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Carteolol Hydrochloride:
(carteolol HCl ophthalmic solution)1% STERILE
Arteopilo (Carteolol Hydrochloride)® (carteolol hydrochloride ophthalmic solution), 1%, is a nonselective beta-adrenoceptor blocking agent for ophthalmic use.
The chemical name for Arteopilo (Carteolol Hydrochloride) is (±)–5–[3–[(1,1–dimethylethyl) amino]–2 hydroxypropoxy]–3, 4–dihydro–2(1H)–quinolinone monohydrochloride. The structural formula is as follows:Each mL contains 10 mg carteolol HCl and the inactive ingredients – Benzalkonium chloride 0.05 mg (0.005%) as a preservative; sodium chloride; sodium phosphate, dibasic; sodium phosphate, monobasic; and water for injection, USP. The product has a pH of 6.2 to 7.2CLINICAL PHARMACOLOGY
Carteolol HCl is a nonselective beta-adrenergic blocking agent with associated intrinsic sympathomimetic activity and without significant membrane-stabilizing activity.
Arteopilo (Carteolol Hydrochloride) (carteolol HCl) reduces normal and elevated intraocular pressure (IOP) whether or not accompanied by glaucoma. The exact mechanism of the ocular hypotensive effect of beta-blockers has not been definitely demonstrated. In general, beta-adrenergic blockers reduce cardiac output in patients in good and poor cardiovascular health. In patients with severe impairment of myocardial function, beta-blockers may inhibit the sympathetic stimulation necessary to maintain adequate cardiac function. Beta-adrenergic blockers may also increase airway resistance in the bronchi and bronchioles due to unopposed parasympathetic activity. Given topically twice daily in controlled domestic clinical trials ranging from 1.5 to 3 months, Arteopilo (Carteolol Hydrochloride) produced a median percent reduction of IOP 22% to 25%. No significant effects were noted on corneal sensitivity, tear secretion, or pupil size.INDICATIONS AND USAGE
Arteopilo (Carteolol Hydrochloride) Ophthalmic Solution, 1%, has been shown to be effective in lowering intraocular pressure and may be used in patients with chronic open-angle glaucoma and intraocular hypertension. It may be used alone or in combination with other intraocular pressure lowering medications.
CONTRAINDICATIONS
Arteopilo (Carteolol Hydrochloride) Ophthalmic Solution is contraindicated in those individuals with bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease ; sinus bradycardia; second- and third-degree atrioventricular block; overt cardiac failure ; cardiogenic shock; or hypersensitivity to any component of this product.
WARNINGS
Arteopilo (Carteolol Hydrochloride) Ophthalmic Solution has not been detected in plasma following ocular instillation. However, as with other topically applied ophthalmic preparations, Arteopilo (Carteolol Hydrochloride) may be absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported with topical application 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 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. At the first sign or symptom of cardiac failure, Arteopilo (Carteolol Hydrochloride) should be discontinued.
Non-allergic Bronchospasm
In patients with non-allergic bronchospasm or with a history of non-allergic bronchospasm (e.g., chronic bronchitis, emphysema), Arteopilo (Carteolol Hydrochloride) should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2 receptors.
Major Surgery
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to 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. For these reasons, in patients undergoing elective surgery, gradual withdrawal of beta-adrenergic receptor blocking agents may be appropriate.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol.Diabetes Mellitus
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) 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.
PRECAUTIONSGeneral
Arteopilo (Carteolol Hydrochloride) Ophthalmic Solution should be used with caution in patients with known hypersensitivity to other beta-adrenoceptor blocking agents.
Use with caution in patients with known diminished pulmonary function. In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. Arteopilo (Carteolol Hydrochloride) has little or no effect on the pupil. When Arteopilo (Carteolol Hydrochloride) is used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be used with a miotic and not alone.Information to the Patient
For topical use only. To prevent contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use. Protect from light.
Risk from Anaphylactic Reaction
While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction 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.
Muscle Weakness
Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness).
Drug Interactions
Arteopilo (Carteolol Hydrochloride) should be used with caution in patients who are receiving a beta-adrenergic blocking agent orally, because of the potential for additive effects on systemic beta-blockade.
