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
Relpax Side Effects, and Drug Interactions - Eletriptan hydrobromide
Relpax Side Effects, and Drug Interactions - Eletriptan hydrobromide
SIDE EFFECTS
Serious cardiac events, including some that have been fatal,
have occurred following the use of 5-HT1 agonists. These events are
extremely rare and most have been reported in patients with risk factors predictive
of CAD. Events reported have included coronary artery vasospasm, transient myocardial
ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation
(see CONTRAINDICATIONS, WARNINGS
and PRECAUTIONS). Incidence in Controlled Clinical
Trials:
Among 4,597 patients who treated the first migraine headache
with RELPAX in short-term placebo-controlled trials, the most common adverse
events reported with treatment with RELPAX were asthenia, nausea, dizziness,
and somnolence. These events appear to be dose related. In long-term open-label
studies where patients were allowed to treat multiple migraine attacks for up
to 1 year, 128 (8.3%) out of 1,544 patients discontinued
treatment due to adverse events. Table 2 lists adverse events that occurred
in the subset of 5,125 migraineurs who received eletriptan doses of 20 mg, 40
mg and 80 mg or placebo in worldwide placebo-controlled clinical trials. The
events cited reflect experience gained under closely monitored conditions of
clinical trials in a highly selected patient population. In actual clinical
practice or in other clinical trials, those frequency estimates may not apply,
as the conditions of use, reporting behavior, and the kinds of patients treated
may differ. Only adverse events that were more frequent in a RELPAX treatment
group compared to the placebo group with an incidence greater than or equal
to 2% are included in Table 2.
|
Table 2: Adverse Experience Incidence in Placebo-Controlled
Migraine Clinical Trials: Events Reported by ³
2% Patients Treated with RELPAX and More Than Placebo
|
|
Adverse Event Type
|
Placebo (n=988)
|
RELPAX 20 mg (n=431)
|
RELPAX 40 mg (n=1774)
|
RELPAX 80 mg (n=1932)
|
|
ATYPICAL SENSATIONS
|
|
Paresthesia
|
2%
|
3%
|
3%
|
4%
|
|
Flushing/feeling of
|
2%
|
2%
|
2%
|
2%
|
|
warmth
|
|
|
|
|
|
PAIN AND PRESSURE SENSATIONS
|
|
Chest –
|
1%
|
1%
|
2%
|
4%
|
|
tightness/pain/pressure
|
|
|
|
|
|
Abdominal –pain/discomfort/ stomach pain/ cramps/pressure
|
1%
|
1%
|
2%
|
2%
|
|
DIGESTIVE
|
|
Dry mouth
|
2%
|
2%
|
3%
|
4%
|
|
Dyspepsia
|
1%
|
1%
|
2%
|
2%
|
|
Dysphagia – throat tightness/ difficulty swallowing
|
0.2%
|
1%
|
2%
|
2%
|
|
Nausea
|
5%
|
4%
|
5%
|
8%
|
|
NEUROLOGICAL
|
|
Dizziness
|
3%
|
3%
|
6%
|
7%
|
|
Somnolence
|
4%
|
3%
|
6%
|
7%
|
|
Headache
|
3%
|
4%
|
3%
|
4%
|
|
OTHER
|
|
Asthenia
|
3%
|
4%
|
5%
|
10%
|
RELPAX is generally well-tolerated. Across all doses, most
adverse reactions were mild and transient. The frequency of adverse events in
clinical trials did not increase when up to 2 doses of RELPAX were taken within
24 hours. The incidence of adverse events in controlled clinical trials was
not affected by gender, age, or race of the patients. Adverse event frequencies
were also unchanged by concomitant use of drugs commonly taken for migraine
prophylaxis (e.g., SSRIs, beta blockers, calcium channel blockers, tricyclic
antidepressants), estrogen replacement therapy and oral contraceptives.
