Public Assessment Report. Decentralised Procedure

Transcription

1 Public Assessment Report Decentralised Procedure Ondansetron 4mg Orodispersible Tablets Ondansetron 8mg Orodispersible Tablets UK/H/1360/ /DC UK licence no: PL 31774/ Bluefish Pharamceuticals AB 1

2 LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted Bluefish Pharmaceuticals AB Marketing Authorisations (licences) for the medicinal products Ondansetron 4mg Orodispersible Tablets (PL 31774/0004) and Ondansetron 8mg Orodispersible Tablets (PL 31774/0005). These are prescription-only medicines (POM) used in the management of nausea or vomiting as a result of cancer chemotherapy/radiotherapy, and for the prevention of post-operative nausea and vomiting in adults and children. Ondansetron Injection contains the active ingredient ondansetron which is an antiemetic medicine. The test product was considered equivalent to the reference product Zofran Zydis 8mg licensed to GlaxoSmithKline, Spain, since 1 st May No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking Ondansetron 4mg and 8mg Orodispersible Tablets outweigh the risks; hence Marketing Authorisations have been granted. 2

3 TABLE OF CONTENTS Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 22 Module 4: Labelling Page 24 Module 5: Scientific Discussion Page 26 1 Introduction Page 26 2 Quality aspects Page 28 3 Non-clinical aspects Page 30 4 Clinical aspects Page 30 5 Overall conclusions Page 37 Module 6 Steps taken after initial procedure Page 38 3

4 Module 1 Product Name Ondansetron 4mg and 8mg Orodispersible Tablets Type of Application Generic, Article 10.1 Active Substance Form Strength MA Holder RMS CMS Procedure Number Ondansetron base Orodispersible Tablets 4mg 8mg Bluefish Pharmaceuticals AB Birger Jarlsgatan 37, Stockholm Sweden UK Germany, Denmark, Finland, The Netherlands, Norway, Poland Spain and Sweden Timetable Day th November

5 Module 2 SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT Ondansetron 4 mg Orodispersible Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each orodispersible tablet contains: 4 mg ondansetron. Excipient: Aspartame (E951) 0.88mg per 4 mg tablet. Sorbitol (E420) up to 8.442mg per 4 mg tablet. Glucose and sulphur dioxide (E220). For a full list of excipients, see section PHARMACEUTICAL FORM Orodispersible tablet. White, flat, round, bevel-edged tablet. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications Adults: The management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention of post-operative nausea and vomiting in adults. Paediatric Population: Management of chemotherapy-induced nausea and vomiting in children aged 6 months. Prevention and treatment of postoperative nausea and vomiting in children aged 1 month. 4.2 Posology and method of administration For oral use. Place the orodispersible tablet on top of the tongue, where it will disperse within seconds. For the different dosage regimens appropriate strengths and formulations are available. Chemotherapy and radiotherapy induced nausea and vomiting. Adults: The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of Ondansetron should be flexible and selected as shown below. Emetogenic chemotherapy and radiotherapy: For patients receiving emetogenic chemotherapy or radiotherapy ondansetron can be given either by oral or intravenous administration. For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron should initially be administered intravenously immediately before treatment, followed by 8 mg orally twelve hourly. For oral administration: 8 mg 1-2 hours before treatment, followed by 8 mg 12 hours later. To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8mg twice daily. Highly emetogenic chemotherapy : 5

6 For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given by intravenous administration. To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8mg twice daily. Children (aged 2 years and over) and adolescents (< 18 years): Experience in paediatric patients is limited. In children older than two years, ondansetron may be administered as a single intravenous dose of 5 mg/m 2 over 15 minutes immediately before chemotherapy, followed by 4 mg orally twelve hours later. Oral treatment with a dose according to the body area should be continued for up to 5 days after a course of treatment. Children with a total body area between 0.6 and 1.2 m 2 should receive a dosage schedule of 4 mg 2 times a day, while children with a body area above 1.2 m 2 should receive 8 mg 2 times a day. Paediatric Population: Chemotherapy-induced nausea and vomiting in children aged 6 months and adolescents: The dose of chemotherapy-induced nausea and vomiting can be calculated based on body surface area (BSA) or weight see below. Weight-based dosing results in higher total daily doses compared to BSA-based dosing see sections 4.4 and 5.1 There are no data from controlled clinical trials on the use of Ondansetron in the prevention of chemotherapy-induced delayed or prolonged nausea and vomiting. There are no data from controlled clinical trials on the use of Ondansetron for radiotherapy-induced nausea and vomiting in children. Dosing by BSA: Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 5mg/m2. The intravenous dose must not exceed 8mg. Oral dosing can commence twelve hours later and may be continued for up to 5 days. See Table 1 below. The total daily dose must not exceed adult dose of 32mg Table 1: BSA-based dosing for Chemotherapy - Children aged 6 months and adolescents BSA Day 1 (a,b) Days 2-6 (b) < 0.6 m 2 5 mg/m 2 i.v. plus 2 mg syrup after 12 hrs 0.6 m 2 5 mg/m 2 i.v. plus 4 mg syrup or tablet after 12 hrs a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg 2 mg syrup every 12 hrs 4 mg syrup or tablet every 12 hrs Dosing by bodyweight: Weight-based dosing results in higher total daily doses compared to BSA-based dosing see sections 4.4 and 5.1. Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15mg/Kg. The intravenous dose must not exceed 8mg. Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32mg. Oral dosing can commence twelve hours later and may be continued for up to 5 days. See Table 2 below. Table 2: Weight-based dosing for Chemotherapy - Children aged 6 months and adolescents Weight Day 1 (a,b) Days 2-6 (b) 10 kg Up to 3 doses of 0.15 mg/kg every 4 hrs 2 mg syrup every 12 hrs > 10 kg Up to 3 doses of 0.15 mg/kg every 4 hrs 4 mg syrup or tablet every 12 hrs a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg. Elderly: 6

