DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
MANAGEMENT OF OVERDOSE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
EVOXAC®
Capsules
(cevimeline hydrochloride)
DESCRIPTION
Cevimeline is cis-2’-methylspiro {1-azabicyclo [2.2.2] octane-3,
5’ -[1,3] oxathiolane} hydrochloride, hydrate (2:1). Its empirical
formula is C
10H
17NOS.HCl.½ H
2O,
and its structural formula is:
Cevimeline has a molecular weight of 244.79. It is a white to off
white crystalline powder with a melting point range of 201 to 203°C.
It is freely soluble in alcohol and chloroform, very soluble in water,
and virtually insoluble in ether. The pH of a 1% solution ranges from
4.6 to 5.6. Inactive ingredients include lactose monohydrate, hydroxypropyl
cellulose, and magnesium stearate.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cevimeline is a cholinergic agonist which binds to muscarinic receptors.
Muscarinic agonists in sufficient dosage can increase secretion of
exocrine glands, such as salivary and sweat glands and increase tone
of the smooth muscle in the gastrointestinal and urinary tracts.
Pharmacokinetics
Absorption: After administration of a single 30 mg capsule,
cevimeline was rapidly absorbed with a mean time to peak concentration
of 1.5 to 2 hours. No accumulation of active drug or its metabolites
was observed following multiple dose administration. When administered
with food, there is a decrease in the rate of absorption, with a fasting
T
MAX of 1.53 hours and a T
MAX of 2.86 hours after a meal; the peak
concentration is reduced by 17.3%. Single oral doses across the clinical
dose range are dose proportional.
Distribution: Cevimeline has a volume of distribution of approximately
6L/kg and is <20% bound to human plasma proteins. This suggests
that cevimeline is extensively bound to tissues; however, the specific
binding sites are unknown.
Metabolism: Isozymes CYP2D6 and CYP3A3/4 are responsible for
the metabolism of cevimeline. After 24 hours, 86.7% of the dose was
recovered (16.0% unchanged, 44.5% as cis and trans-sulfoxide, 22.3%
of the dose as glucuronic acid conjugate and 4% of the dose as N-oxide
of cevimeline). Approximately 8% of the trans-sulfoxide metabolite
is then converted into the corresponding glucuronic acid conjugate
and eliminated. Cevimeline did not inhibit cytochrome P450 isozymes
1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4.
Excretion: The mean half-life of cevimeline is 5+/-1 hours.
After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in
urine. After seven days, 97% of the dose was recovered in the urine
and 0.5% was recovered in the feces.
Special Populations: The effects of renal impairment, hepatic
impairment, or ethnicity on the pharmacokinetics of cevimeline have
not been investigated.
Clinical Studies
Cevimeline has been shown to improve the symptoms of dry mouth in
patients with Sjögren’s Syndrome.
A 6-week, randomized, double blind, placebo-controlled study was conducted
in 75 patients (10 men, 65 women) with a mean age of 53.6 years (range
33-75). The racial distribution was Caucasian 92%, Black 1% and other
7%. The effects of cevimeline at 30 mg tid (90 mg/day) and 60 mg tid
(180 mg/day) were compared to those of placebo. Patients were evaluated
by a measure called global improvement, which is defined as a response
of "better" to the question, "Please rate the overall
condition of your dry mouth now compared with how you felt before
starting treatment in this study." Patients also had the option
of selecting "worse" or "no change" as answers.
Seventy-six percent of the patients in the 30 mg tid group reported
a global improvement in their dry mouth symptoms compared to 35% of
the patients in the placebo group. This difference was statistically
significant at p=0.0043. There was no evidence that patients in the
60 mg tid group had better global evaluation scores than the patients
in the 30 mg tid group.
A 12-week, randomized, double-blind, placebo-controlled study was
conducted in 197 patients (10 men, 187 women) with a mean age of 54.5
years (range 23-74). The racial distribution was Caucasian 91.4%,
Black 3% and other 5.6%. The effects of cevimeline at 15 mg tid (45
mg/day) and 30 mg tid (90 mg/day) were compared to those of placebo.
Statistically significant global improvement in the symptoms of dry
mouth (p=0.0004) was seen for the 30 mg tid group compared to placebo,
but not for the 15 mg group compared to placebo. Salivary flow showed
statistically significant increases at both doses of cevimeline during
the study compared to placebo.
