Dicyclomine Hydrochloride

RECENT MAJOR CHANGES Warnings and Precautions, Peripheral and Central Nervous System ( 5.3 ) 07/2012 Warnings and Precautions, Peripheral and Central Nervous System ( 5.3 ) 07/2012

1 INDICATIONS AND USAGE Dicyclomine hydrochloride tablets are indicated for the treatment of patients with functional bowel/irritable bowel syndrome. Dicyclomine hydrochloride tablets 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 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.

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.

3 DOSAGE FORMS AND STRENGTHS Dicyclomine hydrochloride USP, 10 mg capsules: Size 4 hard gelatin capsules, with dark blue clear cap and body. Rectified axial imprinted with white ink WATSON over 794 on cap and 10 mg on the body. Dicyclomine hydrochloride USP, 20 mg tablets: Blue, round, flat-faced, beveled-edge tablets, debossed WATSON in a semi-circle around the top edge and 795 across the bottom on one side and plain on the other side. Dicyclomine hydrochloride capsules 10 mg ( 3 ) Dicyclomine hydrochloride tablets 20 mg ( 3 )

4 CONTRAINDICATIONS Dicyclomine hydrochloride is contraindicated in infants less than 6 months of age [see Use in Specific P opu l a ti on s ( 8.4 )], nursing mothers [see Use in Specific Populations ( 8.3 )] and in patients with: • unstable cardiovascular status in acute hemorrhage • myasthenia gravis [see Warnings and Precautions ( 5.4 )] • glaucoma [see Adverse Reactions ( 6.3 ) and Drug Interactions ( 7.1 )] • obstructive uropathy [see Warnings and Precautions ( 5.8 )] • obstructive disease of the gastrointestinal tract [see Warnings and Precautions ( 5.5 )] • severe ulcerative colitis [see Warnings and Precautions ( 5.7 )] • reflux esophagitis • Infants less than 6 months of age ( 4 ) • Nursing mothers ( 4 ) • Unstable cardiovascular status in acute hemorrhage ( 4 ) • Myasthenia gravis ( 4 ) • Glaucoma ( 4 ) • Obstructive uropathy ( 4 ) • Obstructive disease of the gastrointestinal tract ( 4 ) • Severe ulcerative colitis ( 4 ) • Reflux esophagitis ( 4 )

6 ADVERSE REACTIONS The pattern of adverse effects seen with dicylomine 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 Solaris Pharma Corporation at 1-833-919-0527 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Post marketing 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 anti-cholinergic 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 …

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.

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 Clinical studies of buprenorphine and naloxone sublingual tablets, buprenorphine and naloxone sublingual film, or buprenorphine sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Due to possible decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe buprenorphine and naloxone sublingual tablet should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose. 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.

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.

11 DESCRIPTION Dicyclomine hydrochloride, USP is an antispasmodic and anticholinergic (antimuscarinic) agent available in the following dosage forms: Dicyclomine hydrochloride capsules, USP for oral use contain 10 mg dicyclomine hydrochloride, USP. Dicyclomine hydrochloride USP, 10 mg capsules also contain inactive ingredients: ammonium hydroxide, D&C Red No. 28, FD&C Blue No. 1, gelatin, magnesium stearate, pregelatinized corn starch, propylene glycol, shellac, simethicone, and titanium dioxide. Dicyclomine hydrochloride tablets, USP for oral use contain 20 mg dicyclomine hydrochloride, USP. Dicyclomine hydrochloride USP, 20 mg tablets also contain the following inactive ingredients: colloidal silicon dioxide, corn starch, FD&C Blue No. 1 Aluminum Lake, hypromellose, lactose monohydrate, sodium starch glycolate, and stearic acid. Dicyclomine hydrochloride, USP is [bicyclohexyl]-1-carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C 19 H 35 NO 2 •HCl and the following structural formula: Molecular weight: 345.95 Dicyclomine hydrochloride, USP occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether. Dicyclomine Hydrochloride structural formula

10 OVERDOSAGE In case of an overdose, patients should contact a physician, poison control center (1-800-222-1222), or emergency room. The signs and symptoms of overdosage include: headache; nausea; vomiting; blurred vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth; difficulty in swallowing; and CNS stimulation including convulsion. A curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). One reported event included a 37-year-old who reported numbness on the left side, cold fingertips, blurred vision, abdominal and flank pain, decreased appetite, dry mouth, and nervousness following ingestion of 320 mg daily (four 20 mg tablets four times daily). These events resolved after discontinuing the dicyclomine. The acute oral LD 50 of the drug is 625 mg/kg in mice. The amount of drug in a single dose that is ordinarily associated with symptoms of overdosage or that is likely to be life-threatening, has not been defined. The maximum human oral dose recorded was 600 mg by mouth in a 10-month-old child and approximately 1500 mg in an adult, each of whom survived. In three of the infants who died following administration of dicyclomine hydrochloride tablets [see Warnings and Precautions (5.1)], the blood concentrations of drug were 200, 220, and 505 ng/mL. It is not known if dicyclomine hydrochloride is dialyzable. Treatment should consist of gastric lavage, emetics, and activated charcoal. Sedatives (e.g., short-acting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote.

16 HOW SUPPLIED/STORAGE AND HANDLING Dicyclomine hydrochloride tablets, USP 20 mg are blue, round, unscored, speckled, flat-faced, beveled-edge tablets, debossed “ DC” on one side and plain on the other side. NDC: 71335-2506-1: 30 Tablets in a BOTTLE, NDC: 71335-2506-2: 40 Tablets in a BOTTLE, NDC: 71335-2506-3: 60 Tablets in a BOTTLE, NDC: 71335-2506-4: 90 Tablets in a BOTTLE, NDC: 71335-2506-5: 20 Tablets in a BOTTLE, NDC: 71335-2506-6: 21 Tablets in a BOTTLE, NDC: 71335-2506-7: 120 Tablets in a BOTTLE, NDC: 71335-2506-8: 100 Tablets in a BOTTLE NDC: 71335-2506-9: 28 Tablets in a BOTTLE, NDC: 71335-2506-0: 10 Tablets in a BOTTLE. To prevent fading, avoid exposure to direct sunlight. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep out of the reach of children. Dispense in a well-closed container as defined in USP/NF. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504