Dropiltim

Pilocarpine:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Management of overdose
• Dosage and administration
• How supplied
• Dropiltim (Pilocarpine) reviews

DESCRIPTION

Dropiltim (Pilocarpine) hydrochloride tablets, USP contain Dropiltim (Pilocarpine) hydrochloride, a cholinergic agonist for oral use. Dropiltim (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. Dropiltim (Pilocarpine) hydrochloride, USP with a chemical name of (3S-cis)-2(3H)-Furanone, 3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl) methyl] monohydrochloride, has a molecular weight of 244.72.

Each 5 mg Dropiltim (Pilocarpine) Hydrochloride Tablet, USP for oral administration contains 5 mg of Dropiltim (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 Dropiltim (Pilocarpine) Hydrochloride Tablet, USP for oral administration contains 7.5 mg of Dropiltim (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.

Chemical Structure

CLINICAL PHARMACOLOGY

Pharmacodynamics

Dropiltim is a cholinergic parasympathomimetic agent exerting a broad spectrum of pharmacologic effects with predominant muscarinic action. Dropiltim (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. Dropiltim (Pilocarpine) may have paradoxical effects on the cardiovascular system. The expected effect of a muscarinic agonist is vasodepression, but administration of Dropiltim (Pilocarpine) may produce hypertension after a brief episode of hypotension. Bradycardia and tachycardia have both been reported with use of Dropiltim (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 Dropiltim (Pilocarpine) hydrochloride tablets. This effect of Dropiltim (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 Dropiltim (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, the ability of Dropiltim (Pilocarpine) hydrochloride tablets to stimulate saliva production was assessed. In these trials using varying doses of Dropiltim (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 Dropiltim (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 Dropiltim (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 Dropiltim (Pilocarpine) from Dropiltim (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 Dropiltim (Pilocarpine) in humans. Inactivation of Dropiltim (Pilocarpine) is thought to occur at neuronal synapses and probably in plasma. Dropiltim (Pilocarpine) and its minimally active or inactive degradation products, including pilocarpic acid, are excreted in the urine. Dropiltim (Pilocarpine) does not bind to human or rat plasma proteins over a concentration range of 5 to 25,000 ng/mL. The effect of Dropiltim (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 Dropiltim (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 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 Dropiltim (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 Dropiltim (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 Dropiltim (Pilocarpine) hydrochloride tablets and in 7 of 66 patients treated with 10 mg of Dropiltim (Pilocarpine) hydrochloride tablets. After 4 weeks of treatment, 2.5 mg of Dropiltim (Pilocarpine) hydrochloride tablets three times a day was comparable to placebo in relieving dryness. In patients treated with 5 mg and 10 mg of Dropiltim (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 Dropiltim (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 Dropiltim (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 Dropiltim (Pilocarpine) tablets, 5 mg Dropiltim (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 Dropiltim (Pilocarpine) hydrochloride tablets use.

INDICATIONS AND USAGE

Dropiltim (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.

CONTRAINDICATIONS

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

WARNINGS

Cardiovascular Disease

Patients with significant cardiovascular disease may be unable to compensate for transient changes in hemodynamics or rhythm induced by Dropiltim (Pilocarpine). Pulmonary edema has been reported as a complication of Dropiltim (Pilocarpine) toxicity from high ocular doses given for acute angle-closure glaucoma. Dropiltim (Pilocarpine) should be administered with caution in and under close medical supervision of patients with significant cardiovascular disease.

Ocular

Ocular formulations of Dropiltim (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

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

PRECAUTIONS

General

Dropiltim toxicity is characterized by an exaggeration of its parasympathomimetic effects. These may include: headache, visual disturbance, lacrimation, sweating, respiratory distress, gastrointestinal spasm, nausea, vomiting, diarrhea, atrioventricular block, tachycardia, bradycardia, hypotension, hypertension, shock, mental confusion, cardiac arrhythmia, and tremors.

The dose-related cardiovascular pharmacologic effects of Dropiltim (Pilocarpine) include hypotension, hypertension, bradycardia, and tachycardia.

Dropiltim (Pilocarpine) should be administered with caution to patients with known or suspected cholelithiasis or biliary tract disease. Contractions of the gallbladder or biliary smooth muscle could precipitate complications including cholecystitis, cholangitis, and biliary obstruction.

