DICYCLOMINE HCL
DESCRIPTION:
Chemically, DICYCLOMINE (dicyclomine hydrochloride) is (bicyclohexyl)-1-carboxylic
acid, 2-(diethylamino)ethylester, hydrochloride
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.
ACTIONS/CLINICAL PHARMACOLOGY:
Dicyclomine relieves smooth muscle spasm of the gastrointestinal tract. Animal
studies indicate that this action is achieved via a dual mechanism: (1) 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 (2) 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.
In man, dicyclomine is rapidly absorbed after oral administration, reaching peak
values within 60-90 minutes. The principal route of elimination 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. Mean volume of distribution for a 20 mg oral
dose is approximately 3.65 L/kg suggesting extensive distribution in tissues.
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 q.i.d.)
demonstrated a favorable clinical response compared with 55% treated with
placebo. (P <.05). In these trials, most of the side effects were typically
anticholinergic in nature (see table) and were reported by 61% of the patients.
Dicyclomine
Hydrochloride
Side (40 mg q.i.d.) Placebo
Effect % %
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Dry Mouth 33 5
Dizziness 29 2
Blurred Vision 27 2
Nausea 14 6
Light-Headedness 11 3
Drowsiness 9 1
Weakness 7 1
Nervousness 6 2
Nine percent (9%) of patients were discontinued from the drug 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. (See ADVERSE REACTIONS.)
INDICATIONS AND USAGE:
For the treatment of functional bowel/irritable bowel syndrome.
CONTRAINDICATIONS:
1. Obstructive uropathy
2. Obstructive disease of the gastrointestinal tract
3. Severe ulcerative colitis (See PRECAUTIONS)
4. Reflux esophagitis
5. Unstable cardiovascular status in acute hemorrhage
6. Glaucoma
7. Myasthenia gravis
8. Evidence of prior hypersensitivity to dicyclomine hydrochloride or other
ingredients of these formulations
9. Infants less than 6 months of age (See WARNINGS and PRECAUTIONS: Information
for Patients.)
10. Nursing Mothers (See WARNINGS and PRECAUTIONS: Information for Patients.)
WARNINGS:
In the presence of a high environmental temperature, heat prostration can occur
with drug use (fever and heat stroke due to decreased sweating). If symptoms
occur, the drug should be discontinued and supportive measures instituted.
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.
DICYCLOMINE may produce drowsiness or blurred vision. The patient should be warned
not to engage in activities requiring mental alertness, such as operating a
motor vehicle or other machinery or performing hazardous work while taking this
drug.
Psychosis has been reported in sensitive individuals given anticholinergic
drugs. CNS signs and symptoms include confusion, disorientation, short-term
memory loss, hallucinations, dysarthria, ataxia, coma, euphoria, decreased
anxiety, fatigue, insomnia, agitation and mannerisms, and inappropriate affect.
These CNS signs and symptoms usually resolve within 12 to 24 hours after
discontinuation of the drug.
There are reports that administration of dicyclomine hydrochloride syrup to
infants has been followed by serious respiratory symptoms (dyspnea, shortness of
breath, breathlessness, respiratory collapse, apnea, asphyxia), seizures,
syncope, pulse rate fluctuations, muscular hypotonia, and coma. Death has been
reported. No causal relationship between these effects observed in infants and
dicyclomine administration has been established. DICYCLOMINE IS CONTRAINDICATED IN
INFANTS LESS THAN 6 MONTHS OF AGE AND IN NURSING MOTHERS. (See CONTRAINDICATIONS
and PRECAUTIONS: Nursing Mothers and Pediatric Use.)
Safety and efficacy of dicyclomine hydrochloride in pediatric patients have not
been established.
