CONTRAINDICATIONS

RESCRIPTOR (delavirdine mesylate) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulation. 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 3. Also, see PRECAUTIONS, Table 4, Drugs That Should Not Be Coadministered With RESCRIPTOR.

WARNINGS

Drug Interactions

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 monograph: Table 3, Drugs That Are Contraindicated With RESCRIPTOR; Table 5, 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 (statins) that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin) or CYP2C9 pathway (e.g., fluvastatin). 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 suboptimal levels of RESCRIPTOR and lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.

PRECAUTIONS

Hepatic Impairment:

Delavirdine is metabolized primarily by the liver. Therefore, caution should be exercised when administering RESCRIPTOR (delavirdine mesylate) to patients with impaired hepatic function.

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.

Skin Rash: Patients may experience a skin rash, which is usually temporary. Skin rash attributable to RESCRIPTOR has occurred in 18% of all patients on combination regimens in phase II and III controlled trials who received RESCRIPTOR 400 mg tid. Dose titration does not significantly reduce the incidence of rash. Skin rash is more common in patients with lower CD4 cell counts and typically occurs within 1 to 3 weeks of treatment.

Severe and life threatening skin reactions have occurred on rare occasions in patients treated with RESCRIPTOR, including Stevens-Johnson syndrome and erythema multiforme

. None of them were associated with fatalities. RESCRIPTOR must be discontinued in patients developing a severe rash or a rash accompanied by symptoms such as fever, blistering, oral lesions, conjunctivitis,

swelling, muscle or joint aches, or general malaise. As there are currently insufficient data on patients who have had a skin reaction to nevirapine or efavirenz and were further treated with RESCRIPTOR, close monitoring of these patients is recommended. Symptomatic relief has been obtained using diphenhydramine hydrochloride, hydroxyzine hydrochloride, and/or topical corticosteroids.

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.

Pregnancy:

No adequate and well-controlled studies in pregnant women have been conducted. Since delavirdine has been shown to be teratogenic in rats (see TOXICOLOGY), 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 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 or via the internet at http://www.apregistry.com.

Nursing Mothers:

It is recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether delavirdine is excreted in human milk. Since delavirdine has been found to be excreted in the milk of lactating rats (see TOXICOLOGY), mothers should be instructed not to breast-feed their babies if they are receiving RESCRIPTOR.

Pediatric Use:

Safety and effectiveness of RESCRIPTOR has 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.

Drug Interactions (see also CONTRAINDICATIONS, WARNINGS, AND CLINICAL PHARMACOLOGY-Pharmacokinetics-Drug Interactions):

Delavirdine is an inhibitor of CYP3A4 isoform and other 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 effect 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 reduce 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 (See Table 4, Drugs That Should Not Be Coadministered With RESCRIPTOR, and Table 5, Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction.)

*See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2.

Table 5. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

1. Indicates increase

2. Indicates decrease

*See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 1 and 2.

Information to be Provided to the Patient:

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 a 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, muscle or joint aches should be advised to 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 (eg, 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 one hour apart. Because RESCRIPTOR may interact with certain drugs, patients should be advised to report to their doctor the use of any prescription and non-prescription medications 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. Patients taking RESCRIPTOR as a dispersion, should rinse the glass with water and swallow the rinse to ensure that the entire dose is consumed.

PHARMACOLOGY

Clinical Studies

For clinical studies 21 Part II and 13C described below, efficacy was evaluated by the percentage of patients with a plasma HIV RNA level < 400 copies/mL and < 50 copies/mL through Week 52 as measured by the Roche Amplicor Assay (> 400 copies/mL) or the Roche Ultrasensitive Assay (> 50 copies/mL. 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 13 C 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.

a. Studies in Antiretroviral Treatment Naive Patients or in Patients with Limited Nucleoside Experience

Study 21 Part II: RESCRIPTOR + zidovudine + lamivudine versus RESCRIPTOR + zidovudine versus zidovudine + lamivudine