Other Events Observed in Association With the Administration
of RELPAX Tablets:
In the paragraphs that follow, the frequencies of less commonly
reported adverse clinical events are presented. Because the reports include
events observed in open studies, the role of RELPAX Tablets in their causation
cannot be reliably determined. Furthermore, variability associated with adverse
event reporting, the terminology used to describe adverse events, etc., limit
the value of the quantitative frequency estimates provided. Event frequencies
are calculated as the number of patients reporting an event divided by the total
number of patients (N=4,719) exposed to RELPAX. All reported events are included
except those already listed in Table 2, those too general to be informative,
and those not reasonably associated with the use of the drug. Events are further
classified within body system categories and enumerated in order of decreasing
frequency using the following definitions: frequent adverse events are those
occurring in at least 1/100 patients, infrequent adverse events are those occurring
in 1/100 to 1/1000 patients and rare adverse events are those occurring in fewer
than 1/1000 patients.
General: Frequent were back pain, chills and
pain. Infrequent were face edema and malaise. Rare were abdomen enlarged, abscess,
accidental injury, allergic reaction, fever, flu syndrome, halitosis, hernia,
hypothermia, lab test abnormal, moniliasis, rheumatoid arthritis and shock.
Cardiovascular: Frequent was palpitation. Infrequent
were hypertension, migraine, peripheral vascular disorder and tachycardia. Rare
were angina pectoris, arrhythmia, atrial fibrillation, AV block, bradycardia,
hypotension, syncope, thrombophlebitis, cerebrovascular disorder, vasospasm
and ventricular arrhythmia.
Digestive: Infrequent were anorexia, constipation,
diarrhea, eructation, esophagitis, flatulence, gastritis, gastrointestinal disorder,
glossitis, increased salivation and liver function tests abnormal. Rare were
gingivitis, hematemesis, increased appetite, rectal disorder, stomatitis, tongue
disorder, tongue edema and tooth disorder.
Endocrine: Rare were goiter, thyroid adenoma
and thyroiditis.
Hemic and Lymphatic: Rare were anemia, cyanosis,
leukopenia, lymphadenopathy, monocytosis and purpura.
Metabolic: Infrequent were creatine phosphokinase
increased, edema, peripheral edema and thirst. Rare were alkaline phosphatase
increased, bilirubinemia, hyperglycemia, weight gain and weight loss.
Musculoskeletal: Infrequent were arthralgia,
arthritis, arthrosis, bone pain, myalgia and myasthenia. Rare were bone neoplasm,
joint disorder, myopathy and tenosynovitis. Neurological: Frequent
were hypertonia, hypesthesia and vertigo. Infrequent were abnormal dreams, agitation,
anxiety, apathy, ataxia, confusion, depersonalization, depression, emotional
lability, euphoria, hyperesthesia, hyperkinesia, incoordination, insomnia, nervousness,
speech disorder, stupor, thinking abnormal and tremor. Rare were abnormal gait,
amnesia, aphasia, catatonic reaction, dementia, diplopia, dystonia, hallucinations,
hemiplegia, hyperalgesia, hypokinesia, hysteria, manic reaction, neuropathy,
neurosis, oculogyric crisis, paralysis, psychotic depression, sleep disorder
and twitching.
Respiratory: Frequent was pharyngitis. Infrequent
were asthma, dyspnea, respiratory disorder, respiratory tract infection, rhinitis,
voice alteration and yawn. Rare were bronchitis, choking sensation, cough increased,
epistaxis, hiccup, hyperventilation, laryngitis, sinusitis and sputum increased.
Skin and Appendages: Frequent was sweating.
Infrequent were pruritus, rash and skin disorder. Rare were alopecia, dry skin,
eczema, exfoliative dermatitis, maculopapular rash, psoriasis, skin discoloration,
skin hypertrophy and urticaria.
Special Senses: Infrequent was abnormal vision,
conjunctivitis, ear pain, eye pain, lacrimation disorder, photophobia, taste
perversion and tinnitus. Rare were abnormality of accommodation, dry eyes, ear
disorder, eye hemorrhage, otitis media, parosmia and ptosis.