7 Ondansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required. Please refer also to Special populations. Post-operative nausea and vomiting Adults: Prevention of post-operative nausea and vomiting For the prevention of post-operative nausea and vomiting ondansetron can be administered orally or by intravenous injection. For oral administration: 16 mg one hour prior to anesthesia. Alternatively, 8 mg one hour prior to anesthesia followed by two further doses of 8 mg at eight hourly intervals. Treatment of established post-operative nausea and vomiting For the treatment of established post-operative nausea and vomiting intravenous administration is recommended. Children (aged 2 years and over) and adolescents (< 18 years): For the prevention and treatment of post-operative nausea and vomiting slow intravenous injection is recommended Paediatric population: Post-operative nausea and vomiting in children aged 1 month and adolescents Oral Formulation: No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post operative nausea and vomiting; slow i.v. injection is recommended for this purpose. Injection: For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 secounds) at a dose 0.1mg/Kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia. There are no data on the use of Ondansetron for the treatment of postoperative vomiting 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. Please refer also to Special populations. Special populations Patients with renal impairment: No alteration of daily dosage or frequency of dosing, or route of administration are 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 8mg 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 medical product exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required. 7

8 4.3 Contraindications Hypersensitivity to ondansetron or to other selective 5-HT3-receptor antagonists (e.g.granisetron, dolasetron) or to any of the excipients. 4.4 Special warnings and precautions for use Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT 3 receptor antagonists. As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration. Very rarely and predominantly with intravenous Ondansetron, transient ECG changes including QT interval prolongation have been reported. Therefore caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic agents or betaadrenergic blocking agents and in patients with significant electrolyte disturbances. Paediatric Population: Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitive reactions. Paediatric population receiving ondansetron with hepatotoxic chemotherapeutical agents should be monitored closely for impaired hepatic function. Chemotherapy-induced nausea and vomiting: When calculating the dose on a mg/kg basis and administering three doses at 4 hourly intervals, the total daily dose will be higher than if one single dose of 5mg/m2 followed by an oral dose is given. The comparative efficacy of these two different dosing regimens has not been investigated in clinical trials. Cross trial comparing indicate similar efficacy for both regimens see section 5.1 Warnings on excipients: Aspartame, which contains a source of phenylalanine. May be harmful for people with phenylketonuria because aspartame is metabolized to fenylalanine. Patients with rare hereditary problems of fructose intolerance or glucose-galactose malabsorption should not take this medicine because it contains sorbitol, mannitol and dextrose. Strawberry flavour contains sulphur dioxide (E220) which may rarely cause severe hypersensitivity reactions and bronchospasm. 4.5 Interaction with other medicinal products and other forms of interaction 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 pharamcokinetic interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, propofol and thiopental. Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. 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. 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 4-fold and ondansetron blood concentrations were significantly decreased. Dose adjustment of ondansetron is probably necessary. Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol. Use of Ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of Ondansetron with cardiotoxic drugs (e.g. anthracyclines) may increase the risk of arrhythmias (See section 4.4) 8

9 4.6 Pregnancy and lactation 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 the fetus, the course of gestation and peri- and post-natal development. However, as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended. Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving Ondansetron orodispersible tablets should not breast-feed their babies. 4.7 Effects on ability to drive and use machines In psychomotor testing Ondansetron orodispersible tablets do not impair performance nor cause sedation. 4.8 Undesirable effects Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common ( 1/10), common ( 1/100 and <1/10), uncommon ( 1/1000 and <1/100), rare ( 1/10,000 and <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 according to indication and formulation. Cardiac disorders Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia. Very rarely transient ECG changes including QT-interval prolongation have been reported. 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. Respiratory, thoracic and mediastinal disorders Uncommon: Hiccups. Gastrointestinal disorders Common: Constipation. Vascular disorders Common: Sensation of warmth or flushing. Uncommon: Hypotension. Immune system disorders Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis. Hepatobiliary disorders Uncommon: Asymptomatic increases in liver function tests. These events were observed commonly in patients receiving chemotherapy with cisplatin. Rare: Dizziness during i.v. administration, which in most cases is prevented or resolved by lengthening the infusion period. Eye disorders Rare: Transient visual disturbances (eg. blurred vision) during i.v. administration. Very rare: Transient blindness predominantly during intravenous administration 9

10 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. 4.9 Overdose 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. 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. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Serotonin (5HT 3 ) antagonists ATC code: A04AA01 Ondansetron is a potent, highly selective 5HT 3 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 5HT 3 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 5HT 3 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. Paediatric Population: Chemotherapy-induced nausea and vomiting The efficacy of Ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a doubleblind randomised trial in 415 patients aged 1 to 18 years. On the days of chemotherapy, patients received either ondansetron 5mg/m2 i.v. + after 8-12hrs ondansetron 4 mg p.o. or ondansetron 0.45 mg/kg i.v. + after 8-12hrs placebo p.o. Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49 % (5mg/m2 i.v. + ondansetron 4mg p.o.) and 41 % (0.45 mg/kg i.v. + placebo p.o.). Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. A double-blind randomise placebo-controlled trial in 438 aged 1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy in 73% of patients when ondansetron was administered intravenously at a dose of 5mg/m2 i.v. together with 2-4 mg dexamethasone p.o. and in 71% of the patients when ondansetron was administered as a syrup at a dose of 8mg mg dexamethasone p.o. on the days of chemotherapy. Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, noncomparative, singlearm study. All children receive three 0.15mg/Kg doses of intravenous ondansetron, administered at 30 minutes before the start of chemotherapy and then at four and eight hours after the first dose. Complete control of emesis was achieved in 56% of patients. Another open-label, non-operative, single-arm study investigated the efficacy of one intravenous dose of 0.15mg/Kg ondansetron followed by two ondansetron doses of 4mg for children aged < 12 yrs and 8 mg for children aged 12yrs (total no. of children n = 28). Complete control of emesis was achieved in 42% of patients. Prevention of post-operative nausea and vomiting The efficacy of a single dose of Ondansetron in the prevention of post-operative nausea and vomiting was investigated in a randomised, double-blind, placebo-controlled study in 670children aged 1 to 24 10