Study 21 Part II was a double-blind, randomized, placebo controlled trial comparing treatment with RESCRIPTOR (DLV; 400 mg tid), zidovudine (ZDV; 200 mg tid) and lamivudine (3TC; 150 mg bid) versus RESCRIPTOR (400 mg tid) and zidovudine (200 mg tid) versus zidovudine (200 mg tid) and lamivudine (150 mg bid) 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 RNA was 4.412 log10 copies/mL. Results showed that the mean increase from baseline in CD4 count at 52 weeks was 111 cells/mL for RESCRIPTOR + ZDV+ 3TC, 27 cells/mL for RESCRIPTOR + ZDV, and 74 cells/mL for ZDV +3TC. The intent-to-treat analyses of the percentage of patients with a plasma HIV RNA level < 400 copies/mL and 50 copies/mL are summarized in Figure 1. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 52 weeks are summarized in Table 9. 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 2 Intent-to-Treat Analysis

Percentage of Patients with HIV-1 RNA

<400 copies/mL

ZDV+3TC

DLV+ZDV 40

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Study Week

Table 9. Outcomes of Randomized Treatment Through Week 52 for Protocol 21 Part II

*

Corresponds to rates at Week 52 in proportion curve.

* * Virologic failures at or before Week 52.

++ Considered to be treatment failure in the analysis.

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

Percentage of Patients with HIV RNA Below 50 copies/mL

Ultra Sensitive PCR Assay Protocol 21 Part 2: Intent-to-Treat Patients

Intent-to-Treat Analysis: Noncompleters Assumed As Failures

<50 copies/mL

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Study Week

Study 13C: RESCRIPTOR + zidovudine +didanosine or zalcitabine or lamivudine versus zidovudine + didanosine/zalcitabine/lamivudine

Study 13C was a double-blind, randomized, placebo controlled trial comparing treatment with RESCRIPTOR (400 mg tid), zidovudine (200 mg tid or 300 mg bid) and either didanosine (ddI; 200 mg bid), zalcitabine (ddC; 0.75 mg tid) or lamivudine (150 mg bid) versus zidovudine (200 mg tid or 300 mg bid) and either didanosine (200 mg bid), zalcitabine (0.75 mg tid) or lamivudine (150 mg bid) 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 210cells/mm3 and mean baseline plasma HIV RNA was 4.855 log10 copies/mL. Results showed that the mean increase from baseline in CD4 count at 54 weeks was 102 cells/mL for RESCRIPTOR + ZDV + ddI or ddC or 3TC and 56 cells/mL for ZDV + ddI or ddC or 3TC. The intent-to-treat analyses of the percentage of patients with a plasma HIV RNA level < 400 copies/mL and 50 copies/mL are summarized in Figure 2. HIV-1 RNA status and reasons for discontinuation of randomized treatment at 54 weeks are summarized in Table 10. 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

Percentage of Patients With HIV-1 RNA

<400 copies/mL

ZDV+ddx+DLV 50

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Study Week

* Corresponds to rates at Week 54 in proportion curve.

# ddX = ddI or ddC or 3TC.

++ Virologic failures at or before Week 54.

SS

Considered to be treatment failure in the analysis.

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

P ercentage of Patients w ith H IV R NA B elow 50 copies/m L

U ltra Sensitive PC R Assay

P rotocol 13C : Intent-to-Treat P atients

Intent-to-Treat Analysis: N oncom pleters Assum ed As Failures

Percentage of Patients with HIV-1 RNA

<50 copies/mL

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Stud y W eek

Preliminary findings from an additional small controlled study in naive adults (Study 74) using indinavir plus two reverse transcriptase inhibitors supports the efficacy of RESCRIPTOR in combination with indinavir plus two RT inhibitors through 24 weeks of treatment.

Pharmacokinetics

Absorption and Bioavailability:

Delavirdine is rapidly absorbed following oral administration of delavirdine tablets to healthy volunteers and HIV-1-infected patients, with peak plasma concentrations occurring at about 1 hour. The extent of drug absorption is at least 50% based on urinary recovery of a radiolabeled dose of a delavirdine solution. The single-dose bioavailability of delavirdine tablets relative to an equivalent dose of oral solution averaged 85% +- 25% (mean +- SD) in 16 healthy volunteers. The effect of food on delavirdine was studied in 13 HIV-1-infected patients who took delavirdine tablets 400 mg tid for 14 days with meals and for 14 days under fasted conditions (1 hour before or 2 hours after food). The peak plasma delavirdine concentration (Cmax) was decreased by about 22%, the time to peak (Tmax) was unchanged, and the extent of absorption as measured by the area under the plasma concentration versus time curve (AUC) and Cmin was unaltered when delavirdine was taken with meals compared with drug administration in the fasted state. Thus, delavirdine tablets may be taken either on an empty stomach or with meals. Single-dose bioavailability of delavirdine is about 20% higher when a slurry of drug is prepared by allowing delavirdine tablets to disintegrate in water before administration.

