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
Emend Side Effects, and Drug Interactions - Aprepitant
Emend Side Effects, and Drug Interactions - Aprepitant
SIDE EFFECTS
The overall safety of aprepitant was evaluated in approximately
3300 individuals.
In 2 well-controlled clinical trials in patients receiving
highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant
during Cycle 1 of chemotherapy and 413 of these patients continued into the
Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given
in combination with ondansetron and dexamethasone and was generally well tolerated.
Most adverse experiences reported in these clinical studies were described as
mild to moderate in intensity.
In Cycle 1, clinical adverse experiences were reported in approximately
69% of patients treated with the aprepitant regimen compared with approximately
68% of patients treated with standard therapy. Table 3 shows the percent of
patients with clinical adverse experiences reported at an incidence 23% during
Cycle 1 of the 2 combined Phase III studies.
|
Table 3
|
|
Percent of Patients With Clinical Adverse Experiences
(Incidence 23%) in CINV Phase III Studies (Cycle 1)
|
|
|
Aprepitant Regimen (N = 544)
|
Standard Therapy (N = 550)
|
|
Bodyas a Whole/ Site Unspecified
|
|
Abdominal Pain
|
4.6
|
3.3
|
|
Asthenia/Fatigue
|
17.8
|
11.8
|
|
Dehydration
|
5.9
|
5.1
|
|
Dizziness
|
6.6
|
4.4
|
|
Fever
|
2.9
|
3.5
|
|
Mucous Membrane Disorder
|
2.6
|
3.1
|
|
Digestive System
|
|
Constipation
|
10.3
|
12.2
|
|
Diarrhea
|
10.3
|
7.5
|
|
Epigastric Discomfort
|
4.0
|
3.1
|
|
Gastritis
|
4.2
|
3.1
|
|
Heartburn
|
5.3
|
4.9
|
|
Nausea
|
12.7
|
11.8
|
|
Vomiting
|
7.5
|
7.6
|
|
Eyes, Ears, Nose, and Throat
|
|
Tinnitus
|
3.7
|
3.8
|
|
Hemic and Lymphatic System
|
|
Neutropenia
|
3.1
|
2.9
|
|
Metabolism and Nutrition
|
|
Anorexia
|
10.1
|
9.5
|
|
Nervous System
|
|
Headache
|
8.5
|
8.7
|
|
Insomnia
|
2.9
|
3.1
|
|
Respiratory System
|
|
Hiccups
|
10.8
|
5.6
|
The following additional clinical adverse experiences (incidence
>0.5% and greater than standard therapy), regardless of causality, were reported
in patients treated with aprepitant regimen:
Body as a whole: diaphoresis, edema, flushing, malaise,
malignant neoplasm, pelvic pain, septic shock, upper respiratory infection.
Cardiovascular system: deep venous thrombosis, hypertension,
hypotension, myocardial infarction, pulmonary embolism, tachycardia.
Digestive system: acid reflux, deglutition disorder,
dysgeusia, dyspepsia, dysphagia, flatulence, obstipation, salivation increased,
taste disturbance.
Endocrine system: diabetes mellitus. Eyes, ears, nose,
and throat: nasal secretion, pharyngitis, vocal disturbance.
Hemic and lymphatic system: anemia, febrile neutropenia,
thrombocytopenia.
Metabolism and nutrition: appetite decreased, hypokalemia,
weight loss.
Musculoskeletal sysfem: muscular weakness, musculoskeletal
pain, myalgia.
Nervous system: peripheral neuropathy, sensory neuropathy.
Psychiatric disorder: anxiety disorder, confusion, depression.
Respiratory system: cough, dyspnea, lower respiratory
infection, non-small cell lung carcinoma, pneumonitis, respiratory insufficiency.
Skin and skin appendages: alopecia, rash.
Urogenital system: dysuria, renal insufficiency.
Laboratory Adverse Experiences
Table 4shows the percent of patients with laboratory adverse
experiences reported at an incidence 23% during Cycle 1 of the 2 combined Phase
III studies.
|
Table 4
|
|
Percent of Patients With Laboratory Adverse Experiences
(Incidence >3%) in CINV Phase III Studies (Cycle 1)
|
|
|
Aprepitant Regimen (N = 544)
|
Standard Therapy (N = 550)
|
|
ALT Increased
|
6.0
|
4.3
|
|
AST Increased
|
3.0
|
1 .3
|
|
Blood Urea Nitrogen increased
|
4.7
|
3.5
|
|
Serum Creatine Increased
|
3.7
|
4.3
|
|
Proteinuria
|
6.8
|
5.3
|
The following additional laboratory adverse experiences (incidence
>0.5% and greater than standard therapy), regardless of causality, were reported
in patients treated with aprepitant regimen: alkaline phosphatase increased,
hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia.
The adverse experiences of increased AST and ALT were generally
mild and transient.
The adverse experience profile in the Multiple-Cycle extension
for up to 6 cycles of chemotherapy was generally similar to that observed in
Cycle 1.
In addition, isolated cases of serious adverse experiences,
regardless of causality, of bradycardia, disorientation, and perforating duodenal
ulcer were reported in CINV clinical studies.
Stevens-Johnson syndrome was reported in a patient receiving
aprepitant with cancer chemotherapy in another ClNV study. Angioedema and urticaria
were reported in a patient receiving aprepitant in a non-CINV study.
DRUG INTERACTIONS
Aprepitant is a substrate, a moderate inhibitor, and an inducer
of CYP3A4. Aprepitant is also an inducer of CYP2C9.
Effect of aprepitant on the pharmacokinetics of other agents
As a moderate inhibitor of CYP3A4, aprepitant can increase
plasma concentrations of coadministered medicinal products that are metabolized
through CYP3A4 (see CONTRAINDICATIONS).
Aprepitant has been shown to induce the metabolism of S(-)
warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration
of EMEND with these drugs or other drugs that are known to be metabolized by
CYP2C9, such as phenytoin, may result in lower plasma concentrations of these
drugs.
EMEND is unlikely to interact with drugs that are substrates
for the P-glycoprotein transporter, as demonstrated by the lack of interaction
of EMEND with digoxin in a clinical drug interaction study.
5-HT3 antagonists: In clinical drug interaction
studies, aprepitant did not have clinically important effects on the pharmacokinetics
of ondansetron or granisetron. No clinical or drug interaction study was conducted
with dolasetron.
Corticosteroids:
Dexamethasone: EMEND, when given as a regimen of 125mg with
dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when
given as 80 mg/day with dexamethasone coadministered orally as 8 mg on
Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate
by 2.2-fold, on Days 1 and 5. The oral dexamethasone doses should be reduced
by approximately 50% when coadministered with EMEND, to achieve exposures
of dexamethasone similar to those obtained when it is given without EMEND.
The daily dose of dexamethasone administered in clinical studies with
EMEND reflects an approximate 50% reduction of the dose of dexamethasone
(see DOSAGE AND
ADMINISTRATION).
Methylprednisolone
EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day
on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate,
by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was
coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days
2 and 3. The IV methylprednisolone dose should be reduced by approximately 25%,
and the oral methylprednisolone dose should be reduced by approximately 50%
when coadministered with EMEND to achieve exposures of methylprednisolone similar
to those obtained when it is given without EMEND.
Chemotherapeutic agents: See PRECAUTIONS,
General.
Warfarin: A single 125-mg dose of EMEND was administered on
Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized
on chronic warfarin therapy. Although there was no effect of EMEND on the plasma
AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in
S(-)warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14%
decrease in the prothrombin time (reported as International Normalized Ratio
or INR) 5 days after completion of dosing with EMEND. In patients on chronic
warfarin therapy, the prothrombin time (INR) should be closely monitored in
the 2-week period, particularly at 7 to 10 days, following initiation of the
3-day regimen of EMEND with each chemotherapy cycle.
Tolbutamide: EMEND, when given as 125 mg on Day 1 and
80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate)
by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide
500 mg was admini,stered orally prior to the administration of the 3-day regimen
of EMEND and on Days 4,8, and 15.
Oral contraceptives: Aprepitant, when given once daily
for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg
of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl
estradiol by 43%, and decreased the AUC of norethindrone by 8%; therefore, the
efficacy of oral contraceptives during administration of EMEND may be reduced.
Although a 3-day regimen of EMEND given concomitantly with oral contraceptives
has not been studied, alternative or back-up methods of contraception should
be used.
Midazolam: EMEND increased the AUC of midazolam, a sensitive
CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single
oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen
of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects
of increased plasma concentrations of midazolam or other benzodiazepines metabolized
via CYP3A4 (alprazolam, triazolam) should be considered when coadministering
these agents with EMEND.
