Dicyclomine

12.1 Mechanism of Action Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism: a specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine ( in vitro , guinea pig ileum); and a direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomine’s antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum. Atropine did not affect responses to these two agonists. In vivo studies in cats and dogs showed dicyclomine to be equally potent against acetylcholine (ACh)- or barium chloride (BaCl 2 )-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl 2 . Tests for mydriatic effects in mice showed that dicyclomine was approximately 1/500 as potent as atropine; antisialagogue tests in rabbits showed dicyclomine to be 1/300 as potent as atropine.

1 INDICATIONS AND USAGE Dicyclomine hydrochloride capsules, USP are indicated for the treatment of patients with functional bowel/irritable bowel syndrome. Dicyclomine hydrochloride capsules, USP are an antispasmodic and anticholinergic (antimuscarinic) agent indicated for the treatment of functional bowel/irritable bowel syndrome (1)

2 DOSAGE AND ADMINISTRATION Dosage must be adjusted to individual patient needs. Dosage for dicyclomine hydrochloride capsules must be adjusted to individual patient needs (2) . If a dose is missed, patients should continue the normal dosing schedule (2) . Oral in adults (2.1 ) : Starting dose: 20 mg four times a day. After a week treatment with the starting dose, the dose may be escalated to 40 mg four times a day, unless side effects limit dosage escalation Discontinue dicyclomine hydrochloride if efficacy not achieved or side effects require doses less than 80 mg per day after two weeks of treatment 2.1 Oral Dosage and Administration in Adults The recommended initial dose is 20 mg four times a day. After one week treatment with the initial dose, the dose may be increased to 40 mg four times a day unless side effects limit dosage escalation. If efficacy is not achieved within 2 weeks or side effects require doses below 80 mg per day, the drug should be discontinued. Documented safety data are not available for doses above 80 mg daily for periods longer than 2 weeks.

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.