PRECAUTIONS:
GENERAL
Use with caution in patients with:
1. Autonomic neuropathy
2. Hepatic or renal disease
3. Ulcerative colitis--large doses may suppress intestinal motility to the
point of producing a paralytic ileus and the use of this drug may precipitate or
aggravate the serious complication of toxic megacolon (see CONTRAINDICATIONS)
4. Hyperthyroidism
5. Hypertension
6. Coronary heart disease
7. Congestive heart failure
8. Cardiac tachyarrhythmia
9. Hiatal hernia (see CONTRAINDICATIONS: reflux esophagitis)
10. Known or suspected prostatic hypertrophy.
Investigate any tachycardia before administration of dicyclomine hydrochloride
since it may increase the heart rate.
With overdosage, a curare-like action may occur (i.e., neuromuscular blockade
leading to muscular weakness and possible paralysis).
INFORMATION FOR PATIENTS
DICYCLOMINE may produce drowsiness or blurred vision. The patient should be warned
not to engage in activities requiring mental alertness, such as operating a
motor vehicle or other machinery or to perform hazardous work while taking this
drug.
DICYCLOMINE is contraindicated in infants less than 6 months of age and in nursing
mothers. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Nursing Mothers and
Pediatric Use.)
In the presence of a high environmental temperature, heat prostration can occur
with drug use (fever and heat stroke due to decreased sweating). If symptoms
occur, the drug should be discontinued and a physician contacted.
DRUG INTERACTIONS
The following agents may increase certain actions or side effects of
anticholinergic drugs: 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.
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. (See also
CONTRAINDICATIONS.)
Anticholinergic agents may affect gastrointestinal absorption of various drugs,
such as slowly dissolving dosage forms of digoxin; increased serum digoxin
concentrations may result. Anticholinergic drugs may antagonize the effects of
drugs that alter gastrointestinal motility, such as metoclopramide. Because
antacids may interfere with the absorption of anticholinergic agents,
simultaneous use of these drugs should be avoided.
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.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
There are no known human data on long-term potential for carcinogenicity or
mutagenicity.
Long-term studies in animals to determine carcinogenic potential are not known
to have been conducted.
In studies in rats at doses of up to 100 mg/kg/day, DICYCLOMINE produced no
deleterious effects on breeding, conception, or parturition.
PREGNANCY
TERATOGENIC EFFECTS. Pregnancy Category B. 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
impaired fertility or harm to the fetus due to dicyclomine. Epidemiologic
studies in pregnant women with products containing dicyclomine hydrochloride (at
doses up to 40 mg/day) have not shown that dicyclomine increases the risk of
fetal abnormalities if administered during the first trimester of pregnancy.
There are, however, no adequate and well-controlled studies in pregnant women at
the recommended doses (80-160 mg/day). Because animal reproduction studies are
not always predictive of human response, DICYCLOMINE as indicated for functional
bowel/irritable bowel syndrome should be used during pregnancy only if clearly
needed.
NURSING MOTHERS
Since dicyclomine hydrochloride has been reported to be excreted in human milk,
DICYCLOMINE IS CONTRAINDICATED IN NURSING MOTHERS. (See CONTRAINDICATIONS, WARNINGS,
PRECAUTIONS: Pediatric Use and ADVERSE REACTIONS.)
PEDIATRIC USE
(See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Nursing Mothers.) DICYCLOMINE IS
CONTRAINDICATED IN INFANTS LESS THAN 6 MONTHS OF AGE. Safety and effectiveness
in pediatric patients have not been established.
DRUG INTERACTIONS:
The following agents may increase certain actions or side effects of
anticholinergic drugs: 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.
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. (See Also
CONTRAINDICATIONS.)
Anticholinergic agents may affect gastrointestinal absorption of various drugs,
such as slowly dissolving dosage forms of digoxin; increased serum digoxin
concentrations may result. Anticholinergic drugs may antagonize the effects of
drugs that alter gastrointestinal motility, such as metoclopramide. Because
antacids may interfere with the absorption of anticholinergic agents,
simultaneous use of these drugs should be avoided.