Dropiltim (Pilocarpine) may increase ureteral smooth muscle tone and could theoretically precipitate renal colic (or "ureteral reflux"), particularly in patients with nephrolithiasis.

Cholinergic agonists may have dose-related central nervous system effects. This should be considered when treating patients with underlying cognitive or psychiatric disturbances.

Hepatic Insufficiency

Based on decreased plasma clearance observed in patients with moderate hepatic impairment, the starting dose in these patients should be 5 mg twice daily, followed by adjustment based on therapeutic response and tolerability. Patients with mild hepatic insufficiency (Child-Pugh score of 5-6) do not require dosage reductions. To date, pharmacokinetic studies in subjects with severe hepatic impairment (Child-Pugh score of 10-15) have not been carried out. The use of Dropiltim (Pilocarpine) in these patients is not recommended.

Reference: Pugh, RNH, Murray-Lyon, IM, Dawson, JL Pietroni, MC, Williams, R. Transection of the Oesophagus for Bleeding Oesophageal Varices, Brit. J. Surg. 1973;60:646-9.

Information for Patients

Patients should be informed that Dropiltim may cause visual disturbances, especially at night, that could impair their ability to drive safely.

If a patient sweats excessively while taking Dropiltim (Pilocarpine) hydrochloride and cannot drink enough liquid, the patient should consult a physician. Dehydration may develop.

Drug Interactions

Dropiltim (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 Dropiltim (Pilocarpine) would be expected to result in additive pharmacologic effects.

Dropiltim (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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime oral carcinogenicity studies were conducted in CD-1 mice and Sprague-Dawley rats. Dropiltim did not induce tumors in mice at any dosage studied (up to 30 mg/kg/day, which yielded a systemic exposure approximately 50 times larger than the maximum systemic exposure observed clinically). In rats, a dosage of 18 mg/kg/day, which yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, resulted in a statistically significant increase in the incidence of benign pheochromocytomas in both males and females, and a statistically significant increase in the incidence of hepatocellular adenomas in female rats. The tumorigenicity observed in rats was observed only at a large multiple of the maximum labeled clinical dose, and may not be relevant to clinical use.

No evidence that Dropiltim (Pilocarpine) has the potential to cause genetic toxicity was obtained in a series of studies that included: 1) bacterial assays (Salmonella and E. coli) for reverse gene mutations; 2) an in vitro chromosome aberration assay in a Chinese hamster ovary cell line; 3) an in vivo chromosome aberration assay (micronucleus test) in mice; and 4) a primary DNA damage assay (unscheduled DNA synthesis) in rat hepatocyte primary cultures.

Oral administration of Dropiltim (Pilocarpine) to male and female rats at a dosage of 18 mg/kg/day, which yielded a systemic exposure approximately 100 times larger than the maximum systemic exposure observed clinically, 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 effects on male animals, female animals, or both males and females. In dogs, exposure to Dropiltim (Pilocarpine) at a dosage of 3 mg/kg/day (approximately 3 times the maximum recommended human dose when compared on the basis of body surface area (mg/m²) estimates) for six months resulted in evidence of impaired spermatogenesis. The data obtained in these studies suggest that Dropiltim (Pilocarpine) may impair the fertility of male and female humans. Dropiltim (Pilocarpine) hydrochloride tablets should be administered to individuals who are attempting to conceive a child only if the potential benefit justifies potential impairment of fertility.

Pregnancy

Teratogenic effects

Pregnancy Category C

Dropiltim 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/m²) estimates). These effects may have been secondary to maternal toxicity. In another study, oral administration of Dropiltim (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/m²) 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/m²) estimates) and above. There are no adequate and well-controlled studies in pregnant women. Dropiltim (Pilocarpine) hydrochloride tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 Dropiltim (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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Head and Neck Cancer Patients

In the placebo-controlled clinical trials the mean age of patients was approximately 58 years (range 19 to 80). Of these patients, 97/369 (61/217 receiving Dropiltim (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. (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).

ADVERSE REACTIONS

Head & Neck Cancer Patients

In controlled studies, 217 patients received Dropiltim, 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 Dropiltim (Pilocarpine) hydrochloride tablets were a consequence of the expected pharmacologic effects of Dropiltim (Pilocarpine).

In addition, the following adverse events (≥3% incidence) were reported at dosages of 15-30 mg/day in the controlled clinical trials:

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, paresthesias, 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 episode of syncope. The association with drug is uncertain.