11 months (post-conceptual age 44 weeks, weight 3Kg).Included subjects were scheduled to undergo elective surgery under general anaesthesia and had an ASA status III. A single dose of ondansetron 0.1mg/Kg was administered within five minutes following induction of anaesthesia. The proportion of subjects who experienced at least one emetic episode during the 24-hour assessment period (ITT) was greater for patients on placebo than those receiving ondansetron (28% vs. 11 % p<0.0001). 5.2 Pharmacokinetic properties Following oral administration of ondansetron, absorption is rapid with maximum peak plasma concentrations of about 30 ng/ml being attained and achieved in approximately 1.5 hours after an 8 mg dose. The syrup and tablet formulations are bioequivalent and have an absolute oral bioavailability of 60%. The disposition of ondansetron following oral, intravenous and intramuscular dosing is similar with a terminal elimination half-life of approximately 3 hours and a steady-state volume of distribution of about 140L. Ondansetron is not highly protein bound (70-76%) and is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no effect on the pharmacokinetics of ondansetron. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing. Studies in healthy elderly volunteers have shown a slight but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5h) of ondansetron. 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 1 month 17 years) In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight normalised clearance was approximately 30% lower 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 months was reported to average 6.7 hours compared to 2.9 hours for the patients in the 5 to 24 months and 3 to 12 year age range. The differences in the pharmacokinetic parameters in the 1 to 4 months patient population can de explained in part by a higher percentage of total body water in neonates and infants and a higher volume of distribution for water soluble drugs like ondansetron. In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and the volume of distribution of ondansetron were reduced in comparison to values with adult patients. Both parameters increased in a linear fashion with weight and by 12 years of age, the values were approaching those of young adults. When clearance and volume of distribution values were normalised by body weight, the values of these parameters were similar between the different age group populations. Use of weight base dosing compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients. Population pharmacokinetic analysis was performed on 74 paediatric cancer patients aged 6 to 48 months and 41 surgery patients aged 1 to 24 months following intravenous administration of ondansetron. Based on the population pharmacokinetic parameters for patients aged 1 month to 48 months, administration of the adult based dose (0.15mg/Kg intravenously every 4 hours for 3 doses) would result in a systemic exposure (AUC) comparable to that observed in paediatric surgery patients (aged 5 to 24 months), paediatric cancer patients (aged 3 to 12 years), at a similar doses, as shown in Table C. This exposure (AUC) is consistent with the exposure-efficacy relationship described previously in paediatric cancer subjects, which showed a 50% to 90% response rate with AUC values ranging from 170 to 250 ng.h/ml. Table C. Pharmacokinetics in Paediatric Patients 1 Month to 18 Years of Age Study S3A Patient population (Intravenous Dose) Age N AUC (ng.h/ml) CL (L/h/kg) Vd ss (L/kg) Geometric Mean Mean Surgery (0.1 or 0.2 mg/kg) 1 to 4 months S3A Surgery 5 to 24 months T ½ (h) 11

12 S3A40320 & S3A40319 Pop PK 2,3 S3KG02 4 S3A.150 (0.1 or 0.2 mg/kg) Cancer/Surgery (0.15 mg/kg q 4h / 0.1 pr 0.2 mg/kg) Surgery (2 mg or 4 mg) Cancer (0.15 mg/kg q 4h ) 1 to 48 months to 12 years to 18 years Ondansetron single intravenous dose: 0.1 or 0.2 mg/kg 2 Population PK Patients: 64% cancer patients and 36% surgery patients. 3 Population estimates shown; AUC based on dose of 0.15 mg/kg. 4 Ondansetron single intravenous dose: 2 mg (3 to 7 years) or 4 mg (8 to 12 years) In patients with renal impairment (creatinine clearance>15 ml/min), systemic clearance and volume of distribution are reduced, resulting in a slight, but clinically insignificant increase in elimination halflife (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged. In patients with severe hepatic impairment, systemic clearance is markedly reduced with prolonged elimination half-lives (15-32h) and an oral bioavailability approaching 100% because of reduced presystemic metabolism. 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. 5.3 Preclinical safety data Preclinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and carcinogenic potential. Ondansetron and its metabolites accumulate in the milk of rats, milk:plasma-ratio of 5.2:1. A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Aspartame (E951) Crospovidone type B Magnesium stearate Microcrystalline cellulose Pharmaburst TM C1, (mannitol E421, sorbitol E420, crospovidone type A and colloidal silicon dioxide) Strawberrry flavouring, (Dextrose, maltodextrin, gum araibc E414, 2.3% and sulphur dioxide E220). Sodium stearyl fumarate 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store in the original package in order to protect from light. Store below 30 o C. 12

13 6.5 Nature and contents of container Ondansetron Orodispersible tablets are packed in OPA/Alu/PVC-Alu unit-dose blister pack as 6x1, 10x1, 14x1, 20x1, 30x1, 50x1, 60x1, 100x1 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7 MARKETING AUTHORISATION HOLDER Bluefish Pharmaceuticals AB, Torsgatan 11, Stockholm, Sweden. 8 MARKETING AUTHORISATION NUMBER(S) PL31774/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 02/12/ DATE OF REVISION OF THE TEXT 02/12/

14 SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT Ondansetron 8 mg Orodispersible Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each orodispersible tablet contains: 8 mg ondansetron. Excipient: Aspartame (E951) 1.76 mg per 8 mg tablet. Sorbitol (E420) up to mg per 8 mg tablet. Glucose and sulphur dioxide (E220). For a full list of excipients, see section PHARMACEUTICAL FORM Orodispersible tablet. White, flat, round, bevel-edged tablet. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications Adults: The management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy, and for the prevention of post-operative nausea and vomiting in adults. Paediatric Population: Management of chemotherapy-induced nausea and vomiting in children aged 6 months. Prevention and treatment of postoperative nausea and vomiting in children aged 1 month. 4.2 Posology and method of administration For oral use. Place the orodispersible tablet on top of the tongue, where it will disperse within seconds. For the different dosage regimens appropriate strengths and formulations are available. Chemotherapy and radiotherapy induced nausea and vomiting. Adults: The emetogenic potential of cancer treatment varies according to the doses and combinations of chemotherapy and radiotherapy regimens used. The route of administration and dose of Ondansetron should be flexible and selected as shown below. Emetogenic chemotherapy and radiotherapy: For patients receiving emetogenic chemotherapy or radiotherapy ondansetron can be given either by oral or intravenous administration. For most patients receiving emetogenic chemotherapy or radiotherapy, ondansetron should initially be administered intravenously immediately before treatment, followed by 8 mg orally twelve hourly. For oral administration: 8 mg 1-2 hours before treatment, followed by 8 mg 12 hours later. To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Ondansetron orodispersible tablets should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8mg twice daily. Highly emetogenic chemotherapy : For patients receiving highly emetogenic chemotherapy, e.g. high-dose cisplatin, ondansetron can be given by intravenous administration. To protect against delayed or prolonged emesis after the first 24 hours, oral treatment with Ondansetron should be continued for up to 5 days after a course of treatment. The recommended dose for oral administration is 8mg twice daily. Children (aged 2 years and over) and adolescents (< 18 years): 14

15 Experience in paediatric patients is limited. In children older than two years, ondansetron may be administered as a single intravenous dose of 5 mg/m 2 over 15 minutes immediately before chemotherapy, followed by 4 mg orally twelve hours later. Oral treatment with a dose according to the body area should be continued for up to 5 days after a course of treatment. Children with a total body area between 0.6 and 1.2 m 2 should receive a dosage schedule of 4 mg 2 times a day, while children with a body area above 1.2 m 2 should receive 8 mg 2 times a day. Paediatric Population: Chemotherapy-induced nausea and vomiting in children aged 6 months and adolescents: The dose of chemotherapy-induced nausea and vomiting can be calculated based on body surface area (BSA) or weight see below. Weight-based dosing results in higher total daily doses compared to BSA-based dosing see sections 4.4 and 5.1 There are no data from controlled clinical trials on the use of Ondansetron in the prevention of chemotherapy-induced delayed or prolonged nausea and vomiting. There are no data from controlled clinical trials on the use of Ondansetron for radiotherapy-induced nausea and vomiting in children. Dosing by BSA: Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 5mg/m2. The intravenous dose must not exceed 8mg. Oral dosing can commence twelve hours later and may be continued for up to 5 days. See Table 1 below. The total daily dose must not exceed adult dose of 32mg Table 1: BSA-based dosing for Chemotherapy - Children aged 6 months and adolescents BSA Day 1 (a,b) Days 2-6 (b) < 0.6 m 2 5 mg/m 2 i.v. plus 2 mg syrup after 12 hrs 0.6 m 2 5 mg/m 2 i.v. plus 4 mg syrup or tablet after 12 hrs a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg 2 mg syrup every 12 hrs 4 mg syrup or tablet every 12 hrs Dosing by bodyweight: Weight-based dosing results in higher total daily doses compared to BSA-based dosing see sections 4.4 and 5.1. Ondansetron should be administered immediately before chemotherapy as a single intravenous dose of 0.15mg/Kg. The intravenous dose must not exceed 8mg. Two further intravenous doses may be given in 4-hourly intervals. The total daily dose must not exceed adult dose of 32mg. Oral dosing can commence twelve hours later and may be continued for up to 5 days. See Table 2 below. Table 2: Weight-based dosing for Chemotherapy - Children aged 6 months and adolescents Weight Day 1 (a,b) Days 2-6 (b) 10 kg Up to 3 doses of 0.15 mg/kg every 4 hrs 2 mg syrup every 12 hrs > 10 kg Up to 3 doses of 0.15 mg/kg every 4 hrs 4 mg syrup or tablet every 12 hrs a The intravenous dose must not exceed 8mg. b The total daily dose must not exceed adult dose of 32 mg. Elderly: Ondansetron is well tolerated by patients over 65 years and no alteration of dosage, dosing frequency or route of administration are required. Please refer also to Special populations. 15

16 Post-operative nausea and vomiting Adults: Prevention of post-operative nausea and vomiting For the prevention of post-operative nausea and vomiting ondansetron can be administered orally or by intravenous injection. For oral administration: 16 mg one hour prior to anesthesia. Alternatively, 8 mg one hour prior to anesthesia followed by two further doses of 8 mg at eight hourly intervals. Treatment of established post-operative nausea and vomiting For the treatment of established post-operative nausea and vomiting intravenous administration is recommended. Children (aged 2 years and over) and adolescents (< 18 years): For the prevention and treatment of post-operative nausea and vomiting slow intravenous injection is recommended Paediatric population: Post-operative nausea and vomiting in children aged 1 month and adolescents Oral Formulation: No studies have been conducted on the use of orally administered ondansetron in the prevention or treatment of post operative nausea and vomiting; slow i.v. injection is recommended for this purpose. Injection: For prevention of PONV in paediatric patients having surgery performed under general anaesthesia, a single dose of ondansetron may be administered by slow intravenous injection (not less than 30 secounds) at a dose 0.1mg/Kg up to a maximum of 4mg either prior to, at or after induction of anaesthesia. There are no data on the use of Ondansetron for the treatment of postoperative vomiting 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. Please refer also to Special populations. Special populations Patients with renal impairment: No alteration of daily dosage or frequency of dosing, or route of administration are 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 8mg 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 medical product exposure levels no different from those of the general population. No alteration of daily dosage or frequency of dosing is required. 4.3 Contraindications Hypersensitivity to ondansetron or to other selective 5-HT3-receptor antagonists (e.g.granisetron, dolasetron) or to any of the excipients. 4.4 Special warnings and precautions for use Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5HT 3 receptor antagonists. 16

17 As ondansetron is known to increase large bowel transit time, patients with signs of subacute intestinal obstruction should be monitored following administration. Very rarely and predominantly with intravenous Ondansetron, transient ECG changes including QT interval prolongation have been reported. Therefore caution should be exercised in patients with cardiac rhythm or conduction disturbances, in patients treated with anti-arrhythmic agents or betaadrenergic blocking agents and in patients with significant electrolyte disturbances. Paediatric Population: Respiratory events should be treated symptomatically and clinicians should pay particular attention to them as precursors of hypersensitive reactions. Paediatric population receiving ondansetron with hepatotoxic chemotherapeutical agents should be monitored closely for impaired hepatic function. Chemotherapy-induced nausea and vomiting: When calculating the dose on a mg/kg basis and administering three doses at 4 hourly intervals, the total daily dose will be higher than if one single dose of 5mg/m2 followed by an oral dose is given. The comparative efficacy of these two different dosing regimens has not been investigated in clinical trials. Cross trial comparing indicate similar efficacy for both regimens see section 5.1 Warnings on excipients: Aspartame, which contains a source of phenylalanine. May be harmful for people with phenylketonuria because aspartame is metabolized to fenylalanine. Patients with rare hereditary problems of fructose intolerance or glucose-galactose malabsorption should not take this medicine because it contains sorbitol, mannitol and dextrose. Strawberry flavour contains sulphur dioxide (E220) which may rarely cause severe hypersensitivity reactions and bronchospasm. 4.5 Interaction with other medicinal products and other forms of interaction 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 pharamcokinetic interactions when ondansetron is administered with alcohol, temazepam, furosemide, alfentanil, propofol and thiopental. Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes: CYP3A4, CYP2D6 and CYP1A2. 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. 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 4-fold and ondansetron blood concentrations were significantly decreased. Dose adjustment of ondansetron is probably necessary. Tramadol: Data from small studies indicate that ondansetron may reduce the analgesic effect of tramadol. Use of Ondansetron with QT prolonging drugs may result in additional QT prolongation. Concomitant use of Ondansetron with cardiotoxic drugs (e.g. anthracyclines) may increase the risk of arrhythmias (See section 4.4) 4.6 Pregnancy and lactation 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 the foetus, the course of gestation and peri- and post-natal development. However, as animal studies are not always predictive of human response the use of ondansetron in pregnancy is not recommended. Tests have shown that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers receiving Ondansetron orodispersible tablets should not breast-feed their babies. 17