In another study with intravenous administration of midazolam,
EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam
2 mg IV was given prior to the administration of the 3-day regimen of EMEND
and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day
4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing
of EMEND on Days 1 through 3. These effects were not considered clinically important.
The AUC of midazolam on Day 15 was similar to that observed at baseline.
Effect of other agents on the pharmacokinefics of aprepitant
Aprepitant is a substrate for CYP3A4; therefore, coadministration
of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma
concentrations of aprepitant. Consequently, concomitant administration of EMEND
with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone,
troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached
with caution. Because moderate CYP3A4 inhibitors (e.g., diltiazem) result in
2-fold increase in plasma concentrations of aprepitant, concomitant administration
should also be approached with caution.
Aprepitant is a substrate for CYP3A4; therefore, coadministration
of EMEND with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine,
phenytoin) may result in reduced plasma concentrations of aprepitant that may
result in decreased efficacy of EMEND.
Ketoconazole: When a single 125-mg dose of EMEND was administered
on Day5 of a
10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4
inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean
terminal half-life of aprepitant increased approximately 3-fold. Concomitant
administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously.
Rifampin: When a single 375-mg dose of EMEND was administered
on Day9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer,
the AUC of aprepitant decreased approximately 11-fold and the mean terminal
half-life decreased approximately 3-fold.
Coadministration of EMEND with drugs that induce CYP3A4 activity
may result in reduced plasma concentrations and decreased efficacy of EMEND.
Additional interactions
Diltiazem: In patients with mild to moderate hypertension,
administration of aprepitant once daily, as a tablet formulation comparable
to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for
5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold
increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically
meaningful changes in ECG, heart rate or blood pressure beyond those changes
induced by diltiazem alone.
Paroxetine: Coadministration of once daily doses of
aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule
formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC
by approximately 25% and Cmax, by approximately 20% of both aprepitant
and paroxetine.
Carcinogenesis, Mufagenesis, lmpairment of Fertility
Three 2-year carcinogenicity studies of aprepitant (two in
Sprague-Dawley rats and one in CD-1 mice) were conducted with aprepitant. Dose
selection for the'studies was based on saturation of absorption in both species.
In the rat carcinogenicity studies, animals were treated with oral doses of
0.05, 0.25, 1, 5, 25, 125 mg/kg twice daily. The highest dose tested produced
a systemic exposure to aprepitant (plasma AUC0-24hr) of 0.4 to 1.4
times the human exposure (AUC0-24hr = 19.6 mcg.hr/mL) at the recommended
dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 125 mg/kg twice
per day produced thyroid follicular cell adenomas and carcinomas in male rats.
In female rats, it produced increased incidences of hepatocellular adenoma at
25 and 125 mg/kg twice daily, and thyroid follicular adenoma at the 125 mg/kg
twice daily dose. In the mouse carcinogenicity study, animals were treated with
oral doses of 2.5, 25, 125, and 500 mg/kg/day. The highest tested dose produced
a systemic exposure of about 2.2 to 2.7 times the human exposure at the recommended
dose. Treatment with aprepitant produced skin fibrosarcomas in male mice of
125 and 500 mg/kg/day groups.
Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid
cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese
hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus
test.
Aprepitant did not affect the fertility or general reproductive
performance of male or female rats at doses up to the maximum feasible dose
of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure
at the recommended human dose and exposure in female rats at about 1.6 times
the human exposure).
Pregnancy. Teratogenic Effects: Category B. Teratology
studies have been performed in rats at oral doses up to 1000 mg/kg twice daily
(plasma AUC0-24hr of 31.3 mcg.hr/mL, about 1.6 times the human exposure
at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma
AUC0-24hr of 26.9 mcg.hr/mL, about 1.4 times the human exposure at
the recommended dose) and have revealed no evidence of impaired fertility or
harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only
if clearly needed.
Nursing Mothers
Aprepitant is excreted in the milk of rats. It is not known
whether this drug is excreted in human milk. Because many drugs are excreted
in human milk and because of the potential for possible serious adverse reactions
in nursing infants from aprepitant and because of the potential for tumorigenicity
shown for aprepitant in rodent carcinogenicity studies, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness of EMEND in pediatric patients have
not been established.
Geriatric Use
In 2 well-controlled clinical studies, of the total number
of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were
75 and over. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects. Greater sensitivity of some older
individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.
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