A second 12-week, randomized, double-blind, placebo-controlled study
was conducted in 212 patients (11 men, 201 women) with a mean age
of 55.3 years (range 24-75). The racial distribution was Caucasian
88.7%, Black 1.9% and other 9.4%. The effects of cevimeline at 15
mg tid (45 mg/day) and 30 mg tid (90 mg/day) were compared to those
of placebo. No statistically significant differences were noted in
the patient global evaluations. However, there was a higher placebo
response rate in this study compared to the aforementioned studies.
The 30 mg tid group showed a statistically significant increase in
salivary flow from pre-dose to post-dose compared to placebo (p=0.0017).
INDICATIONS AND USAGE
Cevimeline is indicated for the treatment of symptoms of dry mouth
in patients with Sjögren’s Syndrome.
CONTRAINDICATIONS
Cevimeline is contraindicated in patients with uncontrolled asthma,
known hypersensitivity to cevimeline, and when miosis is undesirable,
e.g., in acute iritis and in narrow-angle (angle-closure) glaucoma.
WARNINGS
Cardiovascular Disease:
Cevimeline can potentially alter cardiac conduction and/or heart rate.
Patients with significant cardiovascular disease may potentially be
unable to compensate for transient changes in hemodynamics or rhythm
induced by EVOXAC
®.
EVOXAC
® should be
used with caution and under close medical supervision in patients
with a history of cardiovascular disease evidenced by angina pectoris
or myocardial infarction.
Pulmonary Disease:
Cevimeline can potentially increase airway resistance, bronchial smooth
muscle tone, and bronchial secretions. Cevimeline should be administered
with caution and with close medical supervision to patients with controlled
asthma, chronic bronchitis, or chronic obstructive pulmonary disease.
Ocular:
Ophthalmic formulations of muscarinic agonists have been reported
to cause visual blurring which may result in decreased visual acuity,
especially at night and in patients with central lens changes, and
to cause impairment of depth perception. Caution should be advised
while driving at night or performing hazardous activities in reduced
lighting.
PRECAUTIONS
General:
Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic
effects. These may include: headache, visual disturbance, lacrimation,
sweating, respiratory distress, gastrointestinal spasm, nausea, vomiting,
diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension,
hypertension, shock, mental confusion, cardiac arrhythmia, and tremors.
Cevimeline should be administered with caution to patients with a
history of nephrolithiasis or cholelithiasis. Contractions of the
gallbladder or biliary smooth muscle could precipitate complications
such as cholecystitis, cholangitis and biliary obstruction. An increase
in the ureteral smooth muscle tone could theoretically precipitate
renal colic or ureteral reflux in patients with nephrolithiasis.
Information for Patients: Patients should be informed that
cevimeline may cause visual disturbances, especially at night, that
could impair their ability to drive safely.
If a patient sweats excessively while taking cevimeline, dehydration
may develop. The patient should drink extra water and consult a health
care provider.
Drug Interactions:
Cevimeline should be administered with caution to patients taking
beta adrenergic antagonists, because of the possibility of conduction
disturbances. Drugs with parasympathomimetic effects administered
concurrently with cevimeline can be expected to have additive effects.
Cevimeline might interfere with desirable antimuscarinic effects of
drugs used concomitantly.
Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism
of cevimeline. Cevimeline should be used with caution in individuals
known or suspected to be deficient in CYP2D6 activity, based on previous
experience, as they may be at a higher risk of adverse events. In
an
in vitro study, cytochrome P450 isozymes 1A2, 2A6, 2C9,
2C19, 2D6, 2E1, and 3A4 were not inhibited by exposure to cevimeline.
Carcinogenesis, Mutagenesis and Impairment of Fertility:
Lifetime carcinogenicity studies were conducted in CD-1 mice and F-344
rats. A statistically significant increase in the incidence of adenocarcinomas
of the uterus was observed in female rats that received cevimeline
at a dosage of 100 mg/kg/day (approximately 8 times the maximum human
exposure based on comparison of AUC data). No other significant differences
in tumor incidence were observed in either mice or rats.
Cevimeline exhibited no evidence of mutagenicity or clastogenicity
in a battery of assays that included an Ames test, an in vitro chromosomal
aberration study in mammalian cells, a mouse lymphoma study in L5178Y
cells, or a micronucleus assay conducted in vivo in ICR mice.
Cevimeline did not adversely affect the reproductive performance or
fertility of male Sprague-Dawley rats when administered for 63 days
prior to mating and throughout the period of mating at dosages up
to 45 mg/kg/day (approximately 5 times the maximum recommended dose
for a 60 kg human following normalization of the data on the basis
of body surface area estimates). Females that were treated with cevimeline
at dosages up to 45 mg/kg/day from 14 days prior to mating through
day seven of gestation exhibited a statistically significantly smaller
number of implantations than did control animals.
