A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rescriptor Side Effects, and Drug Interactions - Delavirdine mesylate
Rescriptor Side Effects, and Drug Interactions - Delavirdine mesylate
SIDE EFFECTS
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
³ 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).
Table 3. , Adverse Events of Moderate or Severe Intensity in
2% of Patients Receiving RESCRIPTOR*
|
Body System/ Adverse Event
|
Study 0017
|
Study 0021
|
|
Didanosine† 200 mg bid (n=591)
|
Delavirdine 400 mg tid+ Didanosine† 200 mg bid (n=594)
|
Zidovudine 200 mg tid (n=271)
|
Delavirdine 400 mg tid + Zidovudine 200 mg tid (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.
† Dose adjusted body weight < 60 kg = 125 mg bid; ³
60 kg = 200 mg bid.
Medical events occurring in less than 2% of patients receiving
RESCRIPTOR (in combination treatment) in all phase II and III 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, eosinophilia,
granulocytosis, neutropenia, pancytopenia, petechia, prolonged partial thromboplastin
time, purpura, spleen disorder, and thrombocytopenia.
Metabolic and Nutritional Disorders: Alcohol intolerance, bilirubinemia,
hyperkalemia, hyperuricemia, hypocalcemia, hyponatremia, hypophosphatemia, increased
gamma glutamyl transpeptidase, increased lipase, increased serum alkaline phosphatase,
increased serum amylase, increased serum creatine phosphokinase, increased serum
creatinine, peripheral edema, and 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, tenosynovitis, and tetany.
Nervous System: Abnormal coordination, agitation, amnesia,
anxiety, change in dreams, cognitive impairment, confusion, decreased libido,
depressive symptoms, disorientation, dizziness, emotional lability, hallucination,
hyperesthesia, hyperreflexia, hypesthesia, impaired concentration, insomnia,
manic symptoms, muscle cramp, nervousness, neuropathy, nightmares, nystagmus,
paralysis, paranoid symptoms, paresthesia, restlessness, somnolence, tingling,
tremor, vertigo, and weakness.
Respiratory System: Bronchitis, chest congestion, cough, dyspnea,
epistaxis, laryngismus, pharyngitis, rhinitis, and sinusitis.
Skin and Appendages: Angioedema, dermal leukocytoclastic vasculitis,
dermatitis, desquamation, diaphoresis, dry skin, erythema, erythema multiforme,
folliculitis, fungal dermatitis, hair loss, nail disorder, petechial rash, seborrhea,
skin disorder, skin nodule, Stevens-Johnson syndrome, urticaria, and vesiculobullous
rash.
Special Senses: Blepharitis, conjunctivitis, diplopia, dry
eyes, ear pain, photophobia, taste perversion, and tinnitus.
Urogenital System: Breast enlargement, calculi of the kidney,
epididymitis, hematuria, hemospermia, impotence, kidney pain, metrorrhagia,
nocturia, polyuria, proteinuria, and vaginal moniliasis.
Laboratory Abnormalities: The frequency of clinically
important laboratory abnormalities observed during therapy in Studies 0017 and
0021 is summarized in Table 4. There was no significant difference in ACTG grades
3 and 4 laboratory abnormalities between treatment groups except a two-fold
reduction in neutropenia in the delavirdine plus zidovudine combination group
compared with the zidovudine monotherapy group in Study 0021.
Table 4. , Frequency (%)* of Clinically Important Laboratory
Abnormalities
|
Laboratory Test
|
Study 0017
|
Study 0021
|
|
Didanosine†
(n=591)
|
Delavirdine 400 mg tid + Didanosine† (n=594)
|
Zidovudine 200 mg tid (n=271)
|
Delavirdine 400 mg tid + Zidovud-ine 200 mg tid (n=287)
|
|
Neutropenia (ANC <750/mm3)
|
6.7
|
5.7
|
7.7‡
|
3.5
|
|
Anemia (Hgb <7.0 g/dL)
|
0.2
|
0.7
|
1.1
|
1.0
|
|
Thrombocytopenia (platelets <50,000/mm3)
|
1.4
|
1.5
|
0.0
|
0.0
|
|
ALT (>5.0 x ULN)
|
4.6
|
6.7
|
3.7
|
3.8
|
|
AST (>5.0 x ULN)
|
4.9
|
5.6
|
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 adjusted by body weight <60 kg = 125 mg bid;
60 kg = 200 mg bid.
