SUMMARY OF PRODUCT CHARACTERISTICS ENGLISH Dolol 50 mg capsules

SUMMARY OF PRODUCT CHARACTERISTICS ENGLISH Dolol 50 mg capsules 1. NAME OF THE MEDICINAL PRODUCT 1

Dolol 50 mg capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 capsule contains 50 mg Tramadol hydrochloride corresponding to 44 mg tramadol. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Capsules, hard White opaque capsules containing a white and odourless powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of moderate to severe pain. 4.2 Posology and method of administration The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected. As for all opioid analgesics the dose of tramadol, with regards to the severity of the pain and sensitivity of the patient, should be administered in the lowest possible dose to offer the individual patient a clinical sufficient pain relief. In patients not requiring fast analgesia, tolerability may be improved by initiating therapy at lower doses and extended intervals and titrating up (e.g. chronic pains and/or cancer patients). After long-term use, psychiatric and physical dependence may develop. Therefore it is very important not to administer tramadol for a longer period of time than absolutely necessary (see 4.4 and 4.8). Careful and regular monitoring should be carried out to establish whether and to what extend further treatment is necessary. Discontinuation of therapy should be carried out gradually in patients who may have developed physical dependence to avoid precipitating withdrawal symptoms. Adults and children over 15 years: 50-100 mg 3-4 times daily. Maximum 400 mg daily. Children Dolol 50 mg capsules are not recommended for use in children below 15 years. Geriatric patients A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient's requirements. Renal insufficiency/dialysis and hepatic impairment In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements. Hepatic impairment: Tramadol is eliminated primarily via hepatic metabolism. Elimination half-life increases to 13.3 hours (oral dosing) in patients with hepatic insufficiency vs. 5.1 hours in normal subjects. 2

In patients with cirrhosis the maximum oral dose is 50 mg every 12 hours. Renal impairment: If creatinine clearance is less than 30 min/ml the dosing interval should be increased to 12 hours. The maximum daily dose is 200 mg. At end stage renal disease (creatinine clearance < 10 ml/min) a dose of 50 mg every 12 hours is recommended. Geriatric patients 4.3 Contraindications Hypersensitivity to tramadol or any of the excipients, or to opioids. Must not be used in patients suffering from uncontrolled epilepsy, acute intoxication by alcohol, hypnotics, analgesics or other medicaments that act on the central nervous system. Simultaneous administration of an MAO-inhibitor or within 2 weeks after stopping treatment with MAOinhibitors. Acute respiratory depression. Tramadol must not be used for narcotic withdrawal treatment. 4.4 Special warnings and precautions for use Tramadol should be used with caution in persons being treated with medicine lowering the convulsion threshold (MAO-inhibitors, tricyclic antidepressants and selective serotonin reuptake inhibitors). Tramadol should also be used with caution in patients suffering from head trauma with increased intracranial pressure, severe liver disease, severe renal failure, seizure liability, shock, severe respiratory depression with concomitant treatment with CNS depressants. (See also 4.5) Tramadol is not suitable as substitute in opioid dependency and cannot suppress morphine abstinence. Tramadol has addictive properties. Increased tolerance and psychological and physical dependence can develop following long-term medication. Cases of dependence to and abuse of tramadol have been reported. Withdrawal symptoms such as anxiety, sweating, nausea, diarrhoea, tremors and insomnia have been reported following discontinuation of treatment. (see Section 4.8). In patients with a history of drug abuse, Dolol should only be prescribed for short-term use and under careful medical supervision. For the moment, should not be used in persons under full anaesthetic. (Experience missing). Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg). In addition, tramadol may lower the seizure threshold (see also 4.5). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances. Patients with impaired lung function e.g. chronic obstructive lung disease or uncontrolled asthma may be at risk for respiratory depression and tramadol should be used with great caution. Decreased liver- or kidney function: Patients with cirrhosis or with end-stage renal disease (creatinine clearance 30 ml/min) have slower elimination of tramadol and its pharmacologically active metabolite. Thus, the dosing interval should be doubled in these patients. (See also 4.2) 4.5 Interaction with other medicinal products and other forms of interaction Alcohol, hypnotics and psychotherapeutic agents with sedative effect may enhance the CNS-depressive effect. (See also 4.8) Should not be administered to patients undergoing or having undergone treatment with MAO-inhibitors within the last two weeks. (See also 4.3) 3

