Ondavell

Ondavell

ondansetron

Manufacturer:

Novell

Distributor:

Goldplus
Full Prescribing Info
Contents
Ondansetron.
Description
FC tab: Each film coated tablet contains ondansetron HCl 2H2O equivalent to ondansetron 8 mg.
Inj: Each mL contains Ondansetron HCl 2H20 equivalent to Ondansetron 2 mg.
Excipients/Inactive Ingredients: FC tab: Lactose, Microcrystalline cellulose, Crospovidone, Povidone, Colloidal Silicone Dioxide, Magnesium Stearate, Ethanol, Macrogol poly (vinylalcohol) grafted copolymer, Talc, Titanium Dioxide, FDC Yellow no. 6 Lake, Purified Water.
Inj: Sodium Chloride, Citric Acid monohydrate, Sodium Citrate Dihydrate, Water for Injection.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. Its precise mode of action in the control of nausea and vomiting is not known. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause a release of 5HT 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 probably due to antagonism of 5HT3 receptors on neurons located both in the peripheral and central nervous system. The mechanisms of action in post-operative nausea and vomiting are not known but there may be common pathways with cytotoxic induced nausea and vomiting. Ondansetron does not alter plasma prolactin concentrations. The role of odansetron in opiate-induced emesis is not yet established.
QT Prolongation: The effect of ondansetron on the QTc interval was evaluated in a double blind, randomised, placebo and positive (moxifloxacin) controlled, crossover study in 58 healthy adult men and women. Ondansetron doses included 8 mg and 32 mg infused intravenously over 15 minutes. At the highest tested dose of 32 mg, the maximum mean (upper limit of 90% Cl) difference in QTcF from placebo after baseline-correction was 19.6 (21.5) msec. At the lower tested dose of 8 mg, the maximum mean (upper limit of 90% Cl) difference in QTcF from placebo after baseline­ correction was 5.8 (7.8) msec. In this study, there were no QTcF measurements greater than 480 msec and no QTcF prolongation was greater than 60 msec. No significant changes were seen in the measured electrocardiographic PR or QRS intervals.
Pharmacokinetics: The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
Absorption: FC tab: Following oral administration, ondansetron is passively and completely absorbed from the gastroinstestinal tract and undergoes first pass metabolism. Peak plasma concentrations are attained approximately 1.5 hours after dosing. For doses above 8 mg the increase in ondansetron systemic exposure with dose is greater than proportional, this may reflect some reduction in first pass metabolism at higher oral doses. Mean bioavaibility in healthy male subjects, following the administration of a single 8 mg tablet, is approximately 55 to 60%. Bioavaibility is slightly enhanced by the presence of food but unaffected by antacids.
Inj: Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.
Distribution: Ondansetron is not highly protein bound (70 to 76%).
The disposition of ondansetron following oral, IM or IV dosing in adults is similar with a steady state volume of distribution of about 140 L.
Metabolism: Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on ondansetron's pharmacokinetics.
Elimination: Ondansetron is cleared from the systemic circulation predominantly by hepatic metabolism. Less than 5% of the absorbed dose is excreted unchanged in the urine.
The disposition of ondansetron following oral, lM or IV dosing is similar with a terminal elimination half-life of about 3 hours.
Special Patient Populations: Gender: Gender differences were shown in the disposition of ondansetron, with females having a greater rate and extent of absorption following an oral dose and reduced systemic clearance and volume of distribution (adjusted for weight).
Children and Adolescents (aged 2 years and over): In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron were reduced in comparison to values with adult patient. Both parameters increased in a linear fashion with weight and by 12 years of age, the values were approaching those of young adult. When clearance and volume of distribution values were normalised by body weight, the values for these parameters were similar between the different age group populations. Use of weight based dosing compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients.
Elderly: Early Phase I studies in healthy elderly volunteers showed a slight age-related decrease in clearance, and an increase in half-life of ondansetron. However, wide inter-subject variability resulted in considerable overlap in pharmacokinetic parameters between young (<65 years of age) and elderly subjects (≥65 years of age) and there were no overall differences in safety or efficacy observed between young and elderly cancer patients enrolled in CINV clinical trials to support a different dosing recommendation for the elderly.
Based on more recent ondansetron plasma concentrations and exposure-response modelling, a greater effect on QTcF is predicted in patient ≥75 years of age compared to young adults. Specific dosing information is provided for patients over 65 years of age and over 75 years of age for intravenous dosing (see Dosage and Administration-CINV and RINV in Elderly).
Renal Impairment: In patients with moderate renal impairment (creatinine clearance 15 to 60 mL/min), both systemic clearance and volume of distribution are reduced following IV administration of ondansetron, resulting in a slight, but clinically insignificant, increase in elimination half-life (5.4 hours). A study in patients with severe renal impairment who required regular hemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.
