Dicyclomine

5 WARNINGS AND PRECAUTIONS Cardiovascular conditions : worsening of conditions (5.2) Peripheral and central nervous system : heat prostration can occur with drug use (fever and heat stroke due to decreased sweating); drug should be discontinued and supportive measures instituted (5.3) Psychosis and delirium have been reported in patients sensitive to anticholinergic drugs (such as elderly patients and/or in patients with mental illness): signs and symptoms resolve within 12 to 24 hours after discontinuation of dicyclomine hydrochloride (5.3) Myasthenia Gravis : overdose may lead to muscular weakness and paralysis. Dicyclomine hydrochloride should be given to patients with myasthenia gravis only to reduce adverse muscarinic effects of an anticholinesterase (5.4) Incomplete intestinal obstruction : diarrhea may be an early symptom especially in patients with ileostomy or colostomy. Treatment with dicyclomine hydrochloride would be inappropriate and possibly fatal (5.5) Salmonella dysenteric patients : due to risk of toxic megacolon (5.6) Ulcerative colitis : dicyclomine hydrochloride should be used with caution in these patients; large doses may suppress intestinal motility or aggravate the serious complications of toxic megacolon (5.7) Prostatic hypertrophy : dicyclomine hydrochloride should be used with caution in these patients; may lead to urinary retention (5.8) Hepatic and renal disease : should be used with caution (5.9) Geriatric : use with caution in elderly who may be more susceptible to dicyclomine hydrochloride’s adverse events (5.10) 5.2 Cardiovascular Conditions Dicyclomine hydrochloride needs to be used with caution in conditions characterized by tachyarrhythmia such as thyrotoxicosis, congestive heart failure and in cardiac surgery, where they may further accelerate the heart rate. Investigate any tachycardia before administration of dicyclomine hydrochloride. Care is required in patients with coronary heart disease, as ischemia and infarction may be worsened, and in patients with hypertension [see Adverse Reactions (6.3) ] . 5.3 Peripheral and Central Nervous System The peripheral effects of dicyclomine hydrochloride are a consequence of their inhibitory effect on muscarinic receptors of the autonomic nervous system. They include dryness of the mouth with difficulty in swallowing and talking, thirst, reduced bronchial secretions, dilatation of the pupils (mydriasis) with loss of accommodation (cycloplegia) and photophobia, flushing and dryness of the skin, transient bradycardia followed by tachycardia, with palpitations and arrhythmias, and difficulty in micturition, as well as reduction in the tone and motility of the gastrointestinal tract leading to constipation [see Adverse Reactions ( 6) ] . In the presence of high environmental temperature heat prostration can occur with drug use (fever and heat stroke due to decreased sweating). It should also be used cautiously in patients with fever. If symptoms occur, the drug should be discontinued and supportive measures instituted. Because of the inhibitory effect on muscarinic receptors within the autonomic nervous system, caution should be taken in patients with autonomic neuropathy. Central nervous system (CNS) signs and symptoms include confusional state, disorientation, amnesia, hallucinations, dysarthria, ataxia, coma, euphoria, fatigue, insomnia, agitation and mannerisms, and inappropriate affect. Psychosis and delirium have been reported in sensitive individuals (such as elderly patients and/or in patients with mental illness) given anticholinergic drugs. These CNS signs and symptoms usually resolve within 12 to 24 hours after discontinuation of the drug. Dicyclomine hydrochloride may produce drowsiness, dizziness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work while taking dicyclomine hydrochloride. 5.4 Myasthenia Gravis With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). It should not be given to patients with myasthenia gravis except to reduce adverse muscarinic effects of an anticholinesterase [see Contraindications (4) ]. 5.5 Intestinal Obstruction Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful [see Contraindications (4) ]. Rarely development of Ogilvie’s syndrome (colonic pseudo-obstruction) has been reported. Ogilvie’s syndrome is a clinical disorder with signs, symptoms, and radiographic appearance of an acute large bowel obstruction but with no evidence of distal colonic obstruction. 5.6 Toxic Dilatation of Intestinemegacolon Toxic dilatation of intestine and intestinal perforation is possible when anticholinergic agents are administered in patients with Salmonella dysentery. 5.7 Ulcerative Colitis Caution should be taken in patients with ulcerative colitis. Large doses may suppress intestinal motility to the point of producing a paralytic ileus and the use of this drug may precipitate or aggravate the serious complication of toxic megacolon [see Adverse Reactions (6.3) ] . Dicyclomine hydrochloride is contraindicated in patients with severe ulcerative colitis [see Contraindications (4) ]. 5.8 Prostatic Hypertrophy Dicyclomine hydrochloride should be used with caution in patients with known or suspected prostatic enlargement, in whom prostatic enlargement may lead to urinary retention [see Adverse Reactions (6.3) ] . 5.9 Hepatic and Renal Disease Dicyclomine hydrochloride should be used with caution in patients with known hepatic and renal impairment. 5.10 Geriatric Population Dicyclomine hydrochloride should be used with caution in elderly who may be more susceptible to its adverse effects.