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 :M. The erythrocyte-to- plasma ratio of delavirdine-related radioactivity averaged 0.14 +- 0.02 in human samples collected from a 14C-delavirdine mesylate study in six healthy volunteers. In a study of five HIV-1-infected patients whose total daily dose of delavirdine ranged from 600 to 1200 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 and semen are 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. The major metabolic pathways for delavirdine are N-desalkylation and pyridine hydroxylation. Delavirdine is primarily metabolized by cytochrome P450 3A (CYP3A), but in vitro data suggest that delavirdine may also be metabolized by cytochrome P450 2D6 (CYP2D6). In a study of

C-delavirdine in six healthy volunteers who received multiple doses of delavirdine tablets 300 mg tid, about 44% of the radiolabeled dose was recovered in feces, with the pyridine-cleaved product and the N-desalkyl metabolite accounting for approximately 29% and 28%, respectively, of fecal recovery. About 51% of the dose was excreted in urine; approximately 85% of the urinary recovery was the N-desalkyl metabolite; and about 5% was unchanged drug. Renal clearance of unchanged drug is, therefore, a minor route of elimination for delavirdine. Delavirdine exhibits nonlinear steady-state elimination pharmacokinetics, with oral clearance decreasing by about 22-fold as the total daily dose of delavirdine increases from 60 to 1200 mg/day. The apparent plasma half-life of delavirdine varies with dose; the mean half-life following 400 mg tid 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 CYP3A by delavirdine is reversible within 1 week after discontinuation of drug.

TOXICOLOGY

Numerous preclinical toxicity studies were conducted with delavirdine administered by systemic (mainly oral) routes. Durations of exposure of up to 3 months in mice and cynomolgus monkeys, 6 months in rats and 1 year in dogs were investigated. In vitro and in vivo genetic toxicology tests were completed and carcinogenicity studies in rats and mice are in progress. The results of these studies indicate that delavirdine mesylate affects multiple organ systems of animals and that toxicity is more closely correlated with serum drug concentrations rather than dose administered. Target organs affected by delavirdine in animals include blood vessels, gastrointestinal tract, endocrine system, liver, kidneys, bone marrow, lymphoid tissue, lung, and reproductive system.

Acute and Long-Term Toxicity Studies

Single oral doses of delavirdine mesylate or delavirdine free base given to rats at doses of 5000 mg/kg or less (250 times the recommended human dose) were not lethal and were practically nontoxic providing a wide margin of safety if the total daily dose were inadvertently consumed as a single dose. Drug-related mortalities (deaths/unscheduled sacrifices) in repeated-dose toxicity studies were associated with high nadir serum concentrations of delavirdine. In rats, drug-related death/unscheduled sacrifice was attributed to multiple organ toxicity at high mean nadir serum concentrations of delavirdine of > 160 :M. In dogs and monkeys, the main cause of death/unscheduled sacrifice was gastrointestinal toxicity (erosions/ulcers). Nadir serum concentrations of delavirdine at the time of gastrointestinal toxicity were > 180 :M in dogs and > 190 :M in monkeys. Vasculitis in arteries occurred in dogs when mean nadir serum concentrations of delavirdine were at least 7-fold higher, than the expected human exposure (mean Cmin = 15 :M) when administered at the recommended dosage. Vasculitis in dogs was not reversible during a 2.5-month recovery period; however, partial resolution of the vascular lesion characterized by reduced inflammation, diminished necrosis, and intimal thickening occurred during this period. The dog is the only species for which there is a defined association between treatment with delavirdine and the development of vasculitis/perivasculitis. Numerous endocrine-related changes were observed in the repeated-dose toxicity studies with delavirdine mesylate, including increased organ weights and hypertrophy of the thyroid gland, adrenal gland, pituitary gland, and reproductive organs. Mechanistic studies in rats demonstrated that these effects were likely secondary to delavirdine's ability to alter hormone levels by enhancing their clearance (thyroxine) or by inhibiting their synthesis (corticosterone). Organ hypertrophy was therefore considered to be compensatory in nature, involving normal regulatory mechanisms attempting to maintain normal hormone levels. Based on species-specific differences in hormone clearance pathways, the human safety profile of other drugs which cause similar effects in rodents and/or the lack of effects of delavirdine mesylate in clinical trials, it is unlikely that similar endocrine-related changes will occur in humans. Pseudopregnancy was observed in mice, in association with the formation of a unique metabolite of delavirdine with a high affinity for the dopamine-D2 receptor, resulting in increased blood prolactin levels. Because of the species-specific nature of the formation of this metabolite, similar effects would not be anticipated in humans. Deposition of delavirdine crystals with or without associated inflammation has been observed in tissues of rats (oral) and dogs (intravenous) and is likely related to prolonged exposure ($3 months) to high maximum serum concentrations (rats: $130 :M; dogs: $ 270 :M) of delavirdine and the relative insolubility of delavirdine in the serum of these species. Based on the relatively higher

