Anti-cholinergics

     >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.

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

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DOSAGE AND ADMINISTRATION:
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Dosage must be adjusted to individual patients needs.

Oral Dosage and Administration in Adults
The recommended initial dose is 20 mg four times a day. After one week treatment with the initial dose, the dose may be increased to 40 mg four times a 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.

Intramuscular Dosage and Administration in Adults
BENTYL Intramuscular Injection must be administered via intramuscular route only. Do not administer by an other route. The recommended intramuscular dose is 10 mg to 20 mg four times a day.

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

Aspirate the syringe before injecting to avoid intravascular injection, since thrombosis may occur if the drug is inadvertently injected intravascularly.

CONTRAINDICATIONS:
BENTYL is contraindicated in infants less than 6 months of age, nursing mothers, and in patients with:

• unstable cardiovascular status in acute hemorrhage
• myasthenia gravis
• glaucoma
• obstructive uropathy
• obstructive disease of the gastrointestinal tract
• severe ulcerative colitis
• reflux esophagitis

WARNINGS AND PRECAUTIONS:

• For Intramuscular injection only; should not be administered by any other route. Intravenous injection may result in thrombosis or thrombophlebitis and injection site reactions
• Cardiovascular conditions: worsening of conditions
• Peripheral 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)
  Psychosis 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 BENTYL
• Myasthenia Gravis: overdose may lead to muscular weakness and paralysis. BENTYL should be given to patients with myasthenia gravis only to reduce adverse muscarinic effects of an anticholinesterase
• Incomplete intestinal obstruction: diarrhea may be an early symptom especially in patients with ileostomy or colostomy. Treatment with BENTYL would be inappropriate and possibly fatal
• Salmonella dysenteric patients: due to risk of toxic megacolon
• Ulcerative colitis: BENTYL should be used with caution in these patients; large doses may suppress intestinal motility or aggravate the serious complications of toxic megacolon
• Prostatic hypertrophy: BENTYL should be used with caution in these patients; may lead to urinary retention
• Hepatic and renal disease: should be used with caution
• Geriatric: use with caution in elderly who may be more susceptible to BENTYL's adverse events

DOSAGE FORMS AND STRENGTHS:
BENTYL capsules 10 mg
BENTYL tablets 20 mg
BENTYL injection 20 mg/2 mL (10 mg/mL)

SOURCE:
Package insert data:

Phenobarbital, USP....................................... 16.2 mg
Hyoscyamine Sulfate, USP...................... 0.1037 mg
Atropine Sulfate, USP ...............................0.0194 mg
Scopolamine Hydrobromide, USP ...........0.0065 mg

INACTIVE INGREDIENTS: Anhydrous Lactose, Calcium Stearate, Colloidal
Silicon Dioxide, Corn Starch, and Microcrystalline Cellulose.

This drug combination provides natural belladonna alkaloids in a specific, fixed ratio combined with phenobarbital to provide peripheral anticholinergic/antispasmodic action and mild sedation.

INDICATIONS AND USAGE:
Based on a review of this drug by the National Academy of Sciences-National Research Council and/or other
information, FDA has classified the following indications as “possibly” effective:

For use as adjunctive therapy in the treatment of irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis.

May also be useful as adjunctive therapy in the treatment of duodenal ulcer. IT HAS NOT BEEN SHOWN
CONCLUSIVELY WHETHER ANTICHOLINERGIC/ANTISPASMODIC DRUGS AID IN THE HEALING OF A
DUODENAL ULCER, DECREASE THE RATE OF RECURRENCES OR PREVENT COMPLICATIONS.

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DOSAGE AND ADMINISTRATION:
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The dosage of Donnatal® should be adjusted to the needs of the dividual patient to assure symptomatic control with a minimum of adverse effects.

Donnatal® Tablets. Adults: One or two Donnatal® tablets three or four times a day according to condition and severity of symptoms.

Extentabs:
The dosage of Donnatal Extentabs® should be adjusted to the needs of the individual patient to assure symptomatic control with a minimum of adverse reactions. The usual dose is one tablet every twelve (12) hours. If indicated, one tablet every eight (8) hours may be given.

CONTRAINDICATIONS:
Glaucoma, obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis, etc.); paralytic ileus, intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis especially if complicated by toxic mega-colon; myasthenia gravis; hiatal hernia associated with reflux esophagitis.

