APICARPIN

gte Administer into the conjunctival cul-de-sac of the eye to be treated Patient information: avoid contact of the tip with the eye and eyelids 1 gte 2-4 times a day 1 gte 1 time this day The information provided on drug interactions results from the synthesis of the sources consulted by the Vidal scientific team.

They do not systematically reflect the information contained in the SPCs.

They are intended for practical purposes for health professionals.

The absence of an AMI in the Vidal database must never be interpreted as proof of safety. name: ISOPTO-PILOCARPINE 2% Eye drops Fl/10 ml cip13:3400933257606 conservation: Cip: 3400933257606 Storage conditions: Before opening: for 4 years After opening: for 15 days status: Marketed.

Chronic simple glaucoma.

Acute attack of glaucoma (by angle closure).

Diagnosis of the causes of mydriasis.

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 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 to 5 hours.

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 to 0.414 and −0.070 to 1.002 mL/min for the 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.

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.

T max values were 1.25 hours and 0.85 hours.

C max values were 15 ng/mL and 41 ng/mL.

AUC trapezoidal values were 33 h(ng/mL) and 108 h(ng/mL), respectively, for the 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 C max 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.

T max's were 1.47 and 0.87 hours, and mean C max'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 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.

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 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 and 10 mg pilocarpine hydrochloride tablet treated patients compared to placebo treated patients.

The 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 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 of 67 patients treated with 5 mg of pilocarpine hydrochloride tablets and in 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 12-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 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 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.

Pilocarpine lowers intraocular pressure by increasing the ease of outflow of aqueous humor and by decreasing ciliary secretory flow.

It acts on accommodation and on the depth of the anterior chamber of the eye (reduction by relaxation of the zonule and forward movement of the lens).

Fatal overdosage with pilocarpine has been reported in the scientific literature at doses presumed to be greater than 100 mg in two hospitalized patients. 100 mg of pilocarpine is considered potentially fatal.

Overdosage should be treated with atropine titration (0.5 mg to 1.0 mg given subcutaneously or intravenously) and supportive measures to maintain respiration and circulation.

Epinephrine (0.3 mg to 1.0 mg, subcutaneously or intramuscularly) may also be of value in the presence of severe cardiovascular depression or bronchoconstriction.

It is not known if pilocarpine is dialyzable.

Patients with significant cardiovascular disease may be unable to compensate for transient changes in hemodynamics or rhythm induced by pilocarpine.

Pulmonary edema has been reported as a complication of pilocarpine toxicity from high ocular doses given for acute angle-closure glaucoma.

Pilocarpine should be administered with caution in and under close medical supervision of patients with significant cardiovascular disease.

Ocular formulations of pilocarpine have been reported to cause visual blurring which may result in decreased visual acuity, especially at night and in patients with central lens changes, and to cause impairment of depth perception.

Caution should be advised while driving at night or performing hazardous activities in reduced lighting.

Pilocarpine has been reported to increase airway resistance, bronchial smooth muscle tone, and bronchial secretions.

Pilocarpine hydrochloride should be administered with caution to and under close medical supervision in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease requiring pharmacotherapy.

Pilocarpine hydrochloride tablets are contraindicated in patients with uncontrolled asthma, known hypersensitivity to pilocarpine, and when miosis is undesirable, e.g., in acute iritis and in narrow-angle (angle closure) glaucoma.

Regardless of the indication, the starting dose in patients with moderate hepatic impairment should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability.

Patients with mild hepatic insufficiency do not require dosage reductions.

The use of pilocarpine in patients with severe hepatic insufficiency is not recommended.

If needed, refer to the Hepatic Insufficiency subsection of the Precautions section of this label for definitions of mild, moderate and severe hepatic impairment.

Head & Neck Cancer Patients: 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 tolerability.

The usual dosage range is 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.

Sjogren's Syndrome Patients: The recommended dose of pilocarpine hydrochloride tablets is one tablet (5 mg) taken four times a day. Efficacy was established by 6 weeks of use.

Pilocarpine hydrochloride tablets

USP, 5 mg are white, film coated, round tablets, debossed LAN on one side and on the other side.

Each tablet contains 5 mg pilocarpine hydrochloride.

They are supplied as follows

Bottles of 100; NDC 72162-1078-1 Store at 20°.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

Teratogenic effects Pregnancy Category C

Pilocarpine was associated with a reduction in the mean fetal body weight and an increase in the incidence of skeletal variations when given to pregnant rats at a dosage of 90 mg/kg/day (approximately 26 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m 2 ) estimates).

These effects may have been secondary to maternal toxicity.

In another study, oral administration of pilocarpine to female rats during gestation and lactation at a dosage of 36 mg/kg/day (approximately 10 times the maximum recommended dose for a 50 kg human when compared on the basis of body surface area (mg/m 2 ) estimates) resulted in an increased incidence of stillbirths; decreased neonatal survival and reduced mean body weight of pups were observed at dosages 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/m 2 ) estimates) and above.

There are no adequate and well-controlled studies in pregnant women.

Pilocarpine hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pilocarpine hydrochloride tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

In the placebo-controlled clinical trials the mean age of patients was approximately 58 years (range to 80).

Of these patients, 97/369 (61/217 receiving pilocarpine) were over the age of 65 years.

In the healthy volunteer studies, 15/150 subjects were over the age of 65 years.

In both study populations, the adverse events reported by those over 65 years and those 65 years and younger were comparable.

Of the 15 elderly volunteers (5 women, 10 men), the 5 women had higher C max's and AUC's than the men.

Sjogren's Syndrome Patients: In the placebo-controlled clinical trials, the mean age of patients was approximately 55 years (range to 85).

The adverse events reported by those over 65 years and those 65 years and younger were comparable except for notable trends for urinary frequency, diarrhea, and dizziness See ADVERSE REACTIONS section.