Dicyclomine (Page 2 of 3)

DRUG INTERACTIONS

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)].

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.

Interaction with other gastrointestinal motility drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide.

Because antacids may interfere with the absorption of anticholinergic agents including dicyclomine hydrochloride, simultaneous use of these drugs should be avoided.

Anticholinergic agents may affect the gastrointestinal absorption of various drugs by affecting the gastrointestinal motility, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentration may result.

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.

USE IN SPECIFIC POPULATIONS

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 of 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.

Dicyclomine hydrochloride is contraindicated in women who are human milk feeding. Dicyclomine hydrochloride is excreted in human milk. Because of the potential for serious adverse reactions in human milk-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)].

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 syrup 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.

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, 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.

Effects of renal impairment on PK, safety and efficacy of dicyclomine hydrochloride have not been studied. Dicyclomine hydrochloride drugs are 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.

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.

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 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.

DESCRIPTION

Dicyclomine hydrochloride 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 10 mg capsules also contain inactive ingredients: Corn Starch, Lactose Monohydrate, Magnesium Stearate, and Microcrystalline Cellulose. Capsule shells contain FD&C Blue No. 1, FD&C Red No. 4, and Gelatin. The imprinting ink contains Titanium Dioxide.
  • Dicyclomine Hydrochloride Tablets, USP for oral use contain 20 mg dicyclomine hydrochloride, USP. Dicyclomine hydrochloride 20 mg tablets also contain inactive ingredients: Anhydrous Lactose, FD&C Blue No. 1, Lactose Monohydrate, Magnesium Stearate, and Microcrystalline Cellulose.

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:

MM1
(click image for full-size original)

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.
MM1

CLINICAL PHARMACOLOGY

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.

Dicyclomine hydrochloride 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.

Absorption and Distribution
In man, dicyclomine is rapidly absorbed after oral administration, reaching peak values within 60-90 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.

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