Urogenital: Infrequent were impotence, polyuria,
urinary frequency and urinary tract disorder. Rare were breast pain, kidney
pain, leukorrhea, menorrhagia, menstrual disorder and vaginitis.
DRUG ABUSE AND DEPENDENCE
Although the abuse potential of RELPAX has not been assessed,
no abuse of, tolerance to, withdrawal from, or drug-seeking behavior was observed
in patients who received RELPAX in clinical trials or their extensions. The
5-HT1B/1D agonists, as a class, have not been associated with drug
abuse.
DRUG INTERACTIONS
Ergot-containing drugs: Ergot-containing drugs have
been reported to cause prolonged vasospastic reactions. Because these effects
may be additive, use of ergotamine-containing or
ergot-type medications (like dihydroergotamine [DHE] or methysergide) and eletriptan
within 24 hours of each other is not recommended (see CONTRAINDICATIONS).
CYP3A4 Inhibitors: Eletriptan is metabolized primarily
by CYP3A4 (see WARNINGS regarding use
with potent CYP3A4 inhibitors).
Monoamine Oxidase Inhibitors: Eletriptan is not a substrate
for monoamine oxidase (MAO) enzymes, therefore there is no expectation of an
interaction between eletriptan and MAO inhibitors.
Propranolol: The Cmax and AUC of eletriptan
were increased by 10 and 33% respectively in the presence of propranolol. No interactive increases in
blood pressure were observed. No dosage adjustment appears to be needed for
patients taking propranolol (see CLINICAL PHARMACOLOGY).
Selective serotonin reuptake inhibitors (SSRIs): SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been
reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with 5-HT1 agonists. If concomitant
treatment with eletriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised.
Other 5-HT1 agonists: Concomitant use of
other 5-HT1 agonists within 24 hours of RELPAX treatment is not recommended
(see CONTRAINDICATIONS).
Drug/Laboratory Test Interactions: RELPAX Tablets are
not known to interfere with commonly employed clinical laboratory tests.
Carcinogenesis: Lifetime carcinogenicity studies, 104
weeks in duration, were carried out in mice and rats by administering eletriptan
in the diet. In rats, the incidence of testicular interstitial cell adenomas
was increased at the high dose of 75 mg/kg/day. The estimated exposure (AUC)
to parent drug at that dose was approximately 6 times that achieved in humans
receiving the maximum recommended daily dose (MRDD) of 80 mg, and at the no-effect
dose of 15 mg/kg/day it was approximately 2 times the human exposure at the
MRDD. In mice, the incidence of hepatocellular adenomas was increased at the
high dose of 400 mg/kg/day. The exposure to parent drug (AUC) at that dose was
approximately 18 times that achieved in humans receiving the MRDD, and the AUC
at the no-effect dose of 90 mg/kg/day was approximately 7 times the human exposure
at the MRDD.
Mutagenesis: Eletriptan was not mutagenic in bacterial
or mammalian cell assays in vitro, testing negative in the Ames reverse
mutation test and the hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
mutation test in Chinese hamster ovary cells. It was not clastogenic in two
in vivo mouse micronucleus assays. Results were equivocal in in vitro
human lymphocyte clastogenicity tests, in which the incidence of polyploidy
was increased in the absence of metabolic activation (-S9 conditions), but not
in the presence of metabolic activation.
Impairment of Fertility: In a rat fertility and early
embryonic development study, doses tested were 50, 100 and 200 mg/kg/day, resulting
in systemic exposures to parent drug in rats, based on AUC, that were 4, 8 and
16 times MRDD, respectively, in males and 7, 14 and 28 times MRDD, respectively,
in females. There was a prolongation of the estrous cycle at the 200 mg/kg/day
dose due to an increase in duration of estrus, based on vaginal smears. There
were also dose-related, statistically significant decreases in mean numbers
of corpora lutea per dam at all 3 doses, resulting in decreases in mean numbers
of implants and viable fetuses per dam. This suggests a partial inhibition of
ovulation by eletriptan. There was no effect on fertility of males and no other
effect on fertility of females.