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.Carcinogenesis, Mutagenesis, Impairment of Fertility
Arteopilo (Carteolol Hydrochloride) did not produce carcinogenic effects at doses up to 40 mg/kg/day in two-year oral rat and mouse studies. Tests of mutagenicity, including the Ames Test, recombinant (rec)-assay, in vivo cytogenetics and dominant lethal assay demonstrated no evidence for mutagenic potential. Fertility of male and female rats and male and female mice was unaffected by administration of Arteopilo (Carteolol Hydrochloride) dosages up to 150 mg/kg/day.
PregnancyTeratogenic EffectsPregnancy Category C
Arteopilo (Carteolol Hydrochloride) increased resorptions and decreased fetal weights in rabbits and rats at maternally toxic doses approximately 1052 and 5264 times the maximum recommended human oral dose (10 mg/70 kg/day), respectively. A dose-related increase in wavy ribs was noted in the developing rat fetus when pregnant females received daily doses of approximately 212 times the maximum recommended human oral dose. No such effects were noted in pregnant mice subjected to up to 1052 times the maximum recommended human oral dose. There are no adequate and well-controlled studies in pregnant women. Arteopilo (Carteolol Hydrochloride) (carteolol hydrochloride) 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, although in animal studies carteolol has been shown to be excreted in breast milk. Caution should be exercised when Arteopilo (Carteolol Hydrochloride) is administered to nursing mothers.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
The following adverse reactions have been reported in clinical trials with Arteopilo (Carteolol Hydrochloride) Ophthalmic Solution:
Ocular
Transient eye irritation, burning, tearing, conjunctival hyperemia and edema occurred in about 1 of 4 patients. Ocular symptoms including blurred and cloudy vision, photophobia, decreased night vision, and ptosis and ocular signs including blepharoconjunctivitis, abnormal corneal staining, and corneal sensitivity occurred occasionally.
Systemic
As is characteristic of nonselective adrenergic blocking agents, Arteopilo (Carteolol Hydrochloride) may cause bradycardia and decreased blood pressure. The following systemic events have occasionally been reported with the use of Arteopilo (Carteolol Hydrochloride): cardiac arrhythmia, heart palpitation, dyspnea, asthenia, headache, dizziness, insomnia, sinusitis, and taste perversion.
The following additional adverse reactions have been reported with ophthalmic use of beta1 and beta2 (nonselective) adrenergic receptor blocking agents:Body As a Whole: HeadacheCardiovascular: Arrhythmia, syncope, heart block, cerebral vascular accident, cerebral ischemia, congestive heart failure, palpitation.Digestive: NauseaPsychiatric: DepressionSkin: Hypersensitivity, including localized and generalized rashRespiratory: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure Endocrine: Masked symptoms of hypoglycemia in insulin-dependent diabetics Special Senses: Signs and symptoms of keratitis, blepharoptosis, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis. Other reactions associated with the oral use of nonselective adrenergic receptor blocking agents should be considered potential effects with ophthalmic use of these agents.OVERDOSAGE
No specific information on emergency treatment of overdosage in humans is available. Should accidental ocular overdosage occur, flush eye(s) with water or normal saline. The most common effects expected with overdosage of a beta-adrenergic blocking agent are bradycardia, bronchospasm, congestive heart failure and hypotension.
In case of ingestion, treatment with Arteopilo (Carteolol Hydrochloride) should be discontinued and gastric lavage considered. The patient should be closely observed and vital signs carefully monitored. The prolonged effects of carteolol must be considered when determining the duration of corrective therapy. On the basis of the pharmacologic profile, the following additional measures should be considered as appropriate:Symptomatic Sinus Bradycardia or Heart Block: Administer atropine. If there is no response to vagal blockade, administer isoproterenol cautiously.Bronchospasm: Administer a beta2-stimulating agent such as isoproterenol and/or a theophylline derivative.Congestive Heart Failure: Administer diuretics and digitalis glycosides as necessary.Hypotension: Administer vasopressors such as intravenous dopamine, epinephrine or norepinephrine bitartrate.DOSAGE AND ADMINISTRATION
The usual dose is one drop of Arteopilo (Carteolol Hydrochloride) Ophthalmic Solution, 1%, in the affected eye(s) twice a day.