Donnatal® is contraindicated in patients with known hypersensitivity to any of the ingredients. Phenobarbital is
contraindicated in acute intermittent porphyria and in those patients in whom phenobarbital produces restlessness and/or excitement.

WARNINGS AND PRECAUTIONS:
WARNINGS
In the presence of a high environmental temperature, heat prostration can occur with belladonna alkaloids (fever and heatstroke due to decreased sweating).

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.

Donnatal® may produce drowsiness or blurred vision. The patient should be warned, should these occur, not to
engage in activities requiring mental alertness, such as operating a motor vehicle or other machinery, and not to perform hazardous work.

Phenobarbital may decrease the effect of anticoagulants, and necessitate larger doses of the anticoagulant for optimal effect. When the phenobarbital is discontinued, the dose of the anticoagulant may have to be decreased.

Phenobarbital may be habit forming and should not be administered to individuals known to be addiction prone or to those with a history of physical and/or psychological dependence upon drugs.

Since barbiturates are metabolized in the liver, they should be used with caution and initial doses should be small in patients with hepatic dysfunction.

DOSAGE FORMS AND STRENGTHS:
Donnatal® Tablets are supplied as: White, D-shaped tablets debossed “D” on one side and “Donnatal” on the other side.

Bottles of 100 tablets.
Bottles of 1000 tablets.
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Each Donnatal Extentabs® tablet contains:
Phenobarbital, USP (3/4 gr.) 48.6 mg
Hyoscyamine Sulfate, USP 0.3111 mg
Atropine Sulfate, USP 0.0582 mg
Scopolamine Hydrobromide, USP .0.0195 mg

Each Donnatal Extentabs® tablet contains the equivalent of three Donnatal® tablets. Extentabs are designed to release the ingredi¬ents gradually to provide effects for up to twelve (12) hours.

SOURCE:
Package insert data:

In a single study of 11 normal male subjects, the time to onset of action was 55 minutes. The peak effect was observed at 112 minutes. 57% of the flavoxate hydrochloride was excreted in the urine within 24 hours.

INDICATIONS AND USAGE:
Flavoxate hydrochloride tablets are indicated for symptomatic relief of dysuria, urgency, nocturia, suprapubic pain, frequency and incontinence as may occur in cystitis, prostatitis, urethritis, urethrocystitis/urethrotrigonitis. Flavoxate hydrochloride tablets are not indicated for definitive treatment, but are compatible with drugs used for the treatment of urinary tract infections.

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DOSAGE AND ADMINISTRATION:
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Adults and children over 12 years of age

One or two 100 mg tablets 3 or 4 times a day. With improvement of symptoms, the dose may be reduced. This drug cannot be recommended for infants and children under 12 years of age because safety and efficacy have not been demonstrated in this age group.

CONTRAINDICATIONS:
Flavoxate hydrochloride is contraindicated in patients who have any of the following obstructive conditions: pyloric or duodenal obstruction, obstructive intestinal lesions or ileus, achalasia, gastrointestinal hemorrhage and obstructive uropathies of the lower urinary tract.

WARNINGS AND PRECAUTIONS:
WARNINGS
Flavoxate hydrochloride should be given cautiously in patients with suspected glaucoma.

PRECAUTIONS-----
Information for Patients

Patients should be informed that if drowsiness and blurred vision occur, they should not operate a motor vehicle or machinery or participate in activities where alertness is required.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of flavoxate hydrochloride have not been performed.

Pregnancy
Teratogenic Effects-Pregnancy Category B.

Reproduction studies have been performed in rats and rabbits at doses up to 34 times the human dose and revealed no evidence of impaired fertility or harm to the fetus due to flavoxate hydrochloride. There are, however, no well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when flavoxate hydrochloride is administered to a nursing woman.

Pediatric Use
Safety and effectiveness in children below the age of 12 years have not been established.

ADVERSE REACTIONS
The following adverse reactions have been observed, but there are not enough data to support an estimate of their frequency.

Gastrointestinal: Nausea, vomiting, dry mouth.

CNS: Vertigo, headache, mental confusion, especially in the elderly, drowsiness, nervousness.

Hematologic: Leukopenia (one case which was reversible upon discontinuation of the drug).

Cardiovascular: Tachycardia and palpitation.

Allergic: Urticaria and other dermatoses, eosinophilia and hyperpyrexia.

Ophthalmic: Increased ocular tension, blurred vision, disturbance in eye accommodation.

