SCHEDULING STATUS: S4

PROPRIETARY NAME (AND DOSAGE FORM):

CIPLA-ONDANSETRON 4 (Tablets)CIPLA-ONDANSETRON 8 (Tablets)COMPOSITION:CIPLA-ONDANSETRON 4: Each tablet contains ondansetron 4 mg (as

hydrochloride dihydrate).CIPLA-ONDANSETRON 8: Each tablet contains ondansetron 8 mg (as

hydrochloride dihydrate).

PHARMACOLOGICAL CLASSIFICATION:A 5.10 Medicines affecting autonomic functions. Serotonin antagonists.

PHARMACOLOGICAL ACTION:Pharmacodynamics:Ondansetron is a selective antagonist of the 5-HT3 receptor. Chemotherapeutic medicines and radiotherapy may give rise to the release of 5-HT in the small intestine setting off a vomiting reflex by activating vagal afferents via 5-HT3 receptors. Ondansetron blocks the commencement of this reflex. Activation of vagal afferents may also lead to the release of 5-HT in the area postrema, located on the floor of the fourth ventricle, and this may also promote vomiting via a central mechanism.Therefore, the effect of ondansetron in the management of nausea and vomiting brought about by chemotherapy and radiotherapy may be due to the antagonism of 5-HT3 receptors on neurons situated both in the peripheral and central nervous systems. Psychomotor testing revealed that ondansetron does not cause sedation nor impair performance.

Pharmacokinetics:Ondansetron does not alter plasma levels of prolactin. Ondansetron is rapidly absorbed following oral administration. Maximum plasma concentrations of approximately 30 ng/ml are reached approximately 1,6 hours after an 8 mg dose. The absolute oral bioavailability of ondansetron is about 60 %. Ondansetron’s disposition is similar following intravenous and oral dosing with a terminal elimination half-life of approximately 3 hours and a steady-state volume of distribution of approximately 140 L. Binding to plasma proteins is between 70 and 76 %. Clearance from the systemic circulation is predominantly by metabolism with less than 5 % of an ondansetron dose excreted unchanged in the urine.

Study results have demonstrated that healthy elderly volunteers have a slightly increased oral bioavailability (65 %) and prolonged elimination half-life (5 hours) for ondansetron.

As a result of reduced presystemic metabolism in patients with severe hepatic impairment, their systemic clearance of ondansetron is markedly reduced with a prolonged elimination half-life (15 – 32 hrs) and an oral bioavailability approaching 100 %.

INDICATIONS:CIPLA-ONDANSETRON is indicated for the management of chemotherapy- and radiotherapy-induced nausea and vomiting.

CIPLA-ONDANSETRON is also indicated to prevent and treat postoperative nausea and vomiting. It is recommended that no routine prophylaxis is administered to patients in whom there is little expectation that nausea and vomiting will occur.

CONTRA-INDICATIONS:CIPLA-ONDANSETRON is contra-indicated: • In patients with known hypersensitivity to ondansetron or any of the ingredients

of the preparation.• For postoperative nausea and vomiting in pregnancy (see "PREGNANCY

AND LACTATION").

WARNINGS:Hepatic impairment:In patients with moderate or severe hepatic impairment, clearance of CIPLA-ONDANSETRON is significantly reduced and serum half-life significantly prolonged. In these patients a maximum daily dose of 8 mg should not be exceeded.

PREGNANCY AND LACTATION:Pregnancy: Safety in pregnancy has not been established.

Lactation: Tests have demonstrated that ondansetron passes into the milk of lactating animals. It is therefore recommended that mothers taking CIPLA- ONDANSETRON should not breastfeed their infants.

DOSAGE AND DIRECTIONS FOR USE:Nausea and vomiting induced by chemotherapy and radiotherapy: The emetogenic potential of cancer therapies vary according to the doses and combinations of chemotherapy and radiotherapy regimens administered.

Adults:Emetogenic chemotherapy and radiotherapy:For the majority of patients receiving emetogenic chemotherapy or radiotherapy, ondansetron 8 mg should be given as a slow IV or IM injection immediately prior to treatment, or orally (CIPLA-ONDANSETRON film-coated tablets) 1 – 2 hours before treatment, followed by CIPLA-ONDANSETRON 8 mg orally every 12 hours.In circumstances where delayed or prolonged emesis is anticipated after the first 24 hours, CIPLA-ONDANSETRON may be continued orally at a dose of 8 mg twice daily for up to five days following a treatment course.

