ADVERSE REACTIONS SECTION.

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 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 Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 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 Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) 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 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 times day).In these trials most of the side effects were typically anticholinergic in nature and were reported by 61% of the patients. Table presents adverse reactions (MedDRA 13.0 preferred terms) by decreasing order of frequency in 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 day) %Placebo Dry Mouth 33 Dizziness 40 Vision Blurred 27 Nausea 14 Somnolence 1 Asthenia 1 Nervousness 2 Nine percent (9%) of patients were discontinued from dicyclomine 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. 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 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. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. oCardiac Disorders: palpitations, tachyarrhythmias oEye Disorders: cycloplegia, mydriasis, vision blurred oGastrointestinal Disorders: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, nausea, vomiting oGeneral Disorders and Administration Site Conditions: fatigue, malaise oImmune System Disorders: drug hypersensitivity including face edema, angioedema, anaphylactic shock oNervous System Disorders: dizziness, headache, somnolence, syncope oPsychiatric 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.oReproductive System and Breast Disorders: suppressed lactation oRespiratory, Thoracic and Mediastinal Disorders: dyspnoea, nasal congestion oSkin and Subcutaneous Tissue Disorder: dermatitis allergic, erythema, rash oCardiac Disorders: palpitations, tachyarrhythmias oEye Disorders: cycloplegia, mydriasis, vision blurred oGastrointestinal Disorders: abdominal distension, abdominal pain, constipation, dry mouth, dyspepsia, nausea, vomiting oGeneral Disorders and Administration Site Conditions: fatigue, malaise oImmune System Disorders: drug hypersensitivity including face edema, angioedema, anaphylactic shock oNervous System Disorders: dizziness, headache, somnolence, syncope oPsychiatric 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.. oReproductive System and Breast Disorders: suppressed lactation oRespiratory, Thoracic and Mediastinal Disorders: dyspnoea, nasal congestion oSkin 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, 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 manifestationsGenitourinary: urinary hesitancy, urinary retention in patients with prostatic hypertrophy Cardiovascular: hypertension Respiratory: apnea Other: decreased sweating, sneezing, throat congestion, impotence.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of dicyclomine. In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding, conception or parturition.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via dual mechanism: oa specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and oa direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomines 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 (BaCl2)-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl2. 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. oa specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and oa direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomines antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum. 12.2 Pharmacodynamics. Dicyclomine can inhibit the secretion of saliva and sweat, decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate and depress motor function. 12.3 Pharmacokinetics. Absorption and Distribution. In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60 to 90 minutes. Mean volume of distribution for 20 mg oral dose is approximately 3.65 L/kg suggesting extensive distribution in tissues. Elimination. The metabolism of dicyclomine was not studied. The principal route of excretion is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for hours after single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after single dose, showing secondary phase of elimination with somewhat longer half-life.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In controlled clinical trials involving over 100 patients who received drug, 82% of patients treated for functional bowel/irritable bowel syndrome with dicyclomine hydrochloride at initial doses of 160 mg daily (40 mg times daily) demonstrated favorable clinical response compared with 55% treated with placebo (p 0.05).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Dicyclomine hydrochloride is contraindicated in infants less than months of age [see Use in Specific Populations (8.4)], nursing mothers [see Use in Specific Populations (8.3)] and in patients with: ounstable cardiovascular status in acute hemorrhage omyasthenia gravis [see Warnings and Precautions (5.4)] oglaucoma [see Adverse Reactions (6.3) and Drug Interactions (7.1)] oobstructive uropathy [see Warnings and Precautions (5.8)] oobstructive disease of the gastrointestinal tract [see Warnings and Precautions (5.5)]osevere ulcerative colitis [see Warnings and Precautions (5.7)] oreflux esophagitis ounstable cardiovascular status in acute hemorrhage omyasthenia gravis [see Warnings and Precautions (5.4)] oglaucoma [see Adverse Reactions (6.3) and Drug Interactions (7.1)] oobstructive uropathy [see Warnings and Precautions (5.8)] oobstructive disease of the gastrointestinal tract [see Warnings and Precautions (5.5)]. osevere ulcerative colitis [see Warnings and Precautions (5.7)] oreflux esophagitis oInfants less than months of age (4) oNursing mothers (4) oUnstable cardiovascular status in acute hemorrhage (4)oMyasthenia gravis (4) oGlaucoma (4)oObstructive uropathy (4)oObstructive disease of the gastrointestinal tract (4)oSevere ulcerative colitis (4)oReflux esophagitis (4) oInfants less than months of age (4) oNursing mothers (4) oUnstable cardiovascular status in acute hemorrhage (4). oMyasthenia gravis (4) oGlaucoma (4). oObstructive uropathy (4). oObstructive disease of the gastrointestinal tract (4). oSevere ulcerative colitis (4). oReflux esophagitis (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Dicyclomine hydrochloride is an antispasmodic and anticholinergic (antimuscarinic) agent.Chemically, dicyclomine hydrochloride is [bicyclohexyl]-1-carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride with the following structural formula, molecular weight, and molecular formula:C19H35NO2 HCl --- M.W. 345.96 Dicyclomine hydrochloride, USP occurs as fine, white, crystalline, practically odorless powder with bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether.Dicyclomine hydrochloride capsules, USP, for oral administration, contain 10 mg of dicyclomine hydrochloride, USP. Each capsule contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, FD&C Blue No. 1, gelatin, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), sodium lauryl sulfate and titanium dioxide. In addition the imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. Aluminum Lake, FD&C Blue No. Aluminum Lake, FD&C Red No. 40 Aluminum Lake, pharmaceutical glaze and propylene glycol.Dicyclomine hydrochloride tablets, USP, for oral administration, contain 20 mg of dicyclomine hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, FD&C Blue No. Aluminum Lake, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn) and sodium lauryl sulfate.. Dicyclomine Hydrochloride Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Dosage must be adjusted to individual patient needs. Dosage for dicyclomine must be adjusted to individual patient needs (2). If dose is missed, patients should continue the normal dosing schedule (2). Oral in adults (2.1): oStarting dose: 20 mg times day. After week treatment with the starting dose, the dose may be escalated to 40 mg times day, unless side effects limit dosage escalation oDiscontinue dicyclomine if efficacy not achieved or side effects require doses less than 80 mg per day after weeks of treatment oStarting dose: 20 mg times day. After week treatment with the starting dose, the dose may be escalated to 40 mg times day, unless side effects limit dosage escalation oDiscontinue dicyclomine if efficacy not achieved or side effects require doses less than 80 mg per day after weeks of treatment 2.1 Oral Dosage and Administration in Adults. The recommended initial dose is 20 mg times day. After one week treatment with the initial dose, the dose may be increased to 40 mg times day unless side effects limit dosage escalation. If efficacy is not achieved within 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 weeks.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Dicyclomine Hydrochloride Capsules, USP are available containing 10 mg of dicyclomine hydrochloride, USP. oThe 10 mg capsules are hard-shell gelatin capsule with light turquoise blue opaque cap and light turquoise blue opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 1610 in black ink on both the cap and the body.Dicyclomine Hydrochloride Tablets, USP are available containing 20 mg of dicyclomine hydrochloride, USP.oThe 20 mg tablets are blue, round, unscored tablets debossed with over D6 on one side of the tablet and blank on the other side.. oThe 10 mg capsules are hard-shell gelatin capsule with light turquoise blue opaque cap and light turquoise blue opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 1610 in black ink on both the cap and the body.. oThe 20 mg tablets are blue, round, unscored tablets debossed with over D6 on one side of the tablet and blank on the other side.. oDicyclomine hydrochloride capsules 10 mg (3)oDicyclomine hydrochloride tablets 20 mg (3). oDicyclomine hydrochloride capsules 10 mg (3). oDicyclomine hydrochloride tablets 20 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oAntiglaucoma agents: anticholinergics antagonize antiglaucoma agents and may increase intraoccular pressure (7) oAnticholinergic agents: may affect the gastrointestinal absorption of various drugs; may also increase certain actions or side effects of other anticholinergic drugs (7) oAntacids: interfere with the absorption of anticholinergic agents (7) oAntiglaucoma agents: anticholinergics antagonize antiglaucoma agents and may increase intraoccular pressure (7) oAnticholinergic agents: may affect the gastrointestinal absorption of various drugs; may also increase certain actions or side effects of other anticholinergic drugs (7) oAntacids: 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 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: amantadine, antiarrhythmic agents of Class (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, 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of dicyclomine 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Dicyclomine Hydrochloride Capsules, USP are available containing 10 mg of dicyclomine hydrochloride, USP.The 10 mg capsules are hard-shell gelatin capsule with light turquoise blue opaque cap and light turquoise blue opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 1610 in black ink on both the cap and the body. They are available as follows:NDC 0378-1610-01bottles of 100 capsulesNDC 0378-1610-05bottles of 500 capsulesStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Dicyclomine Hydrochloride Tablets, USP are available containing 20 mg of dicyclomine hydrochloride, USP. The 20 mg tablets are blue, round, unscored tablets debossed with over D6 on one side of the tablet and blank on the other side. They are available as follows.NDC 0378-1620-01bottles of 100 tabletsNDC 0378-1620-05bottles of 500 tabletsStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]To prevent fading, avoid exposure to direct sunlight.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.2 Use in Infants. Inform parents and caregivers not to administer dicyclomine in infants less than months of age [see Use in Specific Populations (8.4)] . 17.3 Use in Nursing Mothers. Advise lactating women that dicyclomine should not be used while breastfeeding their infants [see Use in Specific Populations (8.3, 8.4)]. 17.4 Peripheral and Central Nervous System. In the presence of high environmental temperature, heat prostration can occur with dicyclomine use (fever and heat stroke due to decreased sweating). If symptoms occur, the drug should be discontinued and physician contacted. Dicyclomine may produce drowsiness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating motor vehicle or other machinery or to perform hazardous work while taking dicyclomine [see Warnings and Precautions (5.3)]. Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.REVISED FEBRUARY 2016DICY:R6.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via dual mechanism: oa specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and oa direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomines 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 (BaCl2)-induced intestinal spasm while atropine was at least 200 times more potent against effects of ACh than BaCl2. 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. oa specific anticholinergic effect (antimuscarinic) at the acetylcholine-receptor sites with approximately 1/8 the milligram potency of atropine (in vitro, guinea pig ileum); and oa direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomines antagonism of bradykinin- and histamine-induced spasms of the isolated guinea pig ileum.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of dicyclomine. In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding, conception or parturition.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. Dicyclomine 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, 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)].

