SUMMARY OF PRODUCT CHARACTERISTICS. Each of Votron 5 ml vial contains 250 microgram palonosetrone (as hydrochloride).

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1 1.NAME OF MEDICINAL PRODUCT: SUMMARY OF PRODUCT CHARACTERISTICS Votron 250 µg/5 ml vials for IV injection of solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Active ingredient: 1 ml solution contains 50 microgram palonosetrone (as hydrochloride). Each of Votron 5 ml vial contains 250 microgram palonosetrone (as hydrochloride). Excipients: mannitole, trisodium citrate, citric acide monohydrate, water for injections, solution of sodium hydroxide and solution of hydrochloric acide. For excipients refer to section PHARMACEUTICAL FORM Injectable solution. Clear, colorless solution. 4. CLINICAL PROPERTIES 4.1.Therapeutical indications VOTRON is indicated for; Prevention of nausea and vomiting related to advanced emetogenic cancer chemotherapy, Prevention of nausea and vomiting related to moderate emetogenic cancer chemotherapy Posology and method of administration Posology: VOTRON must administered by intravenous bolus before 30 minutes from starting of chemotherapy. Efficacy of VOTRON for prevention of nausea and vomiting caused by progressive emetogenic chemotherapy can increase with addition of corticosteroid applied before chemotherapy. Administration frequency and timelines: Repeated dosage of VOTRON within 7 days is not recommended. Administration route: For intravenous usage only. VOTRON must inject within 30 seconds.

2 Additional information related to special populations: Renal/liver insufficiencies: In patients with renal insufficiency dosage arrangement is not necessary. For patients on dialysis with final stage renal disease there is no data. In patients with liver insufficiency dose arrangement is not necessary. Pediatric population: Until obtaining more information, it must not use in children below 18 years of age. Geriatric population: In geriatric patients dose arrangement is not necessary. 4.3.Contrendications It is contrendicated for patients who have got hypersensivity to active ingredient or other constituents (refer to 6.1.) Special warnings and precautions Since palonosetrone increase transition time in large intestine, patients who has got history of constipation or who has got symptoms of intestinal obstruction must follow after administration.related to palonosetrone 750 microgram, two constipation histories are reported which required hospital care and with fecal effects. In patients with hypersensivity to other 5 HT 3 receptor antagonist, hypersensivity reactions to palonosetrone can occur. VOTRON must not use patients with cardiac ritm abnormalities or risks (prolonged QT syndrome). This warning is included also patients with hypocalemia, hypomagnesia, electrone abnormalities and patients using diuretics, antiaritmic drugs, QT prolonged drugs, increasing dosage of anthracycline and patients have got QT syndrome starting from delivery Interaction with other medicines and other interaction types Palonosetrone is metabolised by mainly CYP2D6 and also by additional effects of CYP3A4 and CYP1A2. Based on in vitro studies, palonosetrone does not induct or inhibit citocrom P450 isoensyme at releted concentrations clinically. Chemotherapeutic agents: In pre clinical studies, palonosetrone is inhibited effects of 5 tested chemotherapeutic agents (cisplatin, cyclophosphamide, citarabine, doxurubucine and mitomisin C). Metoclopramide: In clinical study, pharmacokinetical interactions is not seen at oral metoclopramid steady state concentration which is inbitor of CYP2D6 with single, intravenous palonosetrone dosage. Inhibitors and inducers of CYP2D6: In population performed pharmacokinetical analysis, when used with inducers (dexametasone and rifampicine) and inhibitors (amiodarone, celecocsibe, clorpromazine, simetidine, doxurubucine, fluoksetine, haloperidole, paroxsetine, quinidine, ranitidine, ritonavir, sertraline or terbinafine) of CYP2D6, there is no seen any effects on palonosetrone clirens. Corticosteroids: Palonsetrone can use with corticosteroids safety. Other medicines: Palonsetrone can use with analgesics, antiemetics, antispasmodics and anticholinergics safety.

