INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
DANTRON™ 4 mg or 8 mg film-coated tablets

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

DANTRON™ 4 mg or 8 mg film-coated tablets

COMPOSITION
DANTRON 4 mg film-coated tablets:
Each film-coated tablet contains ondansetron 4 mg (as hydrochloride dihydrate).
DANTRON 8 mg film-coated tablets:
Each film-coated contains ondansetron 8 mg (as hydrochloride dihydrate).

PHARMACOLOGICAL CLASSIFICATION
A 5.10 Medicines affecting autonomic functions. Serotonin antagonists.

PHARMACOLOGICAL ACTION
Ondansetron is a potent, highly selective 5-HT3 receptor-antagonist. Ondansetron’s actual mechanism of action in the control of nausea and vomiting is unknown. Chemotherapeutic agents and radiotherapy may cause release of 5-HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5-HT3 receptors. The initiation of this reflex is blocked by ondansetron. Activation of vagal afferents may also cause a release of 5-HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote emesis through a central mechanism.
Thus, the effect of ondansetron in the management of the nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is due to the antagonism of 5-HT3 receptors on neurons located both in the peripheral and central nervous system.
In psychomotor testing, ondansetron does not cause sedation nor impair performance.
Pharmacokinetics:
Plasma prolactin concentrations are not altered by ondansetron. Ondansetron is rapidly absorbed following oral administration, with maximum plasma concentrations of about 30 ng/mL being attained approximately 1,6 hours after an 8 mg dose. The absolute oral bioavailability of the drug is approximately 60%. The disposition of ondansetron following both intravenous and oral dosing is similar with a terminal elimination half-life of about 3 hours and a steady-state volume of distribution of about 140 L. Plasma protein binding is 70-76%. Ondansetron is cleared from the systemic circulation predominantly by metabolism with less than 5% of a dose excreted unchanged in the urine.
Studies in healthy elderly volunteers have shown a prolonged elimination half-life (5 hrs) and slightly increased bioavailability (65%) for ondansetron.
As a result of reduced pre-systemic metabolism in patients with severe hepatic impairment, the systemic clearance of ondansetron is markedly reduced with prolonged elimination half –lives (15 –32 hrs) and an oral bioavailability approaching 100%.

INDICATIONS
DANTRON is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.
DANTRON is also indicated for the prevention and treatment of post-operative nausea and vomiting. Routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and vomiting will occur.

CONTRA-INDICATIONS
DANTRON is contra-indicated in patients known to have hypersensitivity to ondansetron or any of the ingredients of the preparation.
The use of DANTRON for post-operative nausea and vomiting is contra-indicated in pregnancy.

WARNINGS
Patients with hepatic impairment:
In patients with moderate or severe impairment of hepatic function, clearance of ondansetron is significantly reduced and serum half-life significantly prolonged. In such patients, a total daily dose of 8 mg should not be exceeded.

PREGNANCY AND LACTATION
Pregnancy: Safety in pregnancy has not been established.
Lactation: Tests have shown that ondansetron passes into the milk of lactating animals.
It is therefore recommended that mothers receiving DANTRON should not breast feed their babies.

DOSAGE AND DIRECTIONS FOR USE
Chemotherapy and radiotherapy induced nausea and vomiting:
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used.
Adults:
Emetogenic chemotherapy and radiotherapy.
For most patients receiving emetogenic chemotherapy or radiotherapy, DANTRON 8 mg should be administered orally (film-coated tablets) 1-2 hours before treatment, followed by 8 mg orally twelve hourly.
In circumstances where delayed or prolonged emesis is expected after the first 24 hours, DANTRON may be continued orally, 8 mg twice daily for up to five days after a course of treatment.
Highly Emetogenic Chemotherapy:
To protect against delayed or prolonged emesis after the first 24 hours, DANTRON may be continued orally, 8 mg twice daily for up to 5 days after a course of treatment.
Children:
Experience is currently limited, but ondansetron was effective and well tolerated in children over the age of 4 years, when given intravenously, immediately before chemotherapy, followed by oral therapy of doses of DANTRON 4 mg every 12 hours for up to 5 days.
Repeat dosing for paediatric patients who continue to experience nausea and/or vomiting has not been studied, and should thus not been given.
Elderly patients:
Efficacy and tolerance in patients aged over 65 years was similar to that seen in younger adults indicating no need to alter dosage or route of administration in the elderly.