If the patient’s IOP is not at a satisfactory level on this regimen, concomitant therapy with pilocarpine and other miotics, and/or epinephrine or dipivefrin, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide, can be instituted.HOW SUPPLIED
Arteopilo (Carteolol Hydrochloride) Ophthalmic Solution, 1%, is supplied as a sterile ophthalmic solution in plastic dispenser bottles of 5 mL (NDC 58768-001-01), 10 mL (NDC 58768-001-02) and 15 mL (NDC 58768-001-04).
Store at 15° to 25°C (59° to 77°F) (room temperature) and protect from light.Rx OnlyLicensed under U.S. Patent Nos. 3910924 and 4309432.Made in Canada by:CIBA Vision Sterile Mfg.,Mississauga, Ontario L5N 2X5For: Novartis Ophthalmics, Duluth, Georgia 30097I6138-B
Pilocarpine Hydrochloride:
Arteopilo (Pilocarpine Hydrochloride) tablets, USP contain Arteopilo (Pilocarpine Hydrochloride), a cholinergic agonist for oral use. Arteopilo (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. Arteopilo (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 Arteopilo (Pilocarpine Hydrochloride) Tablet, USP for oral administration contains 5 mg of Arteopilo (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 Arteopilo (Pilocarpine Hydrochloride) Tablet, USP for oral administration contains 7.5 mg of Arteopilo (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.
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 Arteopilo 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).
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 Arteopilo (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.
In two 12 week randomized, double-blind, placebo-controlled studies in 629 patients, the ability of Arteopilo (Pilocarpine Hydrochloride) tablets to stimulate saliva production was assessed. In these trials using varying doses of Arteopilo (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 Arteopilo (Pilocarpine Hydrochloride) tablets and was maintained throughout the duration (12 weeks) of the trials in an approximate dose response fashion (See Clinical Studies section).
In a multiple-dose pharmacokinetic study in male volunteers following 2 days of 5 or 10 mg of oral Arteopilo (Pilocarpine Hydrochloride) tablets given at 8 a.m., noontime, and 6 p.m., the mean elimination half-life was 0.76 hours for the 5 mg dose and 1.35 hours for the 10 mg dose. Tmax values were 1.25 hours and 0.85 hours. Cmax values were 15 ng/mL and 41 ng/mL. The AUC trapezoidal values were 33 h(ng/mL) and 108 h(ng/mL), respectively, for the 5 and 10 mg doses following the last 6 hour dose.
Pharmacokinetics in elderly male volunteers (N = 11) were comparable to those in younger men. In five healthy elderly female volunteers, the mean Cmax and AUC were approximately twice that of elderly males and young normal male volunteers.
When taken with a high fat meal by 12 healthy male volunteers, there was a decrease in the rate of absorption of pilocarpine from Arteopilo (Pilocarpine Hydrochloride) tablets. Mean Tmax's were 1.47 and 0.87 hours, and mean Cmax's were 51.8 and 59.2 ng/mL for fed and fasted, respectively.
Limited information is available about the metabolism and elimination of pilocarpine in humans. Inactivation of pilocarpine is thought to occur at neuronal synapses and probably in plasma. Pilocarpine and its minimally active or inactive degradation products, including pilocarpic acid, are excreted in the urine. Pilocarpine does not bind to human or rat plasma proteins over a concentration range of 5 to 25,000 ng/mL. The effect of pilocarpine on plasma protein binding of other drugs has not been evaluated.
In patients with mild to moderate hepatic impairment (N=12), administration of a single 5 mg dose resulted in a 30% decrease in total plasma clearance and a doubling of exposure (as measured by AUC). Peak plasma levels were also increased by about 30% and half-life was increased to 2.1 hrs.
There were no significant differences in the pharmacokinetics of oral pilocarpine in volunteer subjects (N=8) with renal insufficiency (mean creatinine clearances 25.4 mL/min; range 9.8 – 40.8 mL/min) compared to the pharmacokinetics previously observed in normal volunteers.