18 4.7 Effects on ability to drive and use machines In psychomotor testing Ondansetron orodispersible tablets do not impair performance nor cause sedation. 4.8 Undesirable effects Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common ( 1/10), common ( 1/100 and <1/10), uncommon ( 1/1000 and <1/100), rare ( 1/10,000 and <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 according to indication and formulation. Cardiac disorders Uncommon: Arrhythmias, chest pain with or without ST segment depression, bradycardia. Very rarely transient ECG changes including QT-interval prolongation have been reported. 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. Respiratory, thoracic and mediastinal disorders Uncommon: Hiccups. Gastrointestinal disorders Common: Constipation. Vascular disorders Common: Sensation of warmth or flushing. Uncommon: Hypotension. Immune system disorders Rare: Immediate hypersensitivity reactions sometimes severe, including anaphylaxis. Hepatobiliary disorders Uncommon: Asymptomatic increases in liver function tests. These events were observed commonly in patients receiving chemotherapy with cisplatin. Rare: Dizziness during i.v. administration, which in most cases is prevented or resolved by lengthening the infusion period. Eye disorders Rare: Transient visual disturbances (eg. blurred vision) during i.v. administration. Very rare: Transient blindness predominantly during intravenous 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. 4.9 Overdose 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. 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. 18

19 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Serotonin (5HT 3 ) antagonists ATC code: A04AA01 Ondansetron is a potent, highly selective 5HT 3 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 5HT 3 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 5HT 3 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. Paediatric Population: Chemotherapy-induced nausea and vomiting The efficacy of Ondansetron in the control of emesis and nausea induced by cancer chemotherapy was assessed in a doubleblind randomised trial in 415 patients aged 1 to 18 years. On the days of chemotherapy, patients received either ondansetron 5mg/m2 i.v. + after 8-12hrs ondansetron 4 mg p.o. or ondansetron 0.45 mg/kg i.v. + after 8-12hrs placebo p.o. Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. Complete control of emesis on worst day of chemotherapy was 49 % (5mg/m2 i.v. + ondansetron 4mg p.o.) and 41 % (0.45 mg/kg i.v. + placebo p.o.). Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days. A double-blind randomise placebo-controlled trial in 438 aged 1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy in 73% of patients when ondansetron was administered intravenously at a dose of 5mg/m2 i.v. together with 2-4 mg dexamethasone p.o. and in 71% of the patients when ondansetron was administered as a syrup at a dose of 8mg mg dexamethasone p.o. on the days of chemotherapy. Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for 2 days. The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in an open-label, noncomparative, singlearm study. All children receive three 0.15mg/Kg doses of intravenous ondansetron, administered at 30 minutes before the start of chemotherapy and then at four and eight hours after the first dose. Complete control of emesis was achieved in 56% of patients. Another open-label, non-operative, single-arm study investigated the efficacy of one intravenous dose of 0.15mg/Kg ondansetron followed by two ondansetron doses of 4mg for children aged < 12 yrs and 8 mg for children aged 12yrs (total no. of children n = 28). Complete control of emesis was achieved in 42% of patients. Prevention of post-operative nausea and vomiting The efficacy of a single dose of Ondansetron in the prevention of post-operative nausea and vomiting was investigated in a randomised, double-blind, placebo-controlled study in 670children aged 1 to 24 months (post-conceptual age 44 weeks, weight 3Kg).Included subjects were scheduled to undergo elective surgery under general anaesthesia and had an ASA status III. A single dose of ondansetron 0.1mg/Kg was administered within five minutes following induction of anaesthesia. The proportion of subjects who experienced at least one emetic episode during the 24-hour assessment period (ITT) was greater for patients on placebo than those receiving ondansetron (28% vs. 11 % p<0.0001). 5.2 Pharmacokinetic properties Following oral administration of ondansetron, absorption is rapid with maximum peak plasma concentrations of about 30 ng/ml being attained and achieved in approximately 1.5 hours after an 8 mg dose. The syrup and tablet formulations are bioequivalent and have an absolute oral bioavailability of 60%. The disposition of ondansetron following oral, intravenous and intramuscular dosing is similar with a terminal elimination half-life of approximately 3 hours and a steady-state volume of distribution of about 140L. Ondansetron is not highly protein bound (70-76%) and is cleared from the systemic circulation predominantly by hepatic metabolism through multiple enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the urine. The absence of the enzyme CYP2D6 (the 19