Sjogren's Syndrome Patients

In controlled studies, 376 patients received Dropiltim (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 Dropiltim (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 in 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 Dropiltim (Pilocarpine) include the following adverse experiences associated with Dropiltim (Pilocarpine) hydrochloride tablets:

In addition, the following adverse events (≥3% incidence) were reported at dosages of 20 mg/day in the controlled clinical trials:

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, vaginitis.

The following events were reported rarely in treated Sjogren's patients (<1%) at dosing of 10-30 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 Dropiltim (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.

MANAGEMENT OF OVERDOSE

Fatal overdosage with Dropiltim (Pilocarpine) has been reported in the scientific literature at doses presumed to be greater than 100 mg in two hospitalized patients. 100 mg of Dropiltim (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 Dropiltim (Pilocarpine) is dialyzable.

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 Dropiltim 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 Dropiltim (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 Dropiltim (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 Dropiltim (Pilocarpine) hydrochloride tablets is 5 mg taken four times a day. Efficacy was established by 6 weeks of use.

HOW SUPPLIED

Dropiltim (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 Dropiltim (Pilocarpine) hydrochloride. They are supplied as follows:

Bottles of 100; NDC 0527-1313-01

Store at 20°- 25°C(68°-77°F).

Dropiltim (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 Dropiltim (Pilocarpine) hydrochloride. They are supplied as follows:

Bottles of 100; NDC 0527-1407-01

Store at 20°- 25°C(68°-77°F).

Distributed by:

Lannett Company, Inc.

Philadelphia, PA 19136

Made in the USA

CIB70322B

Revised 03/16

Timolol:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Dropiltim (Timolol) reviews

DESCRIPTION

Dropiltim (Timolol)^® (timolol ophthalmic solution), 0.25% and 0.5%, is a non-selective beta-adrenergic antagonist for ophthalmic use. The chemical name of the active ingredient is (S)-1-[(1,1-dimethylethyl)amino]-3-[(4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol. Dropiltim (Timolol) hemihydrate is the levo isomer. Specific rotation is [α]²⁵ _405nm=-16° (C=10% as the hemihydrate form in 1N HCl).

The molecular formula of Dropiltim (Timolol) is Formula C₁₃H₂₄N₄O₃S and its structural formula is:

Dropiltim (Timolol) (as the hemihydrate) is a white, odorless, crystalline powder which is slightly soluble in water and freely soluble in ethanol. Dropiltim (Timolol) hemihydrate is stable at room temperature.

Dropiltim (Timolol)^® is a clear, colorless, isotonic, sterile, microbiologically preserved phosphate buffered aqueous solution.

It is supplied in two dosage strengths, 0.25% and 0.5%.

Each mL of Dropiltim (Timolol)^® 0.25% contains 2.56 mg of Dropiltim (Timolol) hemihydrate equivalent to 2.5 mg Dropiltim (Timolol).

Each mL of Dropiltim (Timolol)^® 0.5% contains 5.12 mg of Dropiltim (Timolol) hemihydrate equivalent to 5.0 mg Dropiltim (Timolol).

Inactive ingredients: monosodium and disodium phosphate dihydrate to adjust pH (6.5 - 7.5) and water for injection, benzalkonium chloride 0.01% added as preservative.

The osmolality of Dropiltim (Timolol)^® is 260 to 320 mOsmol/kg.

Chemical Structure

CLINICAL PHARMACOLOGY

Dropiltim is a non-selective beta-adrenergic antagonist.

It blocks both beta₁-and beta₂-adrenergic receptors. Dropiltim (Timolol) does not have significant intrinsic sympathomimetic activity, local anesthetic (membrane-stabilizing) or direct myocardial depressant activity.

Dropiltim (Timolol), when applied topically in the eye, reduces normal and elevated intraocular pressure (IOP) whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of IOP, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. The predominant mechanism of ocular hypotensive action of topical beta-adrenergic blocking agents is likely due to a reduction in aqueous humor production.

In general, beta-adrenergic blocking agents reduce cardiac output both in healthy subjects and patients with heart diseases. In patients with severe impairment of myocardial function, beta-adrenergic receptor blocking agents may inhibit sympathetic stimulatory effect necessary to maintain adequate cardiac function. In the bronchi and bronchioles, beta-adrenergic receptor blockade may also increase airway resistance because of unopposed parasympathetic activity.