in vitro

solubility of delavirdine in human serum and the low serum concentrations of delavirdine

achieved with therapeutic doses of delavirdine mesylate in humans, it is unlikely that deposition of delavirdine crystals in tissues will occur in humans. The liver, kidney, lung and peripheral blood were target organs in the rat at low serum concentrations of delavirdine (mean nadir serum concentrations of delavirdine $ 5.12 :M). Some kidney, liver and peripheral blood changes were not reversible after a 2-month recovery period in rats which had a mean nadir serum concentration of 37.6 :M or more. Similarly, increased serum cholesterol values in rats, mice and dogs and liver changes in mice were observed at low serum concentrations of delavirdine. The relevance of these findings to human safety is not known.

Reproduction and Teratology Studies

Reproduction studies revealed no impairment of fertility in rats. Delavirdine caused interventricular septal defects in pregnant 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 delavirdine (Cmin =15 :M) after treatment at the recommended dosage. Exposure in rats to concentrations approximately 5-fold higher than the expected human exposure resulted in marked maternal toxicity during late gestation/parturition, embryotoxicity, delay of fetal development, and reduced pup survival. Additionally, reduced pup survival occurred on postpartum day 0 at an exposure (mean Cmin) approximately equal to the expected human exposure. In rabbits, delavirdine at doses of 200 and 400 mg/kg/day when administered during the period of organogenesis caused marked maternal toxicity and embryotoxicity at an exposure (based on median Cmin concentrations of delavirdine) approximately 6-fold higher than the expected human exposure (Cmin = 15 :M ). 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. Excretion of delavirdine occurred in the milk of lactating rats at a concentration 3 to 5 times that of rat serum.

Carcinogenicity and Mutagenicity Studies

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 17 times human exposure at the recommended clinical dose. In mice, submucosal mesenchymal urinary bladder tumours and hepatocellular adenomas/carcinomas were observed in high-dose (500 mg/kg/day) males at an exposure level (AUC) approximately 4 times that in humans at the recommended clinical dose. The Cmax value reported for high dose males was approximately twice the targeted human Cmax. In female mice, hepatocellular adenomas were observed in all delavirdine treatment groups at levels of exposure (AUC) ranging from 0.5 to 3 times human exposure at the recommended clinical dose. Cmax values in delavirdine-treated females approximated 0.4 to 2 times the human targeted Cmax. The urinary bladder tumours in males were associated with a species- specific metabolite of delavirdine and are considered unlikely to be of relevance to humans. Given the frequent occurrence of liver tumours in mouse carcinogenicity studies, the unique genetic susceptibility of many mouse strains to the development of both spontaneous and clinically induced liver tumours, and the lack of genotoxic activity of delavirdine, the relevance to hepatocellular neoplasms in delavirdine-treated mice to humans is unknown. A battery of genetic toxicology tests was conducted with delavirdine, including the Ames assay, in vitro unscheduled DNA synthesis (UDS) assay, an in vitro cytogenetics (chromosome aberration) assay in human peripheral lymphocytes, a mammalian cell mutation assay in Chinese hamster ovary cells, and the micronucleus test in mice. The results were negative, indicating delavirdine is not mutagenic.

Local Tolerance Studies

Local tolerance studies indicate that delavirdine mesylate is a primary eye and dermal irritant. However, since delavirdine mesylate is administered orally as a tablet, eye contamination and skin irritation are considered remote consequences of drug therapy and not a health concern. Delavirdine mesylate was practically nontoxic when administered intratracheally to rats at a dose of 25 mg/kg.

REFERENCES

1. Bellman PC: Clinical experience with adding DLV to combination therapy in patients in whom multiple antiretroviral treatment including protease inhibitors has failed. AIDS 1998; 12:1333-1340.