Highly emetogenic chemotherapy:In patients receiving highly emetogenic chemotherapy, ondansetron should be administered intravenously.

The efficacy of CIPLA-ONDANSETRON in highly emetogenic chemotherapy may be enhanced by the addition of a single intravenous dose of dexamethasone phosphate 20 mg administered 30 – 45 minutes prior to the first CIPLA- ONDANSETRON dose prior to chemotherapy.

To protect patients against delayed or prolonged emesis after the first 24 hours, oral CIPLA-ONDANSETRON may be continued at a dose of 8 mg twice daily for up to 5 days following a treatment course.

Children:Although current experience is limited, ondansetron was effective and well tolerated in paediatric patients over the age of 4 years, when administered intravenously at a dose of 5 mg/m2 over 15 minutes, immediately prior to chemotherapy, followed by oral therapy at doses of CIPLA-ONDANSETRON.4 mg every 12 hours for up to 5 days.

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Elderly patients:Efficacy and tolerance in patients older than 65 years were similar to those observed in younger adults indicating no need to change the dosage or route of administration in the elderly.

Prevention and treatment of postoperative nausea and vomiting:Adults:To prevent postoperative nausea and vomiting, 16 mg may be given orally (two CIPLA-ONDANSETRON 8 film-coated tablets) one hour before induction of anaesthesia.Repeat dosing for subjects who continue to experience nausea and/or vomiting postoperatively has not been investigated. While recommended as a fixed dose for all, few subjects weighing more than 80 kg or less than 40 kg have been studied.

Elderly:Safety and efficacy of CIPLA-ONDANSETRON for the prevention and treatment of postoperative nausea and vomiting in elderly patients have not been established.

Patients with renal impairment: Patients with renal impairment do not require adjustments of daily dosage, frequency of dosing, or route of administration. Information regarding severe impairment of renal function is limited.

Patients with hepatic impairment: In patients with moderate to severe impairment of liver function clearance of CIPLA-ONDANSETRON is significantly reduced while serum half-life is significantly prolonged. In these patients a maximum daily dose of 8 mg should not be exceeded.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:Side-Effects:The following side-effects can occur:

Immune system disorders:Less frequent: Immediate hypersensitivity reactions, sometimes

severe (e.g. anaphylaxis, shock, angioedema, bronchospasm, shortness of breath, hypotension, urticaria) have been reported.

Nervous system disorders:Frequent: Headache.Less frequent: Seizures have been observed rarely.

Extrapyramidal reactions (including oculogyric crisis and dystonic reactions) have been reported without definitive evidence of persistent clinical consequences.

Cardiac disorders:Less frequent: Arrhythmias, bradycardia and chest pain have

rarely been reported.

Vascular disorders:Frequent: Sensation of warmth or flushing.Less frequent: Hypotension.

Respiratory, thoracic and mediastinal disorders:Less frequent: Hiccups.

Gastrointestinal disorders:Frequent: Constipation (increase in large bowl transit time

caused by CIPLA-ONDANSETRON may cause constipation in some patients).

Hepatobiliary disorders:Less frequent: Asymptomatic increases in liver function tests.

Musculoskeletal, bone and connective tissue disorders:Less frequent: There have been rare reports of involuntary

movement disorders without definitive evidence of persistent clinical sequelae.

Special Precautions:Hypersensitivity reactions have occurred in patients who have demonstrated hypersensitivity to other selective 5-HT3 receptor antagonists.

Patients with signs of subacute intestinal obstruction should be monitored following administration, as CIPLA-ONDANSETRON is known to increase large bowl transit time.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:See "SIDE-EFFECTS AND SPECIAL PRECAUTIONS". Reported manifestations include severe constipation, visual disturbances, hypotension and a vasovagal episode with transient second degree AV block. In cases of suspected overdose, symptomatic and supportive therapy should be administered as appropriate, as there is no specific antidote for ondansetron.

IDENTIFICATION:CIPLA-ONDANSETRON 4: White, circular, biconvex, film-coated tablet, marked

“4” on one side and plain on the other side.CIPLA-ONDANSETRON 8: White, circular, biconvex, film-coated tablet, marked

“8” on one side and a central breakline on the other side.