6 ADVERSE REACTIONS The pattern of adverse effects seen with dicyclomine is mostly related to its pharmacological actions at muscarinic receptors [see Clinical Pharmacology (12) ] . They are a consequence of the inhibitory effect on muscarinic receptors within the autonomic nervous system. These effects are dose-related and are usually reversible when treatment is discontinued. The most serious adverse reactions reported with dicyclomine hydrochloride include cardiovascular and central nervous system symptoms [see Warnings and Precautions (5.2, 5.3) ]. The most serious adverse reactions include cardiovascular and central nervous system symptoms. The most common adverse reactions (> 5% of patients) are dizziness, dry mouth, vision blurred, nausea, somnolence, asthenia and nervousness (6) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure in controlled clinical trials involving over 100 patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg four times a day). In these trials most of the side effects were typically anticholinergic in nature and were reported by 61% of the patients. Table 1 presents adverse reactions ( MedDRA 13.0 preferred terms) by decreasing order of frequency in a side-by-side comparison with placebo. Table 1: Adverse reactions experienced in controlled clinical trials with decreasing order of frequency MedDRA Preferred Term Dicyclomine Hydrochloride(40 mg four times a day) % Placebo % Dry Mouth 33 5 Dizziness 40 5 Vision blurred 27 2 Nausea 14 6 Somnolence 9 1 Asthenia 7 1 Nervousness 6 2 Nine percent (9%) of patients were discontinued from dicyclomine hydrochloride because of one or more of these side effects (compared with 2% in the placebo group). In 41% of the patients with side effects, side effects disappeared or were tolerated at the 160 mg daily dose without reduction. A dose reduction from 160 mg daily to an average daily dose of 90 mg was required in 46% of the patients with side effects who then continued to experience a favorable clinical response; their side effects either disappeared or were tolerated. 6.2 Postmarketing Experience The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of dicyclomine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: palpitations, tachyarrhythmias Eye Disorders: cycloplegia, mydriasis, vision blurred Gastrointestinal Disorders: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, nausea, vomiting General Disorders and Administration Site Conditions: fatigue, malaise Immune System Disorders: drug hypersensitivity including face edema, angioedema, anaphylactic shock Nervous System Disorders: dizziness, headache, somnolence, syncope Psychiatric Disorders: As with the other anticholinergic drugs, cases of delirium or symptoms of delirium such as amnesia (or transient global amnesia), agitation, confusional state, delusion, disorientation, hallucination (including visual hallucination) as well as mania, mood altered and pseudodementia, have been reported with the use of dicyclomine. Nervousness and insomnia have also been reported. Reproductive System and Breast Disorders: suppressed lactation Respiratory, Thoracic and Mediastinal Disorders: dyspnoea, nasal congestion Skin and Subcutaneous Tissue Disorder: dermatitis allergic, erythema, rash 6.3 Adverse Reactions Reported with Similar Drugs with Anticholinergic/Antispasmodic Action Gastrointestinal: anorexia Central Nervous System: tingling, numbness, dyskinesia, speech disturbance, insomnia Peripheral Nervous System: With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis) Ophthalmologic: diplopia, increased ocular tension Dermatologic/Allergic: urticaria, itching, and other dermal manifestations Genitourinary: urinary hesitancy, urinary retention in patients with prostatic hypertrophy Cardiovascular: hypertension Respiratory: apnea Other: decreased sweating, sneezing, throat congestion, impotence. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com

