Emodan

Each ampule contains Ondansetron Hydrochloride equivalent to Ondansetron, USP 8 mg.

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 ondansetron in opiate-induced emesis is not yet established.
Pharmacokinetics: The pharmacokinetic properties of ondansetron are unchanged on repeat dosing.
A direct correlation of plasma concentration and anti-emetic effect has not been established.
Absorption: Following oral administration, ondansetron is passively and completely absorbed from the gastrointestinal tract and undergoes first pass metabolism (Bioavailability is about 60%.). Peak plasma concentrations of about 30 ng/ml are attained approximately 1.5 hours after an 8 mg dose. 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. Bioavailability, following oral administration, is slightly enhanced by the presence of food but unaffected by antacids.
A 4 mg intravenous infusion of ondansetron given over 5 minutes results in peak plasma concentrations of about 65 ng/ml. Following intramuscular administration of ondansetron, peak plasma concentrations of about 25 ng/ml are attained within 10 minutes of injection.
Distribution: The disposition of ondansetron following oral, intramuscular (IM) and intravenous (IV) dosing is similar with a steady state volume of distribution of about 140 L. Equivalent systemic exposure is achieved after IM and IV administration of ondansetron.
Ondansetron is not highly protein bound (70-76%).
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.
Excretion: Less than 5% of the absorbed dose is excreted unchanged in the urine. Terminal half life is about 3 hours.
Special Patient Populations: Children and Adolescents (aged 1 month to 17 years): In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight normalised clearance was approximately 30% slower than in patients aged 5 to 24 months (n=22) but comparable to the patients aged 3 to 12 years. The half-life in the patient population aged 1 to 4 month was reported to average 6.7 hours compared to 2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The differences in pharmacokinetic parameters in the 1 to 4 month patient population can be explained in part by the higher percentage of total body water in neonates and infants and a higher volume of distribution for water soluble drugs like ondansetron.
In a study of 21 paediatric patients aged between 3 and 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and volume of distribution of ondansetron following a single intravenous dose of 2 mg (3-7 years old) or 4 mg (8-12 years old) were reduced. The magnitude of the change was age-related, with clearance falling from about 300 ml/min at 12 years of age to 100 ml/min at 3 years. Volume of distribution fell from about 75 L at 12 years to 17 L at 3 years. Use of weight-based dosing (0.1 mg/kg up to 4 mg maximum) compensates for these changes and is effective in normalising systemic exposure in paediatric patients.
Based on the population pharmacokinetic parameters for subjects aged 1 month to 48 months, administration of a 0.15 mg/kg i.v. dose of ondansetron every 4 hours for 3 doses would result in a systematic exposure (AUC) comparable to that observed in paediatric surgery subjects aged 5 to 24 months and previous paediatric studies in cancer (aged 4 to 18 years) and surgical (aged 3 to 12 years) subjects, at similar doses.
Population pharmacokinetic analysis was performed on 428 subjects (cancer patients, surgery patients and healthy volunteers) aged 1 month to 44 years following intravenous administration of ondansetron. Based on this analysis, systemic exposure (AUC) of ondansetron following oral or IV dosing in children and adolescents was comparable to adults, with the exception of infants aged 1 to 4 months. Volume was related to age and was lower in adults than in infants and children. Clearance was related to weight but not to age with the exception of infants aged 1 to 4 months. It is difficult to conclude whether there was an additional reduction in clearance related to age in infants 1 to 4 months or simply inherent variability due to the low number of subjects studied in this age group. Since patients less than 6 months of age will only receive a single dose in PONV a decreased clearance is not likely to be clinically relevant.
Elderly persons: Studies in healthy elderly volunteers have shown slight age-related increases in both oral bioavailability (65%) and half-life (5 hours).
Renal impairment: In patients with renal impairment (creatinine clearance 15-60 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 h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged following IV administration.
Hepatic impairment: Following oral, intravenous or intramuscular dosing in patients with severe hepatic impairment, ondansetron's systemic clearance is markedly reduced with prolonged elimination half-lives (15-32 h) and an oral bioavailability approaching 100% due to reduced pre-systemic metabolism.
Gender differences: 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).

It is used in the management of nausea and vomiting induced by cytotoxic chemotherapy and in the prevention and treatment of post-operative nausea and vomiting.