Hepatic Impairment: In patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15 to 32 hours) and an oral bioavaibility approaching 100% due to reduced pre-systemic metabolism.
Toxicology: Preclinical safety data: A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blokade of hERG potassium channels at clinically relevant concentrations. Dose-dependent QT prolongation has been observed in a through QT study in human volunteers (see Pharmacology: Pharmacodynamics: QT prolongation under Actions).
Indications/Uses
Adult: Ondansetron is indicated to manage nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy.
Ondansetron is also indicated for the prevention of post-operative nausea and vomiting.
Paediatric Population: Injections and oral formulations: Ondansetron is indicated for the management of nausea and vomiting induced by cytotoxic chemotherapy. No studies have been conducted on the use of orally admimistered ondansetron in the prevention or treatment of post-operative nausea and vomiting; IV injection is recommended for this purpose.
Dosage/Direction for Use
Ondansetron is available for oral and parenteral use to allow the route of administration and dosing to be flexible.
Chemotherapy and Radiotherapy Induced Nausea and Vomiting (CINV and RINV):
The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The selection of dose regimen should be determined by the severity of the emetogenic challenge.
CINV and RINV in Adults: The recommended intravenous (IV) or intramuscular (IM) dose of ONDANSETRON is 8 mg administered immediately before treatment.
For highly emetogenic chemotherapy, a maximum initial ondansetron dose of 16 mg IV infused over 15 minutes may be used. A single IV dose greater than 16 mg should not be given due to dose-dependent increase of QT prolongation risk (see Pharmacology: Pharmacodynamics under Actions, Precautions and Side Effects).
The efficacy of Ondansetron in highly emetogenic chemotherapy may be enhanced by the addition of a single IV dose of dexamethasone sodium phosphate 20 mg, administered prior to chemotherapy.
IV doses greater than 8 mg and up to a maximum of 16 mg must be diluted in 50 mL to 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection before administration and infused over not less than 15 minutes (see Instructions for Use and Handling under Cautions for Usage). Ondansetron doses of 8 mg or less, do not need to be diluted and may be administered as a slow IM or IV injection in not less than 30 seconds.
The initial dose of Ondansetron may be followed by 2 additional IV or IM doses of 8 mg 2 to 4 hours apart, or by a constant infusion of 1 mg/h for up to 24 hours.
Oral treatment is recommended to protect against delayed or prolonged emesis after the first 24 hours.
CINV in Children and Adolescents (aged 2 years and over): In children with a body surface area of 0.6 to 1.2 m2 ondansetron is administered as a single IV dose of 5 mg/m2 immediately before chemotherapy, followed by 4 mg orally 12 hours later. 4 mg orally twice daily can be continued for up to five days after a course of treatment.
CINV and RINV in Elderly: FC tab: No alteration of oral dose or frequency of administration is required.
Inj: In patients 65 to 74 years of age, the initial IV dose of Ondansetron 8 mg or 16 mg, infused over 15 minutes, may be followed by 2 doses of 8 mg infused over 15 minutes and given no less than 4 hours apart. All IV doses should be diluted in 50-100 mL of saline or other compatible infusion fluid and infused over 15 minutes.
In patients 75 years of age or older, the initial IV dose of Ondansetron should not exceed 8 mg infused over 15 minutes. The initial dose of 8 mg may be followed by 2 doses of 8 mg, infused over 15 minutes and given no less than 4 hours apart (see Special Patient Populations, Elderly). All IV doses should be diluted in 50-100 mL of saline or other compatible infusion fluid and infused over 15 minutes.
Renal Impairment: No alteration of daily dosage, frequency of dosing, or route of administration are required.
Hepatic Impairment: A significant reduction in ondansetron clearance and significant increase in half life in patient with moderate or severe liver impairment. In some patient a total daily dose should not exceed 8 mg.
Inj: Clearance of ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg IV or oral should not be exceeded.
Patient with Poor Sparteine/Debrisoquine Metabolism: The elimination half-life of Ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.
Post-operative nausea and vomiting: PONV in Adults: For prevention of post-operative nausea and vomiting, the recommended dose of Ondansetron injection is a single dose of 4 mg by IM or slow IV injection administered at the induction of anaesthesia.
For treatment of established post-operative nausea and vomiting a single dose of 4 mg given by IM or slow IV injection is recommended.
PONV in Children and Adolescents (aged 2 years and over): For prevention and treatment of PONV in paediatric patients having surgery performed under general anaesthesia, Ondansetron may be administered by slow IV injection (not less than 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg either prior to, at or after induction of anaesthesia, or after surgery.
There is limited data on the use of Ondansetron in the prevention and treatment of PONV in children under 2 years of age.
Elderly: There is limited experience in the use of Ondansetron in the prevention and treatment of post-operative nausea and vomiting in the elderly, however Ondansetron is well tolerated in patients over 65 years receiving chemotherapy.
