Odaniqe 2mg/ml 4ml 5 ampoules

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5

Ondaniqe Ondansetron Injection USP 8 mg/4 mL 1. Name of the medicinal product: Ondaniqe (Ondansetron Injection USP 8 mg/4 mL) 2. Qualitative and quantitative composition: Each 4 mL contains: Ondansetron hydrochloride USP equivalent to Ondansetron 8 mg Water for injections ad 3. Pharmaceutical form: Solution for injection, a clear colorless solution. 4. Clinical particulars 4.1 Therapeutic indications: Ondansetron is indicated for the prevention and treatment of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention and treatment of postoperative nausea and vomiting. Paediatric population: Ondansetron is indicated for the treatment of chemotherapy-induced nausea and vomiting (CINV) in children aged ≥6 months and for the prevention and treatment of postoperative nausea and vomiting (PONV) in children aged ≥1 month. 4.2 Posology and method of administration: Posology Nausea and vomiting due to chemotherapy and radiotherapy Adults: The emetogenic potential of cancer treatments varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route and dose of Ondaniqe should be flexible in the range of 8-32 mg per day and selected as follows: Emetogenic chemotherapy and radiotherapy: Ondaniqe can be administered rectally, orally (tablets or syrup), intravenously or intramuscularly. For most patients receiving emetogenic chemotherapy or radiotherapy, the recommended intravenous (IV) dose of ondansetron is 8 mg and should be administered as a slow intravenous injection (over at least 30 seconds) or intramuscular injection, immediately before treatment, followed by 8 mg orally twelve hours later. To protect against delayed or prolonged vomiting after the first 24 hours, oral or rectal treatment with Ondaniqe should be continued for up to 5 days after the course of treatment. Highly emetogenic chemotherapy: For patients receiving highly emetogenic chemotherapy, such as high-dose cisplatin, Ondaniqe can be administered orally, rectally, intravenously or intramuscularly. Ondaniqe has been shown to be equally effective with the following dosage regimens during the first 24 hours of chemotherapy: · 8 mg single dose by slow intravenous injection (over at least 30 seconds) or intramuscular injection immediately before chemotherapy. · 8 mg dose by slow intravenous injection (over at least 30 seconds) or intramuscular injection immediately before chemotherapy, followed by two further intravenous injections (over at least 30 seconds) or intramuscular doses of 8 mg at 4-hour intervals, or by continuous infusion at 1 mg/hr for up to 24 hours. · A maximum initial intravenous dose of 16 mg should be diluted in 50-100 mL of saline or other compatible infusion fluid and infused over at least 15 minutes immediately before chemotherapy. Following the initial dose of Ondaniqe, two further 8 mg intravenous doses (over at least 30 seconds) or intramuscular doses may be administered at four-hour intervals. A single dose greater than 16 mg is not used due to the dose-dependent increase in the risk of QT prolongation. The dosing regimen should be determined by the severity of the emetogenic challenge. The efficacy of Ondaniqe in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone sodium phosphate, 20 mg, administered before chemotherapy. To protect against delayed or prolonged vomiting after the first 24 hours, oral or rectal treatment with Ondaniqe should be continued for up to 5 days after the course of treatment. Paediatric population: Chemotherapy-induced nausea and vomiting (CINV) in children and adolescents (6 months to 17 years) For chemotherapy-induced nausea and vomiting, the dose may be calculated on the basis of body surface area or weight - see below. In paediatric clinical trials, ondansetron was administered by IV infusion, diluted in 25-50 mL of saline or other compatible infusion fluid and infused over at least 15 minutes. Total daily doses are higher when dosed by weight than when dosed by body surface area (BSA). Ondaniqe injection should be diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid and administered intravenously over at least 15 minutes. There are no data from controlled clinical trials on the use of Ondaniqe for the prophylaxis of delayed or prolonged chemotherapy-induced nausea and vomiting (CINV). There are no data from controlled clinical trials on the use of Ondaniqe in children for radiotherapy-induced nausea and vomiting. Dosing by body surface area (BSA) Ondaniqe should be administered immediately before the start of chemotherapy as a single intravenous dose of 5 mg/m². The single intravenous dose should not exceed 8 mg. Oral dosing may commence 12 hours later and may continue for up to 5 days (Table 1). The total dose over 24 hours (in divided doses) should not exceed the adult dose of 32 mg. Table 1: BSA-based dose for chemotherapy-induced nausea and vomiting (CINV) (age >6 months to 17 years) Body surface area (BSA) Day 1 (a,b) Days 2-6 (b) <0.6 m² 5 mg/m² IV plus 2 mg syrup 12 hours later 12 mg syrup every 12 hours >0.6 m² - <1.2 m² 5 mg/m² IV plus 4 mg syrup or tablet 12 hours later 4 mg syrup or tablet every 12 hours >1.2 m² 5 mg/m² or 8 mg IV plus 8 mg syrup or tablet 12 hours later 8 mg syrup or tablet every 12 hours a IV dose should not exceed 8 mg. b Total dose over 24 hours (in divided doses) should not exceed the adult dose of 32 mg. Dosing by body weight When dosed by weight, total daily doses are higher than when dosed by body surface area (BSA). Ondaniqe is administered immediately before the start of chemotherapy as a single intravenous dose of 0.15 mg/kg. The single intravenous dose should not exceed 8 mg. Two further intravenous doses may be administered at 4-hour intervals. Oral dosing may commence 12 hours later and may continue for up to 5 days (Table 2). The total dose over 24 hours (in divided doses) should not exceed the adult dose of 32 mg. Table 2: Weight-based dosing for chemotherapy-induced nausea and vomiting (CINV) (age >6 months to 17 years) Body weight Day 1 (a,b) Days 2-6 (b) <10 kg 0.15 mg/kg up to 3 doses IV every 4 hours 2 mg syrup every 12 hours >10 kg 0.15 mg/kg up to 3 doses IV every 4 hours 4 mg syrup or tablet every 12 hours a IV dose should not exceed 8 mg. b Total dose over 24 hours (in divided doses) should not exceed the adult dose of 32 mg. Elderly patients For patients aged 65 to 74 years, the adult dosing regimen may be used. All intravenous doses should be diluted in 50-100 mL of saline or other compatible infusion fluid and infused over 15 minutes. For patients aged 75 years and over, the initial intravenous dose of Ondaniqe should not exceed 8 mg. All intravenous doses should be diluted in 50-100 mL of saline or other compatible infusion fluid and infused over 15 minutes. Following the initial 8 mg dose, two further 8 mg intravenous doses may be administered over 15 minutes at intervals of at least four hours. Patients with renal impairment No dose or frequency of dose or route of administration adjustment is needed. Patients with hepatic impairment The clearance of ondansetron is significantly reduced and the serum half-life is significantly prolonged in subjects with moderate or severe hepatic impairment. In such patients, the total daily dose should not exceed 8 mg and parenteral or oral administration is therefore recommended. Patients who are poor metabolizers of sparteine/debrisoquine The half-life of ondansetron is not altered in subjects who are classified as poor metabolizers of sparteine and debrisoquine. Consequently, the level of drug exposure in such patients is not different from that of the general population on repeated dosing. No dose or frequency of dose adjustment is needed. Postoperative nausea and vomiting (PONV): Adults For the prophylaxis of postoperative nausea and vomiting (PONV), ondansetron may be administered orally or intravenously or by intramuscular injection. The recommended dose is a single dose of 4 mg administered intramuscularly or by slow intravenous injection at the time of induction of anaesthesia. For the treatment of established postoperative nausea and vomiting (PONV), a single dose of 4 mg administered intramuscularly or by slow intravenous injection is recommended. Paediatric population Postoperative nausea and vomiting (PONV) in children and adolescents (1 month to 17 years) For the prophylaxis of postoperative nausea and vomiting (PONV) in paediatric patients undergoing surgery under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (over at least 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg prior to or following induction of anaesthesia. For the treatment of postoperative nausea and vomiting (PONV) in paediatric patients undergoing surgery under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (over at least 30 seconds) at a dose of 0.1 mg/kg up to a maximum of 4 mg. There are no data on the use of ondansetron for the treatment of postoperative nausea and vomiting in children under 2 years of age. Elderly patients There is limited experience of the use of ondansetron in the prophylaxis and treatment of postoperative nausea and vomiting in the elderly, however, ondansetron is well tolerated in patients over 65 years of age receiving chemotherapy. Patients with renal impairment No dose or frequency of dose or route of administration adjustment is needed. Patients with hepatic impairment The clearance of ondansetron is significantly reduced and the serum half-life is significantly prolonged in subjects with moderate or severe hepatic impairment. In such patients, the total daily dose should not exceed 8 mg and parenteral or oral administration is therefore recommended. Patients who are poor metabolizers of sparteine/debrisoquine The half-life of ondansetron is not altered in subjects who are classified as poor metabolizers of sparteine and debrisoquine. Consequently, the level of drug exposure in such patients is not different from that of the general population on repeated dosing. No dose or frequency of dose adjustment is needed. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients or to other selective 5-HT3 receptor antagonists (e.g. granisetron, dolasetron). Concomitant use with apomorphine. 4.4 Special warnings and precautions for use Hypersensitivity reactions have been reported in patients who have demonstrated hypersensitivity to other selective 5-HT3 receptor antagonists. Treatment of respiratory events should be symptomatic and clinicians should pay particular attention to them as precursors of hypersensitivity reactions. Ondansetron prolongs the QT interval in a dose-dependent manner. Furthermore, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid the use of ondansetron in patients with congenital long QT syndrome. Ondansetron should be administered with caution to patients who have or may develop QTc prolongation. This includes patients with electrolyte disturbances, congestive heart failure, bradyarrhythmias or patients taking other medicinal products which prolong the QT interval or cause electrolyte disturbances. Cases of myocardial ischaemia have been reported in patients treated with ondansetron. In some patients, particularly with intravenous administration, symptoms occurred immediately after administration of ondansetron. Patients should be warned of the signs and symptoms of myocardial ischaemia. Hypokalaemia and hypomagnesaemia must be corrected before administration of ondansetron. There have been post-marketing reports describing patients with serotonin syndrome (including changes in mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with ondansetron and other serotonergic agents is clinically justified, the patient should be appropriately monitored. As ondansetron is known to increase colonic transit time, patients with signs of subacute intestinal obstruction should be monitored following administration. In patients undergoing adenotonsillar surgery, prophylaxis of nausea and vomiting with ondansetron may mask occult bleeding. Therefore, such patients should be carefully monitored following administration of ondansetron. Paediatric population: In paediatric patients where ondansetron is used in conjunction with hepatotoxic chemotherapy agents, close monitoring for hepatic impairment is necessary. Chemotherapy-induced nausea and vomiting (CINV) When calculating the dose on a mg/kg basis and administering three doses at 4-hour intervals, the total daily dose will be higher than a single dose of 5 mg/m² followed by an oral dose. The comparative efficacy of these two different dosing regimens has not been investigated in clinical trials. A cross-over trial comparison indicated similar efficacy for both regimens. 4.5 Interaction with other medicinal products and other forms of interaction Effects of ondansetron on other medicinal products. There is no evidence that ondansetron causes or inhibits the metabolism of other drugs commonly used with it. Specific studies have shown that ondansetron does not interact with alcohol, temazepam, furosemide, alfentanil, morphine, lignocaine, propofol and thiopentone. Effects of other medicinal products on ondansetron Ondansetron is metabolised by hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic enzymes capable of metabolising ondansetron, enzyme induction or depression of activity of one enzyme (e.g. genetic deficiency of CYP2D6) is normally compensated by other enzymes and should result in little or no change in the overall clearance or dose requirement of ondansetron. Caution is advised when ondansetron is used concomitantly with drugs that prolong the QT interval and/or cause electrolyte disturbances. The use of ondansetron with QT-prolonging drugs may result in additional QT interval prolongation. Concomitant use of ondansetron with cardiotoxic agents (e.g. anthracyclines such as doxorubicin, daunorubicin or trastuzumab), antibiotics (e.g. erythromycin or ketoconazole), antiarrhythmics (e.g. amiodarone) and beta-blockers (e.g. atenolol or timolol) may increase the risk of arrhythmias. There have been post-marketing reports describing patients with serotonin syndrome (including changes in mental status, autonomic instability and neuromuscular abnormalities) following the concomitant use of ondansetron and other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs)). Apomorphine: Based on reports of profound hypotension and loss of consciousness when administered with apomorphine hydrochloride, concomitant use with apomorphine is contraindicated. Phenytoin, carbamazepine and rifampicin: In patients treated with potent inducers of CYP3A4 (e.g. phenytoin, carbamazepine and rifampicin), the oral clearance of ondansetron was increased and the plasma concentration of ondansetron was reduced. Tramadol: Limited study data indicate that ondansetron may reduce the analgesic effect of tramadol. 