Renal: Dysuria.

DOSAGE FORMS AND STRENGTHS:
Flavoxate hydrochloride 100 mg tablets are available as white, round biconvex, film-coated tablets, debossed “? 58” on one side and plain on the other side, and are available in bottles of 100 and 1000.

Store at 20° - 25°C (68° - 77°F) [see USP Controlled Room Temperature]. Dispense contents in a tight, light-resistant container.

SOURCE:
Package insert data:

Glycopyrrolate antagonizes muscarinic symptoms (e.g., bronchorrhea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases.

The highly polar quaternary ammonium group of glycopyrrolate limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulfate and scopolamine hydrobromide, which are non-polar tertiary amines which penetrate lipid barriers easily.

INDICATIONS AND USAGE:
For use as adjunctive therapy in the treatment of peptic ulcer.

Other:  Adjunct in the treatment of PUD; inhibits salivation and excessive secretions of the respiratory tract preoperatively; reversal of neuromuscular blockade; control of upper airway secretions. Onset: Oral: with in 50 min; IM: 20-40min ; IV: 10-15min.   

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DOSAGE AND ADMINISTRATION:
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Tablets:
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 The dosage of Glycopyrrolate Tablets, USP should be adjusted to the needs of the individual patient to assure symptomatic controlwith a minimum of adverse reactions. The presently recommended maximum daily dosage of glycopyrrolate is 8 mg.

Glycopyrrolate Tablets, USP 1 mg. The recommended initial dosage of Glycopyrrolate 1 mg tablets for adults is one tablet three times daily (in the morning, early afternoon, and at bedtime). Some patients may require two tablets at bedtime to assure overnight control of symptoms.

For maintenance, a dosage of one tablet twice a day is frequently adequate.

Glycopyrrolate Tablets, USP 2 mg. The recommended dosage of Glycopyrrolate 2 mg tablets for adults is one tablet two or three times daily at equally spaced intervals.

Glycopyrrolate Tablets, USP 1.5 mg. The Glycopyrrolate 1.5 mg tablets may be used to provide intermediate titration doses based on response of the patient.

Glycopyrrolate Tablets, USP are not recommended for use in pediatric patients under the age of 12 years.
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Injection:   NOTE: CONTAINS BENZYL ALCOHOL
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Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Glycopyrrolate Injection may be administered intramuscularly, or intravenously, without dilution, in the following indications.

Adults
Preanesthetic Medication
The recommended dose of Glycopyrrolate Injection is 0.004 mg/kg by intramuscular injection, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia or at the time the preanesthetic narcotic and/or sedative are administered.

Intraoperative Medication
Glycopyrrolate Injection may be used during surgery to counteract drug-induced or vagal reflexes and their associated arrhythmias (e.g., bradycardia). It should be administered intravenously as single doses of 0.1 mg and repeated, as needed, at intervals of 2 to 3 minutes. The usual attempts should be made to determine the etiology of the arrhythmia, and the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance should be performed.

Reversal of Neuromuscular Blockade
The recommended dose of Glycopyrrolate Injection is 0.2 mg for each 1.0 mg of neostigmine or 5.0 mg of pyridostigmine. In order to minimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection and may be mixed in the same syringe.

Peptic Ulcer
The usual recommended dose of Glycopyrrolate Injection is 0.1 mg administered at 4-hour intervals, 3 or 4 times daily intravenously or intramuscularly. Where more profound effect is required, 0.2 mg may be given. Some patients may need only a single dose, and frequency of administration should be dictated by patient response up to a maximum of four times daily.

Glycopyrrolate Injection is not recommended for the treatment of peptic ulcer in pediatric patients .

Pediatric Patients (see PRECAUTIONS - Pediatric Use)

Preanesthetic Medication
The recommended dose of Glycopyrrolate Injection in pediatric patients is 0.004 mg/kg intramuscularly, given 30 to 60 minutes prior to the anticipated time of induction of anesthesia or at the time the preanesthetic narcotic and/or sedative are administered.

Infants
(1 month to 2 years of age) may require up to 0.009 mg/kg.

Intraoperative Medication
Because of the long duration of action of Glycopyrrolate Injection if used as preanesthetic medication, additional Glycopyrrolate Injection for anticholinergic effect intraoperatively is rarely needed; in the event it is required the recommended pediatric dose is 0.004 mg/kg intravenously, not to exceed 0.1 mg in a single dose which may be repeated, as needed, at intervals of 2 to 3 minutes. The usual attempts should be made to determine the etiology of the arrhythmia, and the surgical or anesthetic manipulations necessary to correct parasympathetic imbalance should be performed.