20 debrisoquine polymorphism) has no effect on the pharmacokinetics of ondansetron. The pharmacokinetic properties of ondansetron are unchanged on repeat dosing. Studies in healthy elderly volunteers have shown a slight but clinically insignificant, age-related increases in both oral bioavailability (65%) and half-life (5h) of ondansetron. 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 1 month 17 years) In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight normalised clearance was approximately 30% lower 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 months was reported to average 6.7 hours compared to 2.9 hours for the patients in the 5 to 24 months and 3 to 12 year age range. The differences in the pharmacokinetic parameters in the 1 to 4 months patient population can de explained in part by a higher percentage of total body water in neonates and infants and a higher volume of distribution for water soluble drugs like ondansetron. In paediatric patients aged 3 to 12 years undergoing elective surgery with general anaesthesia, the absolute values for both the clearance and the volume of distribution of ondansetron were reduced in comparison to values with adult patients. Both parameters increased in a linear fashion with weight and by 12 years of age, the values were approaching those of young adults. When clearance and volume of distribution values were normalised by body weight, the values of these parameters were similar between the different age group populations. Use of weight base dosing compensates for age-related changes and is effective in normalising systemic exposure in paediatric patients. Population pharmacokinetic analysis was performed on 74 paediatric cancer patients aged 6 to 48 months and 41 surgery patients aged 1 to 24 months following intravenous administration of ondansetron. Based on the population pharmacokinetic parameters for patients aged 1 month to 48 months, administration of the adult based dose (0.15mg/Kg intravenously every 4 hours for 3 doses) would result in a systemic exposure (AUC) comparable to that observed in paediatric surgery patients (aged 5 to 24 months), paediatric cancer patients (aged 3 to 12 years), at a similar doses, as shown in Table C. This exposure (AUC) is consistent with the exposure-efficacy relationship described previously in paediatric cancer subjects, which showed a 50% to 90% response rate with AUC values ranging from 170 to 250 ng.h/ml. Table C. Pharmacokinetics in Paediatric Patients 1 Month to 18 Years of Age Study S3A S3A S3A40320 & S3A40319 Pop PK 2,3 Patient population (Intravenous Dose) Age N AUC (ng.h/ml) CL (L/h/kg) Vd ss (L/kg) Geometric Mean Mean Surgery (0.1 or 0.2 mg/kg) 1 to 4 months Surgery (0.1 or 0.2 mg/kg) Cancer/Surgery (0.15 mg/kg q 4h / 0.1 pr 0.2 mg/kg) T ½ (h) 5 to 24 months to 48 months S3KG02 4 S3A.150 Surgery (2 mg or 4 mg) Cancer (0.15 mg/kg q 4h ) 3 to 12 years to 18 years Ondansetron single intravenous dose: 0.1 or 0.2 mg/kg 2 Population PK Patients: 64% cancer patients and 36% surgery patients. 3 Population estimates shown; AUC based on dose of 0.15 mg/kg. 4 Ondansetron single intravenous dose: 2 mg (3 to 7 years) or 4 mg (8 to 12 years) In patients with renal impairment (creatinine clearance>15 ml/min), systemic clearance and volume of distribution are reduced, resulting in a slight, but clinically insignificant increase in elimination half- 20

21 life (5.4h). A study in patients with severe renal impairment who required regular haemodialysis (studied between dialyses) showed ondansetron's pharmacokinetics to be essentially unchanged. In patients with severe hepatic impairment, systemic clearance is markedly reduced with prolonged elimination half-lives (15-32h) and an oral bioavailability approaching 100% because of reduced presystemic metabolism. 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. 5.3 Preclinical safety data Preclinical data revealed no special hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and carcinogenic potential. Ondansetron and its metabolites accumulate in the milk of rats, milk:plasma-ratio of 5.2:1. A study in cloned human cardiac ion channels has shown ondansetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Aspartame (E951) Crospovidone type B Magnesium stearate Microcrystalline cellulose Pharmaburst TM C1, (mannitol E421, sorbitol E420, crospovidone type A and colloidal silicon dioxide) Strawberrry flavouring, (Dextrose, maltodextrin, gum araibc E414, 2.3% and sulphur dioxide E220) Sodium stearyl fumarate 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store in the original package in order to protect from light. Store below 30 o C. 6.5 Nature and contents of container Ondansetron Orodispersible tablets are packed in OPA/Alu/PVC-Alu unit-dose blister pack as 6x1, 10x1, 14x1, 20x1, 30x1, 50x1, 60x1, 100x1 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7 MARKETING AUTHORISATION HOLDER Bluefish Pharmaceuticals AB, Torsgatan 11, Stockholm, Sweden. 8 MARKETING AUTHORISATION NUMBER(S) PL31774/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 02/12/ DATE OF REVISION OF THE TEXT 02/12/

22 Product Information Leaflet 22

23 23

24 Module 4 Labelling Ondansetron 4mg Orodispersible Tablets Carton Blister 24

25 Ondansetron 8mg Orodispersible Tablets Carton Blister 25

26 Module 5 Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Ondansetron 4mg and 8mg Orodispersible Tablets, used in the management of nausea or vomiting as a result of cancer chemotherapy/radiotherapy, and for the prevention of post-operative nausea and vomiting in adults and children, is approvable. These applications are submitted under Article 10(1) of Directive 2001/83 (as amended) for Ondansetron 4mg and 8mg Orodispersible Tablets. They have been shown to be generic medicinal products of the originator product Zofran Smeltetabbletter 4mg and Zofran Smeltetabbletter 8mg first authorised in 1 st May 1990 in Denmark; hence the 10 year rule is fulfilled. The product contains the active ingredient ondansetron, a potent, highly selective serotonin (5HT 3 ) receptor antagonist. The 5HT 3 antagonists are a class of medications which act as receptor antagonists at the 5-hydroxytryptamine-3 receptor (5HT 3 receptor), a subtype of serotonin receptor found in terminals endings of the vagus nerve and in certain areas of the brain. Most 5HT 3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. Chemotherapeutic agents and radiotherapy may cause release of 5HT in the small intestine initiating a vomiting reflex by activating vagal afferents via 5HT 3 receptors. Ondansetron blocks the initiation of this reflex. 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. The applications are in accordance with Article 10(1) of Directive 2001/83/EC as amended. The submitted documentation in relation to the proposed product is of sufficient quality and is consistent with the current EU regulatory requirements. Satisfactory quality, pre-clinical and clinical overviews have been submitted. A formal Environment Assessment was not submitted. This is acceptable as no increase in environmental risk is to be expected compared to that of the reference product. No Risk Management Plan other than documentation of pharmacovigilance system has been provided since the application concerns a medicinal product containing a known active substance for which no safety concern requiring additional risk minimisation activities has been identified. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. Since a literature review has been presented for the Non-clinical Overview, it is not known whether the studies cited were conducted in accordance with the GLP regulations. However, it is assumed that the studies conducted by the innovator would have been in compliance with the standards prevailing at the time. 26

27 No new clinical study was submitted. The PIL is in compliance with current guidelines and user testing results have been submitted. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. II. ABOUT THE PRODUCT Name of the product in the Reference Member State Ondansetron 4mg Orodispersible Tablets Ondansetron 8mg Orodispersible Tablets Name(s) of the active substance(s) (INN) Ondansetron base Pharmacotherapeutic classification (ATC code) Serotonin (5HT 3 ) antagonists (A04AA) Pharmaceutical form and strength(s) Orodispersible tablets 4mg and 8mg Reference numbers for the Mutual Recognition Procedure Reference Member State United Kingdom Member States concerned Germany, Denmark, Finland, The Netherlands, Norway, Poland, Spain and Sweden Marketing Authorisation Number(s) PL 31774/ Name and address of the Bluefish Pharmaceuticals AB authorisation holder Birger Jarlsgatan 37, Stockholm Sweden. 27

