משרד הבריאות ותוכנו נבדק ואושר על ידו ע"י

Transcription

1 משרד הבריאות ותוכנו נבדק ואושר על ידו ע"י עלון זה נקבע ע פורמט TRAMAL/TRAMAL RETARD NAME OF THE PHARMACEUTICAL PRODUCT: TRAMAL capsules TRAMAL Drops TRAMAL RETARD 50 Tablets, extended release TRAMAL RETARD 100 Tablets, extended release TRAMAL Suppositories ACTIVE SUBSTANCE: Tramadol hydrochloride TRAMAL Capsules: 1 capsule contains 50 mg Tramadolhydrochloride TRAMAL Drop: 100 mg of tramadol hydrochloride per 1ml TRAMAL suppositories: 1 suppository contains 100 mg Tramadol hydrochloride TRAMAL RETARD Tablets: 1 Tablet contains 50mg or 100 mgtramadol hydrochloride PHARMACODYNAMICALLY RELEVANT AUXILIARY MATERIALS: TRAMAL Drops: 0.5 ml oral drops contains 100mg sucrose and 0.5mg macrogol hydroxystearate Tramal retard 50 and Tramal retard 100: Each tablet contains 2.5mg lactose monohydrate PHARMACEUTICAL FORM: Tramal drops: clear slightly viscous colorless to weakly yellow solution Tramal retard 50: Round, Biconvex, film-coated pale-yellow tablets, marked with the manufacturer's logo on one side and T0 on the other side. Tramal retard 100: Round, Biconvex, film-coated white tablets, marked with the manufacturer's logo on one side and T1 on the other side. Tramal suppositories: White to pale-yellow wax-like appearance. Tramal capsules: Green/pale yellow hard gelatine capsules for oral administration, imprinted with Grünenthal logo. CLINICAL PARTICULARS: THERAPEUTIC INDICATION: Treatment of moderate to severe pain. POSOLOGY AND METHOD OF ADMINISTRATION: The dose of Tramal should be adjusted to the intensity of the pain and the sensitivity of the individual patient.

2 Unless otherwise prescribed, Tramal should be administered as follows: Adults and adolescents above the age of 14 years: Capsules, Drops, Suppositories mg tramadol hydrochloride 4-6 hourly Retard Tablets- The usual initial dose is mg twice daily, morning and evening. If pain relief is insufficient, the dose may be titrated upwards to 150 or 200 mg tramadol twice daily. The lowest analgesically effective dose should be generally selected. Daily doses of 400 mg active substance should not be exceeded except in special clinical circumstances. Elderly patients: A dose adjustment is not usually necessary in elderly patients (up to 75 years) without clinically manifest hepatic or renal insufficiency. In elderly patients (over 75 years) the elimination may be prolonged. Therefore, if necessary, the dosage interval is to be extended according to the patients requirements. Patients with renal insufficiency/dialysis and hepatic insufficiency: In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients the prolongation of the dosage interval should be carefully considered according to the patients requirements. In cases of severe renal and/or severe hepatic insufficiency Tramadol retard tablets are not recommended. Children: Over 14 years: Dosage as for adults. Not recommended for children under 14 years. Method of administration: Tramal capsules and Tramal retard are to be taken whole, not divided or chewed, with sufficient liquid, with or without food. Tramal oral drops are to be taken with a little liquid or on sugar, with or without food Tramal suppositories are to be inserted into the rectums, preferably after defecation. Duration of administration: Tramdol should under no circumstances be administered for longer that absolutely necessary. If long-term treatment with tramadol is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary. CONTRA-INDICATIONS: Tramal is contraindicated: In hypersensitivity to tramadol or any of the excipients. In acute intoxication with alcohol, hypnotics, analgesics, opioids or other psychotropic medicinal products. In patients who are receiving monoamine oxidase inhibitors or within 2 weeks (14 days) of their withdrawal. In patients with epilepsy not adequately controlled by treatment. For use in narcotic withdrawal treatment. SPECIAL WARNINGS AND PRECAUTIONS FOR USE: In patients sensitive to opiates, tramadol should only be used with caution. Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered (see section Interaction with other medicaments and other forms of interaction), or if the recommended dosage is significantly exceeded (see section Overdose) as the possibility of respiratory depression cannot be excluded in these situations. In addition, tramadol may increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold (see section Interaction with other medicaments and other forms of interaction). Patients with epilepsy or those susceptible to seizures should be only treated with tramadol if there are compelling circumstances. Tramadol has a low dependence potential. On long-term use, tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision. Tramal is not a suitable substitute in opioid dependent patients. The product does not suppress morphine withdrawal symptoms although it is an opioid agonist. עמוד 2 מתוך 8

