Cevimeline is a quinuclidine derivative of acetylcholine and acts as a cholinergic agonist. Cevimeline improves the symptoms of dry mouth (xerostomia) in patients with Sjogren's syndrome. Prior to the approval of cevimeline, pilocarpine was the only other agent approved for this indication; however, significant advantages of cevimeline over pilocarpine have yet to be determined. In studies comparing cevimeline at various dosages per day, there was no difference between the 180 mg/day and 90 mg/day dosages; however, the 90 mg/day dosage was preferred by patients over the 45 mg/day dosage. An increase in salivary flow was reported at all dosages. Animal studies suggest potential usefulness of cevimeline in patients with xerostomia secondary to radiation therapy of the head or neck area. As a cholinergic agonist, cevimeline is in Phase III trials to study its usefulness as an adjunct in the treatment of Alzheimer's disease. The FDA approved cevimeline in January 2000.
General Administration Information
For storage information, see the specific product information within the the How Supplied section.
Route-Specific Administration
Oral Administration
-May be administered with food to decrease GI upset.
During clinical trials of cevimeline for Sjogren's Syndrome, the following adverse gastrointestinal (GI) effects were reported more frequently in cevimeline-treated patients than placebo-treated patients: nausea (13.8% vs 7.9%), hypersalivation (2.2% vs 0.6%), abdominal pain (7.6% vs 6.7%), and vomiting (4.6% vs 2.4%). Nausea and hypersalivation are associated with the muscarinic agonist effects of the drug. Diarrhea was reported equally in patients receiving active drug and placebo (10.3%). The following GI events were reported at incidences of at least 1% but less than 3%: constipation, anorexia, xerostomia, salivary gland pain, sialoadenitis, salivary gland enlargement, gastroesophageal reflux, tooth disorder, epistaxis, flatulence, toothache (dental pain), ulcerative stomatitis, and eructation. Rarely reported effects (< 1%) for which causality to the drug has not been established include: appendicitis, appetite stimulation, ulcerative colitis, diverticulitis, duodenitis, dysphagia, enterocolitis, gastritis, gastroenteritis, GI bleeding, gingivitis, glossitis, rectal 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, weight gain, and weight loss. Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic effects; gastrointestinal effects seen with toxicity include gastrointestinal spasm, nausea, vomiting, and diarrhea.
During clinical trials of cevimeline for Sjogren's Syndrome, the following centrally-mediated (CNS) effects were reported more frequently in cevimeline-treated patients than placebo-treated patients: asthenia (0.5% vs 0%), fatigue (3.3% vs 1.2%), insomnia (2.4% vs 1.2%), and anxiety (1.3% vs 1.2%). Asthenia is associated with the muscarinic agonist effects of the drug. The following CNS events were reported at incidences of at least 1% but less than 3%: tremor, hypertonia, vertigo, depression, hyporeflexia, migraine or headache, and hypoesthesia. Rarely reported effects (< 1%) for which causality to the drug has not been established include: carpal tunnel syndrome, coma, abnormal coordination, dysesthesia, dyskinesia, dysphonia, aggravated multiple sclerosis, involuntary muscle contractions, neuralgia, neuropathic pain, paresthesias, speech disorder (dysarthria), agitation, confusion, depersonalization, aggravated depression, abnormal dreaming, emotional lability, mania, paroniria, somnolence, abnormal thinking, hyperkinesis, and hallucinations. Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic effects and these may include headache, mental confusion, and tremors.
During clinical trials of cevimeline for Sjogren's Syndrome, the following adverse cardiovascular effects or related symptoms were reported in at least 1% of patients but less than 3% of patients: chest pain (unspecified) and palpitations. Rarely reported effects (< 1%) for which causality to the drug has not been established include: abnormal ECG, heart disorder, heart murmur, aggravated hypertension, hypotension, arrhythmias, extrasystoles, ST-T wave changes, sinus tachycardia, supraventricular tachycardia (SVT), angina pectoris, myocardial infarction, pericarditis, precordial chest pain, pulmonary embolism, peripheral ischemia, superficial phlebitis, purpura, deep vein thrombophlebitis or thromboembolism, vascular disorder, vasculitis, and hypertension. Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic effects and these may include: AV block, tachycardia, bradycardia, hypotension, hypertension, shock, and cardiac arrhythmia.
