INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ZOFER Range

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ZOFER Range

ZOFER 4 MG TABLETS
ZOFER 8 MG TABLETS
ZOFER RAPITAB 4 (dispersible tablets)
ZOFER RAPITAB 8 (dispersible tablets)
ZOFER 4 MG INJECTION
ZOFER 8 MG INJECTION

COMPOSITION:
ZOFER 4 MG TABLETS: Each tablet contains ondansetron hydrochloride equivalent to
ondansetron 4 mg.
ZOFER 8 MG TABLETS: Each tablet contains ondansetron hydrochloride equivalent to ondansetron 8 mg.
ZOFER RAPITAB 4: Each dispersible tablet contains 4 mg ondansetron.
ZOFER RAPITAB 8: Each dispersible tablet contains 8 mg ondansetron.
ZOFER 4 MG INJECTION: Each ampoule contains ondansetron 4 mg (as hydrochloride) in 2 mL aqueous solution for intramuscular or intravenous administration.
ZOFER 8 MG INJECTION: Each ampoule contains ondansetron 8 mg (as hydrochloride) in 4 mL aqueous solution for intramuscular or intravenous administration.
ZOFER RAPITAB contains aspartame.

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

PHARMACOLOGICAL ACTION
Ondansetron is a selective 5-HT
3 receptor-antagonist. 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 chemotherapy and radiotherapy may be due to the antagonism of 5-HT
3 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 to 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 to 32 hours) and an oral bioavailability approaching 100%.

INDICATIONS
ZOFER is indicated for the management of nausea and vomiting induced by chemotherapy and radiotherapy.
ZOFER 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
ZOFER is contra-indicated in patients known to have hypersensitivity to ondansetron or any of the ingredients of the preparation.
The use of ZOFER 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 ZOFER 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 ZOFER should not breastfeed 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.
ZOFER RAPITAB is a dispersible tablet and should be placed on the top of the tongue, where it will disperse within seconds, thereafter it should be swallowed.
Adults
Emetogenic chemotherapy and radiotherapy: For most patients receiving emetogenic chemotherapy or radiotherapy, ZOFER 8 mg should be administered as a slow IV or IM injection immediately before treatment, or orally (film-coated tablets/dispersible tablets) 1 to 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, ZOFER may be continued orally, 8 mg twice daily for up to five days after a course of treatment.
Highly Emetogenic Chemotherapy: A single dose of ZOFER 8 mg by slow IV or IM injection immediately before chemotherapy has been shown to be effective in many patients.
Higher doses may be required in some patients, particularly those on high dose cisplatin, and the doses should be adjusted according to the severity of the emetogenic challenge.
In these patients the following dose schedules have been shown to be effective:
A dose of 8 mg by slow IV or IM injection immediately before chemotherapy, followed by two further IV or IM doses of 8 mg two to four hours apart, or by a constant infusion of 1 mg/hour for up to 24 hours.
OR
A single dose of 32 mg diluted in 50 to 100 mL of saline or other compatible infusion fluid, infused over not less than 15 minutes immediately before chemotherapy.
The efficacy of ZOFER in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone phosphate 20 mg administered 30 to 45 minutes prior to the first ZOFER dose prior to chemotherapy.
To protect against delayed or prolonged emesis after the first 24 hours, ZOFER 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 at a dose of 5 mg/m2 over 15 minutes, immediately before chemotherapy, followed by oral therapy of doses of ZOFER 4 mg every 12 hours for up to 5 days.
For prevention of postoperative nausea and vomiting in paediatric patients two years and older having surgery performed under general anaesthesia, ZOFER may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia. For the treatment of established postoperative nausea and vomiting in paediatric patients two years and older, ZOFER may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg.
Repeat dosing for paediatric patients who continue to experience nausea and/or vomiting has not been studied, and should thus not be 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
Immediately before induction of anaesthesia, or postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery, administer 4 mg undiluted intramuscularly or intravenously. If given intravenously, it must be administered in not less than 30 seconds, preferable over 2 to 5 minutes. Alternatively, for the prevention of post-operative nausea and vomiting, 16 mg may be given orally (film-coated tablets/dispersible 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
For prevention of postoperative nausea and vomiting in paediatric patients two years and older having surgery performed under general anaesthesia, ZOFER may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia.
For the treatment of established postoperative nausea and vomiting in paediatric patients two years and older, ZOFER may be administered by slow intravenous injection at a dose of 0.1 mg/kg up to a maximum of 4 mg.
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
Safety and efficacy have not been established with the use of ZOFER in the prevention and treatment of postoperative 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 ZOFER 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.

