Get your patient on Pilocarpine Hydrochloride - Pilocarpine Hydrochloride tablet, Film Coated (Pilocarpine Hydrochloride)
Pilocarpine Hydrochloride - Pilocarpine Hydrochloride tablet, Film Coated prescribing information
INDICATIONS AND USAGE Pilocarpine hydrochloride tablets 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.
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 to 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.
CONTRAINDICATIONS
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.
ADVERSE REACTIONS
Head & Neck Cancer Patients: In controlled studies, 217 patients received pilocarpine, of whom 68% were men and 32% were women. Race distribution was 91% Caucasian, 8% Black, and 1% of other origin. Mean age was approximately 58 years. The majority of patients were between 50 and 64 years (51%), 33% were 65 years and older and 16% were younger than 50 years of age. The most frequent adverse experiences associated with pilocarpine hydrochloride tablets were a consequence of the expected pharmacologic effects of pilocarpine.
| Adverse Event | Pilocarpine Hydrochloride | Placebo | |
| 10 mg t.i.d. (30 mg/day) | 5 mg t.i.d. (15 mg/day) | (t.i.d.) | |
| Sweating | N=121/68% | N=141/29% | N=152/9% |
| Nausea | 15 | 6 | 4 |
| Rhinitis | 14 | 5 | 7 |
| Diarrhea | 7 | 4 | 5 |
| Chills | 15 | 3 | <1 |
| Flushing | 13 | 8 | 3 |
| Urinary Frequency | 12 | 9 | 7 |
| Dizziness | 12 | 5 | 4 |
| Asthenia | 12 | 6 | 3 |
In addition, the following adverse events (≥3% incidence) were reported at dosages of 15 to 30 mg/day in the controlled clinical trials:
| Adverse Event | Pilocarpine Hydrochloride | Placebo |
| 5 to10 mg t.i.d. (15 to 30 mg/day) | (t.i.d.) | |
| Headache | N=212/11% | N=152/8% |
| Dyspepsia | 7 | 5 |
| Lacrimation | 6 | 8 |
| Edema | 5 | 4 |
| Abdominal Pain | 4 | 4 |
| Amblyopia | 4 | 2 |
| Vomiting | 4 | 1 |
| Pharyngitis | 3 | 8 |
| Hypertension | 3 | 1 |
The following events were reported with treated head and neck cancer patients at incidences of 1% to 2% at dosages of 7.5 to 30 mg/day: abnormal vision, conjunctivitis, dysphagia, epistaxis, myalgias, pruritus, rash, sinusitis, tachycardia, taste perversion, tremor, voice alteration.
The following events were reported rarely in treated head and neck cancer patients (<1%): Causal relation is unknown.
Body as a whole: body odor, hypothermia, mucous membrane abnormality
Cardiovascular: bradycardia, ECG abnormality, palpitations, syncope
Digestive: anorexia, increased appetite, esophagitis, gastrointestinal disorder, tongue disorder
Hematologic: leukopenia, lymphadenopathy
Nervous: anxiety, confusion, depression, abnormal dreams, hyperkinesia, hypesthesia, nervousness, parethesias, speech disorder, twitching
Respiratory: increased sputum, stridor, yawning
Skin: seborrhea Special senses: deafness, eye pain, glaucoma
Urogenital: dysuria, metrorrhagia, urinary impairment
In long-term treatment were two patients with underlying cardiovascular disease of whom one experienced a myocardial infarct and another an episode of syncope. The association with drug is uncertain.
Sjogren's Syndrome Patients: In controlled studies, 376 patients received pilocarpine, of whom 5% were men and 95% were women. Race distribution was 84% Caucasian, 9% Oriental, 3% Black, and 4% of other origin. Mean age was 55 years. The majority of patients were between 40 and 69 years (70%), 16% were 70 years and older and 14% were younger than 40 years of age. Of these patients, 161/629 (89/376 receiving pilocarpine) were over the age of 65 years. 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. The incidences of urinary frequency and diarrhea in the elderly were about double those of the non-elderly. The incidence of dizziness was about three times as high in the elderly as in the non-elderly. These adverse experiences were not considered to be serious. In the 2 placebo-controlled studies, the most common adverse events related to drug use were sweating, urinary frequency, chills, and vasodilatation (flushing). The most commonly reported reason for patient discontinuation of treatment was sweating. Expected pharmacologic effects of pilocarpine include the following adverse experiences associated with pilocarpine hydrochloride tablets:
| Adverse Event | Pilocarpine Hydrochloride | Placebo |
| 5 mg q.i.d. (20 mg/day) | (q.i.d) | |
| Sweating | N=255/40% | N=253/7% |
| Urinary Frequency | 10 | 4 |
| Nausea | 9 | 9 |
| Flushing | 9 | 2 |
| Rhinitis | 7 | 8 |
| Diarrhea | 6 | 7 |
| Chills | 4 | 2 |
| Increased Salivation | 3 | 0 |
| Asthenia | 2 | 2 |
In addition, the following adverse events (≥3% incidence) were reported at dosages of 20 mg/day in the controlled clinical trials:
| Adverse Event | Pilocarpine Hydrochloride | Placebo |
| 5 mg q.i.d. (20 mg/day) | (q.i.d) | |
| Headache | N=255/13% | N=253/19% |
| Flu Syndrome | 9 | 9 |
| Dyspepsia | 7 | 7 |
| Dizziness | 6 | 7 |
| Pain | 4 | 2 |
| Sinusitis | 4 | 5 |
| Abdominal Pain | 3 | 4 |
| Vomiting | 3 | 1 |
| Pharyngitis | 2 | 5 |
| Rash | 2 | 3 |
| Infection | 2 | 6 |
The following events were reported in Sjogren's patients at incidences of 1% to 2% at dosing of 20 mg/day: accidental injury, allergic reaction, back pain, blurred vision, constipation, increased cough, edema, epistaxis, face edema, fever, flatulence, glossitis, lab test abnormalities, including chemistry, hematology, and urinalysis, myalgia, palpitation, pruritus, somnolence, stomatitis, tachycardia, tinnitus, urinary incontinence, urinary tract infection, and vaginitis.
