Professional Drug Information > Pilocarpine Hydrochloride

Pilocarpine (Systemic)

VA CLASSIFICATION
Primary: AU300

Commonly used brand name(s): Salagen.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Cholinergic—

Indications

Accepted

Xerostomia (treatment)—Pilocarpine is indicated for the treatment of xerostomia from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck.^{{02}{04} {05}{06}{07}{08} {09}{10}{11}{12}} Pilocarpine is also indicated for the treatment of symptoms of xerostomia in patients with Sjogren's syndrome. ^{19}{20}

[Xerophthalmia (treatment)]—Pilocarpine is indicated for the treatment of xerophthalmia in patients with Sjogren's syndrome.^{19}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    —Obtained from the naturally-occurring alkaloid pilocarpine found in the leaves of the South American shrub, Pilocarpus jaborandi.^{19}
Molecular weight—
    Pilocarpine hydrochloride: 244.72^{01}

pKa—
    7.15 ^{03}

Mechanism of action/Effect:

Pilocarpine is a cholinergic parasympathomimetic agent that exerts a broad spectrum of pharmacologic effects with predominantly muscarinic action, including stimulation of exocrine function. This stimulation results in increased secretion by the exocrine glands, including the salivary glands.^{02}{19}{20}


Other actions/effects:

Other exocrine glands, such as the sweat, lacrimal, gastric, pancreatic, and intestinal glands, may be stimulated.^{{02}{15}{19}{20}}

Pulmonary effects may include stimulation of the mucous cells of the respiratory tract, increased airway resistance, and increased bronchial smooth muscle tone and secretions. ^{02}{15}

Cardiovascular effects may include changes in hemodynamics and cardiac rhythm. However, pilocarpine may have paradoxical effects. Instead of the expected muscarinic effect of vasodepression occurring, pilocarpine may produce short-lived hypotension followed by hypertension. In addition, both bradycardia and tachycardia have been reported.^{{02} {15}}

Gastrointestinal effects include smooth muscle stimulation of the intestinal tract that may result in increased tone and motility, spasm, and tenesmus. The tone and motility of the urinary tract, gallbladder, and biliary duct smooth muscle may be enhanced. ^{02}{15}

Biotransformation:

Not fully understood; inactivation of pilocarpine is thought to occur at the neuronal synapses and in the plasma.^{02}{19}{20}

Half-life:

Elimination—0.76 hours after 2 days of 5 mg of pilocarpine administered orally 3 times daily; 1.35 hours after 2 days of 10 mg of pilocarpine administered orally 3 times daily. ^{02}{19}{20}

Onset of action:

20 minutes. ^{02}

Time to peak concentration:

1.25 or 0.85 hours, after 2 days of 5 or 10 mg, respectively, of pilocarpine administered orally 3 times daily.^{{02}{15}{19}{20}}

Peak serum concentration:

15 or 41 nanograms per mL (72 or 196.8 nanomoles per L), after 2 days of 5 or 10 mg, respectively, of pilocarpine administered orally 3 times daily.^{15}{20}

Pharmacokinetic studies were done in young men and men and women over 65 years of age after administration of 5 or 10 mg oral pilocarpine 3 times daily for 2 days. The pharmacokinetics were comparable in men under and over 65 years. However, all 5 of the women over 65 years of age in the study had mean maximum concentrations (C _max) that were approximately twice as high as the men's values. The men's C _max values were 15 and 41 nanograms per mL (72 and 196.8 nanomoles per L) after the 5 and 10 mg dosage, respectively. ^{02} No pharmacokinetic values are available for younger women. ^{15}

Time to peak effect:

1 hour. ^{02}

Duration of action:

3 to 5 hours. ^{02}

Elimination:
    Not fully understood; in the urine, as unchanged pilocarpine and its minimally active or inactive degradation products, such as pilocarpic acid.^{02}{19}{20}
    In dialysis—It is not known if pilocarpine is dialyzable. ^{02}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to ophthalmic pilocarpine may be sensitive to oral pilocarpine also.

Carcinogenicity

Studies have not been done.^{02}{20}

Mutagenicity

Pilocarpine did not cause genetic toxicity in bacterial assays (Salmonella andE. coli) for reverse gene mutations, in vitrochromosome aberration assay (micronucleus test) in Chinese hamster ovary cell line, in vivochromosome aberration assay (micronucleus test) in mice, and primary DNA damage assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures.^{20}

Pregnancy/Reproduction
Fertility—
Studies have not been done in humans.^{02}{20}

Oral administration of pilocarpine to male and female rats at a dosage of 18 mg/kg/day (approximately 5 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m²) estimates) resulted in impaired reproductive function including reduced fertility, decreased sperm motility, and morphologic evidence of abnormal sperm. It is unclear whether the reduction in fertility was due to male animals, female animals, or both. In dogs, exposure to pilocarpine at a dosage of 3 mg/kg/day (approximately 3 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area mg/m²for 6 months) resulted in evidence of impaired spermatogenesis. The data obtained in these studies suggest that pilocarpine may impair fertility in male and female humans. ^{20}

Pregnancy—
Studies have not been done in humans.^{02}{20}

Fetuses of pregnant rats given 90 mg/kg per day of pilocarpine (approximately 26 times the maximum recommended human dose) had reduced mean body weight and an increased incidence of skeletal variations. However, these effects may have been secondary to maternal toxicity.^{02}{15}{20}

FDA Pregnancy Category C.^{02}{20}

Breast-feeding

It is not known whether pilocarpine is distributed into breast milk.^{{02} {19}{20}}

Pediatrics

Appropriate studies on the relationship of age to the effects of oral pilocarpine have not been performed in the pediatric population. Safety and efficacy have not been established. ^{{02}{15}{19}{20}}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of oral pilocarpine in the elderly.

Clinical trials were conducted in both men and women under and over 65 years of age. The adverse events reported by these 4 groups were comparable. In addition, pharmacokinetic studies were done in young men and men and women over 65 years of age after administration of 5 or 10 mg oral pilocarpine 3 times daily for 2 days. The pharmacokinetics were comparable in men under and over 65 years. However, all 5 of the women over 65 years of age in the study had mean maximum concentrations (C _max) and trapezoidal values of the areas under the curve (AUC) that were approximately twice as high as the men's values. The men's C _max values were 15 and 41 nanograms per mL (72 and 196.8 nanomoles per L) after the 5 and 10 mg dosage, respectively. The men's AUC trapezoidal values were 33 and 108 h (nanograms per mL) after the 5 and 10 mg dosage, respectively. ^{02}{15}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Anticholinergics or other medications with anticholinergic activity (See Appendix II )    (concurrent use may cause an antagonism of pilocarpine's therapeutic cholinergic effect ^{14}{19}{20})

    (concurrent use may cause an antagonism of the anticholinergic drug's anticholinergic effects; this may be important not only when the drug is being used therapeutically for its anticholinergic effects, but also when the drug has other therapeutic effects and its anticholinergic side effects are being used as indicators of impending adverse effects ^{02}{13}{14})


» Antiglaucoma agents, cholinergic, long acting, ophthalmic or
» Antiglaucoma agents, cholinergic, short acting, ophthalmic or
» Bethanechol or
» Cholinergics, other, or other medications with cholinergic activity, such as antimyasthenics    (concurrent use with pilocarpine may result in additive cholinergic effects ^{{02}{13}{19}{20}})


» Beta-adrenergic blocking agents, systemic and ophthalmic     (concurrent use with pilocarpine may increase the possibility of conduction disturbances ^{19}{20})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Asthma, uncontrolled    (pilocarpine may stimulate the mucous cells of the respiratory tract and may increase airway resistance and bronchial smooth muscle tone^{02}{19}{20})


» Glaucoma, angle closure or
» Iritis, acute    (pilocarpine may cause miosis^{02}{19}{20})


» Sensitivity to pilocarpine^{02}{19}{20}
Risk-benefit should be considered when the following medical problems exist
» Asthma, controlled or
» Bronchitis, chronic or
» Chronic obstructive pulmonary disease    (pilocarpine may stimulate the mucous cells of the respiratory tract and may increase airway resistance and bronchial smooth muscle tone^{02}{19}{20})


» Biliary tract disease or
» Cholelithiasis, known or suspected    (pilocarpine may cause contractions of the gallbladder or biliary smooth muscle and cholecystitis, cholangitis, or biliary obstruction may occur^{{02} {17}{20}})


» Cardiovascular disease    (patients with significant cardiovascular disease may be unable to compensate for the transient changes in hemodynamics or heart rhythm that are induced by pilocarpine; pulmonary edema has occurred as a complication of pilocarpine toxicity from high ophthalmic doses and may occur with oral pilocarpine also^{02}{19}{20})


» Cognitive disturbances or
» Psychiatric disturbances    (pilocarpine may have central nervous system effects, which may exacerbate these conditions^{02}{19}{20})


Nephrolithiasis    (pilocarpine may increase ureteral smooth muscle tone and may theoretically precipitate renal colic, especially in patients with nephrolithiasis^{02}{19}{20})


Peptic ulcer disease, acute    (pilocarpine may increase acid secretion ^{19})


» Retinal detachment, predisposition to or
» Retinal disease    (an association between use of ophthalmic pilocarpine and retinal detachment has been reported in patients with pre-existing retinal disease; it is not known whether this association may occur with oral pilocarpine^{02}{15})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Fundus examination    (should be performed periodically in patients with pre-existing retinal disease, since an association between use of ophthalmic pilocarpine and retinal detachment has been reported in patients with pre-existing retinal disease; it is not known whether this association may occur with oral pilocarpine ^{{02} {15}})




Side/Adverse Effects

Note: Pilocarpine toxicity is characterized by an exaggeration of its parasympathomimetic effects.^{02}
The following side/adverse effects have occurred in less than 1% of patients treated with pilocarpine; however, the causal relationship is unknown: anorexia, anxiety, deafness, depression, dysuria, electrocardiogram abnormality, esophagitis, eye pain, glaucoma, hyperkinesia, hypoesthesia, hypothermia, leukopenia, lymphadenopathy, metrorrhagia, paresthesias, seborrhea, speech disorder, stridor, syncope, and urinary impairment. In addition, 1 patient experienced a myocardial infarction, and 1 patient had an episode of syncope; both patients had underlying cardiovascular disease.^{02}
The following side/adverse effects have occurred rarely in patients treated with ophthalmic pilocarpine: agitation, atrioventricular block, ciliary congestion, confusion, delusion, depression, dermatitis, iris cysts, macular hole, malignant glaucoma, middle ear disturbance, shock, and visual hallucination. ^{02}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Chills
    
diarrhea
    
flu-like syndrome ( cough ; fever ; joint pain; muscle aches and pains ; unusual tiredness or weakness)
    
dyspepsia (indigestion)
    
nausea
    
rhinitis (runny nose)
    
sweating^{{02}{04}{05}{19}}
    
urinary frequency^{19} (increased need to urinate; passing urine more often)
    
vasodilation^{19} (feeling of warmth or heat; flushing or redness of skin especially on face and neck)

Incidence less frequent or rare
    
Amblyopia (trouble seeing)
    
asthenia (unusual weak feeling)
    
dysphagia (trouble swallowing )
    
edema (holding more body water; swelling of face, fingers, ankles, or feet )
    
epistaxis ( nosebleeds)
    
headache
    
hypertension
    
tachycardia (fast heartbeat)
    
tremors (trembling or shaking )
    
voice change
    
vomiting^{02}{04}{05}





Overdose
For specific information on the agents used in the management of systemic pilocarpine overdose, see:
   • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph; and/or
   • Epinephrine in Bronchodilators, Adrenergic (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Pilocarpine toxicity is characterized by an exaggeration of its parasympathomimetic effects. ^{02} One hundred mg of pilocarpine is considered to be potentially fatal.

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
    
Arrhythmia (irregular heartbeat, continuing or severe)
    
atrioventricular block (chest pain or fainting)
    
bradycardia (slow heartbeat, continuing or severe)
    
confusion
    
diarrhea, continuing or severe
    
gastrointestinal spasm (stomach cramps or pain)
    
headache, continuing or severe
    
hypertension
    
hypotension ( tiredness or weakness, continuing or severe)
    
nausea, continuing or severe
    
respiratory distress (shortness of breath or troubled breathing)
    
shock (fainting or tiredness or weakness, continuing or severe)
    
tachycardia (fast heartbeat, continuing or severe)
    
tremors (trembling or shaking, continuing or severe)
    
visual disturbance, continuing or severe (trouble seeing, continuing or severe)
    
vomiting, continuing or severe ^{{02} {17}}


Treatment of overdose
0.5 to 1 mg of atropine should be administered subcutaneously or intravenously. ^{02}

Supportive measures to maintain respiration and circulation should be used. ^{02}

For severe cardiovascular depression or bronchoconstriction, 0.3 to 1 mg of epinephrine should be administered subcutaneously or intramuscularly. ^{02}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Pilocarpine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to ophthalmic or oral pilocarpine





Use in children—Safety and efficacy have not been established

Other medications, especially anticholinergics or other medications with anticholinergic activity; antiglaucoma agents, cholinergic, long acting, ophthalmic; antiglaucoma agents, cholinergic, short acting, ophthalmic; beta-adrenergic blocking agents, systemic and ophthalmic; bethanechol; or cholinergics, other, or other medications with cholinergic activity
Other medical problems, especially asthma, controlled; asthma, uncontrolled; biliary tract disease; bronchitis, chronic; cardiovascular disease; cholelithiasis, known or suspected; chronic obstructive pulmonary disease; cognitive disturbances; glaucoma, angle closure; iritis, acute;; psychiatric disturbances; retinal detachment, predisposition to; or retinal disease

Proper use of this medication
» Taking medication only as directed; not taking it more often and not taking larger dose than directed; doing so may increase chance of side/adverse effects

Importance of seeing dentist regularly to prevent dental and other mouth problems, which are more likely to occur in patients with xerostomia

» Proper dosing
Missed dose: Taking as soon as possible; skipping missed dose if it is almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Caution if difficulty in reading or other vision problems occur; ^{17} caution if dizziness or lightheadedness occurs; not driving, using machines, or doing anything else that could be dangerous if not alert or able to see well; checking with physician if reactions are especially bothersome

» Importance of drinking enough liquids to offset the sweating that medication may cause ^{{02} {15}}


Side/adverse effects
Signs of potential side effects, especially signs of overdose


General Dosing Information
The lowest dosage that is effective should be used, since the incidence of side/adverse effects is dose dependent.^{02}{19}{20}

To achieve maximum benefit, pilocarpine tablets may need to be used for 12 weeks or more. The onset and degree of symptom relief varies among patients. ^{19}


Oral Dosage Forms

PILOCARPINE HYDROCHLORIDE TABLETS

Usual adult and adolescent dose
Xerostomia (treatment)—
Oral, 5 mg three times a day for patients with head and neck cancer . Dosage may be increased up to 10 mg three times a day for patients who do not respond to lower doses; however, increasing the dose also increases the incidence of side/adverse effects. The lowest dose that is tolerated and effective should be used for maintenance.^{02}{20} The Canadian manufacturer recommends 5 mg three or four times a day. ^{19}

Xerostomia (treatment)—
Oral, 5 mg four times a day for patients with Sjogren's syndrome. ^{20}The Canadian manufacturer recommends 5 mg three or four times a day.^{19}

[Xerophthalmia (treatment) ]
Oral, 5 mg three or four times a day for patients with Sjogren's syndrome.^{19}