Pregnancy:
Pregnancy Category C.
Cevimeline was associated with a reduction in the mean number of implantations
when given to pregnant Sprague-Dawley rats from 14 days prior to mating
through day seven of gestation at a dosage of 45 mg/kg/day (approximately
5 times the maximum recommended dose for a 60 kg human when compared
on the basis of body surface area estimates). This effect may have
been secondary to maternal toxicity. There are no adequate and well-controlled
studies in pregnant women. Cevimeline should be used during pregnancy
only if the potential benefit justifies the potential risk to the
fetus.
Nursing Mothers:
It is not known whether this drug is secreted in human milk. Because
many drugs are excreted in human milk, and because of the potential
for serious adverse reactions in nursing infants from EVOXAC
®,
a decision should be made whether to discontinue nursing or discontinue
the drug, taking into account the importance of the drug to the mother.
Pediatric Use:
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use:
Although clinical studies of cevimeline included subjects over the
age of 65, the numbers were not sufficient to determine whether they
respond differently from younger subjects. Special care should be
exercised when cevimeline treatment is initiated in an elderly patient,
considering the greater frequency of decreased hepatic, renal, or
cardiac function, and of concomitant disease or other drug therapy
in the elderly.
ADVERSE REACTIONS
Cevimeline was administered to 1777 patients during clinical trials
worldwide, including Sjögren’s patients and patients with
other conditions. In placebo-controlled Sjögren’s studies
in the U.S., 320 patients received cevimeline doses ranging from 15
mg tid to 60 mg tid, of whom 93% were women and 7% were men. Demographic
distribution was 90% Caucasian, 5% Hispanic, 3% Black and 2% of other
origin. In these studies, 14.6% of patients discontinued treatment
with cevimeline due to adverse events.
The following adverse events associated with muscarinic agonism were
observed in the clinical trials of cevimeline in Sjögren’s
syndrome patients:
| Adverse
Event |
Cevimeline
30 mg
(tid)
n*=533
|
Placebo
(tid)
n=164
|
| Excessive Sweating |
18.7% |
2.4% |
| Nausea |
13.8% |
7.9% |
| Rhinitis |
11.2% |
5.4% |
| Diarrhea |
10.3% |
10.3% |
| Excessive Salivation |
2.2% |
0.6% |
| Urinary Frequency |
0.9% |
1.8% |
| Asthenia |
0.5% |
0.0% |
| Flushing |
0.3% |
0.6% |
| Polyuria |
0.1% |
0.6% |
|
*n is the total number of
patients exposed to the dose at any time during the study.
In addition, the following adverse events (≥3% incidence) were
reported in the Sjögren’s clinical trials:
| Adverse
Event |
Cevimeline
30 mg
(tid)
n*=533
|
Placebo
(tid)
n=164
|
| Headache |
14.4% |
20.1% |
| Sinusitis |
12.3% |
10.9% |
| Upper Respiratory Tract Infection |
11.4% |
9.1% |
| Dyspepsia |
7.8% |
8.5% |
| Abdominal Pain |
7.6% |
6.7% |
| Urinary Tract
Infection |
6.1% |
3.0% |
| Coughing |
6.1% |
3.0% |
| Pharyngitis |
5.2% |
5.4%
|
| Vomiting |
4.6% |
2.4% |
| Injury |
4.5% |
2.4% |
| Back Pain |
4.5% |
4.2% |
| Rash |
4.3% |
6.0% |
| Conjunctivitis |
4.3% |
3.6% |
| Dizziness |
4.1% |
7.3% |
| Bronchitis |
4.1% |
1.2% |
| Arthralgia |
3.7% |
1.8%
|
| Surgical Intervention |
3.3% |
3.0% |
| Fatigue |
3.3%
|
1.2%
|
| Pain |
3.3% |
3.0% |
| Skeletal Pain
|
2.8%
|
1.8%
|
| Insomnia |
2.4% |
1.2% |
| Hot Flushes
|
2.4%
|
0.0%
|
| Rigors |
1.3% |
1.2% |
| Anxiety |
1.3%
|
1.2%
|
|
*n is the total number of
patients exposed to the dose at any time during the study.