Reversal of Neuromuscular Blockade
The recommended pediatric dose of Glycopyrrolate Injection is 0.2 mg for each 1.0 mg of neostigmine or 5.0 mg of pyridostigmine. In order to minimize the appearance of cardiac side effects, the drugs may be administered simultaneously by intravenous injection and may be mixed in the same syringe.

Peptic Ulcer
Glycopyrrolate Injection is not recommended for the treatment of peptic ulcer in pediatric patients (see PRECAUTIONS – Pediatric Use).

Diluent Compatibilities
Dextrose 5% and 10% in water, or saline, dextrose 5% in sodium chloride 0.45%, sodium chloride 0.9%, and Ringer’s Injection.

Diluent Incompatibilities
Lactated Ringer’s solution

CONTRAINDICATIONS:
Glaucoma; obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis, etc.); paralytic ileus; intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis. Glycopyrrolate tablets are contraindicated in those patients with a hypersensitivity to glycopyrrolate.

WARNINGS AND PRECAUTIONS:
WARNINGS

In the presence of a high environmental temperature, heal prostration (fever and heat stroke due to decreased sweating) can occur with the use of Glycopyrrolate Tablets, USP.

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.

Glycopyrrolate Tablets, USP may produce drowsiness or blurred vision. In this event, 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.

Theoretically, with overdosage, a curare-like action may occur, i.e., neuro-muscular blockade leading to muscular weakness and possible paralysis.

PRECAUTIONS

Use Glycopyrrolate Tablets, USP with caution in the elderly and in all patients with:

• Autonomic neuropathy.

• Hepatic or renal disease.

• Ulcerative colitis - large doses may suppress intestinal motility to the point of producing a paralytic ileus and for this reason may precipitate or aggravate the "toxic megacolon," a serious complication of the disease.

• Hyperthyroidism, coronary heart disease, congestive heart failure, cardiac tachyarrhythmias, tachycardia, hypertension and prostatic hypertrophy.

• Hiatal hernia associated with reflux esophagitis, since anticholinergic drugs may aggravate this condition.

Precautions - Pediatric:
Pediatric Use
Due to its benzyl alcohol content, Glycopyrrolate Injection should not be used in neonates, i.e., patients less than 1 month of age.

Safety and effectiveness in pediatric patients below the age of 16 years have not been established.

Safety and effectiveness in pediatric patients have not been established for the management of peptic ulcer.

Dysrhythmias associated with the use of glycopyrrolate intravenously as a premedicant or during anesthesia have been observed in pediatric patients.

Infants, patients with Down’s syndrome, and pediatric patients with spastic paralysis or brain damage may experience an increased response to anticholinergics, thus increasing the potential for side effects.

A paradoxical reaction characterized by hyperexcitability may occur in pediatric patients taking large doses of anticholinergics including Glycopyrrolate Injection. Infants and young children are especially susceptible to the toxic effects of anticholinergics.

Benzyl alcohol, a component of this drug product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hemotologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

ADVERSE REACTIONS:
Anticholinergics produce certain effects, most of which are extensions of their fundamental pharmacological actions. Adverse reactions to anticholinergics in general may include xerostomia; decreased sweating; urinary hesitancy and retention; blurred vision; tachycardia; palpitations; dilation of the pupil; cycloplegia; increased ocular tension; loss of taste; headaches; nervousness; mental confusion; drowsiness; weakness; dizziness; insomnia; nausea; vomiting; constipation; bloated feeling; impotence; suppression of lactation; severe allergic reaction or drug idiosyncrasies including anaphylaxis, urticaria and other dermal manifestations.

Glycopyrrolate Tablets, USP is chemically a quaternary ammonium compound; hence, its passage across lipid membranes, such as the blood-brain barrier, is limited in contrast to atropine sulfate and scopolamine hydrobromide. For this reason the occurrence of CNS related side effects is lower, in comparison to their incidence following administration of anticholinergics which are chemically tertiary amines that can cross this barrier readily.

DOSAGE FORMS AND STRENGTHS:
Glycopyrrolate Tablets, USP 1.5 mg are compressed white tablets debossed GP on one side and 1.5 on the other and are supplied in bottles of 100 (NDC 0722-7097-01).

