Bentyl

DESCRIPTION

BENTYL is anantispasmodicandanticholinergic(antimuscarinic) agent available in the following dosage form:

• BENTYL injection is a sterile, pyrogen-free, aqueous solution forintramuscularinjection (NOT FOR INTRAVENOUS USE) supplied as an ampoule containing 20 mg/2 mL (10 mg/mL). Each mL contains 10 mg dicyclomine hydrochloride USP in sterile water for injection, made isotonic with sodium chloride.

BENTYL (dicyclomine hydrochloride) is [bicyclohexyl]-1-carboxylic acid, 2-(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C₁₉H₃₅NO₂•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 andchloroform, and very slightly soluble in ether.

INDICATIONS

BENTYL® (dicyclomine hydrochloride) is indicated for the treatment of patients with functional bowel/irritable bowel syndrome.

DOSAGE AND ADMINISTRATION

Dosage must be adjusted to individual patient needs.

Intramuscular Dosage And Administration In Adults

BENTYL Intramuscular Injection must be administered via intramuscular route only. Do not administer by any other route.

The recommended intramuscular dose is 10 mg to 20 mg four times a day [seeCLINICAL PHARMACOLOGY].

The intramuscular injection is to be used only for 1 or 2 days when the patient cannot take oral medication.

Intramuscular injection is about twice as bioavailable as oral dosage forms.

Preparation For Intramuscular Administration

Parenteraldrug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Aspiratethe syringe before injecting to avoid intravascular injection, sincethrombosismay occur if the drug is inadvertently injected intravascularly.

HOW SUPPLIED

Dosage Forms And Strengths

• BENTYL注入20毫克/ 2mL (10 mg/mL)

Storage And Handling

BENTYL Injection

20 mg/2 mL (10 mg/mL) injection supplied in boxes of five 20 mg/2 mL ampules (10 mg/mL). Store at room temperature, preferably below 86°F (30°C). Protect from freezing.

NDC58914-080-52.

Distributed by: Allergan USA, Inc., Madison, NJ 07940. Revised: Jan 2019

SIDE EFFECTS

The pattern of adverse effects seen with dicylomine is mostly related to its pharmacological actions at muscarinic receptors [seeCLINICAL PHARMACOLOGY]. They are a consequence of the inhibitory effect on muscarinic receptors within theautonomic nervous system. These effects are dose-related and are usually reversible when treatment is discontinued.

The most serious adverse reactions reported with dicyclomine hydrochloride includecardiovascularandcentral nervous systemsymptoms [see警告AND PRECAUTIONS].

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)

在这些试验中大部分的副作用被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 BENTYL 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.

Postmarketing Experience

The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post approval use of BENTYL. 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.

心脏疾病:palpitations, tachyarrhythmias

Eye disorders:cycloplegia,mydriasis, vision blurred

胃肠道功能紊乱: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,嗜眠症,syncope

Psychiatric disorders:As with the other anti-cholinergic drugs, cases ofdeliriumor symptoms of delirium such asamnesia(ortransient global amnesia), agitation, confusional state,delusion, disorientation,hallucination(including visual hallucination) as well as躁狂, mood altered andpseudodementia, 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,nasalcongestion

Skin and subcutaneous tissue disorder:dermatitisallergic,erythema, rash

Cases of thrombosis,thrombophlebitisand injection site reactions such as local pain, edema, skin color change and evenreflex sympathetic dystrophy syndromehave been reported following Inadvertent IV injection of BENTYL.

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, acurare-like action may occur (i.e.,neuromuscularblockade leading tomuscularweakness and possibleparalysis)

Ophthalmologic:diplopia, increasedoculartension

Dermatologic/Allergic:urticaria, itching, and otherdermalmanifestations

Genitourinary:urinary hesitancy, urinary retention in patients with prostatichypertrophy

Cardiovascular:hypertension

Respiratory:apnea

Other:decreased sweating, sneezing, throat congestion,impotence. With the injectable form, there may be temporary sensation of light-headedness. Some local irritation andfocalcoagulationnecrosismay occur following the intramuscular injection of BENTYL.