OVERDOSAGE SECTION.

10 OVERDOSAGE. In case of an overdose, patients should contact 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. curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). One reported event included 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 times daily). These events resolved after discontinuing the dicyclomine. The acute oral LD50 of the drug is 625 mg/kg in mice. The amount of drug in 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 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 [see Warnings and Precautions (5.1)], the blood concentrations of drug were 200 ng/mL, 220 ng/mL, and 505 ng/mL. It is not known if dicyclomine 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 exctextent. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 10 mg Capsules. NDC 0378-1610-01DicyclomineHydrochlorideCapsules, USP10 mgRx only 100 CapsulesEach capsule contains:Dicyclominehydrochloride, USP 10 mgDispense in tight, light-resistantcontainer as defined in the USPusing child-resistant closure.Keep container tightly closed.Keep this and all medicationout of the reach of children.Store at 20 to 25C (68 to 77F).[See USP Controlled RoomTemperature.]Usual Dosage: See accompanyingprescribing information.Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.Mylan.comRM1610A4. Dicyclomine Hydrochloride Capsules 10 mg Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established. Dicyclomine is contraindicated in infants less than 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Dicyclomine can inhibit the secretion of saliva and sweat, decrease gastrointestinal secretions and motility, cause drowsiness, dilate the pupils, increase heart rate and depress motor function.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption and Distribution. In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60 to 90 minutes. Mean volume of distribution for 20 mg oral dose is approximately 3.65 L/kg suggesting extensive distribution in tissues. Elimination. The metabolism of dicyclomine was not studied. The principal route of excretion is via the urine (79.5% of the dose). Excretion also occurs in the feces, but to lesser extent (8.4%). Mean half-life of plasma elimination in one study was determined to be approximately 1.8 hours when plasma concentrations were measured for hours after single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after single dose, showing secondary phase of elimination with somewhat longer half-life.

PREGNANCY SECTION.

