the triple-therapy arms in both studies produced significantly greater antiviral benefit than the dual-therapy arms, and early termination of the studies was recommended.

Study 21 Part II

Study 21 Part II was a double-blind, randomized, placebo-controlled trial comparing treatment with Rescriptor (DLV; 400 mg 3 times daily), zidovudine (ZDV; 200 mg 3 times daily), and lamivudine (3TC; 150 mg twice daily) versus Rescriptor (400 mg 3 times daily) and zidovudine (200 mg 3 times daily) versus zidovudine (200 mg 3 times daily) and lamivudine (150 mg twice daily) in 373 HIV-1–infected patients (mean age 35 years [range: 17 to 67], 87% male, and 60% Caucasian) who were antiretroviral treatment naive (84%) or had limited nucleoside experience (16%). Mean baseline CD4 cell count was 359 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.4 log10 copies/mL.

Results showed that the mean increases from baseline in CD4 cell counts at 52 weeks were 111 cells/mL for Rescriptor + ZDV + 3TC, 27 cells/mL for Rescriptor + ZDV, and 74 cells/mL for ZDV + 3TC.

The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL are presented in Figure 1. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 52 weeks are summarized in Table 3. Subjects who were never suppressed before discontinuation were placed in the discontinuation category.

Figure 1: Percentage of Patients With HIV RNA Below 400 copies/mL Standard PCR Assay Protocol 21 Part II: Intent-to–Treat Analysis

Table 3: Outcomes of Randomized Treatment Through Week 52 for Protocol 21 Part II

Outcome	ZDV + 3TC (n = 124) %	DLV + ZDV (n = 125) %	DLV + ZDV + 3TC (n = 124) %
HIV-1 RNA <400 copies/mLa	14	2	45
HIV-1 RNA ≥400 copies/mLb,c	64	52	31
Discontinued due to adverse eventsc	8	13	10
Discontinued due to other reasonsc,d	14	33	14

a Corresponds to rates at Week 52 in proportion curve.

b Virologic failures at or before Week 52.

c Considered to be treatment failure in the analysis.

d Includes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons.

Study 13C was a double-blind, randomized, placebo-controlled trial comparing treatment with Rescriptor (400 mg 3 times daily), zidovudine (200 mg 3 times daily or 300 mg twice daily), and either didanosine (ddI; 200 mg twice daily), zalcitabine (ddC; 0.75 mg 3 times daily), or lamivudine (150 mg twice daily) versus zidovudine (200 mg 3 times daily or 300 mg twice daily) and either didanosine (200 mg twice), zalcitabine (0.75 mg 3 times daily), or lamivudine (150 mg twice daily) in 345 HIV-1–infected patients (mean age 35.8 years [range: 18 to 72], 66% male, and 63% Caucasian) who were antiretroviral treatment naive (63%) or had limited antiretroviral experience (37%). Mean baseline CD4 cell count was 210 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL.

Results showed that the mean increases from baseline in CD4 cell counts at 54 weeks were 102 cells/mL for Rescriptor + ZDV + ddI or ddC or 3TC and 56 cells/mL for ZDV + ddI or ddC or 3TC.

The results of the intent-to-treat analysis of the percentage of patients with a plasma HIV-1 RNA level <400 copies/mL are presented in Figure 2. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 54 weeks are summarized in Table 4. Subjects who were never suppressed before discontinuation were placed in the discontinuation category.

Figure 2: Percentage of Patients With HIV RNA Below 400 copies/mL Standard PCR Assay Protocol 13C: Intent-to–Treat Analysis

Table 4. Outcomes of Randomized Treatment Through Week 54 for Protocol 13C

Outcome	ZDV + ddxa (n = 173) %	ZDV + ddxa + DLV (n = 172) %
HIV-1 RNA <400 copies/mLb	10	29
HIV-1 RNA ≥400 copies/mLc,d	69	42
Discontinued due to adverse eventsd	7	12
Discontinued due to other reasonsd.e	14	17

a ddx = ddI or ddC or 3TC.

b Corresponds to rates at Week 54 in proportion curve.

c Virologic failures at or before Week 54.

d Considered to be treatment failure in the analysis.

e Includes discontinuations due to consent withdrawn, loss to follow-up, protocol violations, non-compliance, pregnancy, never treated, and other reasons.

Results from several smaller supportive studies evaluating the use of Rescriptor in treatment-naive patients suggest that it may have activity when used in combination with protease inhibitors and NRTIs in 3- or 4-drug combinations.

Contraindications

Rescriptor Tablets are contraindicated in patients with known hypersensitivity to any of its ingredients. Coadministration of Rescriptor is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 5. Also, see PRECAUTIONS, Table 6, Drugs That Should Not Be Coadministered With Rescriptor.

Table 5. Drugs That Are Contraindicated With Rescriptor

Drug Class	Drugs Within Class That Are Contraindicated With Rescriptor
Antihistamines	Astemizole, terfenadine
Ergot derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI motility agent	Cisapride
Neuroleptic	Pimozide
Sedative/hypnotics	Alprazolam, midazolam, triazolam

Warnings

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

Drug Interactions

Because delavirdine may inhibit the metabolism of many different drugs (e.g., 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 Coadministered 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 (e.g., 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 NNRTIs, including Rescriptor, is expected to substantially decrease NNRTI concentrations and may result in suboptimal levels of Rescriptor and lead to loss of virologic response and possible resistance to Rescriptor or to the class of NNRTIs.

Precautions

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 systems respond 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

NNRTIs, when used alone or in combination, may confer cross-resistance to other NNRTIs.

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 3 times daily (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 3 times daily (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 2 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 1 month is uncommon. Symptomatic relief has been obtained using diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.

Information for Patients

A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with Rescriptor. A patient package insert (PPI) for Rescriptor is available for patient information.

Patients should be informed that Rescriptor is not a cure for HIV-1 infection and that they may continue to acquire illnesses associated with HIV-1 infection, including opportunistic infections. Treatment with Rescriptor has not been shown to reduce the incidence or frequency of such illnesses, and patients should be advised to remain under the care of a physician when using Rescriptor.

Patients should be advised that the use of Rescriptor has not been shown to reduce the risk of transmission of HIV-1.

Patients should be instructed that the major toxicity of Rescriptor is rash and should be advised to promptly notify their physician should rash occur. The majority of rashes associated with Rescriptor occur within 1 to 3 weeks after initiating treatment with Rescriptor. The rash normally resolves in 3 to 14 days and may be treated symptomatically while therapy with Rescriptor is continued. 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 medication and consult a physician.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.

Patients should be informed to take Rescriptor every day as prescribed. Patients should not alter the dose of Rescriptor without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose.

Patients with achlorhydria should take Rescriptor with an acidic beverage (e.g., orange or cranberry juice). However, the effect of an acidic beverage on the absorption of delavirdine in patients with achlorhydria has not been investigated.

Patients taking both Rescriptor and antacids should be advised to take them at least 1 hour apart.

Because Rescriptor may interact with certain drugs, patients should be advised to report to their doctor the use of any prescription, nonprescription medication, or herbal products, particularly St. John’s wort.

Patients receiving sildenafil and Rescriptor should be advised that they may be at an increased risk of sildenafil-associated adverse events, including hypotension, visual changes, and prolonged penile erection, and should promptly report any symptoms to their doctor.

Drug Interactions

(See also CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Drug Interactions.)

Delavirdine is an inhibitor of CYP3A isoform and other CYP isoforms to a lesser extent including CYP2C9, CYP2D6, and CYP2C19. Coadministration of Rescriptor and drugs primarily metabolized by CYP3A (e.g., HMG-CoA reductase inhibitors and sildenafil) may result in increased plasma concentrations of the coadministered drug that could increase or prolong both its therapeutic or adverse effects.

Delavirdine is metabolized primarily by CYP3A, but in vitro data suggest that delavirdine may also be metabolized by CYP2D6. Coadministration of Rescriptor and drugs that induce CYP3A, such as rifampin, may decrease delavirdine plasma concentrations and reduce its therapeutic effect. Coadministration of Rescriptor and drugs that inhibit CYP3A may increase delavirdine plasma concentrations. (SeeTable 6, Drugs That Should Not Be Coadministered 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.)

Table 6. Drugs That Should Not Be Coadministered With RESCRIPTO

Drug Class: Drug Name	Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine	May lead to loss of virologic response and possible resistance to Rescriptor or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,a rifampin a	May lead to loss of virologic response and possible resistance to Rescriptor or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort ( hypericum perforatum)	May lead to loss of virologic response and possible resistance to Rescriptor or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.