Dicyclomine Hydrochloride (Page 3 of 4)

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, 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 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 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.

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 LD₅₀ 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 [see Warnings and Precautions (5.1)] , the blood concentrations of drug were 200, 220, 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 excitement. If indicated, an appropriate parenteral cholinergic agent may be used as an antidote.

11 DESCRIPTION

Dicyclomine is an antispasmodic and anticholinergic (antimuscarinic) agent.

Dicyclomine Hydrochloride Injection, USP is a sterile, pyrogen-free, aqueous solution for intramuscular injection (NOT FOR INTRAVENOUS USE). Each mL contains 10 mg dicyclomine hydrochloride USP in sterile water for injection, made isotonic with sodium chloride.

Dicyclomine hydrochloride is [bicyclohexyl]-1-carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C₁₉ H₃₅ NO₂ •HCl and the following structural formula:

Molecular weight: 345.95

Dicyclomine hydrochloride 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.

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 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 (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.

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 a 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 a 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 9 hours after a single dose. In subsequent studies, plasma concentrations were followed for up to 24 hours after a single dose, showing a secondary phase of elimination with a somewhat longer half-life.

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.

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 four times daily) demonstrated a favorable clinical response compared with 55% treated with placebo (p<0.05).