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 30mg (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.
| Adverse Event | Cevimeline 30mg (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 less than 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
(less than 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 EVOXAC®. 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