Usual adult prescribing limits
Up to 10 mg per dose^{19}, 30 mg per day.^{19}{20}

Usual pediatric dose
Safety and efficacy have not been established.^{02}{19}{20}

Usual geriatric dose
See Usual adult dose^{19}

Usual geriatric prescribing limits
See See usual adult prescribing limits^{19}

Strength(s) usually available
U.S.—


5 mg (Rx) [Salagen (carnauba wax) (hydroxypropyl methylcellulose) (iron oxide) (microcrystalline cellulose) (stearic acid) (titanium dioxide)^{20}]

Canada—


5 mg (Rx) [Salagen (microcrystalline cellulose) (stearic acid) (hydroxypropyl methylcellulose ) (titanium dioxide) ( polyethylene glycol) (polysorbate 80) (shellac) (ethanol) ( synthetic black iron oxide) (N-butyl alcohol) (propylene glycol) (ethylene glycol monoethyl ether) (lecithin) ( methyl alcohol) (carnauba wax)^{19}]

Packaging and storage:
Store at controlled room temperature between 15 and 30 °C (59 and 86 °F).^{{02}{18}{19}{20}}

Revised: 10/02/2000

References

1. Fleeger CA, editor. USAN 1995. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 528.
   

2. Salagen package insert (MGI Pharma—US), Rev 3/94, Rec 6/94.
   

3. Pharmacologic therapy for radiation-induced xerostomia in head and neck cancer patients. American Hospital Formulary Service Product Information Form. Minneapolis: MGI Pharma, Inc, 1994.
   

4. LeVeque FG, Montgomery M, Potter D, et al. A multicenter, randomized, double-blind, placebo-controlled, dose-titration study of oral pilocarpine for treatment of radiation-induced xerostomia in head and neck cancer patients. J Clin Oncol 1993 Jun; 11(6): 1124-31.
   

5. Johnson JT, Ferretti GA, Nethery WJ, et al. Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 1993 Aug 5; 329(6): 390-5.
   

6. Valdez IH, Wolff A, Atkinson JC, et al. Use of pilocarpine during head and neck radiation therapy to reduce xerostomia and salivary dysfunction. Cancer 1993 Mar 1; 71(5): 1848-51.
   

7. Joensuu H, Bostrom P, Makkonen T. Pilocarpine and carbacholine in treatment of radiation-induced xerostomia. Radiother Oncol 1993 Jan; 26(1): 33-7.
   

8. Fox PC, Atkinson JC, Macynski AA, et al. Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med 1991 Jun; 151(6): 1149-52.
   

9. Schuller DE, Stevens P, Clausen KP, et al. Treatment of radiation side effects with oral pilocarpine. J Surg Oncol 1989 Dec; 42(4): 272-6.
   

10. Wolff A, Atkinson JC, Macynski AA, et al. Oral complications of cancer therapies. Pretherapy interventions to modify salivary dysfunction. NCI Monogr 1990; (9): 87-90.
    

11. Greenspan D. Oral complications of cancer therapies. Management of salivary dysfunction. NCI Monogr 1990; (9): 159-61.
    

12. Fox PC, van der Ven PF, Baum BJ, et al. Pilocarpine for the treatment of xerostomia associated with salivary gland dysfunction. Oral Surg Oral Med Oral Pathol 1986 Mar; 61(3): 243-8.
    

13. Reviewers" consensus on monograph revision of 8/23/94.
    

14. Panel comments, 11/23/94.
    

15. Panel comments, 11/23/94.
    

16. Open.
    

17. Reviewer comments on oral pilocarpine introductory leaflet of 10/94.
    

18. Reviewer comment, 3/10/95.
    

19. Product Information: Salagen, pilocarpine hydrochloride. Pharmacia & Upjohn, Ontario, Canada. PI reviewed 9/2000.
    

20. Product Information: Salagen, pilocarpine hydrochloride. MGI PHARMA, Inc. Minneapolis, MN. (PI revised 4/1998), PI reviewed 9/2000.
    

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