DRUG INTERACTIONS

Antiglaucoma Agents

Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increasedintraocular pressuremay be hazardous when taken concurrently with agents such as corticosteroids. Use of BENTYL in patients withglaucomais not recommended [seeCONTRAINDICATIONS].

Other Drugs With Anticholinergic Activity

The following agents may increase certain actions or side effects of anticholinergic drugs including BENTYL: amantadine, antiarrhythmic agents of Class I (e.g., quinidine),antihistamines,antipsychoticagents (e.g., phenothiazines),benzodiazepinesnarcoticanalgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents,tricyclic antidepressants, and other drugs having anticholinergic activity.

Other Gastrointestinal Motility Drugs

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

Effect of Antacids

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

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.

Effect On Gastric Acid Secretion

The inhibiting effects of anticholinergic drugs ongastrichydrochloric acid secretion are antagonized by agents used to treatachlorhydriaand those used to test gastric secretion.

警告

Included as part of the"PRECAUTIONS"Section

PRECAUTIONS

Inadvertent Intravenous Administration

BENTYL solution is for intramuscular administration only. Do not administer by any other route. Inadvertent intravenous administration may result in thrombosis, thrombophlebitis and injection site reactions such as pain, edema, skin color change, andreflex sympathetic dystrophysyndrome [seeADVERSE REACTIONS].

Cardiovascular Conditions

Dicyclomine hydrochloride needs to be used with caution in conditions characterized by tachyarrhythmia such as thyrotoxicosis,congestive heart failureand in cardiac surgery, where they may further accelerate the heart rate. Investigate anytachycardiabefore administration of dicyclomine hydrochloride. Care is required in patients with coronaryheart disease, asischemiaandinfarctionmay be worsened, and in patients with hypertension [seeADVERSE REACTIONS].

Peripheral And Central Nervous System

的外围影响dicyclomine hydrochloride are a 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,dilatationof the pupils (mydriasis) with loss ofaccommodation(cycloplegia) andphotophobia, flushing and dryness of the skin, transientbradycardiafollowed by tachycardia, with palpitations and arrhythmias, and difficulty inmicturition, as well as reduction in the tone and motility of thegastrointestinal tractleading to constipation [seeADVERSE REACTIONS].

In the presence of high environmental temperatureheat prostrationcan occur with drug use (fever andheat strokedue 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 withautonomic neuropathy.

中枢神经system (CNS) signs and symptoms include confusional state, disorientation, amnesia, hallucinations,dysarthria,ataxia, coma,euphoria, fatigue, insomnia, agitation and mannerisms, and inappropriate affect.

Psychosisand 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.

BENTYL may produce drowsiness, dizziness 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 BENTYL.

Myasthenia Gravis

With overdosage, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). It should not be given to patients withmyasthenia gravisexcept to reduce adverse muscarinic effects of an anticholinesterase [seeCONTRAINDICATIONS]

Intestinal Obstruction

Diarrhea may be an early symptom of incompleteintestinal obstruction, especially in patients withileostomyorcolostomy. In this instance, treatment with this drug would be inappropriate and possibly harmful [seeCONTRAINDICATIONS].

Rarely development of Ogilvie's syndrome (colonicpseudo-obstruction) has been reported. Ogilvie's syndrome is a clinical disorder with signs, symptoms, and radiographic appearance of an acute large bowel obstruction but with no evidence ofdistalcolonic obstruction

Toxic Dilatation Of Intestinemegacolon

Toxic dilatation of intestine and intestinal perforation is possible when anticholinergic agents are administered in patients withSalmonelladysentery.

Ulcerative Colitis

Caution should be taken in patients withulcerative colitis. Large doses may suppress intestinal motility to the point of producing aparalytic ileusand the use of this drug may precipitate or aggravate the seriouscomplicationoftoxic megacolon[seeADVERSE REACTIONS]. BENTYL is contraindicated in patients with severe ulcerativecolitis[seeCONTRAINDICATIONS].

Prostatic Hypertrophy

BENTYL should be used with caution in patients with known or suspected prostatic enlargement, in whom prostatic enlargement may lead to urinary retention [seeADVERSE REACTIONS]

Hepatic And Renal Disease

BENTYL should be used with caution in patients with known hepatic and renal impairment.