2. Borin MT, Cox, SR, Driver MR, et al. Effect of rifabutin on delavirdine pharmacokinetics in HIV+ patients. Intersci Con Antimicrob Agents Chemother October 4-7, 1994:81.

3. Borin MT, Cox, SR, Chambers JH, et al. Effect of rifampin on delavirdine pharmacokinetics in HIV+ patients. Intersci Con Antimicrob Agents Chemother October 4-7, 1994:82.

4. Chang M, Sood VK, Wilson GJ, Kloosterman DA, Sanders PE, Hauer MJ, Zhang W, Branstetter DG. Metabolism of the HIV-1 reverse transcriptase inhibitor delavirdine in mice. Drug Metab Dispos 1997; 25:828-39.

5. Chang M, Sood VK, Wilson GJ, Kloosterman DA, Sanders PE, Hauer MJ, Fagerness PE. Metabolism of the human immunodeficiency virus type 1 reverse transcriptase inhibitor delavirdine in rats. Drug Metab Dispos 1997; 25:228-42.

6. Chang M, Sood VK, Kloosterman DA, Hauer MJ, Fagerness PE, Sanders PE, Vrbanac JJ. Identification of the metabolites of the HIV-1 reverse transcriptase inhibitor delavirdine in monkeys. Drug Metab Dispos 1997; 25:814-27.

7. Cheng CL, Smith DE, Cox, SR, et al. Correlation between ERBMT and oral exposure to delavirdine mesylate in HIV-positive patients. Pharm Res 1995; 12:S-374.

8. Chong, KT, Pagano PJ, Hinshaw RR. Bisheteroarylpiperazine reverese transcriptase inhibitor in combination with 3'-Azido-3'-Deoxythymidine or 2',3'-Dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro. Antimicrob Agents Chemother 1994; 38(2):288-93.

9. Cox SR, Della-Coletta AA, Turner SW, et al. Single-dose pharmacokinetic studies with delavirdine mesylate: dose proportionality and effects of food and antacid. Intersci Con Antimicrob Agents Chemother October 4-7, 1994:82.

10. Cox Sr, Phillips L, Grasela TH. Development of a nonlinear population pharmacokinetic model for delavirdine mesylate in HIV-1 patients. International Conference on AIDS July 7- 12, 1996; 11(1):321, Abstract TUB2324.

11. Cox SR, Borin MT, Driver MR, al. Effect of clarithromycin on the steady-state pharmacokinetics of delavirdine in HIV-1 patients. Natl Conf Hum Retroviruses Relat Infect (2nd) January 29-February 2, 1995:145.

12. Cox SR, Schneck DW, Herman BD, et al. Delavirdine (DLV) and nelfinavir (NFV): a pharmacokinetic (PK) drug-drug interaction study in healthy adult volunteers [Abstract 345]. Proceedings of the 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1 to 5; Chicago, IL.

13. Cox S, Conway B, Freimuth W, et al. Pilot study of BID and TID combinations of saquinavir-SGC(S), delavirdine (D), zidovudine (ZDV) and lamivudine (3TC) as initial therapy: pharmacokinetic (pK) interaction between S-SGC and D [Abstract 82]. Proceedings of the 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30-Feb 2; San Francisco, Calif., USA

14. Davey RT, Chaitt, DG, Reed GF, et al. Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother 1996; 40(7):1657-1664.

15. Demeter LD, Meehan PM, Morse GD, et al. HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine. J Acquired Immune Defic Syndr Hum Retrovirol 1997; 14(2):136-144.

16. Demeter L, Shafer R, Para M, et al. Delavirdine susceptibility of HIV-1 isolates obtained from patients receiving DLV monotherapy (ACTG 260) Third Conf Retro and Opportun Infect January 28-February 1, 1996:113.

17. Descamps D, Collin G, Loussert-Ajaka I, Saragosti S, Simon F, Brun-Vezinet F. HIV-1 group O sensitivity to antiretroviral drugs. AIDS 1995; 9(8):977-8.

18. Dueweke TJ, Poppe SM, Romero DL, Swaney SM, So AG, Downey KM, et al. U-90152, A potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother 1993; 37(5):1127-31.