Injection:
Glycopyrrolate Injection, USP, 0.2 mg/mL, is available in:

1 mL single dose vials packaged in 25s (NDC 10019-016-81)

2 mL single dose vials packaged in 25s (NDC 10019-016-17)

5 mL multiple dose vials packaged in 25s (NDC 10019-016-54)

20 mL multiple dose vials in 10s (NDC 10019-016-02)

SOURCE:
Package insert data:

INDICATIONS AND USAGE:
This product may be used in functional intestinal disorders to reduce symptoms such as those seen in mild dysenteries and diverticulitis. It can also be used to control gastric secretion, visceral spasm and hypermotility in cystitis, pylorospasm and associated abdominal cramps. Along with appropriate analgesics, this product is indicated in symptomatic relief of biliary and renal colic and as a drying agent in the relief of symptoms of acute rhinitis. This product is effective as adjunctive therapy in the treatment of peptic ulcer and irritable bowel syndrome, acute enterocolitis and other functional gastrointestinal disorders.

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DOSAGE AND ADMINISTRATION:
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Adults and pediatric patients 12 years of age or older:

1 to 2 sublingual tablets three to four times a day, thirty minutes to one hour before meals and at bedtime, the dosage being adjusted as needed and tolerated. Do not exceed 12 tablets in 24 hours.

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.

Pediatric patients 6 to under 12 years of age:
1/2 to 1 sublingual tablet three to four times a day, thirty minutes to one hour before meals and at bedtime. Dosage should be individualized by physician according to patient's needs and tolerance. Do not exceed 6 tablets in 24 hours.

Note: This product is not recommended for use in children under six years of age.
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Extended release tablets (0.375 mg):
Adults and pediatric patients 12 years or older:
1 or 2 tablets every 12 hours. Dosage may be adjusted to 1 tablet every 8 hours if needed. Do not exceed 4 tablets in 24 hours. Tablets should be swallowed whole.

Note: Geriatric patients may be more sensitive to the effects of the usual adult dose.

Pediatric patients 6 to under 12 years of age:
1 tablet every 12 hours. Do not exceed 2 tablets in 24 hours. Tablets should be swallowed whole.
Note: This product is not recommended for use in children under six years of age
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Solution/Drops:
Dosage may be adjusted according to the conditions and severity of symptoms. Measure dosage very carefully.

Adults and pediatric patients 12 years of age and older: 1 to 2 mL every four hours or as needed. Do not exceed 12 mL in 24 hours.

Pediatric patients 2 to under 12 years of age: 1/4 to 1 mL every four hours or as needed. Do not exceed 6 mL in 24 hours.

CONTRAINDICATIONS:
Glaucoma, obstructive uropathy, obstructive diseases of the gastrointestinal tract, paralytic ileum, intestinal atony of elderly or debilitated patients, unstable cardiovascular status, severe ulcerative colitis, toxic megacolon, myasthenia gravis, and myocardial ischemia.

This product is not recommended for use in children under six years of age.

WARNINGS AND PRECAUTIONS:
WARNINGS:
Heat prostration can occur with drug use in the event of high environmental temperature. Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy; in this instance, treatment would be inappropriate and possibly harmful. This product may cause drowsiness or blurred vision. Patients taking this product should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery or to perform hazardous tasks while taking this drug.

ADVERSE REACTIONS:
Not all of the following reactions have been reported with hyoscyamine sulfate. The following adverse reactions have been reported for pharmacologically similar drugs with anticholinergic-antispasmodic action. Adverse reactions may include dryness of the mouth, urinary hesitancy and retention; blurred vision; tachycardia; palpitations; mydriasis; cycloplegia; increased ocular tension; loss of taste; headache; nervousness; drowsiness; weakness; dizziness; insomnia; nausea; vomiting; impotence; suppression of lactation; constipation; bloated feeling; allergic reactions or drug idiosyncrasies; urticaria and other dermal manifestations; ataxia; speech disturbance; some degree of mental confusion and/or excitement (especially in elderly persons); and decreased sweating.

DOSAGE FORMS AND STRENGTHS:
Hyoscyamine Sulfate Tablets, USP 0.125 mg are round, white to off-white, mint flavored tablets with "PAD" debossed on one side and "H" on the other side.

Hyoscyamine Sulfate Extended-Release Tablets, 0.375 mg are capsule-shaped, white to off-white tablets with "P251" debossed on one side and scored on the other side.

