Data Sheet
DIASTOP
Diphenoxylate hydrochloride 2.5 mg & Atropine sulphate 0.025 mg
Presentation
White biconvex tablet, 7/32" in diameter and blank on both sides. Each DIASTOP tablet contains 2.5 mg of diphenoxylate hydrochloride and 0.025 mg of atropine sulphate.
Uses
Actions
Diphenoxylate is an opiate derivative. The antidiarrhoeal effects of opioids may be due to their effects on the opiate receptors controlling smooth muscle contraction in the small intestine and colon. The resulting increase in tone and segmenting activity increases the resistance to flow of luminal contents.
Atropine is a non-selective muscarinic antagonist. A sub therapeutic dose of atropine is included in Diastop to prevent abuse by deliberate overdose.
Pharmacokinetics
Diphenoxylate hydrochloride
Diphenoxylate is rapidly absorbed reaching peak blood levels in about two hours. Its relatively short plasma half-life (about 2.5 hours) and large plasma clearance suggests its rapid biotransformation. Metabolism is principally in the liver. The major metabolic pathway of diphenoxylate in man is the hydrolysis of the ester group to give diphenoxylic acid - a pharmacologically active metabolite. Diphenoxylate metabolites probably undergo enterohepatic circulation. Diphenoxylic acid has a greater average peak plasma concentration, and a shorter time to maximum plasma concentration, than diphenoxylate. The AUC is about five times greater for diphenoxylic acid than for diphenoxylate, and may reflect enhanced bioavailability of diphenoxylic acid. Onset of pharmacological effect is 45 to 60 minutes, and duration of effect is about 3 to 4 hours. Diphenoxylate has a volume of distribution of 3.8 L/kg, with penetration into the cerebrospinal fluid. Plasma levels decline in a biphasic manner, with plasma half-lives of about 6 hours (for 2-24 hours) and 23 hours (for 24-72 hours). Approximately 10% of a dose of diphenoxylate is excreted in the urine and 40% in the faeces. Urinary excretion is mainly in the form of metabolites, while faecal excretion is mainly as unchanged drug. Diphenoxylic acid is also eliminated from plasma in a biphasic manner, and is excreted principally in urine.
Atropine
Atropine is rapidly absorbed from the gastrointestinal tract, with a time to peak plasma concentration of 30 minutes. Time to peak pharmacological effect is 4 to 6 hours. About 50% of a dose is bound to plasma proteins. Atropine is partially metabolised by hepatic oxidation, and distribution is throughout the body, including the CNS. Atropine has a half-life of about 4 hours. The principal route of elimination is in urine; with about 30% to 50% of a dose excreted as unchanged drug. Only trace amounts are in the faeces.
Indications
DIASTOP is indicated as an adjunctive therapy to proper rehydration in acute and chronic diarrhoea; after colostomy or ileostomy for control of stool formation; and for relief of symptoms in ulcerative colitis (see Warnings and Precautions).
Dosage and Administration
Each DIASTOP tablet contains 2.5 mg diphenoxylate hydrochloride plus 0.025 mg atropine sulphate.
Adults:
The usual initial dose is 5 mg (two tablets) three or four times daily. In cases of acute diarrhoea an initial dose of up to 10 mg (four tablets) may be given, followed by 5 mg (two tablets) every six or eight hours, not to exceed a maximum daily dose of 20 mg. After initial control is achieved, the dosage should be reduced to meet the requirements of the individual patients. Do not exceed recommended dosage.
Children:
NOTE: DIASTOP is not recommended for use in children under two years of age.
The recommended initial dosage is 0.3 to 0.4 mg/kg diphenoxylate hydrochloride daily administered in divided doses.
| Age | Approximate body weight |
Dosage |
|---|---|---|
| 2 to 5 years | 15 - 20 kg | 1 tablet b.i.d. |
| 5 to 8 years | 20 - 27 kg | 1 tablet t.i.d. |
| 8 to 12 years | 27 - 36 kg | 1 tablet q.i.d. |
| 12 years and over | 2 tablets t.i.d. - q.i.d. (adult dosage) |
These paediatric schedules are the best approximation of an average dose
recommendation which should be adjusted according to the overall nutritional
status and degree of dehydration encountered in the sick child. The
recommended doses must not be exceeded. (See Overdosage).
This dosage should be reduced commensurate with the patient's needs once initial control of symptoms is achieved. Doses as low as 0.25 mg/kg per day have proven effective in severely malnourished children in underdeveloped countries.
If no improvement in acute diarrhoea has been observed after 48 hours, DIASTOP should be discontinued. If clinical improvement in chronic diarrhoea is not observed after 10 days' treatment with the maximum daily dose of 20 mg (in adults), further administration is unlikely to result in any benefit.
Contraindications
DIASTOP is contraindicated in patients with known hypersensitivity to diphenoxylate hydrochloride or atropine, and in patients with jaundice. DIASTOP is also contraindicated in treatment of diarrhoea associated with the use of certain antibiotics (pseudomembranous enterocolitis) as well as diarrhoea caused by enterotoxin producing bacteria or acute ulcerative colitis.