During clinical trials of cevimeline for Sjogren's Syndrome, the following adverse respiratory effects or infections were reported more frequently in cevimeline-treated patients than placebo-treated patients: rhinitis (11.2% vs 5.4%), sinusitis (12.3% vs 10.9%), upper respiratory tract infection (11.4% vs 9.1%), cough (6.1% vs 3%), and bronchitis (4.1% vs 1.2%). Rhinitis is associated with the muscarinic agonist effects of the drug. The following respiratory events or infections were reported at incidences of at least 1% but less than 3%: fever, influenza-like symptoms, ocular infection, hiccups, infection, fungal infection, otitis media, candidiasis (moniliasis), and pneumonia. Rarely reported effects (< 1%) for which causality to the drug has not been established include: asthma, basal cell carcinoma, bacterial infection, bronchospasm, cellulitis, chronic obstructive airway disease, dyspnea, hemoptysis, herpes simplex, herpes zoster, laryngitis, nasal ulcer, pleural effusion, pleurisy, pulmonary congestion, pulmonary fibrosis, respiratory disorder (unspecified), viral infection, sepsis, and squamous carcinoma.
During clinical trials of cevimeline for Sjogren's Syndrome, conjunctivitis was reported more frequently in cevimeline-treated patients than placebo-treated patients (4.3% vs 3.6%). The following effects related to the special senses were reported at incidences of at least 1% but less than 3%: abnormal vision (visual impairment), ocular pain, earache (otalgia), eye abnormality, and xerophthalmia. Rarely reported effects (< 1%) for which causality to the drug has not been established include: deafness (hearing loss), decreased hearing, motion sickness, parosmia, taste perversion (dysgeusia), blepharitis, cataracts, corneal opacity, corneal ulceration, diplopia, glaucoma (ocular hypertension), anterior chamber ocular hemorrhage, keratitis, keratoconjunctivitis, mydriasis, myopia, periorbital swelling, photopsia, retinal deposits, retinal disorder, scleritis, vitreous detachment, and tinnitus. Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic effects and these may include lacrimation.
During clinical trials of cevimeline for Sjogren's Syndrome, the following dermatologic effects were reported more frequently in cevimeline-treated patients than placebo-treated patients: hyperhidrosis (18.7% vs 2.4%) and hot flashes (2.4% vs 0%). Hyperhidrosis is associated with the muscarinic agonist effects of the drug. The following dermatologic effects were reported at incidences of at least 1% but less than 3%: pruritus, skin disorder (unspecified), erythematous rash, and abscess. Rarely reported effects (< 1%) for which causality to the drug has not been established include: acne vulgaris, alopecia, burn, dermatitis, contact dermatitis, lichenoid dermatitis, atopic dermatitis, furunculosis, hyperkeratosis, lichen planus, nail discoloration, nail disorder, onychia, onychomycosis, paronychia, photosensitivity reaction, rosacea, scleroderma, seborrhea, skin discoloration, xerosis, skin exfoliation, skin hypertrophy, skin ulcer, urticaria, verruca, bullous rash, and cold clammy skin. Cevimeline toxicity is characterized by an exaggeration of its parasympathomimetic effects and these may include profuse sweating (hyperhidrosis).
During clinical trials of cevimeline for Sjogren's Syndrome, urinary tract infection was reported more frequently in cevimeline-treated patients than placebo-treated patients (6.1% vs 3%). The following genitourinary or reproductive effects were reported at incidences of at least 1% but less than 3%: vaginitis and cystitis. Rarely reported effects (< 1%) for which causality to the drug has not been established include: epididymitis, prostatic disorder, abnormal sexual function, amenorrhea, female breast neoplasm, genital candidiasis (moniliasis), malignant female breast neoplasm, mastalgia, positive cervical smear test, dysmenorrhea, endometrial disorder, intermenstrual bleeding (dysmenorrhea), leukorrhea, menorrhagia, menstrual disorder, ovarian cyst, ovarian disorder, genital pruritus, uterine hemorrhage, vaginal bleeding, atrophic vaginitis, proteinuria, bladder discomfort, increased blood urea nitrogen, dysuria, hematuria, micturition disorder, nephrosis, nocturia, increased nonprotein nitrogen, pyelonephritis, renal calculus (nephrolithiasis), abnormal renal function, renal pain, strangury, urethral disorder, abnormal urine, urinary incontinence, decreased urine flow, and pyuria.