3 Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the recommended upper daily dose limit (400mg). Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see Interactions section). In opioid-dependant patients, patients with, head injury, increased intracranial pressure, or patients in shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory center or function, Tramal should be used with caution. Suicide Risk Do not prescribe tramal for patients who are suicidal or addiction-prone. Prescribe tramal with caution for patients taking tranquilizers or antidepressant drugs and for patients who use alcohol in excess. Serious potential consequences of overdosage with tramal are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (see OVERDOSAGE). Tramal retard tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this product. Tramal drops contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product. INTERACTION WITH OTHER MEDICAMENTS AND OTHER FORMS OF INTERACTION: Tramadol should not be combined with MAO inhibitors. In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine, life-threatening interactions on the central nervous system, respiratory and cardiovascular function have been observed. The same interaction with MAO inhibitors cannot be ruled out during treatment with tramadol. Tramal may potentiate the CNS effects of other centrally acting drugs (including alcohol) when administered concomitantly with such drugs. Tramadol may increase the potential for both selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), anti-psychotics and other seizure-lowering medicinal products to cause convulsions (See Special Warnings and Precautions and Pharmacokinetic Properties sections). In isolated cases there have been reports of "serotonin syndrome" in a temporal connection with the therapeutic use of tramadol in combination with other serotoninergic medicinal products such as selective serotonin re-uptake (SSRIs) or with MAO inhibitors. Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, hyprreflexia, myoclonus and diarrhea. Withdrawal of the serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms. Caution should be exercised during concomitant treatment with tramadol and coummarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding and ecchymoses in some patients. Administration of Tramal together with mixed agonist/antagonist (e.g., pentazocine, nalbuphine or buprenorphine, is not advisable, because the analgesic effect of a pure agonist like tramadol may be theoretically reduced in such cases. The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine, clinically relevant interactions are unlikely to occur. Simultaneous or previous administration of carbamazepine may reduce the analgesic effect and shorten the duration of action. Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied. In a limited number of studies, the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondasteron increased the requirement of tramadol in patients with postoperative pain. PREGNANCY AND LACTATION: Pregnancy: Tramal should not be used in pregnancy as there is inadequate evidence available to assess the safety of tramadol in pregnant women. Animal studies with tramadol revealed at very high doses effect on organ development, ossification and neonatal mortality. Tramadol crosses the placenta. Tramadol administered before or during birth does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Chronic use during pregnancy may lead to neonatal withdrawal symptoms. עמוד 3 מתוך 8

4 Lactation: Tramal is not recommended during breast feeding as tramadol and its metabolites have been detected in breast milk. An infant could ingest 0.1% of the dose administered to the mother. After a single administration of tramadol it is not usually necessary to interrupt breast-feeding. EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Even when taken according to instructions, Tramal may cause somnolence and dizzyness.this effect may be potentiated by alcohol and other CNS depressants. Patients should be warned not to drive or operate machinery if affected. UNDESIRABLE EFFECTS: The most commonly reported adverse reactions are nausea and dizziness, both occurring in more than 10% of the patients. The frequencies are defined as follows: Very common: 1/10 Common: 1/100, <1/10 Uncommon: 1/1000, <1/100 Rare: 1/10 000, <1/1000 Very rare: <1/ Not known: cannot be estimated from the available data Cardiovascular disorders: Uncommon: cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed. rare: bradycardia, increase in blood pressure Nervous system disorders: very common: dizziness common: headache, somnolence rare: changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, and syncope. not known: speech disorders If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly, respiratory depression may occur. Epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with medicinal products which can lower the seizure threshold. Psychiatric disorders: rare: hallucinations, confusion, sleep disturbance, anxiety and nightmares. Psychic adverse reactions may occur following administration of Tramal which vary individually in intensity and nature (depending on personality and duration of treatment). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behavior, perception disorders). Dependence may occur. Eye disorders: rare: blurred vision not known: mydriasis Respiratory disorders: rare: dyspnoea Worsening of asthma has been reported, though a causal relationship has not been established. Gastrointestinal disorders: very common: nausea עמוד 4 מתוך 8

5 common: vomiting, constipation, dry mouth uncommon: retching; gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhea Skin and subcutaneous disorders: common: sweating uncommon: dermal reactions (e.g. pruritus, rash, urticaria) Musculoskeletal disorders: rare: motorial weakness Hepatobiliary disorders: In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol. Renal and urinary disorders: rare: micturition disorders (difficulty in passing urine, dysuria and urinary retention) General disorders: common: fatigue rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis; Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, personalisation, derealisation, paranoia). OVERDOSE: Symptoms In principle, on intoxication with tramadol symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest. Treatment The general emergency measures apply. Keep open the respiratory tract (aspiration!), maintain respiration and circulation depending on the symptoms. The antidote for respiratory depression is naloxone. In animal experiments naloxone had no effect on convulsions. In such cases diazepam should be given intravenously. In case of intoxication orally, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities or prolonged-release formulations. Tramadol is minimally eliminated from the serum by haemodialysis or haemo-filtration. Therefore treatment of acute intoxication with Tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties: Pharmacotherapeutic group: other opioids; ATC-code N 02 AX 02 Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist at µ, δ and κ opioid receptors with a higher affinity for the µ receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Also gastrointestinal motility is less affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth) that of morphine Pharmacokinetic properties More than 90% of tramadol is absorbed after oral administration. The mean absolute bioavailability is approximately 70 %, irrespective of the concomitant intake of food. The difference between absorbed and non-metabolised available tramadol is probably due to the low first-pass effect. The first-pass effect after oral administration is a maximum of 30 %. After oral administration of 100mg tramadol in liquid form the peak plasma concentration C max after 1.2 hours is calculated to be 309±90 ng/ml. עמוד 5 מתוך 8

6 After oral administration of the same dose in a solid form the C max after two hours is 280±49 ng/ml After oral administration of Tramal retard 100mg peal plasma concentrations C max after 4.9 hours is calculated to be 141± 4.9h. The time to reach C max was 1 hour for Tramal drops and 2.2 hours for Tramal capsules reflecting the fast absorption of the oral liquid form. Absolute bioavailability of Tramal suppositories is 78±10% Tramadol has a high tissue affinity (V d,ß = 203 ± 40 l). It has a plasma protein binding of about 20 %. Tramadol passes the blood-brain and placental barriers. Very small amounts of the substance and its O-desmethyl derivative are found in the breast-milk (0.1 % and 0.02 % respectively of the applied dose). The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite. Up to now, clinically relevant interactions have not been reported. Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90 % of the total radioactivity of the administered dose Elimination half-life t1/2,ß is approximately 6 h, irrespective of the mode of administration. In patients above 75 years of age it may be prolonged by a factor of approximately 1.4. In cases of impaired hepatic and renal function the half-life may be slightly prolonged. In patients with cirrhosis of the liver, elimination half-lives of h (tramadol) and h (O-desmethyltramadol), in an extreme case 22.3 h and 36 h respectively, have been determined. In patients with renal insufficiency (creatinine clearance < 5 ml/min) the values were h and h, in an extreme case 19.5 h and 43.2 h respectively. In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O- demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent substance by the factor 2-4. Its half-life t1/2,ß (6 healthy volunteers) is 7.9 h (range h) and is approximately that of tramadol. Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range. The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably in isolated cases. A serum concentration of ng/ml is usually effective Preclinical Safety Data: On repeated oral and parenteral administration of tramadol for 6-26 weeks in rats and dogs and oral administration for 12 months in dogs haematological, clinico-chemical and histological investigations showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses considerably above the therapeutic range: restlessness, salivation, convulsions, and reduced weight gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions. In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams and raised neonate mortality. In the offspring retardation occurred in the form of ossification disorders and delayed vaginal and eye opening. Male fertility was not affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the offspring. In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies showed no such effects. According to knowledge gained so far, tramadol can be classified as non-mutagenic. Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dosedependent) LIST OF EXCIPIENTS TRAMAL Drops: Sucrose, Potassium sorbate, Glycerol 85%, Propylene glycol, Sodium cyclamate, Saccharin sodium, Macrogolglycerol hydroxystearate, Mint oil, Anise flavour,purified water. TRAMAL RETARD Tablets: Core: Microcrystalline cellulose, Hypromellose mpa's, Magnesium stearate, Colloidial anhydrous sillica. Coating: Hypromellose 6 mpa's, Lactose monohydrate, Macrogol 6000, Propylene Glycol, Talc, titanium dioxide (E 171). Tramal retard 50 also contains Yellow iron oxide (E172). עמוד 6 מתוך 8

7 TRAMAL Capsules: Core: Micro-crystalline cellulose, Sodium starch glycollate, Magnesium stearate, colloidial anhydrous sillica. Capsules: Glatin, Yellow iron oxide (E 172), Indigotine (E 132), Titanium dioxide (E 171), Sodium lauryl sulphate, Capsulegel ink 1028 black. TRAMAL suppositories: Hard fat SHELF LIFE Drops: 48 months Retard 50mg Tablets: 36 months Retard 100mg Tablets: 60 months Capsules: 60 months Suppositories: 60 months Do not use after the expiry date printed on the pack. SPECIAL STORAGE CONDITIONS Do not store above 30 C PRESENTATIONS AND PACK SIZES Drops Pack containing 10 ml Instructions for handling: Tramal drops is provided with a child-proof screw-cap. To open, the cap must be pressed down firmly and the unscrewed. After use, screw on cap tightly. To obtain oral drops, turn the bottle upside down and tap slilghtly on the base of the bottle until the first drop appears. Retard 100 Tablets Pack containing 10 Tablets Pack containing 30 Tablets Pack containing 50 Tablets Pack containing 150 Tablets Retard 50 Tablets Pack containing 10 Tablets Pack containing 30 Tablets Capsules Pack containing 10 capsules Pack containing 30 capsules Pack containing 50 capsules עמוד 7 מתוך 8

8 Suppositories Pack containing 5 suppositories Pack containing 10 suppositories REG. NUMBER: Tramal drops: Tramal retard 50: Tramal retard 100: Tramal capsules: Tramal suppositories: MANUFACTURER: Grunenthal GmbH, Aachen, Germany IMPORTER: Tec-O-Pharm-Libra Ltd. Po.Box Jerusalem TRA-LFP עמוד 8 מתוך 8