ZOFER injection should not be administered in the same syringe or infusion as any other medication.
ZOFER injection ampoules should not be autoclaved.

Compatibility with intravenous fluids
In accordance to Good Clinical Practice, intravenous solutions should be prepared just before infusion.
When diluted with compatible infusion solutions, ondansetron HCl is stable for up to seven days at room temperature or under refrigeration in polypropylene-neoprene syringes with syringe caps. Preparation must be under the appropriate aseptic conditions if extended storage periods are required.
ZOFER injection is compatible with the following intravenous infusion fluids:
- Sodium Chloride Intravenous Infusion BP 0.9% m/v.
- Glucose Intravenous Infusion BP 5%.
- Ringers Intravenous Infusion.
- Potassium Chloride 0.3% m/v and Sodium Chloride 0.9% m/v Intravenous Infusion BP.
- Potassium Chloride 0.3% m/v and Glucose 5% m/v Intravenous Infusion BP.
Intravenous infusions of ondansetron retain their potency for 48 hours at room temperature under normal lighting after dilution with 5% dextrose injection, dextrose and sodium chloride injections, 0.9% sodium chloride injection, and 3% sodium chloride injection.
Compatibility with other medicines
ZOFER injection may be administered by intravenous infusion at 1 mg/hour, e.g. from an infusion bag, or syringe pump. The following medicines may be administered via a Y-site:
Cisplatin: Concentrations up to 0.48 mg/mL (e.g. 240 mg in 500 mL) administered over one to eight hours.
Dexamethasone: Dexamethasone sodium phosphate 20 mg may be administered as a slow intravenous injection over 2 to 5 minutes via the Y-site of an infusion set delivering 8 mg of ZOFER diluted in 50 to 100 mL of compatible infusion fluid over approximately 15 minutes. Compatibility between dexamethasone sodium phosphate and ZOFER has been demonstrated supporting administration of these drugs through the same giving set, with resulting in-line concentrations in the ranges of 32 micrograms to 2.5 mg/mL for dexamethasone sodium phosphate and 8 micrograms to 1 mg/mL for ZOFER.
5-Fluorouracil: Concentrations up to 0.8 mg/mL (e.g. 2.4 g in 3 litres, or 400 mg in 500 mL) administered at a rate of at least 20 mL per hour (500 mL per 24 hours). Higher concentrations of 5-fluorouracil infusion may contain up to 0.045% m/v magnesium chloride in addition to other excipients shown to be compatible.
Carboplatin: Concentrations in the range of 0.18 mg/mL to 9.9 mg/mL (e.g. 90 mg in 500 mL to 990 mg in 100 mL), administered over 10 minutes to one hour.
Etoposide: Concentrations in the range of 0.14 mg/mL to 0.25 mg/mL (e.g. 72 mg in 500 mL to 250 mg in 1 litre), administered over thirty minutes to one hour.
Ceftazidime: Doses in the range of 250 mg to 2000 mg reconstituted with Water for Injection BP, as recommended by the manufacturer (e.g. 2.5 mL for 250 mg and 10 mL for 2 g ceftazidime), and given as an intravenous bolus injection over approximately five minutes.
Cyclophosphamide: Doses in the range 100 mg to 1 g, reconstituted with Water for Injection BP, 5 mL per 100 mg cyclophosphamide, as recommended by the manufacturer, and given as an intravenous bolus injection over approximately five minutes.
Doxorubicin: Doses in the range 10 to 100 mg, reconstituted with Water for Injection BP, 5 mL per 10 mg doxorubicin, as recommended by the manufacturer, and given as an intravenous bolus injection over approximately five minutes.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The following side-effects can occur:
Central Nervous System
Frequent: Headache.
Less frequent: Seizures.
Cardiovascular System
Less frequent: Arrhythmias, hypotension, bradycardia and chest pains.
Gastrointestinal System
Frequent: Increase in large bowel transit time is known to be caused by ZOFER which cause constipation in some patients.
Hypersensitivity reactions
Less frequent: Immediate hypersensitivity reactions, sometimes severe (e.g. anaphylaxis, bronchospasm, shortness of breath, hypotension, shock, angioedema, urticaria) have been reported.
Musculoskeletal
Less frequent: Involuntary movement disorders without definitive evidence of persistent clinical sequelae.
Local reactions
Less frequent: Pain, redness and burning at site of injection.
Other
Less frequent: Sensation of warmth or flushing, hiccups and transient, asymptomatic increases in aminotransferases.
Frequent: Dizziness has been observed and transient visual disturbances (e.g. blurred vision) have been reported during or shortly after rapid intravenous administration of ZOFER.
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 ZOFER is known to increase large bowel transit time.
As ZOFER RAPITAB 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 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:
ZOFER 4 MG TABLETS: White, oval shaped film-coated tablets debossed with “130”on one side and plain on the other side.
ZOFER 8 MG TABLETS: Yellow, oval shaped film-coated tablets debossed with “131”on one side and plain on the other.
ZOFER RAPITAB 4: White to off white, oval shape, uncoated tablets debossed with “240”on one side and plain on the other side.
ZOFER RAPITAB 8: White to off white, oval shape, uncoated tablets debossed with “241”on one side and plain on the other side.
ZOFER 4 MG INJECTION: 2 mL clear glass ampoule with a violet dot containing a colourless solution.
ZOFER 8 MG INJECTION: 5 mL clear glass ampoule with a grey dot containing a colourless solution.