4.6 Pregnancy and lactation Women of childbearing potential: Women of childbearing age should consider the use of contraception. Pregnancy: Based on human experience from epidemiological studies, there is a suspicion that ondansetron causes orofacial malformations when used in the first trimester of pregnancy. In one cohort study of 1.8 million pregnancies, first trimester use of ondansetron was associated with an increased risk of cleft lip (3 additional cases per 10,000 women treated; adjusted relative risk, 1.24, (95% CI 1.03-1.48)). Existing epidemiological studies on cardiac malformations show conflicting results. Animal studies do not indicate a direct or indirect harmful effect with respect to reproductive toxicity. However, ondansetron should not be used in the first trimester of pregnancy. Lactation: Tests have shown that ondansetron passes into the milk of lactating animals. Therefore, it is recommended that mothers receiving ondansetron should not breastfeed their infants. 4.7 Effects on ability to drive and use machines Ondansetron 2 mg/mL has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects The following frequency terminology is used: Very common: ≥1/10; Common: ≥1/100 to <1/10; Uncommon: ≥1/1000 to <1/100; Rare: ≥1/10000 to <1/1000; Very rare: <1/10000; Unknown: cannot be estimated from the available data. Disorders of the immune system Rare: Immediate hypersensitivity reactions, sometimes severe including anaphylaxis. Anaphylaxis can be fatal. Hypersensitivity reactions have also been reported in patients who were sensitive to other selective 5-HT3 receptor antagonists. Nervous system disorders Very common: Headache. Uncommon: Reports of involuntary movement disorders such as extrapyramidal reactions, e.g. oculogyric crisis/dystonic reactions and dyskinesia have been reported without definitive evidence of clinical outcome or seizures (e.g. epileptic spasms), although no known pharmacological mechanism can account for ondansetron causing these effects. Rare: Dizziness on rapid intravenous administration. Very rare: Depression. Eye disorders Rare: Transient visual disturbances (e.g. blurred vision) on rapid intravenous administration. Very rare: Transient blindness has been reported in isolated cases in patients receiving chemotherapy agents including cisplatin. Most of the reported cases resolved within 20 minutes. Some cases of transient blindness have been reported as cortical in origin. Cardiac disorders Uncommon: Chest pain with or without ST segment depression, cardiac arrhythmias and bradycardia. Chest pain and cardiac arrhythmias may be fatal in isolated cases. Rare: Transient changes in electrocardiogram, QTc prolongation (including Torsades de Pointes). Unknown: Myocardial ischaemia. Vascular disorders Common: Flushing or sensation of warmth. Uncommon: Hypotension. Respiratory, thoracic and mediastinal disorders Uncommon: Hiccups. Gastrointestinal disorders Common: Ondansetron is known to increase colonic transit time and may cause constipation in some patients. Hepatobiliary disorders Uncommon: Asymptomatic increases in liver function tests have been noted. These reactions were most frequently noted in patients undergoing chemotherapy with cisplatin. Skin and subcutaneous tissue disorders Uncommon: Hypersensitivity reactions at the injection site (e.g. rash, urticaria, itching) may develop, sometimes extending along the vein on administration of the drug. General disorders and administration site conditions Common: Local reactions at the site of intravenous injection. Paediatric population In children and adolescents, the profile of adverse events was comparable to that in adults. 