28 III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS DRUG SUBSTANCE Ondansetron General Information Nomenclature Name: Ondansetron hydrochloride dihydrate (INN: Ondansetron) Chemical name: (RS)-1,2,3,9-Tetrahydro-9-Methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4Hcarbazol-4-one Structure Molecular formula: C 18 H 19 N 3 O Molecular weight: General Properties There is no Ph Eur monograph for ondansetron base. The specification proposed by the finished product manufacturer is based on the active substance manufacturer s specification, which in turn is based on the Ph. Eur monograph for ondansetron hydrochloride dihydrate. The drug substance is a white or almost white powder soluble in chloroform and acetic acid. Manufacture An Active Substance master File (ASMF) has been provided covering the manufacture and control of the active substance ondansertron base. Synthesis of the drug substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant Certificates of Analysis. All potential known impurities have been identified and characterised. Appropriate proof of structure data has been supplied for the active substance. An appropriate specification is provided for the active substance ondansetron base, with suitable test methods and limits. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Batch analyses are provided and comply with the proposed specification. Suitable certificates of analysis have been provided for all reference standards used. Satisfactory certificates of analysis have been provided for all aspects of the containerclosure system working standards used by the active substance manufacturer and finished product manufacturer during validation studies. A declaration has been provided that the primary packaging complies with current regulations concerning contact with foodstuff. 28

29 Appropriate stability data have been generated showing the active substance to be a physically and chemically stable drug and supporting an appropriate re-test period. DRUG PRODUCT Other ingredients Other ingredients consist of pharmaceutical excipients, namely aspartame, crospovidone type B, magnesium stearate, microcrystalline cellulose, pharmaburst TM C1 (containing mannitol, sorbitol, crospovidone type A and colloidal silicon dioxide), strawberry flavouring (containing dextrose, maltodextrin, gum Arabic and sulphur dioxide) and sodium stearyl fumarate. Microcrystalline cellulose, Crospovidone (Type B), aspartame, sodium stearyl fumarate and magnesium stearate are controlled to the specifications of the Ph.Eur. In-house (internal) specifications have been provided for the Pharmaburst C1 and strawberry flavouring. Satisfactory certificates of analysis have been provided for all excipients. None of the excipients used contain material of animal or human origin. Pharmaceutical Development The aim of formulation development was to develop an orodispersible tablet that is bioequivalent to the reference product Zofran Zydis 8mg (Glaxo Wellcome). A step-down, dose-proportional formulation of the 4mg tablets was derived based on the optimisation studies carried out on the 8mg tablets. Dissolution and Impurity profiles As part of the development and to justify biowaiver for the 4mg tablets, comparative dissolution profiles have been presented between the proposed 4mg and 8mg tablets. The release behaviour of the biobatch (8mg) was compared with three 4mg batches and was found to be similar. Impurity profiles of the drug products were found to be similar to those for the reference products. Manufacture A description and flow-chart of the manufacturing method has been provided. Manufacturing process In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out on three pilot-scale batches of each strength of tablet. The results are satisfactory. Finished product specification The finished product specification is satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used. Container Closure System The product is packaged in blisters composed of polyamide/aluminium/polyvinylchloride (opa/alu/pvc-alu). Specifications and a Certificate of Analysis for the package types used have been provided. All primary product packaging complies with EU legislation regarding contact with food. The product is packaged in unit dose blisters of 6x1, 10x1, 14x1, 20x1, 30x1, 50x1, 60x1, 100x1 tablets. Not all pack sizes may be marketed. The Marketing 29

30 Authorisation Holder (MAH) has committed to submitting mock-ups for all packaging for assessment before those pack sizes are commercially marketed. Stability Stability testing was performed according to the relevant ICH guidelines. Based on the results of the stability studies, a shelf life of 3 years with the following storage conditions Store in the original package in order to protect from light and Store below 30 o C has been set; this acceptable. Conclusion It is recommended that Marketing Authorisations are granted for these applications. The requirements for a generic product of the proposed and originator products have been met with respect to qualitative and quantitative content of the active substance. In addition, similar physico-chemical properties have been demonstrated for the proposed and originator products. III.2 PRE-CLINICAL ASPECTS No specific non-clinical studies have been performed, which is acceptable for this application for a generic product. Pharmacodynamic, pharmacokinetic and toxicological properties of ondansetron are well known and further non-clinical studies are not required. The non-clinical overview has been written by a suitably qualified person and cites 16 references; it contains an adequate overview of the data. III.3 CLINICAL ASPECTS INTRODUCTION Ondansetron is an antiemetic indicated for the management of cytotoxic chemotherapy and radiotherapy induced nausea and vomiting, and for the prevention and treatment of postoperative nausea and vomiting (PONV). It is a potent and highly selective 5HT 3 receptorantagonist which competitively blocks vagal 5-HT 3 receptors although the precise mechanism of action is unclear. Ondansetron is approved as an i.v. or oral antiemetic for chemotherapy and radiotherapyinduced nausea and vomiting. The recommended dosage of the i.v. formulation is either a single 32mg dose infused over 15 minutes beginning 30 minutes before the start of chemotherapy or three 0.15 mg/kg doses, the first infused over 15 minutes beginning 30 minutes before the start of chemotherapy and the subsequent doses given 4 and 8 hours after the first. The dosage for tablets is one 8mg tablet three times daily on the day of chemotherapy, the first given 30 minutes before the start of chemotherapy with subsequent doses given 4 and 8 hours after the first, followed by one 8mg tablet every 8 hours for 1 to 2 days after completion of chemotherapy. Ondansetron is readily and rapidly absorbed after all types of enteral administration, probably due to its lipophilic characteristics. Algorithme Pharma (2006) conducted a single dose crossover comparative bioavailability study of ondansetron 8mg orally disintegrating tablets in healthy male and female volunteers in the fasting state. The pharmacokinetic results show that bioavailability of the two formulations of ondansetron was essentially equivalent under fasting conditions. The clinical overview on the clinical pharmacology, efficacy and safety is adequate. 30