PRESENTATION
ZOFER 4 MG TABLETS: PVDC/PVC and aluminium blister strip containing 10 tablets. 1 Blister strip will be packed in an outer carton.
ZOFER 8 MG TABLETS: PVDC/PVC and aluminium blister strip containing 10 tablets. 1 Blister strip will be packed in an outer carton.
ZOFER RAPITAB 4: White PVDC/PVC and aluminium blister strip containing 10 tablets. 1 Blister strip will be packed in an outer carton.
ZOFER RAPITAB 8: White PVDC/PVC and aluminium blister strip containing 10 tablets. 1 Blister strip will be packed in an outer carton.
ZOFER 4 MG INJECTION: Five 2 mL clear glass ampoules packed in plastic rondo tray into an outer carton.
ZOFER 8 MG INJECTION: Five 5 mL clear glass ampoules packed in plastic rondo tray into an outer carton.

STORAGE INSTRUCTIONS
ZOFER TABLETS: Store below 25ºC.
ZOFER RAPITAB: Store below 25ºC.
ZOFER INJECTIONS: Store below 25ºC. Protect from light. Do not refrigerate
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
ZOFER 4 MG TABLETS:         39/5.10/0413
ZOFER 8 MG TABLETS:         39/5.10/0414
ZOFER RAPITAB 4:         42/5.10/0662
ZOFER RAPITAB 8:         42/5.10/0663
ZOFER 4 MG INJECTION:         39/5.10/0448
ZOFER 8 MG INJECTION:         39/5.10/0449

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pharmaplan (Pty) Ltd
106 16th Road
Midrand

DATE OF PUBLICATION OF THE PACKAGE INSERT
4 September 2008

New addition to this site: March 2010
Source: Pharmaceutical Industry

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