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.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
Controlled clinical trials have provided frequency information for reported
adverse effects of dicyclomine hydrochloride listed in a decreasing order of
frequency. (See ACTIONS/CLINICAL PHARMACOLOGY.)
Not all of the following adverse reactions have been reported with dicyclomine
hydrochloride. Adverse reactions are included here that have been reported for
pharmacologically similar drugs with anticholinergic/antispasmodic action.
GASTROINTESTINAL: dry mouth, nausea, vomiting, constipation, bloated feeling,
abdominal pain, taste loss, anorexia
CENTRAL NERVOUS SYSTEM: dizziness, light- headedness, tingling, headache,
drowsiness, weakness, nervousness, numbness, mental confusion and/or excitement
(especially in elderly persons), dyskinesia, lethargy, syncope, speech
disturbance, insomnia
OPHTHALMOLOGIC: blurred vision, diplopia, mydriasis, cycloplegia, increased
ocular tension
DERMATOLOGIC/ALLERGIC: rash, urticaria, itching, and other dermal
manifestations; severe allergic reaction or drug idiosyncrasies including
anaphylaxis
GENITOURINARY: urinary hesitancy, urinary retention
CARDIOVASCULAR: tachycardia, palpitations
RESPIRATORY: Dyspnea, apnea, asphyxia (see WARNINGS)
OTHER: decreased sweating, nasal stuffiness or congestion, sneezing, throat
congestion, impotence, suppression of lactation (see PRECAUTIONS: Nursing
Mothers.)
With the injectable form, there may be temporary sensation of light-headedness.
Some local irritation and focal coagulation necrosis may occur following the
I.M. injection of the drug.
DRUG ABUSE AND DEPENDENCE:
Abuse of and/or dependence on dicyclomine for anticholinergic effects have been
rarely reported.
OVERDOSAGE:
SIGNS AND SYMPTOMS
The signs and symptoms of overdosage are headache; nausea; vomiting; blurred
vision; dilated pupils; hot, dry skin; dizziness; dryness of the mouth;
difficulty in swallowing; and CNS stimulation. A curare-like action may occur
(i.e., neuromuscular blockade leading to muscular weakness and possible
paralysis).
ORAL LD50
The acute oral LD50 of the drug is 625 mg/kg in mice.
MINIMUM HUMAN LETHAL DOSE/MAXIMUM HUMAN DOSE RECORDED
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), the blood concentrations of drug were 200, 220,
and 505 ng/mL, respectively.
DIALYSIS
It is not known if DICYCLOMINE is dialyzable.
TREATMENT
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.
DOSAGE AND ADMINISTRATION:
DOSAGE MUST BE ADJUSTED TO INDIVIDUAL PATIENT NEEDS. (See ACTIONS/CLINICAL
PHARMACOLOGY.)
ADULTS--ORAL. The only oral dose clearly shown to be effective is 160 mg per day
(in 4 equally divided doses). Since this dose is associated with a significant
incidence of side effects, it is prudent to begin with 80 mg per day (in 4
equally divided doses). Depending upon the patient's response during the first
week of therapy, the dose should be increased to 160 mg per 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.
ADULTS--INTRAMUSCULAR INJECTION. NOT FOR INTRAVENOUS USE.
The intramuscular dosage form is to be used temporarily when the patient cannot
take oral medication. Intramuscular injection is about twice as bioavailable as
oral dosage forms; consequently, the recommended intramuscular dose is 80 mg
daily (in 4 equally divided doses).
Oral dicyclomine hydrochloride should be started as soon as possible and the
intramuscular form should not be used for periods longer than 1 or 2 days.
ASPIRATE THE SYRINGE BEFORE INJECTING TO AVOID INTRAVASCULAR INJECTION, SINCE
THROMBOSIS MAY OCCUR IF THE DRUG IS INADVERTENTLY INJECTED INTRAVASCULARLY.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
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