Pregnancy: Pregnancy Category C: In reproductive
toxicity studies in rats and rabbits, oral administration of eletriptan was
associated with developmental toxicity (decreased fetal and pup weights and
an increased incidence of fetal structural abnormalities). Effects on fetal
and pup weights were observed at doses that were, on a mg/m2 basis,
6 to 12 times greater than the clinical maximum recommended daily dose (MRDD)
of 80 mg. The increase in structural alterations occurred in the rat and rabbit
at doses that, on a mg/m2 basis, were 12 times greater than (rat)
and approximately equal to (rabbit) the MRDD. When pregnant rats were administered
eletriptan during the period of organogenesis at doses of 10, 30 or 100 mg/kg/day,
fetal weights were decreased and the incidences of vertebral and sternebral
variations were increased at 100 mg/kg/day (approximately 12 times the MRDD
on a mg/m2 basis). The 100 mg/kg dose was also maternally toxic,
as evidenced by decreased maternal body weight gain during gestation. The no-effect
dose for developmental toxicity in rats exposed during organogenesis was 30
mg/kg, which is approximately 4 times the MRDD on a mg/m2 basis.
When doses of 5, 10 or 50 mg/kg/day were given to New Zealand
White rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg,
which is approximately 12 times the MRDD on a mg/m2 basis. The incidences
of fused sternebrae and vena cava deviations were increased in all treated groups.
Maternal toxicity was not produced at any dose. A no-effect dose for developmental
toxicity in rabbits exposed during organogenesis was not established, and the
5 mg/kg dose is approximately equal to the MRDD on a mg/m2 basis.
There are no adequate and well-controlled studies in pregnant women; therefore,
eletriptan should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Nursing Mothers: Eletriptan is excreted in human breast
milk. In one study of 8 women given a single dose of 80 mg, the mean total amount
of eletriptan in breast milk over 24 hours in this group was approximately 0.02%
of the administered dose. The ratio of eletriptan mean concentration in breast
milk to plasma was 1:4, but there was great variability. The resulting eletriptan
concentration-time profile was similar to that seen in the plasma over 24 hours,
with very low concentrations of drug (mean 1.7 ng/mL) still present in the milk
18-24 hours post dose. The N-desmethyl active metabolite was not measured in
the breast milk. Caution should be exercised when RELPAX is administered to
nursing women.
Pediatric Use: Safety and effectiveness of RELPAX Tablets
in pediatric patients have not been established; therefore, RELPAX is not recommended
for use in patients under 18 years of age.
The efficacy of RELPAX Tablets (40 mg) in patients 11-17 was
not established in a randomized, placebo-controlled trial of 274 adolescent
migraineurs (see CLINICAL STUDIES). Adverse events
observed were similar in nature to those reported in clinical trials in adults.
Postmarketing experience with other triptans includes a limited number of reports
that describe pediatric patients who have experienced clinically serious adverse
events that are similar in nature to those reported rarely in adults. Long-term
safety of eletriptan was studied in 76 adolescent patients who received treatment
for up to one year. A similar profile of adverse events to that of adults was
observed. The long-term safety of eletriptan in pediatric patients has not been
established.
Geriatric Use: Eletriptan has been given to only 50
patients over the age of 65. Blood pressure was increased to a greater extent
in elderly subjects than in young subjects. The pharmacokinetic disposition
of eletriptan in the elderly is similar to that seen in younger adults (see
CLINICAL PHARMACOLOGY). In clinical trials,
there were no apparent differences in efficacy or the incidence of adverse events
between patients under 65 years of age and those 65 and above (n=50).
There is a statistically significantly increased half-life
(from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age)
and younger adult subjects (18 to 45 years of age) (see CLINICAL
PHARMACOLOGY).
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