Pharmacokinetics

When given orally, Dropiltim (Timolol) is well absorbed and undergoes considerable first pass metabolism. Dropiltim (Timolol) and its metabolites are primarily excreted in the urine. The half-life of Dropiltim (Timolol) in plasma is approximately 4 hours.

Clinical Studies

In two controlled multicenter studies in the U.S., Dropiltim (Timolol)^® 0.25% and 0.5% were compared with respective Dropiltim (Timolol) maleate eyedrops. In these studies, the efficacy and safety profile of Dropiltim (Timolol)^® was similar to that of Dropiltim (Timolol) maleate.

INDICATIONS AND USAGE

Dropiltim (Timolol)^® is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

CONTRAINDICATIONS

Dropiltim (Timolol)^® is contraindicated in patients with overt heart failure, cardiogenic shock, sinus bradycardia, second- or third-degree atrioventricular block, bronchial asthma or history of bronchial asthma, or severe chronic obstructive pulmonary disease, or hypersensitivity to any component of this product.

WARNINGS

As with other topically applied ophthalmic drugs, Dropiltim ^® is absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely, death in association with cardiac failure have been reported following systemic or topical administration of beta-adrenergic blocking agents.

Cardiac Failure

Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe cardiac failure.

In patients without a history of cardiac failure, continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. Dropiltim (Timolol)^® should be discontinued at the first sign or symptom of cardiac failure.

Obstructive Pulmonary Disease

Patients with chronic obstructive pulmonary disease of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma which are contraindications) should in general not receive beta-blocking agents.

Major Surgery

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to a major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, gradual withdrawal of beta-adrenergic receptor blocking agents is recommended. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of beta-adrenergic agonists.

Diabetes Mellitus

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis

Beta-adrenergic blocking agents may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents which might precipitate a thyroid storm.

PRECAUTIONS

General

Because of the potential effects of beta-adrenergic blocking agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Dropiltim ^®, alternative therapy should be considered.

There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. dipIopia, ptosis, and generalized weakness). Beta-adrenergic blocking agents have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

In angle-closure glaucoma, the goal of the treatment is to reopen the angle. This requires constricting the pupil. Dropiltim (Timolol)^® has no effect on the pupil. Therefore, if Dropiltim (Timolol) is used in angle-closure glaucoma, it should always be combined with a miotic and not used alone.

Anaphylaxis

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

The preservative benzalkonium chloride may be absorbed by soft contact lenses. Patients who wear soft contact lenses should wait 5 minutes after instilling Dropiltim ^® before they insert their lenses.

Information for Patients

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at least 5 minutes apart.

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrioventricular block, or cardiac failure should be advised not to take this product

Drug Interactions

Beta-adrenergic blocking agents

Patients who are receiving a beta-adrenergic blocking agent orally and Dropiltim ^® should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade.

Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents concurrently.

Catecholamine-depleting drugs

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Calcium antagonists

Caution should be used in the co-administration of beta-adrenergic blocking agents and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided.

Digitalis and calcium antagonists

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

Injectable Epinephrine

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity of Dropiltim (Timolol) (as the maleate) has been studied in mice and rats. In a two-year study orally administrated Dropiltim (Timolol) maleate (300mg/kg/day) (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose) in male rats caused a significant increase in the incidence of adrenal pheochromocytomas; the lower doses, 25 mg or 100 mg/kg daily did not cause any changes.

In a life span study in mice the overall incidence of neoplasms was significantly increased in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Furthermore, significant increases were observed in the incidences of benign and malignant pulmonary tumors, benign uterine polyps, as well as mammary adenocarcinomas. These changes were not seen at the daily dose level of 5 or 50 mg/kg (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). For comparison, the maximum recommended human oral dose of Dropiltim (Timolol) maleate is 1 mg/kg/day.

Mutagenic potential of Dropiltim (Timolol) was evaluated in vivo in the micronucleus test and cytogenetic assay and in vitro in the neoplastic cell transformation assay and Ames test. In the bacterial mutagenicity test (Ames test) high concentrations of Dropiltim (Timolol) maleate (5000 and 10,000 g/plate) statistically significantly increased the number of revertants in Salmonella typhimurium TA100, but not in the other three strains tested. However, no consistent dose-response was observed nor did the number of revertants reach the double of the control value, which is regarded as one of the criteria for a positive result in the Ames test. In vivo genotoxicity tests (the mouse micronucleus test and cytogenetic assay) and in vitro the neoplastic cell transformation assay were negative up to dose levels of 800 mg/kg and 100 g/mL, respectively.

