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Pilocarpine / Salagen® and Cevimeline / Evoxac® for Dry Mouth (Xerostomia)

see also: Management of Xerostomia (Dry Mouth)

Initiated by Piper Wenzel, BS and Henry Hoffman, MD April 2023

Pilocarpine/Salagen®

Indications

A. A double blind randomized trial among 72 patients with Sjogrens Syndrome and xerostomia and xeropthalmia were assigned to either 10 drops of pilocarpine (5 mg) or 10 drops of artifical saliva orally three times a day for 12 weeeks - identified statistically significant improvement in salivary flow and lacrimal flow with pilocarpine - with the most common side-effects being sialorrhoea and nausea (Cifuentes 2018)

B. Salagen  (pilocarpine tablets) as per FDA NDA 20-237/S012 Page 3 addressing salagen® downloaded 4-12-2023 https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/020237s012lbl.... identifies indication for use of  SALAGEN ® Tablets:

1) "the treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck"

2) "the treatment of symptoms of dry mouth in patients with Sjogren's syndrome". 

with contraindications listed: uncontrolled asthma / when miosis is undesirable (narrow angle glaucoma / acute irits) and

other warnings: cardivascular disease / pulmonary disease with precautions identified due to parasympathomomietic effects.

Mechanism of Action

As per Kapourani et al, pilocarpine is a non-specific muscarinic acetylcholine receptor agonist wtih mild beta-adrenergic activity (Kapourani 2022). Pilocarpine is capable of activating all 5 muscarinic receptor subtypes - with the therapeutic effect addressing xerostomia coming from its binding to the muscarinic acetylcholine receptor 3 (M3R) in the salivary glands.  

Precautions

Barbe (2018) identified use of pilocarpine ("5 mg tablets taken up to three times/day for three months to assess treatment effect") and cevimeline ('30 mg tablets taken up to three times/day, also for at least 3 months") should be 'thoroughly supervised by healthcare professionals' in older patients due to 'highly prevalent cholinergic side effects' including nausea, emesis, bronchoconstriction, bradycardia, hypotension and others". These investigators additionally voice concern about drug interaction with other medications including beta-adrenergic antagonists, antidepressants or clozapine. 

References

Barbe AG. Medication-Induced Xerostomia and Hyposalivation in the Elderly: Culprits, Complications, and Management. Drugs Aging. 2018 Oct;35(10):877-885. doi: 10.1007/s40266-018-0588-5. PMID: 30187289.

Thakkar JP, Lane CJ. Hyposalivation and Xerostomia and Burning Mouth Syndrome: Medical Management. Oral Maxillofac Surg Clin North Am. 2022 Feb;34(1):135-146. doi: 10.1016/j.coms.2021.08.002. Epub 2021 Sep 29. PMID: 34598858.

FDA "NDA 20-237/S012 Page 3 addressing salagen® (pilocarpine) accessed 4-12-2023 https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/020237s012lbl.pdf

Cifuentes M, Del Barrio-Díaz P, Vera-Kellet C. Pilocarpine and artificial saliva for the treatment of xerostomia and xerophthalmia in Sjögren syndrome: a double-blind randomized controlled trial. Br J Dermatol. 2018 Nov;179(5):1056-1061. doi: 10.1111/bjd.16442. Epub 2018 May 29. PMID: 29432648.

Panarese V, Moshirfar M. Pilocarpine. 2022 Dec 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32310588.

Kapourani A, Kontogiannopoulos KN, Barmpalexis P. A Review on the Role of Pilocarpine on the Management of Xerostomia and the Importance of the Topical Administration Systems Development. Pharmaceuticals (Basel). 2022 Jun 18;15(6):762. doi: 10.3390/ph15060762. PMID: 35745681; PMCID: PMC9230966.

 

Cevimeline/Evoxac®

Indications

A. The FDA identifies cevimeline as indicated for “the treatment of symptoms of dry mouth in patients with Sjogren’s Syndrome” with their recommended dose is “30 mg taken three times a day.” Cevimeline can be found under the brand name Evoxac (20-989 Evoxac Final Print Label - full reference below).

B. Chambers et al demonstrated that “cevimeline can improve nonstimulated salivary flow in patients with postirradiation xerostomia”. This study involved two double-blind trials including 500 patients total with a history of head and neck cancer who developed xerostomia after radiotherapy. Patients were assigned to cevimeline 30 mg three times a day (with increase to 45 mg three times daily if no improvement described after six weeks) or placebo for 12 weeks. One of the two trials demonstrated a statistically significant improvement in “dry mouth in the final global evaluation of oral dryness”. Neither study demonstrated significant difference in stimulated salivary flow. The most frequent adverse effect was increased sweating (Chambers 2007).

C. Contraindications listed include patients with uncontrolled asthma, known hypersensitivity to cevimeline, and when miosis is undesirable (acute iritis, narrow-angle glaucoma) (20-989 Evoxac Final Print Label).

Mechanism of Action

As per Fife et al, cevimeline is a muscarinic acetylcholine receptor agonist with predominant affinity for the M1 and M3 receptors (Fife 2002). The drug activates these receptors located on salivary gland epithelium to increase salivary secretions. According to Chambers et al, cevimeline has a longer half-life and duration than pilocarpine (Chambers 2007).

Precautions

Warnings include the need to use the drug with caution in patients with cardiovascular disease, pulmonary disease, and ocular abnormalities (20-989 Evoxac Final Print Label).

Precautions identified focus on the drug’s capability to exaggerate parasympathomimetic effects including, but not limited to, visual disturbances, lacrimation, sweating, respiratory distress, nausea, vomiting, diarrhea, hypertension, and cardiac arrhythmia. Additionally, caution should be taken in patients with nephrolithiasis or cholelithiasis as increased contraction of the gallbladder and ureteral smooth muscle could precipitate complications including cholecystitis and ureteral reflux, respectively (20-989 Evoxac Final Print Label).

Administration of cevimeline in a patient taking beta adrenergic antagonists has the potential to contribute to conduction disturbances. Additionally, cevimeline can augment the effects of other drugs with parasympathomimetic activity (20-989 Evoxac Final Print Label).

References

Cevimeline (Evoxac) for dry mouth. Med Lett Drugs Ther. 2000;42(1084):70.

Cevimeline. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; January 23, 2017.

Chambers MS, Posner M, Jones CU, et al. Cevimeline for the treatment of postirradiation xerostomia in patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 2007;68(4):1102-1109. doi:10.1016/j.ijrobp.2007.01.019

Fife RS, Chase WF, Dore RK, et al. Cevimeline for the treatment of xerostomia in patients with Sjögren syndrome: a randomized trial. Arch Intern Med. 2002;162(11):1293-1300. doi:10.1001/archinte.162.11.1293

Petrone D, Condemi JJ, Fife R, Gluck O, Cohen S, Dalgin P. A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren's syndrome patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum. 2002;46(3):748-754. doi:10.1002/art.510

FDA 20-989 Evoxac Final Print Label. U.S. Food and Drug Administration; 2001. Accessed April 18, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20-989_Evoxac_pr...