PRESENTATION:CIPLA-ONDANSETRON 4: Cartons of 10, 15 or 100 tablets, blister-packed in

transparent PVC/PVDC aluminium foil blister strips. CIPLA-ONDANSETRON 8: Cartons of 10, 15 or 100 tablets, blister-packed in

transparent PVC/PVDC aluminium foil blister strips.

STORAGE INSTRUCTIONS:Store below 25 °C. Protect from light.KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS: CIPLA-ONDANSETRON 4: A38/5.10/0435CIPLA-ONDANSETRON 8: A38/5.10/0436

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATES OF REGISTRATION: CIPLA LIFE SCIENCES (PTY) LTDRosen Heights, Pasita StreetRosen Park, Bellville 7530 RSA

DATE OF PUBLICATION OF THIS PACKAGE INSERT:May 2005Revised: September 2011

© CIPLA LIFE SCIENCES (PTY) LTD 2011

SKEDULERINGSTATUS: S4

EIENDOMSNAAM (EN DOSEERVORM):

CIPLA-ONDANSETRON 4 (Tablette)CIPLA-ONDANSETRON 8 (Tablette)SAMESTELLING:CIPLA-ONDANSETRON 4: Elke tablet bevat ondansetron 4 mg (as

hidrochlorieddihidraat).CIPLA-ONDANSETRON 8: Elke tablet bevat ondansetron 8 mg (as

hidrochlorieddihidraat).

FARMAKOLOGIESE KLASSIFIKASIE:A 5.10 Middels wat outonome funksies beïnvloed. Serotonien antagoniste.

FARMAKOLOGIESE WERKING:Farmakodinamika:Ondansetron is ‘n selektiewe antagonis van die 5-HT3 reseptor. Chemoterapeutiese middels en radioterapie mag tot die vrystelling van 5-HT in die dunderm lei wat ‘n brakingsrefleks ontlok deur aktivering van vagale afferente via 5-HT3 reseptore. Ondansetron blokkeer die aanvang van hierdie refleks. Aktivering van vagale afferente mag ook tot die vrystelling van 5-HT in die area postrema, gelokaliseer op die vloer van die vierde ventrikel, lei wat ook braking via ‘n sentrale meganisme mag bevorder.Dus mag die werking van ondansetron in die hantering van naarheid en braking deur chemoterapie en radioterapie teweeggebring vanweë die antagonisme van 5-HT3 reseptore op neurone geleë in beide die perifere en sentrale senusisteme wees.Psigomotoriese toetsing het getoon dat ondansetron nóg sedasie nóg inkorting van werkverrigting tot gevolg het.

Farmakokinetika:Ondansetron verander nie plasmavlakke van prolaktien nie. Ondansetron word vinnig na orale toediening geabsorbeer. Maksimum plasmakonsentrasies van ongeveer 30 ng/ml word binne ongeveer 1,6 uur na ‘n 8 mg dosis bereik. Die absolute orale biobeskikbaarheid van ondansetron is nagenoeg 60 %. Ondansetron se kinetiese profiel is soortgelyk na intraveneuse en orale dosering met ‘n terminale eliminasie halflewe van ongeveer 3 uur en ‘n volume van verspreiding by ewewigsvlak van ongeveer 140 L. Binding aan plasmaproteïene is tussen 70 en 76 %. Opruiming vanuit die sistemiese sirkulasie is hoofsaaklik vanweë metabolisme met minder as 5 % van ‘n ondansetron dosis wat onveranderd in die uriene uitgeskei word.

Studie resultate het daarop gedui dat gesonde bejaarde vrywilligers ‘n effens verhoogde orale biobeskikbaarheid (65 %) en verlengde eliminasie halflewe (5 uur) vir ondansetron het.

As gevolg van verminderde presistemiese metabolisme in pasiënte met erge lewerinkorting, is hulle sistemiese opruiming van ondansetron merkwaardig verminder met ‘n verlengde eliminasie halflewe (15 – 32 uur) en ‘n orale biobeskikbaarheid wat 100 % nader.

INDIKASIES:CIPLA-ONDANSETRON is aangedui vir die behandeling van chemoterapie- en radioterapie-geïnduseerde naarheid en braking.

CIPLA-ONDANSETRON is ook aangedui vir die voorkoming en behandeling van postoperatiewe naarheid en braking. Dit word aanbeveel dat geen roetine profilakse gegee word vir pasiënte vir wie die verwagting dat naarheid en braking sal voorkom gering is nie.