The following events were reported in Sjögren’s patients
at incidences of <3% and
³1%: constipation, tremor, abnormal vision,
hypertonia, peripheral edema, chest pain, myalgia, fever, anorexia,
eye pain, earache, dry mouth, vertigo, salivary gland pain, pruritus,
influenza-like symptoms, eye infection, post-operative pain, vaginitis,
skin disorder, depression, hiccup, hyporeflexia, infection, fungal
infection, sialoadenitis, otitis media, erythematous rash, pneumonia,
edema, salivary gland enlargement, allergy, gastroesophageal reflux,
eye abnormality, migraine, tooth disorder, epistaxis, flatulence,
toothache, ulcerative stomatitis, anemia, hypoesthesia, cystitis,
leg cramps, abscess, eructation, moniliasis, palpitation, increased
amylase, xerophthalmia, allergic reaction.
The following events were reported rarely in treated Sjögren’s
patients (<1%): Causal relation is unknown:
Body as a Whole Disorders: aggravated allergy, precordial
chest pain, abnormal crying, hematoma, leg pain, edema, periorbital
edema, activated pain trauma, pallor, changed sensation temperature,
weight decrease, weight increase, choking, mouth edema, syncope, malaise,
face edema, substernal chest pain
Cardiovascular Disorders: abnormal ECG, heart disorder,
heart murmur, aggravated hypertension, hypotension, arrhythmia, extrasystoles,
t wave inversion, tachycardia, supraventricular tachycardia, angina
pectoris, myocardial infarction, pericarditis, pulmonary embolism,
peripheral ischemia, superficial phlebitis, purpura, deep thrombophlebitis,
vascular disorder, vasculitis, hypertension
Digestive Disorders: appendicitis, increased appetite,
ulcerative colitis, diverticulitis, duodenitis, dysphagia, enterocolitis,
gastric ulcer, gastritis, gastroenteritis, gastrointestinal hemorrhage,
gingivitis, glossitis, rectum hemorrhage, hemorrhoids, ileus, irritable
bowel syndrome, melena, mucositis, esophageal stricture, esophagitis,
oral hemorrhage, peptic ulcer, periodontal destruction, rectal disorder,
stomatitis, tenesmus, tongue discoloration, tongue disorder, geographic
tongue, tongue ulceration, dental caries
Endocrine Disorders: increased glucocorticoids, goiter,
hypothyroidism
Hematologic Disorders: thrombocytopenic purpura, thrombocythemia,
thrombocytopenia, hypochromic anemia, eosinophilia, granulocytopenia,
leucopenia, leukocytosis, cervical lymphadenopathy, lymphadenopathy
Liver and Biliary System Disorders: cholelithiasis,
increased gamma-glutamyl transferase, increased hepatic enzymes, abnormal
hepatic function, viral hepatitis, increased serum glutamate oxaloacetic
transaminase (SGOT) (also called AST-aspartate aminotransferase),
increased serum glutamate pyruvate transaminase (SGPT) (also called
ALT-alanine aminotransferase)
Metabolic and Nutritional Disorders: dehydration, diabetes
mellitus, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperlipemia,
hypertriglyceridemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia,
thirst
Musculoskeletal Disorders: arthritis, aggravated arthritis,
arthropathy, femoral head avascular necrosis, bone disorder, bursitis,
costochondritis, plantar fasciitis, muscle weakness, osteomyelitis,
osteoporosis, synovitis, tendinitis, tenosynovitis
Neoplasms: basal cell carcinoma, squamous carcinoma
Nervous Disorders: carpal tunnel syndrome, coma, abnormal
coordination, dysesthesia, dyskinesia, dysphonia, aggravated multiple
sclerosis, involuntary muscle contractions, neuralgia, neuropathy,
paresthesia, speech disorder, agitation, confusion, depersonalization,
aggravated depression, abnormal dreaming, emotional lability, manic
reaction, paroniria, somnolence, abnormal thinking, hyperkinesia,
hallucination
Miscellaneous Disorders: fall, food poisoning, heat
stroke, joint dislocation, post-operative hemorrhage
Resistance Mechanism Disorders: cellulitis, herpes simplex,
herpes zoster, bacterial infection, viral infection, genital moniliasis,
sepsis
Respiratory Disorders: asthma, bronchospasm, chronic
obstructive airway disease, dyspnea, hemoptysis, laryngitis, nasal
ulcer, pleural effusion, pleurisy, pulmonary congestion, pulmonary
fibrosis, respiratory disorder
Rheumatologic Disorders: aggravated rheumatoid arthritis,
lupus erythematosus rash, lupus erythematosus syndrome