Management of Nausea and Vomiting Induced by Cytotoxic Chemotherapy and Radiography: Adults: The emetogenic potential of cancer treatment varies according to the doses and combination of chemotherapy and radiotherapy regimens used. The route of administration is oral, intravenous and intramuscular. Dose of Ondansetron should be flexible in the range of 8-32 mg as Ondansetron a day and selected as shown as follows.
In less emetogenic chemotherapy and radiotherapy: Ondansetron 8 mg should be administered as a slow intravenous Injection or intramuscular injection immediately before treatment or orally 1 to 2 hours before treatment, followed by 8 mg orally after 12 hours.
To protect against delayed emesis, Ondansetron should be continued orally, 8 mg bid for up to 5 days after a course of treatment.
In highly emetogenic chemotherapy (e.g. regimens containing cisplatin): A dose of 8 mg by slow intravenous injection or intramuscular injection immediately before chemotherapy, followed by two further intravenous doses of 8 mg 2-4 hours apart, prn by a constant infusion of 1 mg/hour for up to 24 hours.
Alternatively, a single dose of 32 mg diluted in 50-100 mL of saline or other compatible infusion fluid and infused over 15 minutes immediately before chemotherapy.
The efficacy of Ondansetron in highly emetogenic chemotherapy may be enhanced by slow intravenous injection of dexamethasone sodium phosphate, 20 mg administered prior to chemotherapy.
To protect against delayed emesis, Ondansetron should be continued orally, 8 mg bid for up to 5 days after a course of treatment.
Children: Ondansetron may be administered as a single intravenous dose of 5 mg/m² over 15 minutes immediately before chemotherapy, followed by four mg orally every 12 hours or twice daily should be continued for up to 5 days after a course of treatment.
Prevention and Treatment of Post-Operative Nausea and Vomiting: Adults: For the prevention of post-operative nausea and vomiting: Ondansetron may be administered orally at a dose of 16 mg given 1 hour prior to anaesthesia.
Ondansetron may be administered orally at a dose of 8 mg given 1 hour prior to anaesthesia, followed by two further doses of 8 mg at 8 hourly intervals.
Alternatively, a single dose of 4 mg may be given by slow intravenous injection at induction of anaesthesia.
For the treatment of established post-operative nausea and vomiting: A single dose of 4 mg given by slow intravenous injection is recommended.
Children: For the prevention and treatment of post-operative nausea and vomiting.
Ondansetron may be slowly administered as a single intravenous dose of 0.1 mg/kg up to 4 mg, before, during or after anesthesia.
Patients With Renal Impairment: No alternation of daily dosage or frequency of dosing, or route of administration is required.
Patients with 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 should not be exceeded.
Patients with poor Sparteine/Debrisoquine metabolism: Patients with metabolism disorder of Sparteine/Debrisoquine, elimination half-life of Ondansetron have not changed. No specific studies have been conducted in patients with metabolism disorder of Sparteine/Debrisoquine. No change for dosage and administration.
Or as prescribed by the physician.

Little is known at present about overdosage with Ondansetron. However, a limited number of patients received overdoses. 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. There is no specific antidote for Ondansetron, therefore in all cases of suspected overdose, symptomatic and supportive therapy should be given as appropriate.

Patients with a history of hypersensitivity to this drug.

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT₃ receptor antagonists.
As Ondansetron is known to increase large bowel transit time, patients with signs of sub-acute intestinal obstruction should be monitored following administration.
Patients with severe hepatic impairment.
In psychomotor testing, Ondansetron does not impair performance nor cause sedation.
Use in Children: The safety in children has not been established sufficiently. Experience of the use of ondansetron in children is limited.
Use in the Elderly: Dosage adjustment is not needed in patients over the age of 65. Prevention of nausea and vomiting in elderly patients was no different than in younger age-groups.
Use in pregnancy & lactation: There are no adequate and controlled studies to date using Ondansetron in pregnant women. Reproduction studies have been performed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no evidence of impaired fertility or harm to the fetus due to Ondansetron. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Animal tests (with rats) have shown that Ondansetron is excreted in the breast milk. It is therefore recommended that mothers receiving this drug should not breast-feed their babies.

There are no adequate and controlled studies to date using Ondansetron in pregnant women. Reproduction studies have been performed in pregnant rats and rabbits at I.V. doses up to 4 mg/kg per day and have revealed no evidence of impaired fertility or harm to the fetus due to Ondansetron. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Animal tests (with rats) have shown that Ondansetron is excreted in the breast milk. It is therefore recommended that mothers receiving this drug should not breast-feed their babies.