31 Assessor's comment: The clinical expert has provided an overview of the well-established clinical pharmacology, efficacy and safety of ondansetron based on published literature. Clinical study reports To support the application, the applicant has submitted one bioequivalence study performed under fasting conditions. The study report is summarised in this assessment report. The reference product used for the bioequivalence study is Zofran Zydis 8mg, GlaxoSmithKline, Spain. The reference medicinal product which has been authorised for not less than 10 years is Zofran Smeltetabletter 4mg and 8mg licensed to GlaxoSmithKline, Denmark on 1 May The reference medicinal products authorised in the UK are: Zofran Melt 4mg licensed to Glaxo Wellcome UK Ltd. (PL 10949/0263), Zofran Melt 8mg licensed to Glaxo Wellcome UK Ltd. (PL 10949/0264). Assessor's comment: A single-dose bioequivalence study is adequate for these applications involving an immediate-release preparation. Biowaiver The applicant put forward the following justification for a biowaiver for the lower strength 4mg tablet: Ondansetron 4mg and 8mg tablets are manufactured by the same manufacturer, using the same manufacturing process. The pharmacokinetics are linear across the therapeutic dose range of 4mg to 16mg (above this level linearity may be lost due to saturation of the first-pass metabolism). Under these circumstances, the 8mg dose will have greater sensitivity for identifying any differences between test and reference formulations and was therefore chosen for the bioequivalence study. The qualitative composition of Ondansetron 4mg tablets is the same as that of Ondansetron 8mg tablets. Ondansetron 4mg tablets are dose proportional with Ondansetron 8mg tablets. Thus, the ratio of amount of active substance and the excipients is the same for both the strengths. The dissolution profiles of the 4mg and 8mg tablets were found to be similar under identical conditions. Furthermore, the applicant has justified conducting only a fasting study, by citing published study data. The results of the study gave no indication that the presence or absence of food or antacids alters the absorption of ondansetron to a clinically significant extent. There are no restrictions regarding administration in relation to food intake in section 4.2 of the SPC for either the proposed product or innovator product. 31

32 Assessor's comment: The biowaiver justifications are valid. Pharmacokinetic studies Methods Study design The applicant has submitted one bioequivalence study, performed under fasting conditions. This was a single centre, single dose, randomized, laboratory-blinded, crossover, two periods, two sequence bioequivalence study of ondansetron 8mg orally disintegrating tablets (Test) and Zofran Zydis 8mg orally disintegrating tablets (Reference) GlaxoSmithKline, S.A., Spain. Each volunteer received a single oral dose of 8 mg ondansetron (1 orally disintegrating tablet in each case) in a random way in two different periods and under fasting conditions (of a minimum 10 hours). The two periods were separated by a wash-out phase of 7 days. Blood sampling points were pre-dose and up-to 24 hours post dose. The applicant states that the study was conducted in accordance with good clinical practice. Assessor's comment: The bioequivalence study design is acceptable, with adequate wash-out period at greater than five times the t 1/2. No issues regarding GCP have been identified. Test and reference products The test product Ondansetron 8mg orodispersible tablet (ODT) has been compared to the Reference product Zofran Zydis 8mg ODT (GlaxoSmithKline S.A., Spain). Assessor's comment: The dissolution values for the test and reference products were comparable for the 8mg tablets, (please see Pharmaceutical assessment for further comments). Population(s) studied Healthy adult male and female subjects, aged between 18 to 55 years were enrolled into the study. There were no dropouts. Assessor's comment: The population studied is appropriate. Analytical methods Analysis of Ondansetron was analysed in human plasma using validated High Performance liquid Chromatography (HPLC) and high performance thin-layer chromatography (HPTLC). Assessor s comment: The analytical methods used are acceptable and appropriate, No issues regarding GLP compliance are identified. 32

33 Pharmacokinetic Variables Main absorption and disposition parameters were measured using a non-compartmental approach: C max T max AUC T AUC AUC T/ K el T 1/2el Maximum plasma concentration Time of Maximum concentration Area under the concentration-time curve using the trapezoidal method Area under the concentration-time curve extrapolated to infinity Relative percentage of AUC T with respect to the AUC Elimination rate constant Terminal half-life Assessor's comment: The pharmacokinetic variables are adequate. Statistical methods Statistical methods used for pharmacokinetics were; Parametric ANOVA on C max, T max, AUC T, and AUC, AUC T/, K el and T 1/2el ; Relative Geometric mean and 90% confidence interval of the relative geometric mean for C max, AUC T and AUC based on ln-transformed data were calculated; T max was rank transformed for all statistical analysis. The bioequivalence criteria were: 90% confidence interval for the exponential of the difference between the test and the reference product for the ln-transformed parameters C max, AUC T and AUC should be between 80 and 125%. Assessor s comment: The appropriate variables were measured and statistical methodology is accepted. Results The results are summarised in the tables and figures below. Summary of Pharmacokinetic Parameters for Ondansetron 8mg ODT Parameter Test Reference F P Mean CV* Mean CV* (Treatment) C max (ng/ml) >0.05 Ln(C max ) (ng/ml) >0.05 T max (Hours) >0.05 AUC T (ng.h/ml) >0.05 Ln(AUC T ) (ng.h/ml) >0.05 AUC (ng.h/ml) >0.05 Ln(AUC ) >0.05 (ng.h/ml) AUC T/ (%) >0.05 Kel (Hours -1 ) >0.05 T 1/2el (Hours) >0.05 * Coefficient of variance 33

34 Comparison of results with Standards for Bioequivalance Parameter Geometric LS means* Ratio (%) 90% Confidence Limits (%) Test Reference Lower Upper C max AUC T AUC *units are ng/ml for C max amd ng.h/ml for AUC T and AUC Linear Profile of the Mean, Logarithmic Profile of the Mean, 34

35 Table Listing of Adverse Events by volunteer Assessor's comment: Bioequivalence has been shown. Pharmacokinetic conclusion Based on the submitted bioequivalence study Ondansetron 8mg orodispersible tablet is considered bioequivalent with Zofran Zydis 8mg. The results of study with Ondansetron 8mg ODT formulation can be extrapolated to Ondansetron 4mg ODT, according to conditions in Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4. Pharmacodynamic studies No new data required. Additional data Nil. Post marketing experience Ondansetron has a well-recognised efficacy and an acceptable level of safety in the indications approved for Ondansetron 4mg and 8mg orodispersible Tablets, and corresponding products have been widely used in many countries. 35