8.1 Pregnancy. Teratogenic Effects. Pregnancy Category B. Adequate and well-controlled studies have not been conducted with dicyclomine in pregnant women at the recommended doses of 80 mg/day 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.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions: Peripheral and Central Nervous System (5.3) 07/2012.

SPL UNCLASSIFIED SECTION.

2.1 Oral Dosage and Administration in Adults. The recommended initial dose is 20 mg times day. After one week treatment with the initial dose, the dose may be increased to 40 mg times day unless side effects limit dosage escalation. If efficacy is not achieved within 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 weeks.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Pregnancy Category B. Adequate and well-controlled studies have not been conducted with dicyclomine in pregnant women at the recommended doses of 80 mg/day 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPregnancy: use only if clearly needed (8.1) oPediatric Use: Safety and effectiveness not established (8.4) oHepatic and renal impairment: caution must be taken with patients with significantly impaired hepatic and renal function (8.6) oPregnancy: use only if clearly needed (8.1) oPediatric Use: Safety and effectiveness not established (8.4) oHepatic and renal impairment: caution must be taken with patients with significantly impaired hepatic and renal function (8.6) 8.1 Pregnancy. Teratogenic Effects. Pregnancy Category B. Adequate and well-controlled studies have not been conducted with dicyclomine in pregnant women at the recommended doses of 80 mg/day 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 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, 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 is contraindicated in infants less than 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 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 have not been studied. Dicyclomine 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 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 have not been studied. Dicyclomine should be administered with caution in patients with hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oCardiovascular conditions: worsening of conditions (5.2) oPeripheral 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) oPsychosis 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 (5.3) oMyasthenia Gravis: overdose may lead to muscular weakness and paralysis. Dicyclomine should be given to patients with myasthenia gravis only to reduce adverse muscarinic effects of an anticholinesterase (5.4) oIncomplete intestinal obstruction: diarrhea may be an early symptom especially in patients with ileostomy or colostomy. Treatment with dicyclomine would be inappropriate and possibly fatal (5.5) oSalmonella dysenteric patients: due to risk of toxic megacolon (5.6) oUlcerative colitis: Dicyclomine should be used with caution in these patients; large doses may suppress intestinal motility or aggravate the serious complications of toxic megacolon (5.7) oProstatic hypertrophy: Dicyclomine should be used with caution in these patients; may lead to urinary retention (5.8) oHepatic and renal disease: should be used with caution (5.9) oGeriatric: use with caution in elderly who may be more susceptible to dicyclomines adverse events (5.10) oCardiovascular conditions: worsening of conditions (5.2) oPeripheral 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) oPsychosis 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 (5.3) oMyasthenia Gravis: overdose may lead to muscular weakness and paralysis. Dicyclomine should be given to patients with myasthenia gravis only to reduce adverse muscarinic effects of an anticholinesterase (5.4) oIncomplete intestinal obstruction: diarrhea may be an early symptom especially in patients with ileostomy or colostomy. Treatment with dicyclomine would be inappropriate and possibly fatal (5.5) oSalmonella dysenteric patients: due to risk of toxic megacolon (5.6) oUlcerative colitis: Dicyclomine should be used with caution in these patients; large doses may suppress intestinal motility or aggravate the serious complications of toxic megacolon (5.7) oProstatic hypertrophy: Dicyclomine should be used with caution in these patients; may lead to urinary retention (5.8) oHepatic and renal disease: should be used with caution (5.9) oGeriatric: use with caution in elderly who may be more susceptible to dicyclomines 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 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 may produce drowsiness, dizziness or blurred vision. The patient should be warned not to engage in activities requiring mental alertness, such as operating motor vehicle or other machinery or performing hazardous work while taking dicyclomine. 5.4 Myasthenia Gravis. With overdosage, 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 Ogilvies syndrome (colonic pseudo-obstruction) has been reported. Ogilvies syndrome is 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 paralytic ileus and the use of this drug may precipitate or aggravate the serious complication of toxic megacolon [see Adverse Reactions (6.3)]. Dicyclomine is contraindicated in patients with severe ulcerative colitis [see Contraindications (4)]. 5.8 Prostatic Hypertrophy. Dicyclomine 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 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.