Skin and Appendages Disorders: acne, alopecia, burn,
dermatitis, contact dermatitis, lichenoid dermatitis, eczema, furunculosis,
hyperkeratosis, lichen planus, nail discoloration, nail disorder,
onychia, onychomycosis, paronychia, photosensitivity reaction, rosacea,
scleroderma, seborrhea, skin discoloration, dry skin, skin exfoliation,
skin hypertrophy, skin ulceration, urticaria, verruca, bullous eruption,
cold clammy skin
Special Senses Disorders: deafness, decreased hearing,
motion sickness, parosmia, taste perversion, blepharitis, cataract,
corneal opacity, corneal ulceration, diplopia, glaucoma, anterior
chamber eye hemorrhage, keratitis, keratoconjunctivitis, mydriasis,
myopia, photopsia, retinal deposits, retinal disorder, scleritis,
vitreous detachment, tinnitus
Urogenital Disorders: epididymitis, prostatic disorder,
abnormal sexual function, amenorrhea, female breast neoplasm, malignant
female breast neoplasm, female breast pain, positive cervical smear
test, dysmenorrhea, endometrial disorder, intermenstrual bleeding,
leukorrhea, menorrhagia, menstrual disorder, ovarian cyst, ovarian
disorder, genital pruritus, uterine hemorrhage, vaginal hemorrhage,
atrophic vaginitis, albuminuria, bladder discomfort, increased blood
urea nitrogen, dysuria, hematuria, micturition disorder, nephrosis,
nocturia, increased nonprotein nitrogen, pyelonephritis, renal calculus,
abnormal renal function, renal pain, strangury, urethral disorder,
abnormal urine, urinary incontinence, decreased urine flow, pyuria
In one subject with lupus erythematosus receiving concomitant multiple
drug therapy, a highly elevated ALT level was noted after the fourth
week of cevimeline therapy. In two other subjects receiving cevimeline
in the clinical trials, very high AST levels were noted. The significance
of these findings is unknown.
Additional adverse events (relationship unknown) which occurred in
other clinical studies (patient population different from Sjögren's
patients) are as follows:
cholinergic syndrome, blood pressure fluctuation, cardiomegaly, postural
hypotension, aphasia, convulsions, abnormal gait, hyperesthesia, paralysis,
abnormal sexual function, enlarged abdomen, change in bowel habits,
gum hyperplasia, intestinal obstruction, bundle branch block, increased
creatine phosphokinase, electrolyte abnormality, glycosuria, gout,
hyperkalemia, hyperproteinemia, increased lactic dehydrogenase (LDH),
increased alkaline phosphatase, failure to thrive, abnormal platelets,
aggressive reaction, amnesia, apathy, delirium, delusion, dementia,
illusion, impotence, neurosis, paranoid reaction, personality disorder,
hyperhemoglobinemia, apnea, atelectasis, yawning, oliguria, urinary
retention, distended vein, lymphocytosis
Post-marketing Adverse Events: Cholecystitis
MANAGEMENT OF OVERDOSE
Management of the signs and symptoms of acute overdosage should be
handled in a manner consistent with that indicated for other muscarinic
agonists: general supportive measures should be instituted. If medically
indicated, atropine, an anti-cholinergic agent, may be of value as
an antidote for emergency use in patients who have had an overdose
of cevimeline. If medically indicated, epinephrine may also be of
value in the presence of severe cardiovascular depression or bronchoconstriction.
It is not known if cevimeline is dialyzable.
DOSAGE AND ADMINISTRATION
The recommended dose of cevimeline hydrochloride is 30 mg taken three
times a day. There is insufficient safety information to support doses
greater than 30 mg tid. There is also insufficient evidence for additional
efficacy of cevimeline hydrochloride at doses greater than 30 mg tid.
HOW SUPPLIED
EVOXAC
® is available
as white, hard gelatin capsules containing 30 mg of cevimeline hydrochloride.
EVOXAC
® capsules
have a white opaque cap and a white opaque body. The capsules are
imprinted with "EVOXAC" on the cap and "30 mg"
on the body with a black bar above "30 mg". It is supplied
in child resistant bottles of:
100 capsules (NDC 63395-201-13)
Store at 25°C (77°F) excursion
permitted to 15°-30°C (59°-86°F)
Rx Only
Distributed and Marketed by:
Daiichi Pharmaceutical Corporation
Montvale, NJ 07645
EVOXAC is a registered trademark of
Daiichi Pharmaceutical, Co., Ltd.
PRT30 Revised 04/2005 Printed in U.S.A.
