Cevimeline Hydrochloride

CEVIMELINE HYDROCHLORIDE- cevimeline hydrochloride capsule
Hikma Pharmaceuticals USA Inc.

Rx only

DESCRIPTION

Cevimeline is cis-2’-methylspiro {1-azabicyclo [2.2.2] octane-3, 5’ -[1,3] oxathiolane} hydrochloride, hydrate (2:1). Its molecular formula is C10 H17 NOS.HCl.1/2 H2 O, and its structural formula is:

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(click image for full-size original)

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 hydroxypropyl cellulose, lactose monohydrate, and magnesium stearate. Gelatin capsule shells contain: gelatin, monogramming ink, purified water, sodium lauryl sulfate and titanium dioxide. The monogramming ink contains: ammonium hydroxide, iron oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.

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 TMAX of 1.53 hours and a TMAX 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 6 L/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% 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 to 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 to 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 to 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 hydrochloride is indicated for the treatment of symptoms of dry mouth in patients with Sjögren’s Syndrome.

CONTRAINDICATIONS

Cevimeline hydrochloride 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 cevimeline. Cevimeline 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.

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