Geriatric Population

Dicyclomine hydrochloride should be used with caution in elderly who may be more susceptible to its adverse effects.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term animal studies have not been conducted to evaluate thecarcinogenicpotential of dicyclomine. In studies in rats at doses of up to 100 mg/kg/day, dicyclomine produced no deleterious effects on breeding,conception, orparturition.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Adequate and well-controlled studies have not been conducted with BENTYL 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 amoung 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.

Nursing Mothers

BENTYL 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 BENTYL, a decision should be made whether to discontine nursing or to discontinue the drug, taking into account the importance of the drug to the mother. [seePediatric Use].

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

BENTYL is contraindicated in infants less than 6 months of age. [seeCONTRAINDICATIONS] 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 andasphyxia), seizures, syncope,pulserate fluctuations, muscularhypotonia, and coma, and death, however; no causal relationship has been established.

Geriatric Use

Clinical studies of BENTYL 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.

Renal Impairment

Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL 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. BENTYL should be administered with caution in patients with renal impairment.

Hepatic Impairment

Effects of renal impairment on PK, safety and efficacy of BENTYL have not been studied. BENTYL should be administered with caution in patients with hepatic impairment.

OVERDOSE

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 includingconvulsion. 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 andflankpain, 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警告AND PRECAUTIONS], the blood concentrations of drug were 200, 220, and 505 ng/mL.

It is not known if BENTYL is dialyzable.

Treatment should consist of gastric lavage, emetics, andactivated charcoal. Sedatives (e.g., shortacting barbiturates, benzodiazepines) may be used for management of overt signs of excitement. If indicated, an appropriate parenteral cholinergic agent may be used as anantidote.

CONTRAINDICATIONS

BENTYL is contraindicated in infants less than 6 months of age [seeUse In Specific Populations], nursing mothers [seeUse In Specific Populations], and in patients with:

• unstable cardiovascular status in acutehemorrhage
• myasthenia gravis [see警告AND PRECAUTIONS]
• glaucoma [seeADVERSE REACTIONSandDRUG INTERACTIONS]
• obstructive uropathy [see警告AND PRECAUTIONS]
• obstructive disease of the gastrointestinal tract [see警告AND PRECAUTIONS]
• severe ulcerative colitis [see警告AND PRECAUTIONS]
• reflux食管炎

CLINICAL PHARMACOLOGY

Mechanism Of Action

Dicyclomine relievessmooth musclespasm of the gastrointestinal tract. Animal studies indicate that this action is achieved via a dual mechanism:

a specific anticholinergic effect (antimuscarinic) at theacetylcholine-receptor sites with approximately 1/8 themilligrampotency ofatropine(in vitro,guinea pigileum); and a direct effect upon smooth muscle (musculotropic) as evidenced by dicyclomine’s antagonism of bradykinin- andhistamine-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)- orbarium全身的氯(氯化钡)肠道痉挛时ropine 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.

Pharmacodynamics

BENTYL can inhibit the secretion ofsalivaandsweat, decrease gastrointestinal secretions and motility, cause drowsiness,dilatethe pupils, increase heart rate, and depress motor function

Pharmacokinetics

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

Themetabolismof 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 halflife.

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).

PATIENT INFORMATION

Inadvertent Intravenous Administration

BENTYL Injection is for intramuscular administration only. Do not administer by any other route. Inadvertent administration may result in thrombosis or thrombophlebitis, and injection site such as pain, edema, skin color change and even reflex sympathetic dystrophy syndrome [seeADVERSE REACTIONS].

Use In Infants

Inform parents and caregivers not to administer BENTYL in infants less than 6 months of age [seeUse In Specific Populations].

Use In Nursing Mothers

Advise lactating women that BENTYL should not be used while breastfeeding their infants [seeUse In Specific Populations].

Peripheral And Central Nervous System

In the presence of a high environmental temperature, heat prostration can occur with BENTYL use (fever and heatstrokedue to decreased sweating). If symptoms occur, the drug should be discontinued and a physician contacted. BENTYL 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 BENTYL [see警告AND PRECAUTIONS].