‡ Significant (P<.05) delavirdine + zidovudine vs zidovudine.
ANC = Absolute neutrophil count; ULN = upper limit of normal.
DRUG INTERACTIONS
(see
also CLINICAL PHARMACOLOGY-Pharmacokinetics-Drug
Interactions)
General: Coadministration of RESCRIPTOR with certain
nonsedating antihistamines, sedative hypnotics, antiarrhythmics, calcium channel
blockers, ergot alkaloid preparations, amphetamines, cisapride, and sildenafil,
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:
|
terfenadine, † astemizole†
|
|
Antimicrobial agents:
|
clarithromycin, dapsone, rifabutin
|
|
Anti-migraine agents:
|
ergot derivatives
|
|
Benzodiazepines:
|
alprazolam, † midazolam,
† triazolam†
|
|
Calcium channel blockers:
|
dihydropyridines, eg, nifedipine
|
|
GI motility agents:
|
cisapride†
|
|
Other:
|
sildenafil, quinidine, warfarin
|
* This table is not all inclusive.
† See WARNINGS.
Table 2. Selected Drugs that are Predicted to Decrease Plasma
Delavirdine Concentrations ‡ §
|
Anticonvulsants:
|
Carbamazepine phenobarbital phenytoin
|
|
Antimycobacterial agents:
|
Rifabutin rifampin
|
‡ This table is not all inclusive.
§ RESCRIPTOR may not be effective when administered
concomitantly with these drugs.
Antacids: Doses 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 substantial reduction in plasma delavirdine
concentrations may result (see CLINICAL PHARMACOLOGY-Pharmacokinetics).
Antimycobacterial Agents:
Rifabutin: Coadministration of delavirdine and rifabutin is
not recommended, because rifabutin 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 PHARMACOLOGY-Pharmacokinetics).
Erectile Dysfunction Agents:
Sildenafil: Caution should be used when prescribing sildenafil
in patients receiving delavirdine, because delavirdine inhibits CYP3A4 which
may result in an increase of sildenafil concentrations. Patients receiving delavirdine
and sildenafil should be advised that they may be at an increased risk for sildenafil-associated
adverse events, including hypotension, visual changes, and prolonged erection,
and should report these symptoms promptly to their physician. Currently, there
are no safety and efficacy data available from the use of this combination.
If delavirdine and sildenafil are used concomitantly, a single sildenafil dose
of 25 mg in a 48-hour period should not be exceeded. This recommendation is
based on data from a ritonavir/sildenafil drug-interaction study.
H2Receptor Antagonists:
Cimetidine, famotidine, nizatidine, and ranitidine: These agents
increase gastric pH and may reduce the absorption of delavirdine. Although the
effect of these drugs on delavirdine absorption has not been evaluated, chronic
use of these drugs with delavirdine is not recommended.
Nucleoside Analogue Reverse Transcriptase Inhibitors:
Didanosine: 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).
Protease Inhibitors (see CLINICAL
PHARMACOLOGY-Pharmacokinetics):
Amprenavir: Delavirdine has the potential to increase serum
concentrations of amprenavir. 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 (Cmin»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 Cmin) 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 (Cmin»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 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 pregnancy.
Nursing Mothers: The U.S. Public Health Services Centers
for Disease Control and Prevention advises HIV-infected women not to breast-feed
to avoid postnatal transmission of HIV 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.
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