The following events were reported rarely in treated Sjogren's patients (<1%) at dosing of 10 to 30 mg/day: Causal relation is unknown. Body as a whole: chest pain, cyst, death, moniliasis, neck pain, neck rigidity, photosensitivity reaction
Cardiovascular: angina pectoris, arrhythmia, ECG abnormality, hypotension, hypertension, intracranial hemorrhage, migraine, myocardial infarction
Digestive: anorexia, bilirubinemia, cholelithiasis, colitis, dry mouth, eructation, gastritis, gastroenteritis, gastrointestinal disorder, gingivitis, hepatitis, abnormal liver function tests, melena, nausea & vomiting, pancreatitis, parotid gland enlargement, salivary gland enlargement, sputum increased, taste loss, tongue disorder, tooth disorder
Hematologic: hematuria, lymphadenopathy, abnormal platelets, thrombocythemia, thrombocytopenia, thrombosis, abnormal WBC
Metabolic and Nutritional: peripheral edema, hypoglycemia
Musculoskeletal: arthralgia, arthritis, bone disorder, spontaneous bone fracture, pathological fracture, myasthenia, tendon disorder, tenosynovitis
Nervous: aphasia, confusion, depression, abnormal dreams, emotional lability, hyperkinesia, hypesthesia, insomnia, leg cramps, nervousness, parethesias, abnormal thinking, tremor Respiratory: bronchitis, dyspnea, hiccup, laryngismus, laryngitis, pneumonia, viral infection, voice alteration
Skin: alopecia, contact dermatitis, dry skin, eczema, erythema nodosum, exfoliative dermatitis, herpes simplex, skin ulcer, vesiculobullous rash
Special Senses: cataract, conjunctivitis, dry eyes, ear disorder, ear pain, eye disorder, eye hemorrhage, glaucoma, lacrimation disorder, retinal disorder, taste perversion, abnormal vision Urogenital: breast pain, dysuria, mastitis, menorrhagia, metrorrhagia, ovarian disorder, pyuria, salpingitis, urethral pain, urinary urgency, vaginal hemorrhage, vaginal moniliasis The following adverse experiences have been reported rarely with ocular pilocarpine: A-V block, agitation, ciliary congestion, confusion, delusion, depression, dermatitis, middle ear disturbance, eyelid twitching, malignant glaucoma, iris cysts, macular hole, shock, and visual hallucination.
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.
DESCRIPTION
Pilocarpine hydrochloride tablets, USP contain pilocarpine hydrochloride, a cholinergic agonist for oral use. Pilocarpine hydrochloride is a white or almost white, crystalline powder or colorless crystals, hygroscopic which is very soluble in water and freely soluble in ethanol (96 percent). Pilocarpine hydrochloride, with a chemical name of (3 S - 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 USP. Inactive ingredients in the tablet are: hypromellose, microcrystalline cellulose, polyethylene glycol, stearic acid and titanium dioxide. Each 7.5 mg pilocarpine hydrochloride tablet, USP for oral administration contains 7.5 mg of pilocarpine hydrochloride USP. Inactive ingredients in the tablet are: FD&C blue # 2, hypromellose, microcrystalline cellulose, polyethylene glycol, stearic acid and titanium dioxide. FDA approved dissolution test specifications differ from USP.
CLINICAL PHARMACOLOGY
Pharmacodynamics:
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 to 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 to 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. T max values were 1.25 hours and 0.85 hours. C max 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 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. Mean 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 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 to 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% ). Sj ogren'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. 1993; 36:340 to 347.)] 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 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 (10 mg/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 to 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 off white to white colour, biconvex round shaped film-coated tablet debossed with “PIL” on one side and “5” on the other side. Each tablet contains 5 mg pilocarpine hydrochloride USP. They are supplied as follows:
Bottles of 100 NDC 59651-224-01
Pilocarpine Hydrochloride Tablets, USP 7.5 mg are light blue to blue colour, biconvex round shaped film-coated tablet debossed with “PIL” on one side and “7.5” on the other side. Each tablet contains 7.5 mg pilocarpine hydrochloride USP. They are supplied as follows:
Bottles of 100 NDC 59651-225-01
Store at 20 o to 25 o C (68 o to 77 o F) [see USP Controlled Room Temperature].
Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 038, India Revised: 09/2019