No adverse effects on male and female fertility were reported in rats at Dropiltim (Timolol) oral doses of up to 150 mg/kg/day (21,000 times the systemic exposure following the maximum recommended human ophthalmic dose).

Pregnancy Teratogenic effects

Category C

Teratogenicity of Dropiltim (as the maleate) after oral administration was studied in mice and rabbits. No fetal malformations were reported in mice or rabbits at a daily oral dose of 50 mg/kg (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women. Dropiltim (Timolol)^® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

Because of the potential for serious adverse reactions in nursing infants from Dropiltim (Timolol), 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.

Pediatric use

Safety and efficacy in pediatric patients have not been established.

ADVERSE REACTIONS

The most frequently reported ocular event in clinical trials was burning/stinging on instillation and was comparable between Dropiltim (Timolol)^® and Dropiltim (Timolol) maleate (approximately one in eight patients).

The following adverse events were associated with use of Dropiltim (Timolol)^® in frequencies of more than 5% in two controlled, double-masked clinical studies in which 184 patients received 0.25% or 0.5% Dropiltim (Timolol)^®:

OCULAR:

Dry eyes, itching, foreign body sensation, discomfort in the eye, eyelid erythema, conjunctival injection, and headache.

BODY AS A WHOLE:

Headache.

The following side effects were reported in frequencies of 1 to 5%:

OCULAR:

Eye pain, epiphora, photophobia, blurred or abnormal vision, corneal fluorescein staining, keratitis, blepharitis and cataract.

BODY AS A WHOLE:

Allergic reaction, asthenia, common cold and pain in extremities.

CARDIOVASCULAR:

Hypertension.

DIGESTIVE:

Nausea.

METABOLlC/NUTRITIONAL:

Peripheral edema.

NERVOUS SYSTEM/PSYCHIATRY:

Dizziness and dry mouth.

RESPIRATORY:

Respiratory infection and sinusitis.

In addition, the following adverse reactions have been reported with ophthalmic use of beta blockers:

OCULAR:

Conjunctivitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes, diplopia and retinal vascular disorder.

BODY AS A WHOLE:

Chest pain.

CARDIOVASCULAR:

Arrhythmia, palpitation, bradycardia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure and cardiac arrest.

DIGESTIVE:

Diarrhea.

ENDOCRINE:

Masked symptoms of hypoglycemia in insulin dependent diabetics.

NERVOUS SYSTEM/PSYCHIATRY:

Depression, impotence, increase in signs and symptoms of myasthenia gravis and paresthesia.

RESPIRATORY:

Dyspnea, bronchospasm, respiratory failure and nasal congestion.

SKIN:

AIOPecia, hypersensitivity including localized and generalized rash, urticaria.

OVERDOSAGE

No information is available on overdosage with Dropiltim (Timolol)^®. Symptoms that might be expected with an overdose of a beta-adrenergic receptor blocking agent are bronchospasm, hypotension, bradycardia, and acute cardiac failure.

DOSAGE AND ADMINISTRATION

Dropiltim (Timolol)^® Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Dropiltim (Timolol)^® in the affected eye(s) twice a day. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) twice a day.

If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to one drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure, satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure at different times during the day.

Since in some patients the pressure-lowering response to Dropiltim (Timolol)^® may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Dropiltim (Timolol)^®.

Dosages above one drop of 0.5 percent Dropiltim (Timolol)^® twice a day generally have not been shown to produce further reduction in intraocular pressure. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy with pilocarpine and other miotics, and/or epinephrine, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide, can be instituted.

HOW SUPPLIED

Dropiltim ^® (timolol ophthalmic solution) is a clear, colorless solution.

Dropiltim (Timolol)^® 0.25% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:

Dropiltim (Timolol)^® 0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:

Rx Only

STORAGE

Store between 15-25°C (59-77°F). Do not freeze. Protect from light.

MARKETED BY:

VISTAKON^® Pharmaceuticals, LLC

Jacksonville, FL 32256 USA

MANUFACTURED BY:

Santen Oy, P.O. Box 33

FIN-33721 Tampere, Finland

November 2006 Version

3220660/5