Hypersensitivity: Patients should be carefully observed as this drug may cause hypersensitivity such as occasional rash, pruritus, rarely anaphylaxis. If these are noted, the drug should be discontinued and appropriate measures taken.
Mental-Neurological System: Occasional headache, a feeling of head heaviness, drowsiness, a sensation of flushing or warmth in the head and epigastrium, and transient asymptomatic increase in aminotransferases. Uncommon: seizures and movement disorders have been observed.
Gastrointestinal System: Occasionally, diarrhea and constipation (result from increase of large bowel transit time) may occur.
Cardiovascular System: Occasionally, chest pain, arrhythmia, hypotension and bradycardia may occur.
Liver: Transient increases in AST, ALT, LDH, r-ALT and total bilirubin may occasionally occur.
Others: Visual disturbance and vertigo may occur by rapid injection. Occasionally heat sensation, face flush, febricity, malaise, hiccup and sweating may occur. Occasionally, hypersensitivity reactions (e.g. rash, urticaria, itching) around the injection site, sometimes along the administrated vein, may occur.

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 Ondansetron does not interact with alcohol, temazepam, furosemide, and propofol.

Precaution for Administration: Ondansetron injection should not be administered in the same syringe or infusion as any other medication.
Ondansetron injection should not be autoclaved.
Ondansetron injection should only be admixed with those infusion solutions which are recommended: Normal Saline (0.5% w/v Sodium chloride Intravenous infusion); 5% w/v Glucose intravenous infusion; 10 % w/v Mannitol intravenous infusion; Ringers intravenous infusion; Potassium chloride 0.3 % w/v and Sodium chloride 0.9 % w/v intravenous infusion; Potassium chloride 0.3 % w/v and Glucose 5 % w/v intravenous infusion.
Use immediately after dilution or store at 2-8℃ for no more than 24 hours.
Compatibility studies have been undertaken in polyvinyl chloride infusion bags and polyvinyl chloride administration sets. It is considered that adequate stability would also be conferred by the use of polyethylene infusion bags or Type 1 glass bottles. Dilutions of Ondansetron in sodium chloride 0.9 % w/v or in glucose 5 % w/v have been demonstrated to be stable in polypropylene syringes. It is considered that Ondansetron injection diluted with other compatible infusion fluids would be stable in polypropylene syringes.
Ondansetron may be administered by intravenous infusion at 1 mg/hour, e.g. from an infusion bag or syringe pump.
The following drugs may be administered via the Y-site of the Ondansetron infusion set for Ondansetron concentrations of 16 to 160 micrograms/mL (e.g. 8 mg/500 mL~8 mg/50 mL respectively): Cisplatin: Concentrations up to 0.48 mg/mL (e.g. 240 mg in 500 mL) administered over one to eight hours.
5-Fluorouracil: Concentrations up to 0.8 mg/mL (e.g. 2.4 g in 3 liters 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 may cause precipitation of Ondansetron. The 5-fluorouracil infusion may contain up to 0.045 % w/v magnesium chloride in addition to other excipients shown to be compatible.
Carboplatin: Concentrations in the range 0.18 mg/mL to 9.9 mg/mL (e.g. 90 mg in 500 mg and to 990 mg in 100 mL), administered over ten minutes to one hour.
Etoposide: Concentrations in the range 0.14 mg/mL to 0.25 mg/mL (e.g. 72 mg in 500 mL and 250 mg in 1 liter), administered over thirty minutes to one hour.
Ceftazidime: Doses in range 250 mg to 2000 mg reconstituted with Water for injections 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 injections 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 10-100 mg reconstituted with Water for injections BP, 5 mL per 10 mg doxorubicin, as recommended by the manufacturer and given as an intravenous bolus injection over approximately five minutes.
Dexamethasone: Dexamethasone sodium phosphate 20 mg may be administered as a slow intravenous injection over 2-5 minutes via the Y-site of an infusion set delivering 8 or 32 mg of Ondansetron diluted in 50-100 mL of a compatible infusion fluid over approximately 15 minutes.
Compatibility between dexamethasone sodium phosphate and Ondansetron has been demonstrated supporting administration of these drugs through the same infusion set resulting in concentrations in line of 32 microgram-2.5 mg/mL for dexamethasone sodium phosphate and 8 microgram-1 g/mL for Ondansetron.

Store at temperatures not exceeding 30ºC. Protect from light.

Antiemetics / Supportive Care Therapy

A04AA01 - ondansetron ; Belongs to the class of serotonin (5HT3) antagonists. Used for the prevention of nausea and vomiting.

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