During clinical trials of cevimeline for Sjogren's Syndrome, the following musculoskeletal effects or pain symptoms were reported more frequently in cevimeline-treated patients than placebo-treated patients: injury (4.5% vs 2.4%), back pain (4.5% vs 4.2%), arthralgia (3.7% vs 1.8%), pain (3.3% vs 3%), skeletal pain (2.8% vs 1.8%), and rigors (1.3% vs 1.2). The following musculoskeletal or pain events were reported at incidences of at least 1% but less than 3%: myalgia and muscle cramps. Rarely reported effects (< 1%) for which causality to the drug has not been established include: arthritis, aggravated arthritis, arthropathy, femoral head avascular necrosis, bone disorder, bursitis, costochondritis, plantar fasciitis, joint dislocation, leg pain, myasthenia, osteomyelitis, osteoporosis, synovitis, tendinitis, and tenosynovitis.
During clinical trials of cevimeline for Sjogren's Syndrome, anemia was reported in at least 1% of patients but less than 3% of patients. Rarely reported effects (< 1%) for which causality to the drug has not been established include: thrombotic thrombocytopenic purpura (TTP), thrombocythemia, thrombocytopenia, hematoma, hypochromic anemia, eosinophilia, granulocytopenia, leukopenia, leukocytosis, cervical lymphadenopathy, and lymphadenopathy.
During clinical trials of cevimeline for Sjogren's Syndrome, rarely reported liver and biliary effects (< 1%) for which causality to the drug has not been established include: cholelithiasis, increased gamma-glutamyl transferase, elevated hepatic enzymes, abnormal hepatic function (unspecified), and viral hepatitis. Cholecystitis has been reported during post-market use. In one subject with lupus erythematosus on a multiple drug regimen, a highly elevated ALT level was noted after the fourth week of cevimeline therapy. The same adverse effect was also noted in two other subjects. The significance of these findings is unknown.
During clinical trials of cevimeline for Sjogren's Syndrome, rarely reported endocrine or rheumatologic effects (< 1%) for which causality to the drug has not been established include: increased glucocorticoids, goiter, hypothyroidism, aggravated rheumatoid arthritis, lupus erythematosus rash, and lupus erythematosus syndrome.
During clinical trials of cevimeline for Sjogren's Syndrome, increased amylase was reported in at least 1% of patients but less than 3% of patients. Rarely reported metabolic and nutritional effects (< 1%) for which causality to the drug has not been established include: dehydration, diabetes mellitus, hypercalcemia, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, and thirst (polydipsia).
During clinical trials of cevimeline for Sjogren's Syndrome, the following general effects were reported in at least 1% of patients but less than 3% of patients: edema, peripheral edema, and allergic reaction. Rarely reported effects (< 1%) for which causality to the drug has not been established include: aggravated allergy, abnormal crying, periorbital edema, pallor, changed sensation to temperature, heat stroke, choking, mouth edema, syncope, malaise, substernal chest pain, and face edema.
Cevimeline is contraindicated in conditions where miosis is undesirable (e.g., acute iritis or narrow angle glaucoma). In addition, cevimeline may cause visual changes, which may result in decreased visual acuity especially at night and in patients with central lens changes, and cause changes in depth perception. Caution should be advised while driving or operating machinery at night or in reduced lighting.
Cevimeline can potentially increase airway resistance, bronchial smooth muscle tone, and bronchial secretions. Cevimeline is contraindicated in uncontrolled asthma. Cevimeline should be used with caution and close medical supervision in patients with controlled asthma or chronic obstructive pulmonary disease (COPD) (i.e., emphysema or chronic bronchitis).
Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiac disease or cardiac arrhythmias may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. Cevimeline should be used with caution and close medical supervision in patients with a history of cardiac disease evidenced by angina or myocardial infarction.
Cevimeline should be used with caution in patients with a history of cholelithiasis or nephrolithiasis. Contractions of the gall bladder or biliary smooth muscle could precipitate complications such as cholangitis, cholecystitis, or biliary obstruction. An increase in the ureteral smooth muscle tone could theoretically precipitate renal colic or ureteral reflux in patients with nephrolithiasis.