3 4.6. Pregnancy and lactation General recommendation: Pregnancy category: B Womens with child bearing potantial/ control of delivery (Contraception) There is no enough data related to exposing of palonosetrone at pregnancy. Animal studies are not shown any direct or in direct harmful effects on pregnancy, emrional/ fetal development, delivery and after delivery development. Limited data are obtained related to placental transferring in animal studies (refer to section 5.3). It must not use until necessity. Pregnancy period: Othervise necessity usage not decribed by doctors, VOTRON must not use in pregnant womens. When using in pregnant women, precautions must be taken. Lactation period: It is not known whether palonosetrone is excreted by human milk or not. Because of this, lactation must stop during treatment with VOTRON. Fertility/ reproducing capability: Palonosetron with 60 mg/kg/day dosage (surface area is mainly 1894 recommended human intravenous dose) has not got any effects on fertility and reproducing capability in male and female rats Effects of driving and using machinery There is no any subjected study related to performance of driving and using machinery at target population with regard to pharmacodynamic properties and informed side effects. Since palonosetrone causes dizziness, insomnia or weakness, patients must warn during using machinary Side effects In study conducted on 633 patients with 250 microgram dosage, most seen side effects were headache in 60 patients (9%), constipation (5%) in 29 patients. Furtermore, diarree was seen at 8 patients (1%), dazedness and dizziness in 8 patients (1%), tiredness in 3 patients (<1%), abdominal pain in 1 patient (<1%) and insomnia in 1 patient (<1%). In clinical syudies, following side effects are seen related to VOTRON as possible or availible. These are classified as common ( 1/100, <1/10), non common ( 1/1000, <1/100) and rare (<1/10.000,<1/1000).

4 Cardiovascular abnormalities: Common Intermittent tacycardia, bradicardia, hypotension Hypertension, extracystole, miyocardial ischemia, sinüs tachicardia, sinüs aritmia, supraventricular extrasystole, prolonging QT (in many cases relation with VOTRON is not clear). Dermatological abnormalities: Alergic dermatitis, redness Hearing and visual abnormalities: : Vehicle disturbances, tinnutus, irritation in eyes, amliopy Gastrointestinal abnormalities: Common Diarree Dispepsia, abdominal pain, top of abdominal pain, dryness in mounth, hiccup, flatulans General abnormalities: Common Weakness High temperature, tiredness, flu, hot flushing Liver abnormalities: Transitient and asymptomatic increasing of AST and/or ALT. These side effects are seen mainly in patients with administered high emotogenic chemotherapy.

5 Metabolism abnormalities: Common Hypercalemia Electrolite waving, glycoseuria, metabolic disturbances, anorexia, hyperglycemia, decreasing of apetite. Muscle skeleton system abnormalities: Artralgia Nerve sytem abnormalities: Common Dizziness Insomnia, paresthesia, hypersomnia Psychiatric abnormalities: Common Anxiety Oforic behaviours Renal and urinary abnormalities: Urinary retantion Vascular abnormalities: Changing of vascular color, oedema Hypersensivity reactions:

6 Rare Injection site reactions: Rare Enduration, disturbances and pain, burning 4.9. Over dosage and treatment There is no reported any over dosage cases. In clinical studies, dosage until 6 mg is used. When comparing most highest dosage group with other dosage group advers events are seen at similar incidence and there is no seen any dosage response effects. Non possible over dosage case with VOTRON is treated with supportive treatment. Dialyse studies are not performed but, because of extent distrubution volume, dialyse is not effective treatment on over dosage of VOTRON. 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties Pharmacotherapeutical group: Antiemetics and prevention of nausea, seratonin antagonists (5HT 3 ) ATC code: A04AA05 Palonosetrone is selective antagonist of 5HT 3 receptors with high affinity. Especially, when cancer treatment is performed with cancer chemotherapy agents like cisplatin, mostly nausea and vomiting can occur. 5HT 3 receptors are availible at postrema area in chemoreceptor trigger area (CTZ) and terminals of vagus nerve for central and pheripheric system. It is known that chemotherapeutic agents cause nausea and vomiting by secretion of seratonine in enterocromaffine cells of small intestine. Secreted seratonin induce 5HT3 receptors at vagus nerve afferents to start vomiting reflex. In two randomised, double blind study on 1132 patients taking moderate emetogenic chemotherapy including cisplatin 50 mg/m 2, carboplatine and cyclophosphamide 1500 mg/m 2, doxurubicine > 25 mg/m 2,250 microgram and 750 microgram intravenous administered palonosetrone on 1 day and 32 mg ondansetrone (half life is 4 hours) and 100 mg dolasetrone (half life is 7.3 hours) were compared without dexamethasone. In randomised, double blind study on 667 patients taking advanced emetogenic chemotherapy including cisplatin 60 mg/m 2, cyclophosphamide > 1500 mg/m 2 and dacarbazine, 250 microgram and 750 microgram palonosetrone intravenous administered on 1. day and 32 mg ondansetrone were compared. Dexametasone is administered prophylactic in 67% patients before chemotherapy. Pre studies are designed for evaluation of efficacy for palonosetrone at late started nausea and vomiting. Antiemetic activity are monitored at 0 24 hours, hours and hours. Results for moderate emetogenic chemotherapy study and advanced emetogenic chemotherapy study are summarised at below table.