Renal Impairment: No alteration of daily dosage or frequency of dosing, or route of administration are required.
Hepatic Impairment: Clearance of ondansetron is significantly reduced and serum half-life significantly prolonged in subjects with moderate or severe impairment of hepatic function. In such patients a total daily dose of 8 mg IV or oral should not be exceeded.
Patients with Poor Sparteine/Debrisoquine Metabolism: The elimination half-life of ondansetron is not altered in subjects classified as poor metabolisers of sparteine and debrisoquine. Consequently in such patients repeat dosing will give drug exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required.
Patient with liver impaired: A significant reduction in ondansetron clearance and significant increase in half life in patient with moderate or severe liver impairment. In some patient a total daily dose should not exceed 8 mg.
The infusion solutions that can be used based on compatibility study are: Glucose 5% w/v Infusion Solution; Sodium Chloride 0.9% w/v Infusion Solution; Ringers Infusion Solution; Mannitol 10% w/v Infusion Solution; Potassium Chloride 0.3% w/v & Sodium Chloride 0.9% w/v Infusion Solution; Potassium Chloride 0.3% w/v & Glucose 5% w/v Infusion Solution.
Proposed in-use shelf life for infusion with the above solutions are 168 hours (below 25°C) or 7 days (2 -8°C).
Overdosage
Symptoms and Signs: There is limited experience of Ondansetron overdose. In the majority of cases symptoms were similar to those already reported in patients receiving recommended doses. Manifestations that have been reported include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second degree AV block. In all instances, the events resolved completely.
Ondansetron prolongs QT interval in a dose-dependent fashion. ECG monitoring is recommended in cases of overdose.
FC tab: Cases consistent with serotonin syndrome have been reported in young children following oral overdose.
Treatment: There is no specific antidote for Ondansetron, therefore in cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.
The use of ipecacuanha to treat overdose with Ondansetron is not recommended as patients are unlikely to respond due to the anti-emetic action of Ondansetron itself.
Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
Contraindications
Hypersensitivity to ondansetron.
Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.
Special Precautions
Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT3 receptor antagonists.
Ondansetron prolongs the QT interval in a dose-dependent manner. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop prolongation of QTc, including patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation or electrolyte abnormalities.
Therefore, caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic agents or beta-adrenergic blocking agents and in patients with significant electrolyte disturbances. Hypokalemia and hypomagnesemia should be corrected prior to ondansetron administration.
Serotonin syndrome has been described following the concomitant use of ondansetron and other serotonergic drugs (see Interactions). If concomitant treatment with ondansetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is advised. As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration.
Use in pregnancy: Ondansetron is not teratogenic in animals. There is no experience in humans. As with other medications, ondansetron should not be used during pregnancy, especially during the 1st trimester.
Use in lactation: Tests have shown that ondansetron is excreted in the breast milk of rats. It is therefore recommended that mothers receiving ondansetron should not breastfeed their babies.
Effects on Ability to Drive and Use Machines: In psychomotor testing Ondansetron does not impair performance nor cause sedation. No detrimental effects on such activities are predicted from the pharmacology of Ondansetron.
Use In Pregnancy & Lactation
Pregnancy: Ondansetron is not teratogenic in animals. There is no experience in humans. As with other medications, ondansetron should not be used during pregnancy, especially during the 1st trimester.
The safety of ondansetron for use in human pregnancy has not been established. Evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to the development of the embryo, or foetus, the course of gestation and peri- and post-natal development. However an animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended.
Lactation: Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving ondansetron should not breast-feed their babies.
Adverse Reactions
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000) and very rare (<1/10,000), including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Rare and very rare events were generally determined from post-marketing spontaneous data.
The following frequencies are estimated at the standard recommended doses of ondansetron. The adverse event profiles in children and adolescents were comparable to that seen in adults.
Immune system disorders: Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis.
Nervous system disorders: Very common: Headache. Uncommon: Seizures, movement disorders (including extrapyramidal reactions such as dystonic reactions, oculogyric crisis and dyskinesia) have been observed without definitive evidence of persistent clinical sequelae. Rare: Dizziness predominantly during rapid IV administration.
Eye disorders: Rare: Transient visual disturbances (e.g. blurred vision) predominantly during IV administration.
Very rare: Transient blindness predominantly during IV administration.