Use cevimeline during pregnancy only if the benefit to the mother justifies the potential risk to the infant. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. Passage through the placenta to the infant should be expected based on the drugs' low molecular weight. In animal studies, a reduction in the mean number of implantations were observed in pregnant rats following administration of doses 5-times the maximum recommended human dose. This effect may have been secondary to maternal toxicity.
Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from cevimeline, a decision should be made whether to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother. It is not known whether cevimeline is secreted in human milk.
The safe and effective use of cevimeline in children has not been established.
Special care should be exercised when cevimeline therapy is initiated in geriatric patients due to the increased incidence of decreased hepatic, renal, or cardiac function and of concomitant disease or other medications in this patient population.
For the treatment of xerostomia and/or dry eye disease* in persons with Sjogren's syndrome:
Oral dosage:
Adults: 30 mg PO 3 times daily.
Maximum Dosage Limits:
-Adults
90 mg/day PO.
-Elderly
90 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Acebutolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Amoxapine: (Major) Amoxapine may antagonize some of the effects of parasympathomimetics. However, bethanechol has occasionally been used therapeutically to offset some of the adverse antimuscarinic effects of cyclic antidepressants. Due to their anticholinergic actions, some cyclic antidepressants, such as amoxapine, may potentially antagonize the therapeutic actions of cholinergic agonists.
Anticholinergics: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Atenolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Atenolol; Chlorthalidone: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Atropine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Atropine; Difenoxin: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Belladonna; Opium: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Benztropine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Beta-blockers: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Betaxolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Bethanechol: (Moderate) Cevimeline and bethanechol are both cholinergic agonists. Coadministration is expected to result in additive parasympathomimetic effects.
Bisoprolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Brimonidine; Timolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Budesonide; Glycopyrrolate; Formoterol: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Bupropion: (Moderate) Cevimeline is partially metabolized by CYP2D6. Inhibitors of this isoenzyme, like bupropion, would be expected to lead to an increase in cevimeline plasma concentrations.
Bupropion; Naltrexone: (Moderate) Cevimeline is partially metabolized by CYP2D6. Inhibitors of this isoenzyme, like bupropion, would be expected to lead to an increase in cevimeline plasma concentrations.
Carteolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Carvedilol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Chlordiazepoxide; Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Chlordiazepoxide; Clidinium: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Cholinesterase inhibitors: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
Clomipramine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Dacomitinib: (Moderate) Monitor for increased toxicity of cevimeline if coadministered with dacomitinib. Coadministration may increase serum concentrations of cevimeline. Cevimeline is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
Desipramine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Dextromethorphan; Bupropion: (Moderate) Cevimeline is partially metabolized by CYP2D6. Inhibitors of this isoenzyme, like bupropion, would be expected to lead to an increase in cevimeline plasma concentrations.
Dextromethorphan; Quinidine: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Concurrent administration of inhibitors of these enzymes, such as quinidine, may lead to increased cevimeline plasma concentrations.
Dicyclomine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Diphenoxylate; Atropine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Disopyramide: (Moderate) Disopyramide possesses clinically significant antimuscarinic properties and these appear to be dose-related. It is possible that disopyramide could antagonize the muscarinic actions of cholinergic agonists. Clinicians should be alert to this possibility.
Donepezil: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
Donepezil; Memantine: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
Dorzolamide; Timolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Doxepin: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Esmolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Flavoxate: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Fluoxetine: (Moderate) Monitor for an increase in cevimeline-related adverse effects if concomitant use of fluoxetine is necessary. Concomitant use may increase cevimeline exposure. Cevimeline is a CYP2D6 substrate; fluoxetine is a strong CYP2D6 inhibitor.
Galantamine: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
Glycopyrrolate: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Glycopyrrolate; Formoterol: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Guanidine: (Moderate) Cevimeline and guanidine are both cholinergic agonists. Coadministration is expected to result in additive parasympathomimetic effects.