KONTRA-INDIKASIES:CIPLA-ONDANSETRON is teenaangedui: • In pasiënte met bekende hipersensitiwiteit vir ondansetron of enige van die

bestanddele van die preparaat.• Vir postoperatiewe naarheid en braking in swangerskap (sien

"SWANGERSKAP EN LAKTASIE").

WAARSKUWINGS:Lewerinkorting:In pasiënte met matige of erge lewerinkorting is opruiming van CIPLA-ONDANSETRON merkwaardig verminder en serum halflewe betekenisvol verleng. In hierdie pasiënte moet ‘n maksimum daaglikse dosis van 8 mg nie oorskry word nie.

SWANGERSKAP EN LAKTASIE:Swangerskap: Veiligheid in swangerskap is nog nie vasgestel nie.

Laktasie: Toetse het getoon dat ondansetron in die melk van lakterende diere uitgeskei word. Dit word derhalwe aanbeveel dat moeders wie CIPLA-ONDANSETRON neem nie hulle babas moet borsvoed nie.

DOSIS EN GEBRUIKSAANWYSINGS:Naarheid en braking deur chemoterapie en radioterapie geïnduseer:Die emetogeniese potensiaal van kankerbehandeling varieer na gelang van die dosisse en kombinasies van chemoterapie en radioterapie regimens toegedien.

Volwassenes:Emetogeniese chemoterapie en radioterapie:Vir die meerderheid van pasiënte wie emetogeniese chemoterapie of radioterapie ontvang, behoort ondansetron 8 mg as stadige IV of IM inspuiting onmiddellik voor die behandeling, of oraal (CIPLA-ONDANSETRON filmbedekte tablette) 1 – 2 uur voor behandeling gegee te word, gevolg deur CIPLA-ONDANSETRON 8 mg oraal elke 12 uur.In gevalle waar vertraagde of verlengde braking na die eerste 24 uur verwag word, mag CIPLA-ONDANSETRON oraal teen ‘n dosis van 8 mg twee keer per dag vir tot 5 dae na ‘n kursus behandeling voortgesit word.

Hoogs emetogeniese chemoterapie:In pasiënte wie hoogs emetogeniese chemoterapie ontvang, behoort ondansetron intraveneus toegedien te word.

Die effektiwiteit van CIPLA-ONDANSETRON in hoogs emetogeniese chemoterapie mag bevorder word deur die toevoeging van ‘n enkele intraveneuse dosis van deksametasoonfosfaat 20 mg toegedien 30 – 45 minute voor die eerste CIPLA-ONDANSETRON dosis voor chemoterapie.

Om pasiënte teen vertraagde of verlengde braking na die eerste 24 uur te beskerm, kan orale CIPLA-ONDANSETRON teen ‘n dosis van 8 mg twee keer daagliks vir tot 5 dae na ‘n kursus behandeling voortgesit word.

Kinders:Alhoewel huidige ondervinding beperk is, was ondansetron effektief en goed verdra in pediatriese pasiënte ouer as 4 jaar wanneer intraveneus toegedien teen ‘n dosis van 5 mg/m2 oor 15 minute, onmiddellik voor chemoterapie, gevolg deur orale terapie teen dosisse van CIPLA-ONDANSETRON 4 mg elke 12 uur vir tot 5 dae.

Bejaardes:Effektiwiteit en toleransie in pasiënte ouer as 65 jaar was soortgelyk aan dit in jonger volwassenes waargeneem wat daarop dui dat dit nie nodig is om die dosering of roete van toediening in bejaardes aan te pas nie.

Voorkoming en behandeling van postoperatiewe naarheid en braking:Volwassenes:Om postoperatiewe naarheid en braking te voorkom, kan 16 mg oraal (twee CIPLA-ONDANSETRON 8 filmbedekte tablette) een uur voor induksie van narkose gegee word.Herhaalde dosering vir persone wie voortgaan om naarheid en/of braking te ervaar, is nog nie bestudeer nie. Alhoewel as vasgestelde dosis vir almal aanbeveel, is min pasiënte wie meer as 80 kg of minder as 40 kg weeg bestudeer.

Bejaardes:Veiligheid en effektiwiteit van CIPLA-ONDANSETRON vir die voorkoming en behandeling van postoperatiewe naarheid en braking in bejaardes is nog nie vasgestel nie.