Hyoscyamine Sulfate Oral Drops (hyoscyamine sulfate oral solution, USP, 0.125 mg per mL) is orange colored, flavored and contains 5% alcohol. It is supplied in a 15 mL bottle with a calibrated dropper, NDC 60258-802-15.
----
Supplied
Capsule, timed release, as sulfate (Cystospaz-M® [DSC], Levsinex®): 0.375 mg
Elixir, as sulfate: 0.125 mg/5 mL (480 mL)
Hyosine: 0.125 mg/5 mL (480 mL)
Levsin®: 0.125 mg/5 mL (480 mL) [contains alcohol 20%; orange flavor]

Injection, solution, as sulfate (Levsin®): 0.5 mg/mL (1 mL)
Solution, oral drops, as sulfate: 0.125 mg/mL (15 mL)
Hyosine: 0.125 mg/mL (15 mL)
Levsin®: 0.125 mg/mL (15 mL) [contains alcohol 5%; orange flavor]
Tablet (Cystospaz®): 0.15 mg
Tablet, orally-disintegrating, as sulfate (NuLev™): 0.125 mg [contains phenylalanine 1.7 mg/tablet, mint flavor]
Tablet, sublingual, as sulfate: 0.125 mg
Levsin/SL®: 0.125 mg [peppermint flavor]
Symax SL: 0.125 mg

SOURCE:
Package insert data:

Oxybutynin chloride relaxes bladder smooth muscle. In patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin chloride increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. Oxybutynin chloride thus decreases urgency and the frequency of both incontinent episodes and voluntary urination.

Antimuscarinic activity resides predominately in the R-isomer. A metabolite, desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in invitro studies.

INDICATIONS AND USAGE
Oxybutynin chloride tablets USP are indicated for the relief of symptoms of bladder instability associated with voiding in patients with uninhibited neurogenic or reflex neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence, dysuria).

CONTRAINDICATIONS
Oxybutynin chloride is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions.

Oxybutynin chloride is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product.

WARNINGS
Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

ADVERSE EFFECTS
The most common adverse events reported by patients receiving oxybutynin chloride 5 to 20 mg/day were the expected side effects of anticholinergic agents. The incidence of dry mouth was dose-related.

In addition, the following adverse events were reported by 1 to < 5% of patients using oxybutynin chloride (5 to 20 mg/day) in all studies. Infections and Infestations: nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection; Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders: confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations, sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic and Mediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat, sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders: diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper, dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria, pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased, blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural Complications: fall.

DOSAGE AND ADMINISTRATION
TABLET:
Adults
The usual dose is one 5 mg tablet two to three times a day. The maximum recommended dose is one 5 mg tablet four times a day. A lower starting dose of 2.5 mg two or three times a day is recommended for the frail elderly.

Pediatric Patients Over 5 Years of Age
The usual dose is one 5 mg tablet two times a day. The maximum recommended dose is one 5 mg tablet three times a day.

DITROPAN XL® must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.   DITROPAN XL® may be administered with or without food.

Adults
The recommended starting dose of DITROPAN XL® is 5 or 10 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals.

Pediatric Patients Aged 6 Years of Age and Older
The recommended starting dose of DITROPAN XL® is 5 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).

PATCH:
OXYTROL 3.9 mg/day should be applied to dry, intact skin on the abdomen, hip, or buttock twice weekly (every 3 or 4 days). A new application site should be selected with each new system to avoid re-application to the same site within 7 days.

HOW SUPPLIED
Oxybutynin chloride tablets USP are available as follows:
5 mg – Very pale blue, round, biconvex, scored tablets.
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DITROPAN XL® extended-release tablets are available as 5, 10 and 15 mg tablets for oral use:
5 mg: Pale yellow, round, tablet with "5 XL" printed on one side with black ink.
10 mg: Pink, round, tablet with "10 XL" printed on one side with black ink.
15 mg: Gray, round, tablet with "15 XL" printed on one side with black ink.
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PATCH:  Transdermal System: 3.9 mg/day

SOURCE:
Package insert data:

Propantheline bromide is extensively metabolized in man primarily by hydrolysis to the inactive materials xanthene-9-carboxylic acid and (2-hydroxyethyl) diisopropylmethylammonium bromide. In a bioavailability study, peak plasma concentrations of propantheline were achieved in about one hour, following a single oral dose.

The plasma elimination half-life of propantheline is about 1.6 hours. Approximately 70% of the dose is excreted in the urine, mostly as metabolites. The urinary excretion of propantheline is about 3% after oral tablet administration.

INDICATIONS AND USAGE:
Propantheline bromide is effective as adjunctive therapy in the treatment of peptic ulcer.

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DOSAGE AND ADMINISTRATION:
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The usual initial adult dose of propantheline bromide tablets is 15 mg taken 30 minutes before each meal and 30 mg at bedtime (a total of 75 mg daily). Subsequent dosage adjustment should be made according to the patient’s individual response and tolerance.

CONTRAINDICATIONS:
Propantheline is contraindicated in patients with:

1. Glaucoma, since mydriasis is to be avoided.
2. Obstructive disease of the gastrointestinal tract (pyloroduodenal stenosis, achalasia, paralytic ileus, etc.).
3. Obstructive uropathy (e.g., bladder-neck obstruction due to prostatic hypertrophy).
4. Intestinal atony of elderly or debilitated patients.
5. Severe ulcerative colitis or toxic megacolon complicating ulcerative colitis.
6. Unstable cardiovascular adjustment in acute hemorrhage.
7. Myasthenia gravis.

WARNINGS AND PRECAUTIONS:
WARNINGS
In the presence of a high environmental temperature, heat prostration (fever and heat stroke due to decreased sweating) can occur with the use of propantheline.

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.

With overdose, a curare-like action may occur (i.e., neuromuscular blockade leading to muscular weakness and possible paralysis). Propantheline may cause increased heart rate and therefore, should be used with caution in patients with heart disease.

PRECAUTIONS
General
Propantheline should be used with caution in the elderly and in all patients with autonomic neuropathy, hepatic or renal disease, hyperthyroidism, coronary heart disease, congestive heart failure, cardiac tachyarrhythmias, hypertension, or hiatal hernia associated with reflux esophagitis, since anticholinergics may aggravate this condition.

In patients with ulcerative colitis, large doses of propantheline may suppress intestinal motility to the point of producing paralytic ileus and, for this reason, may precipitate or aggravate toxic megacolon, a serious complication of the disease.

Information for Patients
Propantheline may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness, such as operating a motor vehicle or other machinery or performing hazardous work, while taking this drug.

ADVERSE REACTIONS:
Varying degrees of drying of salivary secretions may occur as well as decreased sweating. Ophthalmic side effects include blurred vision, mydriasis, cycloplegia, and increased ocular tension. Other reported adverse reactions include urinary hesitancy and retention, tachycardia, palpitations, loss of the sense of taste, headache, nervousness, mental confusion, drowsiness, weakness, dizziness, insomnia, nausea, vomiting, constipation, bloated feeling, impotence, suppression of lactation, and allergic reactions or drug idiosyncracies including anaphylaxis, urticaria and other dermal manifestations.

USE IN SPECIFIC POPULATIONS:
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term fertility, carcinogenicity, or mutagenicity studies have been done with propantheline.

Pregnancy
Pregnancy Category C

Animal reproduction studies have not been conducted with propantheline. It is also not known whether propantheline can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Propantheline should be given to a pregnant woman only if clearly needed.

Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when propantheline is administered to a nursing woman. Suppression of lactation may occur with anticholinergic drugs.

Pediatric Use
Safety and effectiveness in children have not been established.

DOSAGE FORMS AND STRENGTHS:
HOW SUPPLIED
Propantheline Bromide Tablets USP

15 mg white film-coated tablets
NDC 0054-4721-25: Bottles of 100 tablets.

Dispense in tight, light-resistant container as defined in the USP/NF.
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]
SOURCE:
Package insert data:

INDICATIONS AND USAGE:
DETROL Tablets are indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

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DOSAGE AND ADMINISTRATION:
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The initial recommended dose of DETROL Tablets is 2 mg twice daily. The dose may be lowered to 1 mg twice daily based on individual response and tolerability. For patients with significantly reduced hepatic or renal function or who are currently taking drugs that are potent inhibitors of CYP3A4, the recommended dose of DETROL is 1 mg twice daily

EXTENDED RELEASE:
Dosing Information
The recommended dose of DETROL LA Capsules is 4 mg once daily with water and swallowed whole. The dose may be lowered to 2 mg daily based on individual response and tolerability; however, limited efficacy data are available for DETROL LA 2 mg.