Homatropine; Hydrocodone: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Hyoscyamine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Imipramine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Indacaterol; Glycopyrrolate: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Labetalol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Levobunolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Maprotiline: (Major) Maprotiline may antagonize some of the effects of parasympathomimetics. However, bethanechol has occasionally been used therapeutically to offset some of the adverse antimuscarinic effects of cyclic antidepressants. Due to their anticholinergic actions, some cyclic antidepressants like maprotiline may potentially antagonize the therapeutic actions of the cholinesterase-inhibitors used for the treatment of dementia.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Methscopolamine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Metoprolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Nadolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Nebivolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Nebivolol; Valsartan: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Neostigmine: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
Neostigmine; Glycopyrrolate: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided. (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Nortriptyline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Olanzapine; Fluoxetine: (Moderate) Monitor for an increase in cevimeline-related adverse effects if concomitant use of fluoxetine is necessary. Concomitant use may increase cevimeline exposure. Cevimeline is a CYP2D6 substrate; fluoxetine is a strong CYP2D6 inhibitor.
Oxybutynin: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Paroxetine: (Moderate) Monitor for an increase in cevimeline-related adverse effects if concomitant use of paroxetine is necessary. Concomitant use may increase cevimeline exposure. Cevimeline is a CYP2D6 substrate; paroxetine is a strong CYP2D6 inhibitor.
Perphenazine; Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Physostigmine: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
Pilocarpine: (Moderate) Cevimeline and pilocarpine are both cholinergic agonists. Coadministration is expected to result in additive parasympathomimetic effects.
Pindolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Pralidoxime: (Moderate) Cevimeline and pralidoxime are both cholinergic agonists. Coadministration is expected to result in additive parasympathomimetic effects.
Propantheline: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Propranolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Protriptyline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Pyridostigmine: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
Quinidine: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Concurrent administration of inhibitors of these enzymes, such as quinidine, may lead to increased cevimeline plasma concentrations.
Rivastigmine: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
Scopolamine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Sotalol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Terbinafine: (Moderate) Cevimeline is partially metabolized by CYP2D6. Inhibitors of this isoenzyme, like terbinafine, would be expected to lead to an increase in cevimeline plasma concentrations.
Timolol: (Major) Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Cevimeline can potentially alter cardiac conduction and/or heart rate. Patients with significant cardiovascular disease treated with beta-blockers may potentially be unable to compensate for transient changes in hemodynamics or rhythm induced by cevimeline. If use of these drugs together cannot be avoided, close monitoring of blood pressure, heart rate and cardiac function is advised.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Trihexyphenidyl: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Trimipramine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation, or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Trospium: (Moderate) Pharmacologically, parasympathomimetic drugs enhance muscarinic/cholinergic function. Because trospium is an antimuscarinic, the muscarinic actions of drugs known as parasympathomimetics, including direct cholinergic agonists, could be antagonized when used concomitantly with trospium.
Cevimeline is a muscarinic receptor agonist. Muscarinic receptors occur in cardiovascular, exocrine gland, gastrointestinal, ocular, pulmonary, and urinary tissues. Effects of muscarinic agonists on these tissues may include bradycardia or other alterations in cardiac conduction, vasodilation, secretion from lacrimal, salivary and sweat glands, increased GI motility, miosis and accommodation, increased bronchial secretions and bronchoconstriction, and biliary or urinary tract contraction. Cevimeline has partial direct M1-receptor agonist activity in the CNS and has high binding affinity for muscarinic M3 receptors on lacrimal and salivary gland epithelium. Binding to other muscarinic receptor subtypes has been reported to varying degrees depending upon the tissue and assay used. As a muscarinic receptor agonist, cevimeline increases secretion of exocrine glands, such salivary and sweat glands and increases tone of the smooth muscle in the gastrointestinal tract and urinary tract.
Cevimeline is administered orally. It has a high volume of distribution with little protein binding, suggesting high binding to tissues; however, specific tissue binding sites are not known. Cevimeline is metabolized by liver cytochrome P450 isoenzymes (CYP) 2D6 and 3A4. It has no induction or inhibitory effects on any CYP isoenzymes. The mean half-life is 5 hours and it is mostly excreted in the urine.
Affected cytochrome P450 isoenzymes: CYP2D6, CYP3A4
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration of cevimeline, Tmax occurs within 1.5-2 hours. When cevimeline is administered with food the Tmax increases to 2.86 hours and the Cmax is decreased by 17.3%.
-Special Populations
Hepatic Impairment
The effects of hepatic impairment on cevimeline have not been studied.
Renal Impairment
The effects of renal impairment on cevimeline have not been studied.