Prevention and treatment of post-operative nausea and vomiting:
Adults:
For the prevention of post-operative nausea and vomiting, 16 mg may be given orally (film-coated tablets) one hour prior to induction of anaesthesia.
Repeat dosing for patients who continue to experience nausea and/or vomiting post-operatively has not been studied. While recommended as a fixed dose for all, few patients above 80 kg or below 40 kg have been studied.
Children:
Repeat dosing for paediatric patients who continue to experience nausea and/or vomiting has not been studied, and should thus not been given.
Elderly:
Safety and efficacy have not been established in the use DANTRON in the prevention and treatment of post-operative nausea and vomiting in the elderly.
Patients with renal/hepatic impairment:
Patients with renal impairment: No alteration of daily dosage or frequency of dosing, or route of administration is required. There is limited information available on severely impaired renal or hepatic impairment.
Patients with hepatic impairment: Clearance of DANTRON is significantly reduced and serum half-life significantly prolonged in patients with moderate or severe impairment of hepatic function. In such patients, a total daily dose of 8 mg should not be exceeded.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The following side-effects can occur:
Central Nervous System:
Headache. Seizures have been observed rarely.
Cardiovascular System:
Arrhythmias, hypotension, bradycardia and chest pain have been rarely reported.
Gastrointestinal System:
Increase in large bowl transit time is known to be caused by ondansetron which may cause constipation in some patients.
Hypersensitivity reactions:
Immediate hypersensitivity reactions, sometimes severe (e.g. anaphylaxis, bronchospasm, shortness of breath, hypotension, shock, angiodema, urticaria) have been reported.
Muskuloskeletal:
There have been rare reports of involuntary movement disorders without definitive evidence of persistent clinical sequelae.
Other:
Hiccups and transient, asymptomatic increases in aminotransferases.
Special precautions:
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.
Patients with signs of subacute intestinal obstructions should be monitored following administration, as ondansetron is known to increase large bowl transit time.
As this product contains aspartame, caution is advised in patients with phenylketonuria.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See SIDE-EFFECTS AND SPECIAL PRECAUTIONS. Manifestations that have been reported include severe constipation, visual disturbances, hypotension and a vasovagal episode with transient second degree AV block. In cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate, as there is no specific antidote for ondansetron.

IDENTIFICATION:

DANTRON 4 mg film-coated tablets	Yellow film-coated tablet, formed like a bean with an embossment “O”on one side and “4”on the other side.
DANTRON 8 mg film-coated tablets	Yellow film-coated tablet, formed like a bean with an embossment “O”on one side and “8”on the other side.

PRESENTATION:

DANTRON 4 mg film-coated tablets	The film-coated tablets are packed into white, opaque PVC/aluminium blister strips containing 5, 15 or 30 film-coated tablets each.
DANTRON 8 mg film-coated tablets	The film-coated tablets are packed into white, opaque PVC/aluminium blister strips containing 5, 15 or 30 film-coated tablets each.

STORAGE INSTRUCTIONS:
Store below 25°C.
DANTRON film-coated tablets: Do not remove blisters from the outer carton until required for use.
Keep out of the reach of children.

REGISTRATION AND REFERENCE NUMBERS:

DANTRON 4 mg film-coated tablets	38/5.10/0198
DANTRON 8 mg film-coated tablets	38/5.10/0199

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
Hexal Pharma (SA) (PTY) Ltd
46 Mahogany Road
Mahogany Ridge
Pinetown, 3610

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
April 2005

New addition to this site: September 2005
Source: Pharmaceutical Industry
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