19. Eron J, McKinley G, Leclerq P, et al. Potent antiviral activity using delavirdine and reduced- dose indinavir combination therapies: a 48-week analysis [Abstract 535]. Proceedings of the 7th Conference on Retroviruses and Opportunistic Infections: 2000 Jan 30-Feb 2; San Francisco, Calif., USA

20. Fan N, Rank KB, Evans DB, Thomas RC, Tarpley WG, Sharma SK. Simultaneous mutations at Tyr-181 and Tyr-188 in HIV-1 reverse transcriptase prevents inhibition of RNA- dependent DNA polymerase activity by the bisheteroarylpiperazine (BHAP) U-90152S. FEBS Lett 1995; 370:59-62.

21. Ferry JJ, Herman BD, Carel BJ et al. Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18:252-259.

22. Gatell J, Kuritzkes D, Green S, et al. Twice daily dosing of delavirdine (DLV) in combination with nelfinavir (NFV), didanosine (ddl), and stavudine (d4T) results in significant decreases in viral burden [Abstract 1981]. Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): 1999 Sept 26-29; San Francisco, Calif., USA

23. Kuritzkes DR, Bassett RL, Johnson VA, et al. Continued lamivudine (3TC) vs. delavirdine (DLV) in combination with indinavir (IDV) and zidovudine (ZDV) or stavudine (d4T) in 3TC- experienced patients: 48-week follow-up of ACTG 370 [Abstract 525]. Proceedings of the 7th Conference on Retroviruses and Opportunistic Infectins: 2000 Jan30-Feb 2; San Francisco, Calif., USA

24. Morse GD, Fischl MA, Shelton MJ, et al. Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1997; 41(1):169-174.

25. Morse GD, Fischl MA, Cox SR et al. Effect of didanosine on the single dose pharmacokinetics of delavirdine in HIV+ patients. Intersci Con Antimicrob Agents Chemother October 4-7, 1994:82

26. Morse GD, Cox, SR, DeRemer MF, et al. Zidovudine pharmacokinetics during an escalating, multiple-dose study of delavirdine mesylate. Intersci Con Antimicrob Agents Chemother October 4-7, 1994:132.

27. Morse GD, Shelton MJ, Hewitt RG, et al: Ritonavir (RIT) pharmacokinetics (PK) during combination therapy with delavirdine (DLV) [Abstract 343]. Proceedings of the 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1 to 5; Chicago IL.

28. Moyle G, De Cian W, Hawkins D, et al. Final 54-week analysis of a placebo-controlled trial (13C) of delavirdine (DLV) plus two nucleoside analogs (NA) versus two NA in drug-naive and -experienced individuals [Abstract 1980]. Proceedings of the 39th Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC); 1999 Sept 26-29; San Francisco, Calif., USA.

29. Olmsted RA, Slade DE, Kopta LA, Poppe SM, Poel TJ, Newport SW, et al. (Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes. J Virol. 1996; 70(6): 3698-705.

30. Para MF, Beal J, Rathbun R, et al. Potent activity with lower doses of indinavir (IDV), using delavirdine (DLV) in combination with zidovudine (ZDV): 48-week analysis [Abstract 1985]. Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): 1999 Sept 26-29; San Francisco, Calif, USA.

31. Para M, Conway B, Green S, et al. Safety and efficacy of delavirdine (DLV) in combination with zidovudine (ZDV) and lamivudine (3TC): Final 52-week analysis [Abstract 1979]. Proceedings of the 39th Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC): 1999 Sept 26-29; San Francisco, Calif., USA

32. Peterson PK, Gekker G, Hu S, Chao CC. Anti-human immunodeficiency virus type 1 activities of U-90152 and U-75875 in human brain cell cultures. Antimicrob Agents Chemother 1994; 38(10):2465-8.

33. Sargent S, Para MF, Cox SR, et al. Plasma viral load reduction in an open-label randomized study of RESCRIPTOR(r) in combination with zidovudine and two dose levels of indinavir compared to zidovudine, lamivudine, and indinavir in HIV-1 infected individuals. Proceedings of the International Conference on the Discovery and Clinical Development of Antiretroviral Therapies (ICDCD); 1198 Dec 13-17; St Thomas, West Indies, US Virgin Islands.

34. Slater L, Goodgame J, Wathen L, et al. Antiviral effect of increasing nelfinavir (NFV) concentations using delavirdine (DLV) in combination with didanosine (ddl) and stavudine (d4T) is maintained throught 48 weeks of therapy [Abstract 1989]. Proceedings of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): 1999 Sept 26- 29; San Francisco, Calif., USA.