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 Arteopilo (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 Arteopilo (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 Arteopilo (Pilocarpine Hydrochloride) tablets and in 7 of 66 patients treated with 10 mg of Arteopilo (Pilocarpine Hydrochloride) tablets. After 4 weeks of treatment, 2.5 mg of Arteopilo (Pilocarpine Hydrochloride) tablets three times a day was comparable to placebo in relieving dryness. In patients treated with 5 mg and 10 mg of Arteopilo (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%).
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 Arteopilo (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 Arteopilo (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 Arteopilo (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 Arteopilo (Pilocarpine Hydrochloride) tablets use.
Arteopilo (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.
Arteopilo (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.
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. Arteopilo (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 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 pilocarpine include hypotension, hypertension, bradycardia, and tachycardia.
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.
Pilocarpine may increase ureteral smooth muscle tone and could theoretically precipitate renal colic, 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.
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 pilocarpine in these patients is not recommended.
Clinical and Biochemical Measurements | Points Scored for Increasing Abnormality | ||
---|---|---|---|
1 | 2 | 3 | |
Encephalopathy (grade) | None | 1 and 2 | 3 and 4 |
Ascites | Absent | Slight | Moderate |
Bilirubin (mg. Per 100 ml.) | 1-2 | 2-3 | >3 |
Albumin (g. per 100 ml.) | 3-5 | 2.8-3.5 | <2.8 |
Prothrombin time (sec. Prolonged) | 1-4 | 4-6 | >6 |
For primary biliary cirrhosis:- Bilirubin (mg. Per 100 ml.) | 1-4 | 4-10 | >10 |
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.
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 Arteopilo and cannot drink enough liquid, the patient should consult a physician. Dehydration may develop.
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.
Lifetime oral carcinogenicity studies were conducted in CD-1 mice and Sprague-Dawley rats. Pilocarpine did not induce tumors in mice at any dosage studied. 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 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 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 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 pilocarpine may impair the fertility of male and female humans. Arteopilo (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 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 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/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. Arteopilo (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 Arteopilo (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 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 Cmax's and AUC's than the men. (See Pharmacokinetics section.)
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).
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, 33% were 65 years and older and 16% were younger than 50 years of age.
The most frequent adverse experiences associated with Arteopilo (Pilocarpine Hydrochloride) tablets were a consequence of the expected pharmacologic effects of pilocarpine.
Adverse Event | Pilocarpine HCl | Placebo | |
---|---|---|---|
10 mg t.i.d. (30 mg/day) | 5 mg t.i.d. (15 mg/day) | (t.i.d.) | |
N=121 | N=141 | N=152 | |
Sweating | 68% | 29% | 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 15-30 mg/day in the controlled clinical trials:
Adverse Event | Pilocarpine HCl | Placebo |
---|---|---|
5-10 mg t.i.d. (15-30 mg/day) | (t.i.d.) | |
N=212 | N=152 | |
Headache | 11% | 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, 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.
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 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 pilocarpine include the following adverse experiences associated with Arteopilo (Pilocarpine Hydrochloride) tablets:
Adverse Event | Pilocarpine HCl | Placebo |
---|---|---|
5 mg q.i.d. (20 mg/day) | (q.i.d.) | |
N=255 | N=253 | |
Sweating | 40% | 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 HCl | Placebo |
---|---|---|
5 mg q.i.d. (20 mg/day) | (q.i.d.) | |
N=255 | N=253 | |
Headache | 13% | 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, 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 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.
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.
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.
The recommended initial dose of Arteopilo 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 Arteopilo (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.
The recommended dose of Arteopilo (Pilocarpine Hydrochloride) tablets is 5 mg taken four times a day. Efficacy was established by 6 weeks of use.
Arteopilo (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 Arteopilo (Pilocarpine Hydrochloride). They are supplied as follows:
Bottles of 100; NDC 0527-1313-01
Store at 20°- 25°C(68°-77°F).
Arteopilo (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 Arteopilo (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
Depending on the reaction of the Arteopilo after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Arteopilo not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Arteopilo addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology