HYOSCINE-N-butylbromide

HYOSCINE-N-butylbromide

10 mg sugar-coated Tablet

20 mg/ml Injection

DRUG CATEGORY: Antispasmodic/Anticholinergic

BRAND NAME:Buscopan®

FORMULATION

1 sugar coated tablet contains 10 mg of Hyoscine-N-butylbromide.

1 ampoule of 1 ml contains 20 mg of Hyoscine-N-butylbromide.

INDICATIONS

Acute gastrointestinal, biliary and genitourinary spasm, including biliary and renal colic.

As an aid in diagnostic and therapeutic procedures, where spasm may be a problem, e.g. gastro-duodenal endoscopy, and in radiology.

DOSAGE AND ADMINISTRATION

Oral Tablet

Unless otherwise prescribed by your physician, the following doses are recommended:

Adults and children over 6 years: 1-2 sugar-coated tablets 3-5 times daily. The tablet should be swallowed whole with adequate fluid.

Parenteral Injection

Adults and adolescents over 12 years:

1-2 ampules of Hyoscine-N-butylbromide (20-40 mg) may be administered by slow intravenous, intramuscular or subcutaneous injection several times daily.

The maximum daily dose of 100 mg should not be exceeded.

Infants and children:

In severe cases: 0.3-0.6 mg/kg body weight, to be administered by slow intravenous, intramuscular or subcutaneous injection several times daily. The maximum daily dose of 1.5 mg/kg body weight should not be exceeded.

Hyoscine-N-butylbromide should not be taken on a continuous daily basis or for extended periods without investigating the cause of abdominal pain.

CONTRAINDICATIONS

Hyoscine-N-butylbromide is contraindicated in:

• patients who have demonstrated prior hypersensitivity to Hyoscine-N-butylbromide or any other components of the product
• untreated narrow-angle glaucoma
• hypertrophy of the prostate with urinary retention
• mechanical stenosis in the gastrointestinal tract retention
• tachycardia
• megacolon
• myasthenia gravis

By intramuscular injection, Hyoscine-N-butylbromide ampules are contraindicated:

• in patients being treated with anticoagulant drugs since intramuscular haematoma may occur. In these patients, the subcutaneous or intravenous routes may be used.

In case of rare hereditary conditions that may be incompatible with an excipient of the product, the use of the product is contraindicated.

SPECIAL WARNINGS AND PRECAUTIONS

In case severe, unexplained abdominal pain persists or worsens, or occurs together with symptoms like fever, nausea, vomiting, changes in bowel movements, abdominal tenderness, decreased blood pressure, fainting or blood in stool, appropriate diagnostic measures are needed to investigate the etiology of the symptoms.

Parenteral Injection

Elevation of intraocular pressure may be produced by administration of anticholinergic agents such as Hyoscine-N-butylbromide in patients with undiagnosed and therefore untreated narrow-angle glaucoma. Therefore, patients should seek urgent develop a painful, red eye with loss of vision after the injection of Hyoscine-N-butylbromide.

After parenteral administration of Hyoscine-N-butylbromide, cases of anaphylaxis including episodes of shock have been observed. As with all drugs causing such reactions, patients receiving Hyoscine-N-butylbromide by injection should be kept under observation.

Oral Tablet

Because of potential risk of anticholinergic complications, caution should be used in patients prone to narrow-angle glaucoma as well as patients susceptible to intestinal or urinary outlet obstruction and in those inclined to tachyarrhythmia.

One sugar-coated tablet of 10 mg contains 41.2mg sucrose, resulting in 411.8 mg sucrose per maximum recommended daily dose. Patients with the hereditary condition of fructose intolerance should not take this medicine.

Abdominal cramps may be temporary or signal the presence of a more serious problem. Consult your doctor if the pain is severe or does not improve within 48 hours of taking Hyoscine-N-butylbromide.

INTERACTIONS

The anticholinergic effect of drugs such as tri- and tetracyclic antidepressants, antihistamines, antipsychotics, quinidine, amantadine, disopyramide and other anticholinergics (e.g. tiotropium, ipratropium, atropine-like compounds) may be intensified by Hyoscine-N-butylbromide.

Concomitant treatment with dopamine antagonists such as metoclopramide may result in diminution of the effects of both drugs on the gastrointestinal tract.

The tachycardic effects of beta-adrenergic agents may be enhanced by Hyoscine-N-butylbromide.

FERTILITY, PREGNANCY AND LACTATION

There is limited data from the use of Hyoscine-N-butylbromide in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (please refer to “toxicology”).

There is insufficient information on the excretion of Hyoscine-N-butylbromide and its metabolites in human milk.

As a precautionary measure, it is preferable to avoid the use of Hyoscine-N-butylbromide during pregnancy and lactation.

No studies on the effects on human fertility have been conducted (please refer to “toxicology”).

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as accommodation disorder or dizziness during treatment with Hyoscine-N-butylbromide. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience accommodation disorder or dizziness, they should avoid potentially hazardous tasks such as driving or operating machinery.

SIDE EFFECTS

Many of the listed undesirable effects can be assigned to the anticholinergic properties of Hyoscine-N-butylbromide. Anticholinergic side effects of Hyoscine-N-butylbromide are generally mild and self-limited.

Immune system disorders

Anaphylactic shock including fatal outcome, anaphylactic reactions, dyspnea, skin reactions (e.g. urticaria, rash erythema, pruritus) and other hypersensitivity.

Eye disorders

Accommodation disorders, mydriasis, increased intraocular pressure.

Cardiac disorders

Tachycardia

Vascular disorders

Blood pressure decreased, dizziness, flushing.

Gastrointestinal disorders

Dry mouth

Skin and subcutaneous tissue disorders

Dyshidrosis

Renal and urinary disorders

Urinary retention

OVERDOSAGE

Symptoms

In the case of overdosage, anticholinergic effects may be observed.

Therapy

If required, parasympathomimetic drugs should be administed. Ophthalmological advice should be sought in cases of glaucoma urgently. Cardiovascular complications should be treated according to usual therapeutic principles. In case of respiratory paralysis: intubation, artificial respiration should be considered. Catheterization may be required for urinary retention. In addition, appropriate supportive measures should be used as required.

PHARMACOLOGICAL PROPERTIES

Hyoscine-N-butylbromide exerts a spasmolytic action on the smooth muscle of the gastrointestinal, biliary and genitourinary tracts. As a quaternary ammonium derivative, Hyoscine-N-butylbromide does not enter the central nervous system. Therefore, anticholinergic side effects at the central nervous system do not occur. Peripheral anticholinergic action results from a ganglion-blocking action within the visceral wall as well as from an anti-muscarinic activity.

PHARMACOKINETICS

Absorption and distribution

After intravenous administration, Hyoscine-N-butylbromide is rapidly distributed (t_{1/2 α}= 4 min, t_{1/2 β} = 29 min) into the tissues. The volume of distribution (Vss) is 128 L (corresponding to approx. 1.7 L/kg). Because of its high affinity for muscarinic receptors and nicotinic receptors, Hyoscine-N-butylbromide is mainly distributed on muscle cells of the abdominal and pelvic area as well as in the intramural ganglia of abdominal organs. Plasma protein binding (albumin) of Hyoscine-N-butylbromide is approximately 4.4%. Animal studies demonstrate that Hyoscine-N-butylbromide does not pass the blood-brain barrier, but no clinical data to this effect is available. Hyoscine-N-butylbromide (1 mM) has been observed to interact with the choline transport (1.4 nM) in epithelial cells of human placenta in vitro.

Metabolism and elimination

The main metabolic pathway is the hydrolytic cleavage of the ester bond. The half-life of the terminal elimination phase (t_{1/2 γ}) is approximately 5 hours. The total clearance is 1.2 L/min. Clinical studies with radiolabeled Hyoscine-N-butylbromide show that after intravenous injection 42 to 61% of the radioactive dose is excreted renally and 28.3 to 37% faecally.

The portion of uchanged active ingredient excreted in the urine is approximately 50%. The metabolites excreted via the renal route bind poorly to the muscarinic receptors and are therefore not considered to contribute to the effect of the hyoscine-N-butylbromide.

TOXICOLOGY

Acutely, hyoscine-N-butylbromide has a low index of toxicity: oral LD₅₀values were 1000-3000 mg/kg in mice, 1040-3300 mg/kg in rats, and 600 mg/kg in dogs. Toxic signs were ataxia and decreased muscle tone, additionally, in mice tremor and convulsions, in dogs mydriasis, dry mucous membranes and tachycardia. Deaths from respiratory arrest occurred within 24 hours. The intravenous LD₅₀values of hyoscine-N-butylbromide were 10-23 mg/kg in mice and 18 mg/kg in rats.

In repeated oral dose toxicity studies over 4 weeks, rats tolerated 500 mg/kg = “ no observed adverse effect level (NOAEL)”. At 2000 mg/kg, by the action on parasympathetic ganglia of visceral area, hyoscine-N-butylbromide paralyzed the gastrointestinal function resulting in obstipation. Eleven out of 50 rats died.

Hematology and clinical chemistry results did not show dose-related variations.

Over 26 weeks, rats tolerated 200 mg/kg, while at 250 and 1000 mg/kg, the gastrointestinal function was depressed and deaths occurred. The NOAEL of the 30-week oral (capsule) dog study was 30 mg/kg. The majority of clinical findings was attributable to acute effects of hyoscine-N-butylbromide at high dosages (200 mg/kg). No adverse histopathological findings were observed.

A repeated intravenous dose of 1 mg/kg was well tolerated by rats in a 4-week study. At 3 mg/kg, convulsions occurred immediately after injection. Rats dosed with 9 mg/kg died from respiratory paralysis.

Dogs treated intravenously over 5 weeks at 2 x 1, 2 x 3 and 2 x 9 mg/kg, showed a dose-dependent mydriasis in all treated animals, in addition at 2 x 9 mg/kg, ataxia, salivation and decreased body weight and food intake were observed. The solution were locally well tolerated.

After repeated IM injection, the dose of 10 mg/kg was systemically well tolerated, but lesions of muscles at the site of injection were distinctly increased if compared to control rats. At 60 and 120 mg/kg, mortality was high and local damages were dose-dependently increased. Hyoscine-N-butylbromide was neither embryotoxic nor teratogenic at oral doses of up to 200 mg/kg in the diet (rat) and 20 mg/kg by gavage or 50 mg/kg SC (rabbit). Fertility was not impaired at doses of up to 200 mg/kg p.o..

Like other cationic drugs, hyoscine-N-butylbromide interacts with choline transport system of human placental epithelial cell in vitro. Transfer of hyoscine-N-butylbromide to the fetal compartment has not been proved.

In special studies concerning local tolerability, a repeated IM injection of 25 mg/kg hyoscine-N-butylbromide over 28 days was studied in dogs and monkeys. Small focal necroses at the site of injection were seen only in dogs. Hyoscine-N-butylbromide was well tolerated in arteries and veins of the rabbit's ear. In vitro, 2% hyoscine-N-butylbromide injectable solution showed no hemolytic action when mixed with 0.1 ml human blood.

Hyoscine-N-butylbromide revealed no mutagenic or clastogenic potential in the Ames test, in the in vitro gene mutation assay in mammalian V79 cells (HPRT test) and in an in vitro chromosome aberration test in human peripheral lymphocytes. In vivo, hyoscine-N-butylbromide was negative in the rat bone marrow micronucleus assay.

There are no in vivo carcinogenicity studies. Nevertheless, hyoscine-N-butylbromide did not show a tumorigenic potential in two oral 26-week-studies in rats given up to 1000 mg/kg.

STORAGE CONDITIONS

Store at temperature not exceeding 30^oC.