4.9 Overdose Little is known about the overdosage of ondansetron; however, overdose has been reported in a limited number of patients. In most cases, the symptoms were the same as in patients receiving recommended doses. Events identified include visual disturbances, severe constipation, hypotension and a vasovagal episode with transient second-degree atrioventricular block. In all cases, the events resolved completely. Ondansetron prolongs the QT interval in a dose-dependent manner. In case of overdose, ECG monitoring is recommended. There is no specific antidote for ondansetron, therefore, in all cases of overdosage, symptomatic and supportive therapy should be administered as required. The use of ipecacuanha to treat ondansetron overdose is not recommended as patients are unlikely to respond due to the antiemetic effect of ondansetron itself. Paediatric population Paediatric cases consistent with serotonin syndrome have been reported following inadvertent oral overdose of oral ondansetron (likely ingestion of 4 mg/kg) in neonates and infants aged 12 months to 2 years. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5HT3) antagonists. ATC code: A04AA01 Ondansetron is a potent, highly selective 5HT3 receptor antagonist. Its precise mechanism of action for controlling nausea and vomiting is not known. Cytotoxic drugs and radiotherapy may cause the release of 5HT from the enterochromaffin cells in the gastrointestinal tract and initiate the vomiting reflex by activating the vagal afferents through 5HT3 receptors. Ondansetron blocks the initiation of this reflex. Activation of vagal afferents may also cause the release of 5HT in the chemoreceptor trigger zone located on the floor of the fourth ventricle and this may also contribute to vomiting via a central mechanism. Thus, the effect of ondansetron in the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy is likely to be due to antagonism of 5HT3 receptors on neurons located in both the peripheral and central nervous systems. The mechanisms of action in postoperative nausea and vomiting are not known but there may be common pathways to those induced by cytotoxic agents. Ondansetron does not alter plasma prolactin concentrations. The role of ondansetron in opioid-induced emesis has not yet been established. The effect of ondansetron on the QTc interval was assessed in a double-blind, randomised, placebo and positive (moxifloxacin) controlled, cross-over study involving 58 healthy adult male and female subjects. Doses of ondansetron included 8 mg and 32 mg intravenously over 15 minutes. At the higher 32 mg dose tested, the maximum mean (90% CI upper bound) difference in QTcF from placebo after baseline correction was 19.6 (21.5) ms. At the lower 8 mg dose tested, the maximum mean (90% CI upper bound) difference in QTcF from placebo after baseline correction was 5.8 (7.8) ms. In this study, QTcF was not greater than 480 ms and QTcF prolongation was not greater than 60 ms. No significant changes in measured electrocardiographic PR or QRS intervals were observed. 5.2 Pharmacokinetic properties The pharmacokinetic properties of ondansetron remain unchanged on repeated dosing. A direct correlation between plasma concentration and antiemetic 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 approximately 60%). Peak plasma concentrations of approximately 30 ng/mL are achieved approximately 1.5 hours after administration of a 8 mg dose. For doses greater than 8 mg, the increase in systemic exposure to ondansetron with dose is greater than dose 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 no effect of antacids is observed. A 4 mg intravenous infusion of ondansetron over 5 minutes results in peak plasma concentrations of approximately 65 ng/mL. Following intramuscular administration of ondansetron, peak plasma concentrations of approximately 25 ng/mL are achieved within 10 minutes of injection. Distribution The distribution of ondansetron following oral, intramuscular (IM) and intravenous (IV) doses is similar to that with a steady-state volume of distribution of approximately 140 L. Equivalent systemic exposure is achieved following intramuscular and intravenous administration of ondansetron. Ondansetron protein binding is not high (70-76%). Metabolism Ondansetron is eliminated from the systemic circulation predominantly by hepatic metabolism via multiple enzymatic pathways. The absence of the CYP2D6 enzyme (debrisoquine polymorphism) does not affect the pharmacokinetics of ondansetron. Elimination Less than 5% of the absorbed dose is excreted unchanged in the urine. The terminal half-life is approximately 3 hours. 6. Pharmaceutical particulars 6.1 List of excipients Methylparaben, propylparaben, sodium chloride, sodium citrate, citric acid, water for injections. 6.2 Shelf life 36 months. 6.3 Special precautions for storage Store below 30°C. Protect from light and moisture. 6.4 Container type and contents 4 mL solution filled in a 5 mL clear glass ampoule with a yellow break ring. 5 such ampoules are placed in a tray, which is then packed in a printed cardboard box with instructions. Dispensing regime: Pharmaceutical product group - II, dispensed with prescription form №3. See also: Yunorm 2mg/mL 4mL 5 ampoules