7 DRUG INTERACTIONS Antiglaucoma agents : anticholinergics antagonize antiglaucoma agents and may increase intraoccular pressure (7) Anticholinergic agents : may affect the gastrointestinal absorption of various drugs; may also increase certain actions or side effects of other anticholinergic drugs (7) Antacids : interfere with the absorption of anticholinergic agents (7) 7.1 Antiglaucoma Agents Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Use of dicyclomine hydrochloride in patients with glaucoma is not recommended [see Contraindications (4) ]. 7.2 Other Drugs with Anticholinergic Activity The following agents may increase certain actions or side effects of anticholinergic drugs including dicyclomine hydrochloride: amantadine, antiarrhythmic agents of Class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. 7.3 Other Gastrointestinal Motility Drugs Interaction with other gastrointestinal motility drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. 7.4 Effect of Antacids Because antacids may interfere with the absorption of anticholinergic agents including dicyclomine hydrochloride, simultaneous use of these drugs should be avoided. 7.5 Effect on Absorption of Other Drugs Anticholinergic agents may affect gastrointestinal absorption of various drugs by affecting on gastrointestinal motility, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentration may result. 7.6 Effect on Gastric Acid Secretion The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion.

8 USE IN SPECIFIC POPULATIONS Pregnancy: use only if clearly needed (8.1) Pediatric Use: Safety and effectiveness not established (8.4) Hepatic and renal impairment: caution must be taken with patients with significantly impaired hepatic and renal function (8.6) 8.1 Pregnancy Pregnancy Category B Adequate and well-controlled studies have not been conducted with dicyclomine hydrochloride in pregnant women at the recommended doses of 80 to 160 mg/day. However, epidemiologic studies did not show an increased risk of structural malformations among babies born to women who took products containing dicyclomine hydrochloride at doses up to 40 mg/day during the first trimester of pregnancy. Reproduction studies have been performed in rats and rabbits at doses up to 33 times the maximum recommended human dose based on 160 mg/day (3 mg/kg) and have revealed no evidence of harm to the fetus due to dicyclomine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers Dicyclomine hydrochloride is contraindicated in women who are breastfeeding. Dicyclomine hydrochloride is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants from dicyclomine hydrochloride, 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 [see Use in Specific Populations (8.4) ] . 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Dicyclomine hydrochloride is contraindicated in infants less than 6 months of age [see Contraindications (4) ] . There are published cases reporting that the administration of dicyclomine hydrochloride to infants has been followed by serious respiratory symptoms (dyspnea, shortness of breath, breathlessness, respiratory collapse, apnea and asphyxia), seizures, syncope, pulse rate fluctuations, muscular hypotonia, and coma, and death, however; no causal relationship has been established. 8.5 Geriatric Use Clinical studies of dicyclomine hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range in adults, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy . Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment Effects of renal impairment on PK, safety and efficacy of dicyclomine hydrochloride have not been studied. Dicyclomine hydrochloride drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Dicyclomine hydrochloride should be administered with caution in patients with renal impairment. 8.7 Hepatic Impairment Effects of renal impairment on PK, safety and efficacy of dicyclomine hydrochloride have not been studied. Dicyclomine hydrochloride should be administered with caution in patients with hepatic impairment.