New Drugs Arriving at Pharmacies

with lower CD4 cell counts and usually occurred within 1 to
3 weeks (median = 11 days) of treatment. Rash classified as
severe was observed in 3.6% of patients in Studies 0021 and
0017. 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 rechallengetwith RESCRIPTOR followingtaetreatment
interruption due to rash. The distribution of the rush 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. Erythema multitorme
and Stevens-Johnson syndrome were rarely seen and resolved
after withdrawal of RESCRIPTOR. Any patient experiencing
severe rash or rash accompanied by symptoms such as fever,
blistering, oral lesions, conjunctivitis, swelling, muscle or joint
aches should discontinue RESCRIPTOR and consult a physician. Occurrence of a delavirdine-related rash after 1 month of
therapy is uncommon unless prolonged interruption of treatment with RESCRIPTOR occurs. Symptomatic relief has been
obtained using diphenhydramine hydrochloride, hydroxyzine
hydrochloride, and/or topical corticosteroids.
Information for Patients: 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 long-term effects of
treatment with RESCRIPTOR are unknown at this time. They
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 in rush 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 bectreated symptomatically while therupy with RESCRIPTOR is continued. Any patient experiencing
severe rash or rash accompanied by symptoms such as fever.
blistering. oral lesions. conlunctivitis, swelling, muscle or joint
aches should discontinue medication and consult a physician.
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. ifa 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 or over-the-counter medications.
Drug tnteractions (see also CLINICAL PHARMACOLOGYPharmacokinetics-Drug Interactions)
General: Coadministration of RESCRIPTOR with certain nonsedating antihistamines, sedative hypnotics, antiarrhythmics, calcium channel blockers, ergot alkaloid preparations, amphetamines. and cisapride, may result in potentially serious and/or
life-threatening adverse events. Due to the inhibitory effect of
delavirdine on CYP3A and CYP2C9. coadministration of
RESCRIPTOR with drugs primarily metabolized by these liver
enzymes may result in increased plasma concentrations.
Higher plasma concentrations of these drugs could increase or
prolong both therapeutic and adverse effects (Table 1).
Therefore. appropriate dose adjustments may be necessary for
these drugs. Drugs that induce CYP3A may also reduce plasma
delavirdine concentrations (Table 2). Physicians should consider using alternatives to drugs that induce CYP3A while a
patient is taking RESCRIPTOR.
Table 1. Selected Drugs that are Predicted to Have Plasma
Concentrations Increased by Delavirdine*
HIV protease inhibitors: indinavir, saquinavir
Antihistamines: tertenadinet. astemizolet
Antimicrobial agents: clarithromycin, dapsone. rifabutin
Anti-migraine agents: ergot derivatives
Benzodiazepines: alprazolamt. midazolamt. triazolamt
Calcium channel blockers: dihydropyridines. eg,
nit edipine
GI motility agents: cisapridet
Other: quinidine. warfarin
Thi tbeN isno all inclusive.
Table 2. Setected Dregs that are Predicted
to Decrease Ptasma Detavirdine Concentrationsttt
Ot Thin table is not all inclusive.
SRESCRIPTOR may not be effective when administered concomitantly with these drugs.
Antacids: hoses of an antacid and RESCRIPTOR should be
separated by at least one hour, because the absorption of
delavirdine is reduced when coadministered with antacids.
Anticonvulsant Agents:
Phenytoin. phenobarbital carbamazepine: Coadministration of
delavirdine with these agents is not recommended, because
limited population pharmacokinetic data indicate that a sub
stantial reduction in plasma delavirdine concentrations may
result (see CLINICAL PHARMACOLOGY-Pharmacokinetics).
Antimycobacterial Agents:
Rilabutin: Coadministration of delavirdine and ritabutin is not
recommended, because ritabutin substantially decreases
plasma delavirdine concentrations and delavirdine increases
plasma concentrations of rifabutin (see CLINICAL PHARMACOLOGY-Pharmacokinetics).
Rifampin: Delavirdine should not be coadministered with
rifampin, because rifampin reduces delavirdine systemic exposure (AUC) by almost 100% (see CLINICAL PHARMACOLOGYPharmacokinetics).

Table 3.- Adverse Events of Moderate or Severe Intensity in z2%
of Patients Receiving RESCRIPTOR*
Study 0017 Study 0021
Body System/ Didanosine t Delavirdine Zidovudine Delavirdine
Adverse Event 200 mg bid 400 mg tid 200 mg tid 400 mg old
(n=591) + Didanosine t (n=271) v Zidovudine
200 mg bid 200 mg tid
(n=594) (n=287)
Body as a Whole
Headache 4.7 5.6 4.8 5.6
Fatigue 2.7 2.9 4.8 5.2
Digestive
Nausea 3.4 4.9 6.6 10.8
Diarrhea 4.4 4.5 2.2 3.5
Vomiting 1.2 2.4 1 1 2.8
Metabolic and
Nutritional
Increased ALT (SGPT) 3.6 5.2 -0.7 2.4
Increased AST (SGOT) 3.0 4.5 0.7 1.7
Skin
Rash 3.0 9.8 1.5 12.5
Maculopapular rash 2.0 6.6 1.1 4.5
Pruritus 1.7 2.2 1.5 3.1
Includes those adverse events at least possibly related to study drug or of unknown relationship and excludes concurrent HIV
conditions.
t Dose adjusted body weight < 60 kg = 125 mg bid; > 60 kg = 200 mg bid.

HReceptor Antagonists:
Cimetidine, famotidine, nizatidine, and ranitidine: These agents
increase gastric pH and may reduce the absorption of delavirdive. Although the effect of these drugs on deiavirdine absorption has not been evaluated, chronic use of these drugs with
delavirdine is not recommended.
Nucleoside Analogue Reverse Transcriptase Inhibitors:
Didanostne: Administration of didanosine and delavirdine
should be separated by at least one hour, because coadministration of didanosine and delavirdine resulted in reduced systemic exposure to both drugs by approximately 20% (see
CLINICAL PHARMACOLOGY-Pharmacokinetics).
Professe Inhibitors (see CLINICAL PHARMACOLOGYPharmacokinetics):
Indinavir: Due to an increase in indinavir plasma concentrations (preliminary results), a dose reduction of indinavir to
600 mg tid should be considered when delavirdine and indinavir are coadministered. Currently, there are no safety and
efficacy data available from the use of this combination.
Ritonavir: No studies have been conducted with combination
therapy of delavirdine and ritonavir at their recommended
doses. Preliminary results indicate there is no evidence of an
interaction at doses of delavirdine 400 mg to 600 mg bid and
ritonavir 300 mg bid. Currently. there are no safety and efficacy
data available from the use of this combination.
Saquinavir: Saquinavir AUC increased 5-fold when delavirdine
(400 mg tid) and saquinavir (600 mg tid) were administered in
combination. Currently. there are limited safety and no efficacy
data available from the use of this combination. In a small, preliminary study, hepatocellular enzyme elevations occurred in
13% of subjects during the first several weeks of the delavirdine and saquinavir combination (6% grade 3 or 4).
Hepatocellular enzymes (ALT/AST) should be monitored frequently if this combination is prescribed.
Carcinogenesis, Mutagenesis and Impairment of Fertility:
Long-term carcinogenicity studies with delavirdine in animals
have not been completed. 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 mutation assay in Chinese hamster
ovary cells, and the micronucleus test in mice. The results
were negative indicating delavirdine is not mutagenic.
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 (Cr=
15 pM) at the recommended dose. Exposure in rats approximately 5-fold higher than the expected human exposure
resulted in marked maternal toxicity. embryxtoxicity, fetal
developmental delay, and reduced pup survival. Additionally.
reduced pup survival on postpartum day 0 occurred at an
exposure (mean Cr) 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
(Cmrm=15 pM) at the recommended dose. The no-observedadverse-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 signiticantly 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 7 unplanned pregnancies reported in premarketing clinical studies, 3 were ectopic pregnancies and 3
pregnancies resulted in healthy live births. One infant was born
prematurely with a small muscular ventricular septal defect to
a patient who received approximately six weeks of treatment
with delavirdine and zidovudine early in the course of the pregnrng Mothers: The US. Public Health Services Centers for
not,: t ':breast-feed d to dpsnatal transmisioo HI to a

child who may not yet be infected.
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.
ADVERSE REACTIONS
The safety of RESCRIPTOR Tablets alone and in combination
with other therapies has been studied in 1,969 patients receiving RESCRIPTOR.
Adverse events of moderate or severe intensity reported in -e
2% of patients receiving RESCRIPTOR in combination with
didanosine or zidovudine in Studies 0017 and 0021 are summarized in Table 3. The median duration of treatment in
Studies 0017 and 0021 was 34 and 42 weeks (up to 107 weeks
for both studies), respectively, at the time of the safety assessment. The most frequently reported drug-related medical event
was rash (see PRECAUTIONS-Skin Rash).
Medical events occurring in less than 2% of patients receiving RESCRIPTOR (in combination treatment) in all phase II and
Ill studies, considered possibly related to treatment. and of at
least ACTG grade 2 in intensity are listed below by body system.
Body as a Whole: Abdominal cramps, abdominal distention,
abdominal pain (generalized or localized). allergic reaction,
asthenia. back pain, chest pain, chills, edema (generalized or
localized), epidermal cyst. fever, flank pain, flu syndrome.
lethargy, lip edema, malaise, neck rigidity, pain (generalized or
localized), sebaceous cyst, trauma, and upper respiratory
infection.
Cardiovascular System: Bradycardia, migraine, pallor, palpitation, postural hypotension, syncope. tachycardia, and vasodilation.
Digestive System: Anorexia, aphthous stomatitis, bloody stool,
colitis, constipation, decreased appetite. diarrhea (Clostridium
difficile), diverticulitis, duodenitis, dry mouth. dyspepsia, dysphagia, enteritis. esophagitis, fecal incontinence, flatulence,
gagging, gastritis, gastroesophageal reflux, gastrointestinal
bleeding, gastrointestinal disorder, gingivitis, gum hemorrhage. increased appetite, increased saliva, increased thirst.
mouth ulcer, nonspecific hepatitis. pancreatitis, rectal disorder,
sialadenitis, stomatitis. and tongue edema or ulceration.
Hemic and Lymphatic System: Anemia, bruise. ecchymosis.
exsinophilia, granulocytosis, neutropenia, pancytopenia,
petechia, prolonged partial thromboplastin time. purpura,
spleen disorder, and thrombocytopenia.
Metabolic and Nutriihonal Disorders: Alcohol intolerance, bilirobinemia, hyperkalemia, hyperuricemia. hypocalcemnia, hyponatremia, hypophosphatemia, increased gamma glutamyl
transpeptidase, increased lipase. increased serum alkaline
phxsphatase, increased serum amylase. increased serum creatine phosphokinase. increased serum creatinine. peripheral
edemaand weight increase or decrease.
Musculoskeletal System: Arthralgia or arthritis of single and
multiple joints, bone disorder, bone pain. leg cramps. muscular
weakness, myalgia, tendon disorder, fenoynovitis, and tetany.
Nervos System: Abnormal coordination, agitation, amnesia,
anxiety. change in dreams, cognitive impairment, confusion,
decreased libido, depressive symptoms, disorientation, dizziness, emotional lability, hallucination, hyperesthesia, hyperreflesia, hypesthesia, impaired concentration, insomnia, manic

symptoms muscle crarn. nervousness neurosalt, nigrl
mares. nystagmus. paralysis. paranoid symptoms. Darestnesiz
restlessness. somnolence, tingling, tremor. vertigo, and weak
ness
Respiratory System: Bronchitis. chest congestion. cough. dvspnea, epistaxis. laryngismus. pharyngitis. rhinitis. and sinus!tin.
Skin and Appendages: Angioedema. dermal leukocytoclasti:
vasculitis. dermatitis. desquamation. diaphoresis. Sr skin
erythema. er-thema multitorme. folliculitis. fungal dermatits
hair loss, nail disorder. petechial rash. seborrhea. skin discorder, skin nodule. Stevens-Johnson syndrome. urticaria. anc
vesiculobullous rash
Special Senses Blephantis. conjunctivitis. diplopia. dry eyes
ear pain, photophobia. taste perversion, and tinnitus
Urogenital System: Breast enlargement. calculi of the kiune
epididymitis. hematuria. hemospermia, impotence. kidney pain
metrorrhagia. nocturia, polyuria, proteinuria. and vagina:
moniliasis
Laboratory Abnormalities: The frequency of clinically impor
tant laboratory abnormalities observed during therapy in
Studies 0017 and 0021 is summarized in Table 4 There was nc
significant difference in ACTG grades 3 and 4 laboratory abnormalities between treatment groups except a two-fold reduction
in neutronenia in the delavirdine plus zidovudine combination
group compared with the zidovudine monotherapy group in
Study 0021.
OVERDOSAGE
No reports of overdose with RESCRIPTOR Tablets are available in humans. Several patients have received up to 850 mg
tid for up to 6 months with no serious drug-related medical
events.
Management of Overdosage: Treatment of overdosage with
RESCRIPTOR Sould consst of general supportive measures,
including monitoring of vital signs and observation of the
patient s clinical status. There is no specific antidote for overdosage with RESCRIPTOR. It indicated, elimination of unabsorhed drug shuld be ache-ed hy enmesis or gastric lavage
Since delavirdine is extensively metabolized by the liver and is
highly protein bound. dialysis is unlikely to be beneficial in significant removal of the drug
DOSAGE AND ADMINISTRATION
The recommended dosage for RESCRIPTOR Tablets is 400
mg (four 100-mg tablets) three times daily. RESCRIPTOR
should be used in combination with appropriate other antiretroviral therapy. The complete prescribing information for
other antiretroviral agents should be consulted for information
on dosage and administration.
RESCRIPTOR Tablets may be dispersed in water prior to
consumption. To prepare a dispersion, add four RESCRIPTOR
Tablets to at least 3 ounces of water, allow to stand for a few
minutes. and then stir until a uniform dispersion occurs (see
CLINICAL PHARMACOLOGY- Pharmacokinetics-Absorption
and Bioavailability). The dispersion should be consumed
promptly. The glass should be rinsed and the rinse swallowed
to insure the entire dose is consumed.
RESCRIPTOR Tablets may be administered with or without
food (see CLINICAL PHARMACOLOGY- PharmacokineticsAbsorption and Bioavailability). 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.
HOW SUPPLIED
RESCRIPTOR Tablets are available as follows:
100 mg: white. capsule-shaped tablets marked with "U 3761'.
Bottles of 360 tablets NDC 0009-3761-03
Store at controlled room temperature 20' to 250C (68 to
770F) (see USPI. Keep container tightly closed. Protect from
high humidity.
Caution: Federal law prohibits dispensing without prescription.
ANIMAL TOXICOLOGY
Toxicities among various organs and organ systems in rats,
mice, rabbits, dogs, and monkeys were observed following the
administration of delavirdine. Necrotizing vasculitis was the
most significant toxicity that occurred in dogs when mean
nadir serum concentrations of delavirdine were at least 1-fold
higher than the expected human exposure to RESCRIPTOR
(C,,- 15 pM) at the recommended dose. 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. Other major target organs
included the gastrointestinal tract, endocrine organs, liver. kidneys, bone marrow, lymphoid tissue, lung, and reproductive

Phamcia & Upjohn Company
Kalamazoo, Michigan 49001, USA
April 1997

816885000

Table 4.- Frequency (%)* of Clinically Important Laboratory Abnormalities
Study 0017 Study 0021
Laboratory Didanosine t Delavirdine Zidovudine Delavirdine
Test (n=591) 400 mg tid 200 mg tid 400 mg tid
+ Didanosinet (n=271) + Zidovudine
(n=594) 200 mg fid
(n=287)
Neutropenia 6.7 5.7 7.7t 3.5
(ANC <750/mm')
Anemia (Hgb <7.0 g/dL) 0.2 0.7 1.1 1.0
Thrombocytopenia 1.4 1.5 0.0 0.0
(platelets <50,000/mm')
ALT (>5.0 x ULN) 4.6 6.7 3.7 3.8
AST (>5.0 x ULN) 4. 95.6 3.0 2.1
Bilirubin (>2.5 ULN) 0.7 0.5 0.4 1.0
Amylase (>2.0 ULN) 6.5 5.2 1.1 0.0
Percentage was based on the number of patients for which data on that laboratory test was available.
Dose adlusted by body weight <60 kg = 125 mg bid 60 kg = 200 mg bid.
Significant (Pt05) delavirdine + zidovudine vs zidovudine.
ANC = Absolute neutrophil count; ULN = upper limit of normal.