Dosage Adjustment in Specific Populations
For patients with mild to moderate hepatic impairment (Child-Pugh Class A or B) or severe renal impairment (CCr 10-30 mL/min), the recommended dose of DETROL LA is 2 mg once daily. DETROL LA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C). Patients with CCr<10 mL/min have not been studied and use of DETROL LA in this population is not recommended [see PACKAGE INSERT - WARNINGS AND PRECAUTIONS (5.6) and USE IN SPECIFIC POPULATIONS (8.6, 8.7)].

Dosage Adjustment in Presence of Concomitant Drugs
For patients who are taking drugs that are potent inhibitors of CYP3A4 [e.g., ketoconazole, clarithromycin, ritonavir], the recommended dose of DETROL LA is 2 mg once daily

CONTRAINDICATIONS:
DETROL Tablets are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. DETROL is also contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients, or to fesoterodine fumarate extended-release tablets which, like DETROL, are metabolized to 5-hydroxymethyl tolterodine.

WARNINGS AND PRECAUTIONS:
WARNINGS
Anaphylaxis and angioedema requiring hospitalization and emergency medical treatment have occurred with the first or subsequent doses of DETROL. In the event of difficulty in breathing, upper airway obstruction, or fall in blood pressure, DETROL should be discontinued and appropriate therapy promptly provided.

PRECAUTIONS
General

Risk of Urinary Retention and Gastric Retention
DETROL Tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention and to patients with gastrointestinal obstructive disorders, such as pyloric stenosis, because of the risk of gastric retention (see CONTRAINDICATIONS).

Decreased Gastrointestinal Motility
DETROL, like other antimuscarinic drugs, should be used with caution in patients with decreased gastrointestinal motility.

Controlled Narrow-Angle Glaucoma
DETROL should be used with caution in patients being treated for narrow-angle glaucoma.

Central Nervous System (CNS) Effects
Detrol is associated with anticholinergic central nervous system (CNS) effects including dizziness and somnolence (see Adverse Reactions). Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until the drug's effects have been determined. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Reduced Hepatic and Renal Function
For patients with significantly reduced hepatic function or renal function, the recommended dose of DETROL is 1 mg twice daily (see package insert: CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations).

Myasthenia Gravis
DETROL should be used with caution in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction.

Patients with Congenital or Acquired QT Prolongation
In a study of the effect of tolterodine immediate release tablets on the QT interval (see package insert - CLINICAL PHARMACOLOGY, Cardiac Electrophysiology), the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs). The effect of tolterodine 8 mg/day was not as large as that observed after four days of therapeutic dosing with the active control moxifloxacin. However, the confidence intervals overlapped. These observations should be considered in clinical decisions to prescribe DETROL for patients with a known history of QT prolongation or patients who are taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications (see PRECAUTIONS, Drug Interactions). There has been no association of Torsade de Pointes in the international post-marketing experience with DETROL or DETROL LA.

Information for Patients
Patients should be informed that antimuscarinic agents such as DETROL may produce the following effects: blurred vision, dizziness, or drowsiness. Patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug's effects have been determined.

Drug Interactions
CYP3A4 Inhibitors
Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see package insert - CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (e.g., itraconazole, miconazole) or macrolide antibiotics (e.g., erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL is 1 mg twice daily (see DOSAGE AND ADMINISTRATION).

USE IN SPECIFIC POPULATIONS:
SEE PACKAGE INSERT

DOSAGE FORMS AND STRENGTHS:
DETROL Tablets 1 mg (white, round, biconvex, film-coated tablets engraved with arcs above and below the letters "TO") and DETROL Tablets 2 mg (white, round, biconvex, film-coated tablets engraved with arcs above and below the letters "DT")
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EXTENDED RELEASE CAPSULES:
DETROL LA Capsules are supplied as follows:
The 2 mg capsules are blue-green with symbol and 2 printed in white ink.
The 4 mg capsules are blue with symbol and 4 printed in white ink.

SOURCE:
Package insert data:

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DOSAGE AND ADMINISTRATION:
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CONTRAINDICATIONS:

WARNINGS AND PRECAUTIONS:

ADVERSE REACTIONS:

DRUG INTERACTIONS:

USE IN SPECIFIC POPULATIONS:

DOSAGE FORMS AND STRENGTHS:

SOURCE:
Package insert data: