PROPOSED PACKAGE INSERT. Each tablet contains 37,5 mg tramadol hydrochloride and 325 mg paracetamol as the active ingredients.

Transcription

1 PROPOSED PACKAGE INSERT SCHEDULING STATUS Schedule 5 PROPRIETARY NAME AND DOSAGE FORM TRAMACET Tablets COMPOSITION Each tablet contains 37,5 mg tramadol hydrochloride and 325 mg paracetamol as the active ingredients. Inactive ingredients include the following: carnauba wax, magnesium stearate, OPADRY Light yellow, powdered cellulose, pregelatinised starch, purified water, sodium starch glycolate, and starch. PHARMACOLOGICAL CLASSIFICATION A.2.9.Other analgesics PHARMACOLOGICAL ACTION Tramadol is a centrally acting synthetic analgesic compound whose analgesic profile can be attributed to the binding of parent and O-demethylated (M1) metabolite to µ-opioid receptors as well as the weak inhibition of neuronal re-uptake of noradrenaline and serotonin. Paracetamol also has centrally acting analgesic effects. Tramadol is well absorbed after oral administration, reaching peak activity in 2 to 3 hours. The mean absolute bioavailability of a single 100 mg oral dose is approximately 75 %, increasing to approximately 90 % with multiple dosing. Oral absorption of paracetamol following administration of TRAMACET gives a peak plasma concentration of paracetamol within one hour and is not affected by co-administration with tramadol.

2 Tramadol and paracetamol are both extensively metabolised in the liver. Approximately 30 % of tramadol is excreted unchanged in the urine. Tramadol and its metabolites are eliminated primarily by the kidney. The plasma elimination half-lives of tramadol and its M1 metabolite are approximately 6 and 7 hours respectively. Paracetamol is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. The half-life of paracetamol is about 2-3 hours in adults. Less than 9 % of paracetamol is excreted unchanged in the urine. INDICATIONS TRAMACET is indicated for the management of moderate to moderately-severe pain in adults. TRAMACET is not recommended for minor pain that may be treated adequately through lesser means. CONTRA-INDICATIONS TRAMACET is contra-indicated in patients with a known hypersensitivity to tramadol, paracetamol or other opioids such as codeine. It is also contraindicated in cases of severe liver function impairment and in acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic medicines. It should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal. TRAMACET must not be used for narcotic withdrawal treatment. TRAMACET should not be given to patients with respiratory depression especially in the presence of cyanosis and excessive bronchial secretions.

3 TRAMACET should not be given to patients with increased intracranial pressure or central nervous system depression due to head injury or cerebral disease. WARNINGS AND SPECIAL PRECAUTIONS This product contains paracetamol, which may be fatal in overdose. In the event of overdosage or suspected overdose and notwithstanding the fact that the person may be asymptomatic, the nearest doctor, hospital or Poison Centre must be contacted immediately. Dosages in excess of those recommended may cause severe liver damage. Patients suffering from liver or kidney disease should take paracetamol containing products under medical supervision. Tramadol may only be taken with special care in opioid dependence, reduced level of consciousness of uncertain origin, disorders of the respiratory function and increased intracranial pressure. Seizures: Seizures have been reported in patients receiving tramadol at dosages within the recommended dosage range. The risk of seizures is enhanced in patients exceeding the recommended dose, or in patients taking tricyclic anti-depressants or other tricyclic compounds e.g. promethazine, selective serotonin reuptake inhibitors, MAO-inhibitors and neuroleptics. The risk of seizures may also be increased in patients with epilepsy, with a history of seizures or in patients with a recognised risk for seizures e.g. drug and alcohol withdrawal, intracranial infections, head trauma, metabolic disorders and naloxone administration with tramadol overdose. Patients known to suffer from cerebral convulsions should be carefully monitored during treatment with tramadol. Drug Abuse and Dependence:

4 Tramadol has a dependence potential and tolerance, psychic and physical dependence of the morphinetype ( opioid) may develop with long-term use. The drug has been associated with craving, drugseeking behaviour and tolerance development. Cases of abuse and dependence on tramadol have been reported. Tramadol should not be used in opioid-dependent patients. Tramadol can reinstate physical dependence in patients that have been previously dependent or chronically using other opioids. In patients with a tendency to drug abuse, a history of drug dependence or who are chronically using opioids, treatment with tramadol is not recommended. Withdrawal symptoms may occur if TRAMACET is discontinued abruptly. Panic attacks, severe anxiety, hallucinations, parathesia, tinnitus, and unusual CNS symptoms have also been reported with abrupt discontinuation of tramadol hydrochloride. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medication. Effects on ability to drive or operate machinery: Tramadol may affect reactions to the extent that driving ability and the ability to operate machinery may be impaired. This applies particularly in conjunction with other psychotropic medicines including alcohol. Serious skin reactions Serious skin reactions such as acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported in patients receiving acetaminophen. Patients should be informed about the signs of serious skin reactions, and use of the medicine should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Do not co-administer TRAMACET with other tramadol or paracetamol containing products. TRAMACET should not be taken with alcohol containing beverages.

5 The administration of TRAMACET concurrently with central nervous system (CNS) depressants such as alcohol, opioids, anaesthetic agents, phenothiazines, tranquilizers or sedative hypnotics is likely to intensify and prolong CNS effects. TRAMACET should be used with caution in patients with impaired renal function and in patients prone to convulsive disorders or in shock. INTERACTIONS Concomitant administration of TRAMACET and carbamazepine may cause significantly decreased tramadol and M1 concentrations. Patients receiving carbamazepine may have significantly reduced analgesic effect from the tramadol component of TRAMACET. Concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, quinidine and amitriptyline could result in some inhibition of the metabolism of tramadol. Simultaneous administration with cimetidine is associated with clinically insignificant changes in serum concentrations of tramadol. Therefore, no alteration of the TRAMACET dosage regimen is recommended for patients receiving chronic cimetidine therapy. TRAMACET must not be combined with a MAO-inhibitor, or within 14 days of discontinuation of it, as potentiation of serotonergic and noradrenergic effects may result. Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity and rare alterations of warfarin effect including elevation of prothrombin times.

6 Periodic evaluation of prothrombin time / INR should be performed when TRAMACET is administered concurrently with warfarin like compounds, due to reports of increased prothrombin time / INR in some patients. Concomitant administration of diflunisal and paracetamol produces a 50 % increase in paracetamol plasma levels in normal volunteers. TRAMACET should be used cautiously and patients should be monitored carefully. PREGNANCY AND LACTATION Safe use in pregnancy and lactation has not been established. TRAMACET is not recommended for pregnant mothers because tramadol has been shown to cross the placenta. DOSAGE AND DIRECTIONS FOR USE To be used in adults and children over 16 years of age. DO NOT EXCEED THE RECOMMENDED DOSE. Adults For the management of pain, the recommended dose of TRAMACET is 1 or 2 tablets every 4 to 6 hours as needed for pain relief up to a maximum of 8 tablets per day. As with all analgesic medicines, a titration period of several days with gradual dose increases at the initiation of TRAMACET therapy may be beneficial for some patients. Clinical studies with tramadol in patients with moderate to moderately severe chronic pain indicate that the tolerability of tramadol can be improved by starting tramadol at a low dose with gradual upward dose titration to reach doses that provide sufficient pain relief. Renal impairment

7 For patients with creatinine clearance < 30 ml/min, the dosing interval of TRAMACET should be increased not to exceed 2 tablets every to 12 hours. SIDE-EFFECTS AND SPECIAL PRECAUTIONS: TRAMACET tablets may have side-effects. These are classified as follows: - very common ( 1/10) - common ( 1/100, < 1/10) - uncommon ( 1/1 000, < 1/100) - rare ( 1/10 000, < 1/1 000) - very rare (< 1/10 000, including isolated reports) The most frequently reported side effects were of the gastrointestinal and central nervous systems. SYSTEM Very Common Uncommon ORGAN common ( 1/100, < 1/10) ( 1/1 000, < 1/100) CLASS ( 1/10) Cardiovascular Hypertension, aggravated Disorders hypertension, hypotension dysrhythmia, palpitation, tachycardia Liver and Liver test abnormalities Biliary System Central and Dizziness, Headache, tremor Ataxia, convulsions, Peripheral somnolence hypertonia, migraine, Nervous aggravated migraine, System involuntary muscle

8 contractions, paraesthesia, stupor, vertigo Gastrointestinal Nausea Abdominal pain, constipation, Dysphagia, melena, tongue System diarrhoea, dyspepsia, flatulence oedema dry mouth, vomiting Hearing Vestibular Disorders Metabolic Nutritional Disorders and and Tinnitus Weight decrease Psychiatric Disorders Anorexia, anxiety, confusion, euphoria, insomnia, nervousness Amnesia, depersonalisation, depression, drug abuse, emotional hallucination, lability, impotence, bad dreams, abnormal thinking Red Blood Cell Anemia Disorders Respiratory Dyspnoea System Urinary System Albuminuria, micturition disorder, oliguria, urinary retention Vision Abnormal vision

9 Disorders Body as a Whole Asthenia, fatigue, hot flushes Chest pain, rigors, syncope, withdrawal syndrome Skin and Pruritus, rash, increased sweating Appendages Clinically significant adverse experiences previously reported in clinical trials or post-marketing reports with tramadol hydrochloride include: Orthostatic hypotension, allergic reactions (including anaphylaxis and urticaria, Stevens Johnson Syndrome/TENS), cognitive dysfunction, suicidal tendency and hepatitis. Reported laboratory abnormalities included elevated creatinine. Serotonin syndrome (whose symptoms may include fever, excitation, shivering and agitation) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAO inhibitors. Post marketing experience with the use of tramadol containing products included reports of delirium, miosis, mydriasis, and speech disorder, and reports of movement disorder. Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times. Cases of hypoglycemia have been reported. Clinically significant adverse experiences previously reported in clinical trials or post-marketing reports with paracetamol include: Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to paracetamol are rare and generally controlled by discontinuation of the drug, and when necessary, symptomatic treatment. There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin like compounds. In other studies, prothrombin time did not change.

10 KNOWN SYMPTOMS OF OVERDOSE AND PARTICULARS OF ITS TREATMENT The clinical presentation of overdosage may include the signs and symptoms of tramadol toxicity, paracetamol toxicity or both. Tramadol The initial symptoms of tramadol overdosage may include respiratory depression and/or seizures. Primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all symptoms caused by overdosage, the risk of seizures is also increased with naloxone administration. Treatment of restlessness and / or convulsions is symptomatic and supportive (benzodiazepines I barbiturates). Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Treatment of acute intoxication with TRAMACET with haemodialysis or haemofiltration alone is therefore not suitable for detoxification. Paracetamol Prompt treatment is essential. In the event of an overdosage, consult a doctor immediately, or take the person to a hospital directly. A delay in starting treatment may mean that antidote is given too late to be effective. Evidence of liver damage is often delayed until after the time for effective treatment has lapsed. Susceptibility to paracetamol toxicity is increased in patients who have taken repeated high doses (greater than 5-10 g/day) of paracetamol for several days, in chronic alcoholism, chronic liver disease, AIDS, malnutrition, and with the use of drugs that induce liver microsomal oxidation such as barbiturates, isoniazid, rifampicin, phenytoin and carbamazepine.

11 Symptoms of paracetamol overdosage in the first 24 hours include pallor, nausea, vomiting, anorexia and possibly abdominal pain. Mild symptoms during the first two days of acute poisoning do not reflect the potential seriousness of the overdosage. Liver damage may become apparent 12 to 48 hours or later after ingestion, initially by elevation of the serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentration and prolongation of the prothrombin time. Liver damage may lead to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Abnormalities of glucose metabolism and metabolic acidosis may occur. Cardiac arrhythmias have been reported. Treatment for paracetamol overdosage: Although evidence is limited it is recommended that any adult person who has ingested 5-10 grams or more of paracetamol (or a child who has had more than 140 mg/kg) within the preceding four hours, should have the stomach emptied by lavage (emesis may be adequate for children) and a single dose of 50 g activated charcoal given via the lavage tube. Ingestion of amounts of paracetamol smaller than this may require treatment in patients susceptible to paracetamol poisoning (see above). In patients who are stuperose or comatose endotracheal intubation should precede gastric lavage in order to avoid aspiration. N-acetylcysteine should be administered to all cases of suspected overdose as soon as possible preferably within eight hours of overdosage, although treatment up to 36 hours after ingestion may still be of benefit, especially if more than 150 mg/kg of paracetamol was taken. An initial dose of 150 mg/kg N- acetylcysteine in 200 ml dextrose injection given intravenously over 15 minutes, followed by an infusion of 50 mg/kg in 500 ml dextrose injection over the next four hours, and then 100 mg/kg in 1000 ml

12 dextrose injection over the next sixteen hours. The volume of intravenous fluid should be modified for children. Although the oral formulation is not the treatment of choice, 140 mg/kg dissolved in water may be administered initially, followed by 70 mg/kg every four hours for seventeen doses. A plasma paracetamol level should be determined four hours after ingestion in all cases of suspected overdosage. Levels done before four hours, unless high may be misleading. Patients at risk of liver damage, and hence requiring continued treatment with N-acetylcysteine, can be identified according to their plasma paracetamol level. The plasma paracetamol level can be plotted against time since ingestion in the normogram below. Source: Goodman & Gilman s The Pharmacological Basis of Therapeutics, 11 th Ed. Those whose plasma paracetamol levels are above the normal treatment line, should continue N- acetylcysteine treatment with 100 mg/kg IV over sixteen hours repeatedly until recovery. Patients with

13 increased susceptibility to liver damage as identified above, should continue treatment if concentrations are above the high risk treatment line. Prothrombin index correlates best with survival. Monitor all patients with significant ingestions for at least ninety six hours. IDENTIFICATION Light yellow, film-coated capsule-shaped tablet engraved J-C on one side and T/P on the other. PRESENTATION Blister packs of 60 tablets. STORAGE INSTRUCTIONS Store in a cool, dry place, at or below 25 ºC. KEEP OUT OF REACH OF CHILDREN. REGISTRATION NUMBER 35/2.9/0010 Nam. Reg. No.: 04/2.9/1728 NS 3 Botswana Reg. No.: A S2 Zimbabwe Reg. No.: 2014/2.2/4850 (PP)

14 NAME AND BUSINESS ADDRESS OF THE HOLDER OF CERTIFICATE OF REGISTRATION JANSSEN PHARMACEUTICA (PTY) LTD (Reg. No. 1980/011122/07) Building 6, Country Club Estate 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) DATE OF PUBLICATION OF THE PACKAGE INSERT 18 July 2014

15 Package Insert (Afrikaans) SKEDULERINGSTATUS Skedule 5 HANDELSNAAM EN DOSEERVORM TRAMACET Tablette SAMESTELLING Elke tablet bevat 37,5 mg tramadolhidrochloried en 325 mg parasetamol as aktiewe bestanddele. Onaktiewe bestanddele sluit die volgende in: palmwas, magnesiumstearaat, OPADRY liggeel, verpoeierde sellulose, pregelatineerde stysel, gesuiwerde water, natriumstyselglikolaat en stysel. FARMAKOLOGIESE KLASSIFIKASIE A.2.9.Ander analgetika FARMAKOLOGIESE WERKING Tramadol is 'n sentraalwerkende, sintetiese analgetiese verbinding, met n analgetiese profiel wat toegeskryf kan word aan die binding van die hoof- en O-demetiel (M1)- metaboliet aan die µ- opiaatreseptore; asook aan die swak remming van neuronale heropname van noradrenalien en serotonien. Parasetamol het ook sentraalwerkende analgetiese effekte. Tramadol word goed na orale inname geabsorbeer; spitsaktiwiteit word binne 2 tot 3 uur bereik. Die gemiddelde absolute biobeskikbaarheid van n enkele 100 mg orale dosis is ongeveer 75 %, wat toeneem tot ongeveer 90 % met veelvuldige doserings. Absorpsie van parasetamol na orale toediening van

16 TRAMACET lewer binne een uur 'n spitsplasmakonsentrasie van parasetamol en dit word nie deur die gelyktydige toediening van tramadol geaffekteer nie. Beide tramadol en parasetamol word uitgebreid deur die lewer gemetaboliseer. Ongeveer 30 % van die tramadol word onveranderd in die urien uitgeskei. Tramadol en sy metaboliete word hoofsaaklik deur die niere verwyder. Die plasma eliminasiehalfleeftyd van tramadol en sy M1- metaboliet is onderskeidelik ongeveer 6 en 7 uur. Parasetamol word hoofsaaklik deur die vorming van die glukuronied- en sulfaatkonjugate op 'n dosisafhanklike wyse deur die liggaam uitgeskei. By volwassenes is parasetamol se halfleeftyd ongeveer 2 3 uur. Minder as 9 % van die parasetamol word onveranderd in die urien uitgeskei. INDIKASIES TRAMACET word aangedui vir die behandeling van matige tot matig-ernstige pyn by volwassenes. TRAMACET word nie aanbeveel vir ligte pyn wat voldoende met 'n ander middel behandel kan word nie. KONTRAÏNDIKASIES TRAMACET word teenaangewys by pasiënte met n bekende hipersensitiwiteit vir tramadol, parasetamol of ander opiate soos kodeïen. Dit word ook teenaangewys by gevalle van erge lewerfunksie ontoereikendheid en by akute bedwelming met alkohol, hipnotika, sentraalwerkende analgetika, opiate of psigotropiese medisyne. Dit moet nie aan pasiënte wat monoamienoksidase remmers ontvang, of binne twee weke na die onttrekking daarvan, toegedien word nie. TRAMACET moet nie gebruik word vir die behandeling van narkotika-onttrekking nie.

17 TRAMACET moet nie aan pasiënte met respiratoriese onderdrukking gegee word nie, veral nie waar sianose en oormatige brongiale sekresie teenwoordig is nie. TRAMACET moet nie aan pasiënte met verhoogde intrakraniale druk of sentrale senuweestelselonderdrukking as gevolg van kopbeserings of serebrale siekte gegee word nie. WAARSKUWINGS EN SPESIALE VOORSORGMAATREËLS Hierdie produk bevat parasetamol, wat noodlottig kan wees met oordosering. In geval van oordosering of vermoedelike oordosering en nieteenstaande die feit dat die persoon moontlik asimptomaties kan wees, moet die naaste dokter, hospitaal of vergiftigingsentrum onmiddellik geskakel word. Ernstige lewerskade kan veroorsaak word indien die aanbevole dosis oorskry word. Pasiënte wat aan lewer- of niersiektes ly, moet parasetamolbevattende produkte slegs onder mediese toesig neem. Tramadol moet slegs onder spesiale toesig geneem word by opiaatafhanklikheid, verminderde vlak van bewussyn van onsekere oorsprong, respiratoriese wanfunksie en verhoogde intrakraniale druk. Toevalle: Toevalle is by pasiënte wat tramadol binne die aanbevole dosisgrense ontvang het, aangemeld. Die risiko van 'n toeval is hoër by pasiënte wat die aanbevole dosis oorskry, of by pasiënte wat trisikliese antidepressante, selektiewe serotonienheropnameremmers, MAO-remmers en neuroleptika neem. Die risiko vir toevalle kan ook verhoog wees by pasiënte met epilepsie, met n geskiedenis van toevalle, of by pasiënte met n erkende risiko vir toevalle, bv. geneesmiddel- en alkoholonttrekking, intrakraniale infeksies, kopbeserings, metaboliese siektes en naloksoontoediening met tramadol-oordosering. Pasiënte wat ly aan serebrale konvulsies moet versigtig gedurende behandeling met tramadol gemoniteer word.

18 Geneesmiddelmisbruik en afhanklikheid: Tramadol het afhanklikheidsvormende potensiaal en toleransie, psigiese en fisiese afhanklikheid van die morfientipe (µ- opioïed) kan met langtermyngebruik ontwikkel. Die geneesmiddel is met geneesmiddelsoekende dranggedrag en ontwikkeling van toleransie geassosieer. Gevalle van misbruik en afhanklikheid van tramadol is aangemeld. Tramadol moet nie by opiaat-afhanklike pasiënte gebruik word nie. Tramadol kan fisiese afhanklikheid weer laat posvat by pasiënte wat voorheen afhanklik was of wat ander opiate chronies gebruik het. By pasiënte met n neiging tot geneesmiddelmisbruik, n geskiedenis van geneesmiddelafhanklikheid of chroniese opiaatgebruik, word behandeling met tramadol nie aanbeveel nie. Onttrekkingsimptome kan voorkom indien TRAMACET skielik gestaak word. Paniekaanvalle, erge angstigheid, hallusinasies, parestesie, tinnitus en ongewone SSS simptome was ook met die skielike staking van tramadolhidrochloried aangemeld. Kliniese ervaring dui daarop dat onttrekkingsimptome verlig kan word deur die medikasie geleidelik te verminder. Effek op die vermoë om te bestuur of masjinerie te hanteer: Tramadol kan reaksies tot so n mate beïnvloed dat bestuursvermoë en vermoë om masjinerie te bedryf, belemmer kan wees. Dit is veral van toepassing saam met ander psigotropiese medisynes, insluitende alkohol. Ernstige velreaksies Ernstige velreaksies soos akute algemene eksanteemagtige pustules ( AGEP ), Stevens-Johnsonsindroom (SJS), en toksiese epidermale nekrolise (TEN), is baie selde by pasiënte wat asetaminofeen ontvang aangemeld. Pasiënte moet ingelig word oor die tekens van ernstige velreaksies en die gebruik van die geneesmiddel moet gestaak word met die eerste tekens van 'n veluitslag of enige ander teken van hipersensitiwiteit.

19 TRAMACET moet nie saam enige ander tramadol- of parasetamolbevattende produkte toegedien word nie. TRAMACET moet nie gelyktydig met alkoholiese drankies geneem word nie. Die gelyktydige toediening van TRAMACET met sentrale senuweestelsel (SSS) depressante soos alkohol, opiate, narkosemiddels, fenotiasiene, kalmeermiddels of kalmerende hipnotika sal waarskynlik die SSS-effek versterk en verleng. TRAMACET moet met omsigtigheid by pasiënte met ingekorte nierfunksie en pasiënte wat geneig is tot konvulsiewe versteurings of wat in 'n skoktoestand verkeer, gebruik word. INTERAKSIES Gelyktydige toediening van TRAMACET en karbamasepien kan die konsentrasie van tramadol en M1 beduidend verlaag. Pasiënte wat karbamasepien ontvang kan beduidend minder pynverligting van die tramadol bestanddeel in TRAMACET ondervind. Gesamentlike toediening met inhibeerders van CYP2D6 soos fluoksetien, paroksitien, kinidien en amitriptilien kan tot 'n mate van remming van die metabolisme van tramadol lei. Gelyktydige toediening met simetidien word geassosieer met klinies onbeduidende veranderinge in die serumkonsentrasie van tramadol. Gevolglik word daar geen aanpassing in die TRAMACET dosisregimen by pasiënte wat chronies simetidienbehandeling ontvang aanbeveel nie. TRAMACET moet nie saam met n MAO-remmer, of binne 14 dae nadat die gebruik daarvan gestaak is, geneem word nie, omdat dit kan lei tot potensiëring van serotonergiese en noradrenergiese effekte.

20 Nabemarkingstoesig oor tramadol het skaars verslae betreffende digoksien toksisiteit en skaars veranderings in die uitwerking van warfarien, insluitende die verhoging van die protrombientyd, geopenbaar. As gevolg van berigte van verhoogde protrombientyd / INR by sommige pasiënte moet periodieke evaluering van die protrombientyd / INR gedoen word wanneer TRAMACET gelyktydig met warfarienagtige verbindings toegedien word. Gelyktydige toediening van diflunisal en parasetamol lewer 'n 50 %-verhoging in die plasmavlakke van parasetamol by normale vrywilligers. TRAMACET moet versigtig gebruik word en pasiënte moet noukeurig gemoniteer word. SWANGERSKAP EN LAKTASIE Veiligheid tydens swangerskap en laktasie is nie bepaal nie. TRAMACET word nie vir swanger moeders aanbeveel nie, want daar is aangetoon dat tramadol die plasenta kruis. DOSIS EN GEBRUIKSAANWYSINGS Vir gebruik by volwassenes en kinders ouer as 16 jaar. MOENIE DIE AANBEVOLE DOSIS OORSKRY NIE. Volwassenes Vir pynbeheer is TRAMACET se aanbevole dosis 1 of 2 tablette elke 4 tot 6 uur, soos benodig vir die verligting van pyn. Die maksimumdosis is 8 tablette per dag. Soos met alle pynmedikasie, kan 'n titrasietydperk van etlike dae, met geleidelike dosisverhoging na aanvang van TRAMACET behandeling, voordelig wees vir sommige pasiënte. Kliniese studies met

21 tramadol in pasiënte met matige tot matig ernstige chroniese pyn dui daarop dat die verdraagbaarheid vir tramadol verbeter kan word deur tramadol by 'n lae dosis te begin, met geleidelike opwaartse dosistitrasie om dosisse wat voldoende verligting van pyn bied, te bereik. Nierinkorting By pasiënte met 'n kreatinienopruiming van < 30 ml/min, moet die dosisinterval van TRAMACET verleng word, sodat nie meer as 2 tablette elke 12 uur geneem word nie. NEWE-EFFEKTE EN SPESIALE VOORSORGMAATREËLS: TRAMACET kan newe-effekte hê. Dit word soos volg geklassifiseer: - baie algemeen ( 1/10) - algemeen ( 1/100, < 1/10) - ongewoon ( 1/1 000, < 1/100) - seldsaam ( 1/10 000, < 1/1 000) - baie seldsaam (< 1/10 000, insluitende enkele berigte) Die mees algemeen aangemelde newe-effekte was van die maag en sentrale senuweestelsels. Baie Algemeen Ongewoon SISTEEMORGAANKLAS algemeen ( 1/100, < 1/10) ( 1/1 000, < 1/100) ( 1/10) Bloedvat versteurings Hipertensie, hipertensie vererger, hipotensie disritmie, palpitasie, tagikardie Lewer- en galsisteem Onreëlmatigheid in

22 lewertoetse Sentrale en perifere Duiseligheid, Hoofpyn, bewing Ataksie, stuiptrekkings, senuweestelsel lomerigheid hipertonie, migraine, verergerde migraine, onwillekeurige spiersametrekkings, parestesie, bedwelming, duiseling. Gastroïntestinale stelsel Naarheid Abdominale pyn, konstipasie diarree, dispepsie, Disfagie, melena, edeem van die tong winderigheid droë mond, braking Gehoor- en vestibulêre Tinnitus versteurings Metabolisme en voeding Gewigsverlies versteurings Psigiatriese versteurings Rooibloedsel versteurings Anoreksie, angs, verwarring, euforie, slapeloosheid, senuweeagtigheid Amnesie, depersonalisasie, depressie, geneesmiddel misbruik, emosionele onstabiliteit, hallusinasies, impotensie, slegte drome, abnormale denke Anemie

23 Respiratoriese stelsel Urinêre stelsel Dispnee Albuminurie, mikturisie versteuring, oligurie, urienretensie Visuele versteurings Liggaam as 'n geheel Vel en aanhangsels Astenie, moegheid, warmgloede Pruritus, uitslag, verhoogde sweet Abnormale visie Borspyn, koue rillings, sinkopee, onttrekkingsindroom Klinies beduidende newe-effekte waarvan voorheen berig is in kliniese toetse of nabemarkingsverslae oor tramadolhidrochloried, sluit in: Ortostatiese hipotensie, allergiese reaksies (insluitende anafilakse en urtikarie, Stevens-Johnsonsindroom/TENS), kognitiewe disfunksie, selfmoordneiging en hepatitis. Laboratorium-abnormaliteite wat aangemeld is het verhoogde kreatinien ingesluit. Serotoniensindroom (die simptome kan koors, eksitasie, bewing en agitasie insluit) was met tramadol aangemeld toe dit gelyktydig met ander serotonergiese middels soos SSRIs en MAO-remmers gebruik is. Nabemarkingservaring met die gebruik van produkte wat tramadol bevat, sluit in seldsame berigte van delirium, miose, midriase en spraakversteuring en baie skaars berigte van bewegingsversteuring. Nabemarkingstoesig oor tramadol het skaars veranderings in die uitwerking van warfarien, insluitende verhoging van protrombientyd, geopenbaar. Gevalle van hipoglukemie is gerapporteer.

24 Klinies beduidende newe-effekte waarvan voorheen berig is in kliniese proewe of nabemarkingsverslae oor parasetamol, sluit in: Allergiese reaksies (hoofsaaklik veluitslag), of gevalle van hipersensitiwiteit sekondêr tot parasetamol, is skaars en word gewoonlik beheer deur die gebruik van die geneesmiddel te staak, en wanneer nodig simptomatiese behandeling toe te pas. Daar is verskeie berigte wat daarop dui dat parasetamol hipoprotrombinemie veroorsaak wanneer dit saam met warfarienagtige verbindings toegedien word. In ander studies het die protrombientye nie verander nie. BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING DAARVAN Die kliniese beeld van oordosering kan tekens en simptome van tramadol oordosering, parasetamol oordosering of van beide toon. Tramadol Die aanvanklike simptome van tramadol oordosering kan respiratoriese onderdrukking en/of toevalle insluit. Aandag moet eerstens aan voldoende en volgehoue lugtoevoer, gepaard met algemene ondersteunende behandeling gegee word. Terwyl naloksoon sommige, maar nie al die simptome van oordosering sal omkeer nie, word die risiko van toevalle ook tydens toediening van naloksoon verhoog. Die behandeling van rusteloosheid en/of stuiptrekkings is simptomaties en ondersteunend (bensodiasepiene/ barbiturate). Tramadol word minimaal deur hemodialise of hemofiltrasie uit die serum verwyder. Die behandeling van akute TRAMACET vergiftiging deur slegs van hemodialise of hemofiltrasie gebruik te maak is dus nie geskik vir ontgiftigingsdoeleindes nie.

25 Parasetamol Vinnige behandeling is noodsaaklik. In geval van oordosering raadpleeg ʼn dokter onmiddellik, of neem die pasiënt direk na ʼn hospitaal. n Vertraging in die aanvang van behandeling kan beteken dat die teenmiddel te laat gegee word om doeltreffend te wees. Tekens van lewerskade verskyn dikwels eers nadat die tyd vir doeltreffende behandeling reeds verstryk het. Vatbaarheid vir parasetamolvergiftiging is hoër by pasiënte wat herhaaldelik hoë dosisse (meer as 5-10 g parasetamol/dag) vir etlike dae gebruik het, by chroniese alkoholisme, chroniese lewersiekte, VIGS, wanvoeding en met die gebruik van geneesmiddels wat oksidasie deur lewermikrosome induseer soos barbiturate, isoniasied, rifampisien, fenitoïen en karbaamasepien. Simptome van oordosering met parasetamol binne die eerste 24 uur is ondermeer bleekheid, naarheid, braking, anoreksie en moontlik buikpyn. Ligte simptome in die eerste twee dae na akute vergiftiging weerspieël nie die moontlike erns van die oordosering nie. Lewerskade kan binne 24 tot 48 uur of langer na inname te voorskyn tree; aanvanklik deur ʼn toename in die konsentrasie van transaminase in die serum en aktiwiteit van melksuurdehidrogenase, hoër vlakke bilirubien in die serum en verlenging van protrombientyd. Lewerskade kan tot enkefalopatie, koma en die dood lei. Akute nierversaking met akute tubulêre nekrose kan ontwikkel selfs al is daar nie ernstige lewerskade nie. Abnormaliteite in glukosemetabolisme en metaboliese asidose kan voorkom. Hartaritmieë is aangemeld. Behandeling van oordosering met parasetamol: Alhoewel daar beperkte bewyse is, word aanbeveel dat enige volwassene wat 5 10 g of meer parasetamol (of ʼn kind wat meer as 140 mg/kg parasetamol) in die voorafgaande vier uur ingeneem het,

26 maaglediging deur maagspoeling moet ondergaan (vir kinders kan emese voldoende wees) en ʼn enkele dosis van 50 g geaktiveerde houtskool moet deur die maagbuis toegedien word. Behandeling van pasiënte wat vatbaar is vir parasetamolvergiftiging (kyk hierbo) kan nodig wees, selfs na inname van minder parasetamol as hierdie. Vir pasiënte wat in stupor of koma is, moet endotrageale intubasie voor maagspoeling gedoen word om aspirasie te voorkom. N-asetielsisteïen moet so gou as moontlik en verkieslik binne agt uur na oordosering aan alle gevalle van vermoedelike oordosering gegee word, alhoewel behandeling tot 36 uur na inname steeds voordelig kan wees, veral as meer as 150 mg/kg parasetamol geneem is. n Aanvanklike dosis van 150 mg/kg N- asetielsisteïen in 200 ml dekstrose-inspuiting word intraveneus oor 15 minute toegedien, gevolg deur ʼn intraveneuse infusie van 50 mg/kg in 500 ml dekstrose-inspuiting oor die volgende vier uur en dan 100 mg/kg in ml dekstrose-inspuiting oor die volgende sestien uur. Die volume intraveneuse vloeistof moet aangepas word vir kinders. Hoewel die mondelike formulering nie die behandeling van keuse is nie, kan 140 mg/kg as ʼn oplossing in water aanvanklik gegee word, gevolg deur 70 mg/kg elke vier uur vir sewentien dosisse. In alle gevalle van vermoedelike oordosering moet die vlak van parasetamol in die plasma vier uur na inname bepaal word. Vlakke wat bepaal word voordat vier uur verloop het kan misleidend wees, tensy dit hoog is. Pasiënte met ʼn risiko vir lewerskade en wat dus voortgesette behandeling met N-asetielsisteïen benodig, kan volgens die konsentrasie parasetamol in hul plasma geïdentifiseer word. In die normogram hieronder kan die konsentrasie parasetamol in die plasma teenoor die tyd sedert inname uitgesit word.

27 PLASMA PARASETAMOL KONSENTRASIE Submitted: 15 April 2014 Normale behandelingslyn Hoë-risiko behandelingslyn URE NA PARASETAMOL INNAME Bron: Goodman & Gilman s The Pharmacological Basis of Therapeutics, 11 de uitgawe. Diegene by wie die plasmaparasetamolkonsentrasie bo die normale behandelingslyn is, moet met N- asetielsisteïen teen 100 mg/kg intraveneus oor sestien uur herhaaldelik voortgaan totdat daar herstel intree. Pasiënte met verhoogde vatbaarheid vir lewerskade, soos hierbo aangedui, moet aanhou met behandeling as konsentrasies bokant die hoë-risiko behandelingslyn is. Die protrombienindeks korreleer die beste met oorlewing. Moniteer alle pasiënte wat beduidende hoeveelhede ingeneem het vir ten minste ses-en-negentig uur. IDENTIFIKASIE Liggeel, filmbedekte kapsulevormige tablet met J-C aan die een kant en T/P aan die anderkant gegraveer. AANBIEDING Stulpverpakkings met 60 tablette.

28 BERGINGSINSTRUKSIES Bewaar op 'n koel, droë plek by of benede 25 C. HOU BUITE BEREIK VAN KINDERS. REGISTRASIENOMMER 35/2.9/0010 NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE REGISTRASIESERTIFIKAAT: JANSSEN PHARMACEUTICA (PTY) LTD (Reg. No. 1980/011122/07) Building 6, Country Club Estate 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET 18 July 2014