Cevimeline

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Cevimeline Prescribing Information

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 ≥1%: 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.

The following adverse reaction has been identified during post-approval use of

cevimeline

. Because post-marketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Post-Marketing Adverse Events

Liver and Biliary

System Disorders: cholecystitis

Cevimeline is cis -2’-methylspiro{1-azabicyclo [2.2.2] octane-3, 5’-[1,3] oxathiolane} hydrochloride, hydrate (2:1). Its empirical formula is C₁₀H₁₇NOS.HCl.½ H₂O, and its structural formula is:

Referenced Image

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^oC. 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.

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.

Pharmacokine

tics

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

/-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).

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