Warnings and Precautions
DIASTOP is not an innocuous drug and dose recommendations should be strictly adhered to, especially in children. Overdose may result in severe respiratory depression and coma, possibly leading to permanent brain damage, or death. Keep this medication out of reach of children. DIASTOP is not recommended for children under 2 years of age. DIASTOP should be used with special caution in young children because they may be predisposed to delayed toxicity and because of the greater variability of response in this age group.
Appropriate fluid and electrolyte therapy should be given to protect against dehydration. If severe dehydration or electrolyte imbalance is present, DIASTOP should be withheld until appropriate corrective therapy has been initiated. Drug-induced inhibition of peristalsis may result in fluid retention in the intestine, which may further aggravate dehydration and electrolyte imbalance.
DIASTOP should be used with extreme caution in patients with advanced hepatorenal disease and in all patients with abnormal liver function, since hepatic coma may be precipitated. Bacterially induced diarrhoea should be treated with appropriate antimicrobial therapy. DIASTOP should be avoided in patients with acute inflammatory bowel disease because it may mask a severe episode or the development of toxic megacolon.
The recommended dose should not be exceeded because addiction to DIASTOP is possible at high doses. A sub-therapeutic dose of atropine has been added to the diphenoxylate hydrochloride. Therefore, consideration should be given to the precautions relating to the use of atropine in children. DIASTOP should be used with caution since signs of atropinism may occur particularly in Down's syndrome.
Pregnancy and lactation
Because atropine crosses the placenta and the safety of DIASTOP in pregnancy has not been established, caution is recommended when DIASTOP is used during pregnancy. The use of any drug during pregnancy or in women of childbearing potential requires that the potential benefits of the drug be weighed against possible hazards to the mother and foetus.
Diphenoxylic acid, the active metabolite of diphenoxylate, and atropine sulphate appear in human breast milk; therefore infants of nursing mothers taking DIASTOP may exhibit some effects of the drug. If use of DIASTOP is necessary, an alternative method of infant feeding should be instituted.
Effects on ability to drive and use machines
DIASTOP can produce drowsiness and dizziness. Caution should be used when driving or operating dangerous machinery.
Adverse Effects
At therapeutic doses, the following have been reported:
- Nervous system: malaise/lethargy, confusion, sedation/drowsiness, dizziness, restlessness, depression, hallucinations, somnolence, euphoria, headache and paraesthesia.
- Allergic: Anaphylaxis, angioneurotic oedema, urticaria, pruritus.
- Gastrointestinal System: toxic megacolon, paralytic ileus, vomiting, nausea, anorexia, abdominal discomfort and abdominal pain.
- Body as a whole: oedema, hypersensitivity reactions (including anaphylaxis).
Atropine sulphate effects are: hyperthermia, tachycardia, urinary retention, flushing, dryness of the skin and mucous membranes.
Interactions
Diphenoxylate may have an additive effect on certain central nervous system depressants, e.g. barbiturates, tranquillisers and alcohol. Concurrent use with MAO inhibitors may, precipitate hypertensive crisis. Close observation is required when these medications are given concomitantly with diphenoxylate hydrochloride.
Overdosage
Initial signs of overdosage may include atropinic effects, such as dryness of the skin and mucous membranes, mydriasis, restlessness, flushing, hyperthermia and tachycardia followed by lethargy or coma, hypotonic reflexes, nystagmus, pinpoint pupils and respiratory depression. However, atropinic effects may mask effects of diphenoxylate toxicity. The narcotic antagonist, naloxone hydrochloride (Narcan®) should be administered if respiratory depression develops. If naloxone hydrochloride is not available, nalorphine hydrochloride should be used. The action of naloxone hydrochloride is of shorter duration than that of diphenoxylate hydrochloride, so repeated injections of the antidote may be required. Establishment of a patient airway, and if necessary, artificial ventilation should be instituted.
If the patient is not comatose, gastric lavage and administration of a slurry of activated charcoal may be indicated.
Respiratory depression may be evidenced as late as 30 hours after ingestion and may recur in spite of an initial response to narcotic antagonists. TREAT ALL POSSIBLE DIASTOP OVERDOSAGES AS SERIOUS AND MAINTAIN MEDICAL OBSERVATION FOR AT LEAST 48 HOURS.
Pharmaceutical Precautions
Store below 25°C.
Medicine Classification
Pharmacy Medicine.
Package Quantities
Blister packs of 20 tablets and 100 tablets.
Further Information
DIASTOP tablets also contain microcrystalline cellulose, pregelatinised maize starch, magnesium stearate and colloidal anhydrous silica.
Name and Address
Mylan New Zealand Ltd
PO Box 11-183
Ellerslie
AUCKLAND
Telephone: 09-579-2792
Date of Preparation
2 February 2009