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Black Box Warning
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Content
Overview
Pilocarpine (oral) is a cholinergic agent that is FDA approved for the treatment of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Angle-closure glaucoma, acute
Dosing Information
Usual dose: Instill 1 drop of 1% or 2% solution topically into affected eye(s) up to 3 times over 30 minutes; pretreatment with a secretory suppressant and hyperosmotic agent may be required to lower pressure below 50 mmHg
Use with laser iridoplasty or iridomy: Instill 1 drop of 4% solution topically into affected eye(s) prior to procedure; afterwards, instill 1 drop of 1% solution topically 4 times daily until iridotomy
Head and neck cancer - Radiation-induced xerostomia
Dosing Information
The recommended initial dose of pilocarpine hydrochloride tablets is 5 mg taken three times a day. Dosage should be titrated according to therapeutic response and tolerance. The usual dosage range is up to 15-30 mg per day. (Not to exceed 10 mg per dose.) Although early improvement may be realized, at least 12 weeks of uninterrupted therapy with pilocarpine hydrochloride tablets may be necessary to assess whether a beneficial response will be achieved. The incidence of the most common adverse events increases with dose. The lowest dose that is tolerated and effective should be used for maintenance.
Miosis induction
Dosing Information
Usual dose: Instill 1 drop (or 2 drops 5 minutes apart) topically into eye(s)
Raised intraocular pressure
Dosing Information
Usual dose: Apply a 0.5-inch ribbon of the 4% gel topically in the lower conjunctival sac of the affected eye(s) once daily at bedtime
Raised intraocular pressure, Associated with laser surgery; Prophylaxis
Dosing Information
Usual dose: Instill 1 drop (or 2 drops 5 minutes apart) topically into eye(s) 15 to 60 minutes prior to surgery
Raised intraocular pressure, Associated with open-angle glaucoma or ocular hypertension
Dosing Information
Usual dose: 1 drop topically into affected eye(s) up to 4 times daily depending on degree of intraocular pressure elevation and miotic response; initiate using 1% solution in pilocarpine-naive patients.
Limiting systemic exposure: Advise punctal occlusion for 2 minutes following instillation.
Study dosage: The 1% and 2% pilocarpine solutions were effective with nasolacrimal occlusion (N=6), which may allow for twice-daily (every 12 hours) dosage.
Effects of eye color: Blue-eyed patients demonstrated near maximal ocular hypotensive effects with 1% pilocarpine, while brown-eyed patients required 4% pilocarpine to produce a therapeutic response. Black patients with dark brown irides required 8% pilocarpine for a similar response.
Sjögren's syndrome - Xerostomia
Dosing Information
The recommended dose of pilocarpine hydrochloride tablets is 5 mg taken four times a day. Efficacy was established by 6 weeks of use.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
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Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
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There is limited information regarding Off-Label Guideline-Supported Use of Pilocarpine (oral) in adult patients.
Non–Guideline-Supported Use
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Dosing Information
Dosage
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There is limited information regarding Off-Label Non–Guideline-Supported Use of Pilocarpine (oral) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Miosis induction
Dosing Information
Prior to goniotomy or trabeculotomy: Instill 1 drop of 1% or 2% solution topically into eye 15 to 60 minutes prior to surgery.
Raised intraocular pressure, Associated with open-angle glaucoma or ocular hypertension
Dosing Information
Under 2 Years Old:
Usual dose: Instill 1 drop of the 1% solution topically into affected eye(s) 3 times daily.
2 Years or Older:
Usual dose: Instill 1 drop topically into affected eye(s) up to 4 times daily; concentration of solution and frequency of administration are dependent on degree of intraocular pressure elevation and miotic response; start at 1% strength in pilocarpine-naive.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
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Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Pilocarpine (oral) in pediatric patients.
Non–Guideline-Supported Use
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Dosing Information
Dosage
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There is limited information regarding Off-Label Non–Guideline-Supported Use of Pilocarpine (oral) in pediatric patients.
Contraindications
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Warnings
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Content
Description
Precautions
Description
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Pilocarpine (oral) in the drug label
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pilocarpine (oral) in the drug label.
Pilocarpine is a cholinergic parasympathomimetic agent exerting a broad spectrum of pharmacologic effects with predominant muscarinic action. Pilocarpine, in appropriate dosage, can increase secretion by the exocrine glands. The sweat, salivary, lacrimal, gastric, pancreatic, and intestinal glands and the mucous cells of the respiratory tract may be stimulated. When applied topically to the eye as a single dose it causes miosis, spasm of accommodation, and may cause a transitory rise in intraocular pressure followed by a more persistent fall. Dose-related smooth muscle stimulation of the intestinal tract may cause increased tone, increased motility, spasm, and tenesmus. Bronchial smooth muscle tone may increase. The tone and motility of urinary tract, gallbladder, and biliary duct smooth muscle may be enhanced. Pilocarpine may have paradoxical effects on the cardiovascular system. The expected effect of a muscarinic agonist is vasodepression, but administration of pilocarpine may produce hypertension after a brief episode of hypotension. Bradycardia and tachycardia have both been reported with use of pilocarpine.
In a study of 12 healthy male volunteers there was a dose-related increase in unstimulated salivary flow following single 5 and 10 mg oral doses of pilocarpine hydrochloride tablets. This effect of pilocarpine on salivary flow was time-related with an onset at 20 minutes and a peak effect at 1 hour with a duration of 3 to 5 hours (See Pharmacokinetics section).
Head & Neck Cancer Patients
In a 12 week randomized, double-blind, placebo-controlled study in 207 patients (placebo, N=65; 5 mg, N=73; 10 mg, N=69), increases from baseline (means 0.072 and 0.112 mL/min, ranges −0.690 to 0.728 and −0.380 to 1.689) of whole saliva flow for the 5 mg (63%) and 10 mg (90%) tablet, respectively, were seen 1 hour after the first dose of pilocarpine hydrochloride tablets. Increases in unstimulated parotid flow were seen following the first dose (means 0.025 and 0.046 mL/min, ranges 0 to 0.414 and −0.070 to 1.002 mL/min for the 5 and 10 mg dose, respectively). In this study, no correlation existed between the amount of increase in salivary flow and the degree of symptomatic relief.
Sjogren's Syndrome Patients
In two 12 week randomized, double-blind, placebo-controlled studies in 629 patients (placebo, N=253; 2.5 mg, N=121; 5 mg, N=255; 5-7.5 mg, N=114), the ability of pilocarpine hydrochloride tablets to stimulate saliva production was assessed. In these trials using varying doses of pilocarpine hydrochloride tablets (2.5-7.5 mg), the rate of saliva production was plotted against time. An Area Under the Curve (AUC) representing the total amount of saliva produced during the observation interval was calculated. Relative to placebo, an increase in the amount of saliva being produced was observed following the first dose of pilocarpine hydrochloride tablets and was maintained throughout the duration (12 weeks) of the trials in an approximate dose response fashion (See Clinical Studies section).
Pharmacokinetics
In a multiple-dose pharmacokinetic study in male volunteers following 2 days of 5 or 10 mg of oral pilocarpine hydrochloride tablets given at 8 a.m., noontime, and 6 p.m., the mean elimination half-life was 0.76 hours for the 5 mg dose and 1.35 hours for the 10 mg dose. Tmax values were 1.25 hours and 0.85 hours. Cmax values were 15 ng/mL and 41 ng/mL. The AUC trapezoidal values were 33 h(ng/mL) and 108 h(ng/mL), respectively, for the 5 and 10 mg doses following the last 6 hour dose.
Pharmacokinetics in elderly male volunteers (N = 11) were comparable to those in younger men. In five healthy elderly female volunteers, the mean Cmax and AUC were approximately twice that of elderly males and young normal male volunteers.
When taken with a high fat meal by 12 healthy male volunteers, there was a decrease in the rate of absorption of pilocarpine from pilocarpine hydrochloride tablets. Mean Tmax's were 1.47 and 0.87 hours, and mean Cmax's were 51.8 and 59.2 ng/mL for fed and fasted, respectively.
Limited information is available about the metabolism and elimination of pilocarpine in humans. Inactivation of pilocarpine is thought to occur at neuronal synapses and probably in plasma. Pilocarpine and its minimally active or inactive degradation products, including pilocarpic acid, are excreted in the urine. Pilocarpine does not bind to human or rat plasma proteins over a concentration range of 5 to 25,000 ng/mL. The effect of pilocarpine on plasma protein binding of other drugs has not been evaluated.
In patients with mild to moderate hepatic impairment (N=12), administration of a single 5 mg dose resulted in a 30% decrease in total plasma clearance and a doubling of exposure (as measured by AUC). Peak plasma levels were also increased by about 30% and half-life was increased to 2.1 hrs.
There were no significant differences in the pharmacokinetics of oral pilocarpine in volunteer subjects (N=8) with renal insufficiency (mean creatinine clearances 25.4 mL/min; range 9.8 – 40.8 mL/min) compared to the pharmacokinetics previously observed in normal volunteers.
Clinical Studies
Head & Neck Cancer Patients
A 12 week randomized, double-blind, placebo-controlled study in 207 patients (142 men, 65 women) was conducted in patients whose mean age was 58.5 years with a range of 19 to 77; the racial distribution was Caucasian 95%, Black 4%, and other 1%. In this population, a statistically significant improvement in mouth dryness occurred in the 5 and 10 mg pilocarpine hydrochloride tablet treated patients compared to placebo treated patients. The 5 and 10 mg treated patients could not be distinguished. (See Pharmacodynamics section for flow study details.)