The majority of the blindness cases reported resolved within 20 minutes. Most patients had received chemotherapeutic agents, which included cisplatin. Some cases of transient blindness were reported as cortical in origin.
Cardiac disorders: Uncommon: Arrhythmias, chest pains with or without ST segment deppresion, bradycardia.
Rare: QTc prolongation (including Torsade de Pointes).
Vascular disorders: Common: Sensation of warmth or flushing.
Uncommon: Hypotension.
Respiratory, thoracic, and mediastinal disorders: Uncommon: Hiccups.
Gastointestinal disorders: Common: Constipation.
Local burning sensation following insertion of suppositories.
Hepatobiliary disorders: Uncommon: Asymptomalic increases in liver function tests#.
#These events were observed commonly in patients receiving chemotherapy with cisplatin.
Skin and subcutaneous tissue disorders: Very rare: Toxic skin eruption, including toxic epidermal necrolysis.
General disorders and administration site conditions: Common: Local IV injection site reactions.
Side Effects
Common side effects are headache, a sensation of flushing or warmth in the head and epigastrium. Asymptomatic increases in aminotransferase is a rare and temporary case. Ondansetron is known to increase large bowel transit time and may cause constipation in some patients. There have been rare reports of immediate hypersensitivity reactions.
Local IV injection site reactions (common).
Seizures, movement disorders have been observed without definitive evidence of persistent clinical sequelae.
Arrhythmias, chest pain with or without ST segment depression, bradycardia (uncommon).
Dizziness, transient visual disturbances predominantly during IV administration. QT prolongation (rare).
Toxic skin eruption, including toxic epidermal necrolysis. Transient blindness predominantly during IV administration (very rare).
Hypotension Hiccups (uncommon).
Drug Interactions
There is no evidence that Ondansetron either induces or inhibits the metabolism of other drugs commonly co­-administered with it. Specific studies have shown that there are no interactions when Ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine, lidocaine, thiopental, or propofol. Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYPIA2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme inhibition or reduced activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally compensated by other enzymes and should result in little or no significant change in overall Ondansetron clearance or dose requirement.
Caution should be exercised when Ondansetron is coadministered with drugs that prolong the QT interval and/or cause electrolyte abnormalities.
Use of Ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of Ondansetron with cardiotoxic drugs (e.g. anthracyclines (such as doxorubicin, daunorubicin) or trastuzumab), antibiotics (such as erythromycin), antifungals (such as ketoconazole), antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or timolol) may increase the risk of arrhythmias.
Serotonergic Drugs (e.g. SSRIs and SNRIs): There have been post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of Ondansetron and other serotonergic drugs (including SSRIs and SNRIs).
Apomorphine: Based on reports of profound hypotension and loss of consciousness when ondansetron was administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated.
Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the oral clearance of Ondansetron was increased and Ondansetron blood concentrations were decreased.
Tramadol: Data from small studies indicate that Ondansetron may reduce the analgesic effect of tramadol.
Caution For Usage
Instructions for Use/Handling: Injection (unpreserved) ampoules: The solution for injection formulation is unpreserved, should only be used once and injected or diluted immediately after opening. Any remaining solution should be discarded.
Ondansetron injection ampoules should not be autoclaved.
Compatibility studies have been carried out in polyvinyl chloride infusion bags and polyvinyl chloride administration sets. Stability is conferred by the use of polyethylene infusion bags or Type 1 glass bottles.
Dilutions of unpreserved ondansetron injection in sodium chloride 0.9%w/v or in dextrose 5%w/v have been demonstrated to be stable in polypropylene syringes. Therefore, it is considered that unpreserved ondansetron injection diluted with compatible infusion fluids recommended below would also be stable in polypropylene syringes. In keeping with good pharmaceutical practice, IV solutions should be prepared at the time of infusion, under appropriate aseptic conditions.
Compatibility with IV fluids:In keeping with good pharmaceutical practice IV solutions should be prepared at the time of infusion or stored at 2-8°C for no more than 24 hours before the start of administration.
Compatibility with other drugs: Ondansetron may be administered by IV infusion at 1 mg/h, from an infusion bag or syringe pump. The following drugs may be administered via the Y-site of the ondansetron giving set for ondansetron concentrations of 16 to 160 micrograms/mL (e.g. 8 mg/500 mL and 8 mg/50 mL respectively): (See table.)

Click on icon to see table/diagram/image
Storage
Store at or below 30°C and protect from light.
Inj: After first opening the medicinal product should be used immediately. Any remaining solution should be discarded.
MIMS Class
ATC Classification
A04AA01 - ondansetron ; Belongs to the class of serotonin (5HT3) antagonists. Used for the prevention of nausea and vomiting.
Presentation/Packing
FC tab 8 mg (orange, round, shallow convex with no breakline) x 2's. Inj 2 mg/ml (amp) (clear and colourless solution) x 2 mL x 5's.
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