7 Plaonosetrone is not different from other medicines when comparing with regard to efficacy in acute phase of emezis. In spite of not shown comparative effects of palonosetrone in controlled clinical studies at multiply cycle, 875 patients recorded to three phase III studies are continued to open extremity safety study. Until 9 additional chemotherapy cycle, ther are treated with 750 mg palonosetrone. During all cycle, exact safety was continued. Table 1: Percentages of patients given response in moderate emetogenic chemotherapy phase and treatment group against to ondansetrone a Palonosetrone Ondansetrone 250 microgram 32 miligram Delta (n=189) (n=185) % % % Exact response (no vomiting and there is no any rescue treatment) %97.5 CI b 0 24 hours [1.8%,22.8%] hours [7.5%,30.3%] hours [7.4%,30.7%] Exact control (not completed response and not more than light nausea) p value c 0 24 hours NS hours hours There is no nausea (Likert scale) 0 24 hours NS hours NS hours NS a group with scoped treatment b study is designed to show equivalent efficacy. In between palonosetrone and comparisonal drug it shows equivalent efficacy more than 15% but more less. c test of Ki square. Significancy level =0.05.

8 Table 2: Percentages of patients given response in moderate emetogenic chemotherapy phase and treatment group against to dolasetrone a Palonosetrone Dolasetrone 250 microgram 100 miligram Delta (n=189) (n=191) % % % Exact response (no vomiting and there is no any rescue treatment) %97.5 CI b 0 24 hours [ 1.7%,21.9%] hours [3.4%,27.1%] hours [0.3%,23.7%] Exact control (not completed response and not more than light nausea) p value c 0 24 hours NS hours hours There is no nausea (Likert scale) 0 24 hours NS hours hours a group with scoped treatment b study is designed to show equivalent efficacy. In between palonosetrone and comparisonal drug it shows equivalent efficacy more than 15% but more less. c test of Ki square. Significancy level =0.05.

9 Table 3: Percentages of patients given response in high emetogenic chemotherapy phase and treatment group against to ondansetrone a Palonosetrone Ondansetrone 250 microgram 32 miligram Delta (n=223) (n=221) % % % Exact response (no vomiting and there is no any rescue treatment) %97.5 CI b 0 24 hours [ 8.8%,13.1%] hours [ 4.6%,17.3%] hours [ 2.9%,18.5%] Exact control (not completed response and not more than light nausea) p value c 0 24 hours NS hours NS hours NS There is no nausea (Likert scale) 0 24 hours NS hours NS hours NS a group with scoped treatment b study is designed to show equivalent efficacy. In between palonosetrone and comparisonal drug it shows equivalent efficacy more than 15% but more less. c test of Ki square. Significancy level = Pharmacokinetical properties General properties: VOTRON (palonosetrone hydrochloride) is agent for antiemetic and prevention of nausea. Palonosetrone is strong 5HT 3 receptor antagonist. It binds to other receptors more less. Palonosetrone hydrochloride is white to almost white crystalline powder. It dissolves in water and prophylene glycole. It dissolves in ethanole and 2 prophanole sparingly. VOTRON injectable solution is sterile, clear, colorless, apyrogenic, isotonic and buffered solution. ph value of solution is

10 Absorbtion: After intravenous administration, it is excreted from body slowly with approximately 40 hours elimination half life following initially rapid decreases of plasma concentrations. Average maximum plasma concentration (C max ) and area under curve of concentration time line (AUC ) are generally proportional to dose and it was between µg/kg dose range in healthy volunteers and cancer patients. Distribution: Palonosetrone at recommended dosages is distributed extently and distribution volume is approximately L/kg. 62% of palonosetrone binds to plasma proteins. Biotransformation: Palonostrone is eliminated by two pathway and by renally 40% of dosage with two metabolites which their activities are more less than 1% 5HT 3 receptor antagonist activity of palonosetrone. In vitro metabolism studies are showed that palonosetrone is metabolised by CYP3A4, CYP1A2 and more less by CYP2D6. But, clinical pharmacokinetical parameters do not show significant degrees of differences between rapid and slow metaboliser of CYP2D6 substrates. Palonosetrone does not inhibit or induce citocrom P450 isoenzymes at related concentrations. Elimination: After administration of single and intravenous dose of 10 microgram/kg [ 14 C] palonosetrone, 80% of dosage is eliminated by urine as un changed active substance within 144 hours. It equivalents to 40% of given dosage. After single, bolus and intravenous dosage in heathy animals total body clerens of palonosetrone is 173±73 ml/minutes and renal clerens is 53±29 ml/minutes. Low total body clerens and extent distribution volume is resulted 40 hours elimination half lives in plasma. 10% of patients have got average elimination half life more than 100 hours. Characteristic properties in patients: Geriatrics: Age does not influence on palonosetrone pharmacokinetics. Dose arrangement is not necessary in geriatric patients. Sex: Sex is not influenced to palonosetrone pharmacokinetics. Based on sex, dose arrangement is not necessary. Pediatric patients: There is no pharmacokinetical data on patients below than 18 years of age. Renal insufficiency: Light or moderate renal insufficiency does not influence to palonosetrone pharmacokinetics importantly. Serious renal insufficieny decrease renal clerens but in these patients total body clerens is similar with healthy volunteers. In patients with renal insufficiency, dose arrangement is not necessary. In hemodialysed patients, there is no pharmacokinetical data. Liver insufficiency: Liver insufficiency when compared with healthy volunteers does not influence to palonosetrone total body clerens. In patients with serious liver insufficieny, half life of palonosetrone and average systemic exposing are increased but, these not required dose arrangement.

11 5.3. Pre clinical safety data In in vitro studies shown that, only very high concentrations of palonosetrone can blocaged ion chanells which addition effects on action potantial time and de or re polarisation of ventricules. Animal studies showed that there was no direct or indirect harmful effects on pregnancy, embryonal/feotal development, born or post natal development. With regard to placental transition, only limited data are availible in animal studies (refer to section 4.6). Palonosetrone is not mutagenic. Palonosetrone with high dosage is administered daily for two years and ratio of liver tumorosis in rats was increased and caused to endocrine neoplasms and skin tumorosis but, there is no seen these side effects in mice. Reason of mechanism did not understand exactly, but, because of administered high dosage and indicated only for single usage thought that these findings are not related to clinical usage. 6.PHARMACEUTICAL PROPERTIES 6.1. List of excipients Mannitole Trisodium citrate Citric acide monohydrate Water for injections Solution of sodium hydroxide Solution of hydrochloric acide 6.2. Incompabilities VOTRON must not mix with other medicines during injection Shelf life Shelf life is 36 months Precautions related to storage This medicinal product must store below 25 0 C at room temperature protecting from light and humudity. Medicinal product must not frezee. If product is freezed, it must not dissolve and use. If this product contain any deteriotion on packaging, it must not use. After opening of vial, un used partas must not store (refer to section 6.6).

12 6.5. Nature and contents of packaging Type 1 glass vial with bromobuthyl rubber stopper and alumunium cap. In packaging 1 vial containing 5 ml solution is availible Disposal of remaining substances from medicinal product and other special precautions For only single usage. Un used solution must discarded. 7. REGISTRATION HOLDER Biem Medical Device and Pharmaceuticals Co.Ltd. Anıttepe Mah. Turgut Reis Cad. No: Tandoğan ANKARA/ TURKEY Phone: (0312) Fax: (0312) REGISTRATION NUMBER 242/83 9.FİRST REGISTRATION DATE/RENEWAL DATE OF REGISTRATION 10.REVISION DATE OF SMPC