Another 12 week, double-blind, randomized, placebo-controlled study was conducted in 162 patients whose mean age was 57.8 years with a range of 27 to 80; the racial distribution was Caucasian 88%, Black 10%, and other 2%. The effects of placebo were compared to 2.5 mg three times a day of pilocarpine hydrochloride tablets for 4 weeks followed by adjustment to 5 mg three times a day and 10 mg three times a day. Lowering of the dose was necessary because of adverse events in 3 of 67 patients treated with 5 mg of pilocarpine hydrochloride tablets and in 7 of 66 patients treated with 10 mg of pilocarpine hydrochloride tablets. After 4 weeks of treatment, 2.5 mg of pilocarpine hydrochloride tablets three times a day was comparable to placebo in relieving dryness. In patients treated with 5 mg and 10 mg of pilocarpine hydrochloride tablets, the greatest improvement in dryness was noted in patients with no measurable salivary flow at baseline.
In both studies, some patients noted improvement in the global assessment of their dry mouth, speaking without liquids, and a reduced need for supplemental oral comfort agents.
In the two placebo-controlled clinical trials, the most common adverse events related to drug, and increasing in rate as dose increases, were sweating, nausea, rhinitis, diarrhea, chills, flushing, urinary frequency, dizziness, and asthenia. The most common adverse experience causing withdrawal from treatment was sweating (5 mg t.i.d. ≤1%; 10 mg t.i.d. =12%).
Sjogren's Syndrome Patients
Two separate studies were conducted in patients with primary or secondary Sjogren's Syndrome. In both studies, the majority of patients best fit the European criteria for having primary Sjogren's Syndrome. ["Criteria for the Classification of Sjogren's Syndrome" (Vitali C, Bombardieri S, Moutsopoulos HM, et al: Preliminary criteria for the classification of Sjogren's syndrome. Arthritis Rheum 36:340-347, 1993.)]
A twelve week, randomized, double-blind, parallel-group, placebo-controlled study was conducted in 256 patients (14 men, 242 women) whose mean age was 57 years with a range of 24 to 85 years. The racial distribution was as follows: Caucasian 91%, Black 6%, and other 3%.
The effects of placebo were compared with those of pilocarpine hydrochloride tablets 5 mg four times a day (20 mg/day) for 6 weeks. At 6 weeks, the patients' dosage was increased from 5 mg pilocarpine hydrochloride tablets q.i.d. to 7.5 mg q.i.d. The data collected during the first 6 weeks of the trial were evaluated for safety and efficacy, and the data of the second 6 weeks of the trial were used to provide additional evidence of safety.
After 6 weeks of treatment, statistically significant global improvement of dry mouth was observed compared to placebo. "Global improvement" is defined as a score of 55 mm or more on a 100 mm visual analogue scale in response to the question, "Please rate your present condition of dry mouth (xerostomia) compared with your condition at the start of this study. Consider the changes to your dry mouth and other symptoms related to your dry mouth that have occurred since you have taken this medication." Patients' assessments of specific dry mouth symptoms such as severity of dry mouth, mouth discomfort, ability to speak without water, ability to sleep without drinking water, ability to swallow food without drinking, and a decreased use of saliva substitutes were found to be consistent with the significant global improvement described.
Another 12 week randomized, double-blind, parallel-group, placebo-controlled study was conducted in 373 patients (16 men, 357 women) whose mean age was 55 years with a range of 21 to 84. The racial distribution was Caucasian 80%, Oriental 14%, Black 2%, and 4% of other origin. The treatment groups were 2.5 mg pilocarpine tablets, 5 mg pilocarpine hydrochloride tablets, and placebo. All treatments were administered on a four times a day regimen.
After 12 weeks of treatment, statistically significant global improvement of dry mouth was observed at a dose of 5 mg compared with placebo. The 2.5 mg (10mg/day) group was not significantly different than placebo. However, a subgroup of patients with rheumatoid arthritis tended to improve in global assessments at both the 2.5 mg q.i.d. (9 patients) and 5 mg q.i.d. (16 patients) dose (10-20 mg/day). The clinical significance of this finding is unknown.
Patients' assessments of specific dry mouth symptoms such as severity of dry mouth, mouth discomfort, ability to sleep without drinking water, and decreased use of saliva substitutes were also found to be consistent with the significant global improvement described when measured after 6 weeks and 12 weeks of pilocarpine hydrochloride tablets use.
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Pilocarpine (oral) in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Pilocarpine (oral) in the drug label.
How Supplied
Storage
There is limited information regarding Pilocarpine (oral) Storage in the drug label.
Images
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