Pasiënte met nierinkorting: Dit is nie nodig om die daaglikse dosis, frekwensie van dosering en roete van toediening in pasiënte met nierinkorting aan te pas nie. Inligting aangaande erge inkorting van nierfunksie is beperk.

Pasiënte met lewerinkorting: In pasiënte met matige tot erge inkorting van lewerfunksie is opruiming van CIPLA-ONDANSETRON betekenisvol verminder terwyl serum halflewe beduidend verleng is. ‘n Maksimum daaglikse dosis van 8 mg moenie in hierdie pasiënte oorskry word nie.

NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS:Newe-Effekte:Die volgende newe-effekte kan voorkom:

Immuunsisteem afwykings:Minder dikwels: Onmiddellike hipersensitiwiteitsreaksies, soms erg

(bv. anafilakse, skok, angio-edeem, brongospasma, kortasemheid, hipotensie, urtikarie) is gemeld.

Senusisteem afwykings:Dikwels: Hoofpyn.Minder dikwels: Konvulsies is in seldsame gevalle gemeld.

Ekstrapiramidale reaksies (insluitende okulogiriese krisis en distoniese reaksies) is gemeld sonder definitiewe bewyse van volgehoue kliniese gevolge.

Kardiale afwykings:Minder dikwels: Aritmieë, bradikardie en borskaspyn is in seldsame

gevalle gemeld.

Vaskulêre afwykings:Dikwels: Sensasie van hitte of blosing.Minder dikwels: Hipotensie.

Respiratoriese, torakale en mediastinale afwykings:Minder dikwels: Hik.

Gastro-intestinale afwykings:Dikwels: Hardlywigheid (toename in kolon deurgangstyd

veroorsaak deur CIPLA-ONDANSETRON mag tot hardlywigheid in sommige pasiënte lei).

Hepatobiliêre afwykings:Minder dikwels: Asimptomatiese toename in lewerfunksietoetse.

Muskuloskeletale, been- en bindweefselafwykings:Minder dikwels: Onwillekeurige bewegingsteurings sonder

definitiewe bewyse van volgehoue kliniese gevolge is seldsaam gemeld.

Spesiale Voorsorgmaatreëls:Hipersensitiwiteitsreaksies het voorgekom in pasiënte wie vantevore hipersensitiwiteit vir ander selektiewe 5-HT3 reseptor antagoniste getoon het.

Pasiënte met tekens van subakute dermobstruksie behoort na toediening gemonitor te word, aangesien CIPLA-ONDANSETRON bekend is om kolon deurgangstyd te verleng.

BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING DAARVAN:Sien "NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS". Aangemelde manifestasies sluit erge hardlywigheid, visuele steurings, hipotensie en ‘n vasovagale episode met verbygaande tweedegraadse AV blok in. In gevalle van vermoedelike oordosis behoort simptomatiese en ondersteunende terapie soos aangedui toegedien te word, aangesien daar geen spesifieke teenmiddel vir ondansetron is nie.

IDENTIFIKASIE:CIPLA-ONDANSETRON 4: Wit, ronde, bikonvekse, filmbedekte tablet, gemerk

“4” aan die een kant en glad aan die ander kant.CIPLA-ONDANSETRON 8: Wit, ronde, bikonvekse, filmbedekte tablet, gemerk

“8” aan die een kant en met ‘n sentrale breeklyn aan die ander kant.

AANBIEDING:CIPLA-ONDANSETRON 4: Kartonne met 10, 15 of 100 tablette stulpverpak in

deursigtige PVC/PVDC aluminiumfoelie stroke. CIPLA-ONDANSETRON 8: Kartonne met 10, 15 of 100 tablette stulpverpak in

deursigtige PVC/PVDC aluminiumfoelie stroke.

BERGINGSINSTRUKSIES:Berg benede 25 °C. Beskerm teen lig.HOU BUITE BEREIK VAN KINDERS.

REGISTRASIENOMMERS: CIPLA-ONDANSETRON 4: A38/5.10/0435CIPLA-ONDANSETRON 8: A38/5.10/0436

NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE SERTIFIKATE VAN REGISTRASIE: CIPLA LIFE SCIENCES (EDMS) BPKRosen Heights, PasitastraatRosenpark, Bellville 7530 RSA

DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET:Mei 2005Hersien: September 2011

© CIPLA LIFE SCIENCES (EDMS) BPK 2011

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