Pilocarpine Hydrochloride 5 MG Oral Tablet
WARNINGS
Cardiovascular Disease 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 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.
Pulmonary Disease 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.
DRUG INTERACTIONS
Drug Interactions Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances.
Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects.
Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly.
These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium).
While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sjogren’s efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone.
OVERDOSAGE
MANAGEMENT OF OVERDOSE 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.
DESCRIPTION
Pilocarpine hydrochloride tablets, USP contain pilocarpine hydrochloride, a cholinergic agonist for oral use.
Pilocarpine hydrochloride, USP is a hygroscopic, odorless, bitter tasting white crystal or powder, which is soluble in water and alcohol and virtually insoluble in most non-polar solvents.
Pilocarpine hydrochloride, USP with a chemical name of (3S- cis )-2(3 H )-Furanone, 3-ethyldihydro-4-[(1-methyl-1 H -imidazol-5-yl) methyl] monohydrochloride, has a molecular weight of 244.72.
Each 5 mg Pilocarpine Hydrochloride Tablet, USP for oral administration contains 5 mg of pilocarpine hydrochloride.
Inactive ingredients in the tablet are microcrystalline cellulose and stearic acid, the tablet’s film coating is: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.
Each 7.5 mg Pilocarpine Hydrochloride Tablet, USP for oral administration contains 7.5 mg of pilocarpine hydrochloride.
Inactive ingredients in the tablet are microcrystalline cellulose and stearic acid, the tablet’s film coating is: FD&C Blue #2/Indigo Carmine aluminum lake, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.
The chemical structure of Pilocarpine hydrochloride.
CLINICAL STUDIES
Clini cal 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.
HOW SUPPLIED
Pilocarpine hydrochloride tablets USP, 5 mg are white, film coated, round tablets, debossed LAN on one side and 1313 on the other side.
Each tablet contains 5 mg pilocarpine hydrochloride.
They are supplied as follows: Bottles of 100; NDC 10135-0589-01 Store at 20°- 25°C (68°-77°F) [see USP Controlled Room Temperature].
Pilocarpine hydrochloride tablets USP, 7.5 mg are blue, film coated, round tablets, debossed LCI on one side and 1407 on the other side.
Each tablet contains 7.5 mg pilocarpine hydrochloride.
They are supplied as follows: Bottles of 100; NDC 10135-0590-01 Store at 20°- 25°C (68°-77°F) [see USP Controlled Room Temperature].
Manufactured by: Lannett Company, Inc.
Philadelphia, PA 19136 Distributed By: Marlex Pharmaceuticals, Inc.
New Castle, DE 19720 Made in the USA Rev.
10/14 LAN
GERIATRIC USE
Geriatric Use Head and Neck Cancer Patients In the placebo-controlled clinical trials (see Clinical Studies section) the mean age of patients was approximately 58 years (range 19 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 and AUC’s than the men.
(See Pharmacokinetics section.) Sjogren’s Syndrome Patients In the placebo-controlled clinical trials (see Clinical Studies section), the mean age of patients was approximately 55 years (range 21 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).
INDICATIONS AND USAGE
INDICATIONS AN D USAGE Pilocarpine hydrochloride tablets, USP are indicated for 1) the treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck; and 2) the treatment of symptoms of dry mouth in patients with Sjogren’s syndrome.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
Pregnancy 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.
NUSRING MOTHERS
Nursing Mothers 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.
INFORMATION FOR PATIENTS
Information for Patients Patients should be informed that pilocarpine may cause visual disturbances, especially at night, that could impair their ability to drive safely.
If a patient sweats excessively while taking pilocarpine hydrochloride and cannot drink enough liquid, the patient should consult a physician.
Dehydration may develop.
DOSAGE AND ADMINISTRATION
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 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.
Sjogren’s Syndrome Patients The recommended dose of pilocarpine hydrochloride tablets is 5 mg taken four times a day.
Efficacy was established by 6 weeks of use.