Enzyme inducers, e.g. carbamazepine, may lower plasma tramadol concentration and diminish or shorten its analgesic effect. Simultaneous administration with antagonist opioids (e.g. nalbuphine, pentazocine) may reduce the analgesic effect by competitive blocking of the receptors. Concomitant administration of opioid agonist (e.g. buprenorphine) can cause addictive CNS depression because the use of other analgesics in combination with tramadol add a significant CNS and respiratory depression. Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions. The risk of convulsions is increased with concomitant administration of other seizure-lowering drugs e.g. selective serotonin reuptake inhibitors, tricyclic anti-depressants, antipsychotics and bupropion. Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely when one of the following is observed: Spontaneous clonus Inducible or ocular clonus with agitation or diaphoresis Tremor and hyperreflexia Hypertonia and body temperature > 38 C and inducible or ocular clonus. Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms. Drugs that inhibit the CYP3A4 enzyme (ketoconazol, itraconazole, fluconazole and erythromycin) may inhibit the elimination of tramadol and its active metabolite and thus, increase the plasma concentrations of the two substances. The clinical effects of this possible interaction have not been studied. With concomitant administration of serotonergic drugs, there have been isolated reports of cases of serotonin syndrome. Discontinuation of treatment with the serotonergic drugs ususally results in a swift improvement of the symptoms. The need for further drug treatment is dependent on the type and seriousness of the symptoms observed. Caution should be exercised during concomitant treatment with tramadol and coumarin anticoagulantia (e.g. warfarin) due to reports of increased INR and ecchymoses in some patients on anticoagulantia. 4.6 Pregnancy and lactation Pregnancy Studies in animals have shown reproductive toxicity under very high doses (See also 5.3). No studies have been performed on the use of tramadol early in human pregnancy, but during labour the analgesic effect of 100 mg of tramadol was reported similar to 75 or 100 mg of pethidine, but with little to no depressant effect on the child. Tramadol administered before or during birth does not affect uterine contractility. The transplacental transfer of tramadol in delivering women occurred with a mean ratio of tramadol concentrations in the umbilical cord and maternal serum of 0.83. As there is insufficient data available on the safety of tramadol in human pregnancy, tramadol should therefore not be used in pregnant women. Lactation 4

During lactation about 0.1% of the maternal dose is secreted into the milk. Available data is inconclusive or is inadequate to determine infant risk when used during breastfeeding. Dolol is not recommended during breast-feeding. After a single administration of tramadol it is not usually necessary to interrupt breast-feeding. 4.7 Effects on ability to drive and use machines Dolol capsules may cause drowsiness and this effect may be potentiated by alcohol, antihistamines and other CNS depressants. If patients are affected, they should be warned not to drive or operate machinery. 4.8 Undesirable effects Physical dependence and withdrawal symptoms (restlessness, anxiety, nervousness, sleeplessness, hyperkinesia, tremor and gastrointestinal disorders) may occur in connection with therapeutic doses (see Section 4.4). Withdrawal symptoms are in accordance with those occurring in connection with opiate withdrawal symptoms. In general, the incidence of predictable undesirable effects is dependent on dosage, timing of administration and duration of treatment (see section 4.2 and 4.4). By using the lowest effective dose for the minimum possible period of time, undesirable effects can be minimised. The more severe adverse effects of tramadol are respiratory depression, circulatory failure and rarely anaphylactic reactions. The most commonly observed adverse reactions are nausea, dizziness, headache, drowsiness, fatigue and restlessness. Cardiac disorders: Uncommon ( 1/1,000 to <1/100): There may be effects on cardiovascular regulation (palpitation, tachycardia, postural hypotension or circulatory failure) especially after intravenous administration or in physically stressed patients. Very rare (<1/10.000): Myocardial ischemia, abnormal electrocardiograms, hypertension. Nervous system disorders: Very common ( 1/10): Dizziness and somnolence, fatigue, headache. Rare ( 1/10,000 to <1/1,000): Hyperkinesia, tremor and epileptiform convulsions Very rare (<1/10.000): Ataxia Eye disorders: Rare ( 1/10,000 to <1/1,000): Blurred vision Respiratory, thoracic and mediastinal disorders Very rare (<1/10.000): Respiratory depression and eventually pulmonary oedema Gastrointestinal disorders: Very common ( 1/10): Nausea, diarrhoea Common ( 1/100 to <1/10): Constipation, vomiting and dry mouth Uncommon ( 1/1,000 to <1/100): Gatrointestinal irritation (bloated stomach) Rare ( 1/10,000 to <1/1,000): Changes in appetite Very rare (<1/10.000): Taste perversion. Hiccups. Renal and urinary disorders: Common ( 1/100 to <1/10): Micturition disorders and urinary retention Rare ( 1/10,000 to <1/1,000): Dysuria Skin and subcutaneous tissue disorders: Common ( 1/100 to <1/10): Increased sweating Uncommon ( 1/1,000 to <1/100): Dermal reactions (e.g. pruritus, urticaria, flush). Very rare (<1/10.000):Stevens-Johnson syndrome, toxic epidermal necrolysis. 5

Musculoskeletal and connective tissue disorders Common ( 1/100 to <1/10): Hypertonia Vascular disorders: Common ( 1/100 to <1/10): Vasodilation General disorders and administration site conditions: Rare ( 1/10,000 to <1/1,000): Allergic reaction (e.g. bronchospasm, angioedema) and anaphylactoid reaction have been reported. Hepatobiliary disorders: In isolated cases: increased liver enzyme values Psychiatric disorders: Rare ( 1/10,000 to <1/1,000): Sleep disturbances, nightmares, confusion and hallucinations. Dependence may occur after a longer period of treatment. Very rare (<1/10.000): Restlessness, anxiety, nervousness and sleeplessness. Changes in cognitive and sensorial capacity, depression, and suicidal ideation. Serotonin syndrome: Mental status changes, agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhoea, incoordination, and fever. Nearly all the patients were taking concomitant medication known to increase brain serotonin levels. Others Very rare (<1/10.000): Psychological and/or physical dependence.withdrawal syndrome/reactions: agitation, anxiety, nervousness, insomnia, sweating, hyperkinesia, tremor, pains, gastrointestinal symptoms, upper respiratory symptoms, piloerection and hallucinations may occur if tramadol is abruptly discontinued. 4.9 Overdose Symptoms: Miosis, vomiting, convulsions, circulatory failure and consciousness disorders up to coma, sedation, respiratory depression up to respiratory arrest, eventually pulmonary oedema, tachycardia, hypertension, lethargy and rarely cardiovascular collapse. Treatment: Symptomatic treatment including maintaining respiration and circulation. The stomach should be emptied by vomiting (conscious patients) or gastric irrigation. Antidote: Naloxone is antidote for respiratory depression. Naloxone showed no effect on tramadol induced convulsions in experimental animals. In such cases diazepam should be given intravenously. Tramadol is not eliminated from the serum by haemodialysis or haemofiltration. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group, ATC code: N 02 AX 02 Tramadol is a cyclohexanol derivative, with morphine-like properties, and with central analgesic activity. Tramadol has a low affinity to opioid receptors, highest to µ-receptors. Furthermore, Tramadol enhances the endogenous pain modulation, partly by inhibition of the reuptake of Noradrenaline and Serotonine in the synaptic cleft, partly by increasing the release of Serotonine. The analgetic effect occurs about 1 hour after oral administration and lasts for a period of 4-8 hours. Respiration is not inhibited by the administration of therapeutic doses, but a respiratory depression may be seen if a dosis higher than that recommended is used, especially after parenteral administration. 5.2 Pharmacokinetic properties 6

Tramadol is quickly and almost completely absorbed from the gastrointestinal tract, independent of a concomitant intake of food. The bioavailability is about 68% due to first pass metabolism. Maximum plasma concentration is obtained after 2 hours. Tramadol is metabolised mainly in the liver by N- and O- demethylation and glucoronide conjugation of O-demethylation metabolites. The N-demethylation and O- demethylation are catalysed by the enzymes CYP3A4 and CYP2D6, respectively. O-desmethyl tramadol is pharmacologically active. The half-life of elimination is about 5-6 hours for Tramadol and 6-7 hours for O- desmethyl tramadol. The volume of distribution is about 300 l, which indicates a high tissue affinity. The protein binding is 20%. Tramadol crosses the blood-brain barrier and the placenta. A very small amount of Tramadol is excreted in breast milk. 90% of the administered dose is eliminated by renal excretion, 15% as unchanged. The remaining 10% is eliminated in the feces. The pharmacokinetic profile is linear within the theraputic dose range. The relationship between serum concentration and analgesic effect is dose dependent but with large deviations in the individual patients. 5.3 Preclinical safety data In animal studies an increased neonatal mortality was observed after administration of Tramadol. Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality. Teratogenic effects were not observed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Calcium hydrogen phosphate, anhydrous Magnesium stearate Silica, colloidal anhydrous Gelatin Titanium dioxide (E 171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Blister packaging made of white opaque PVC film and aluminium foil with a PVC/PVDC heat sealing lacquer. Pack sizes: 20, 100 and 5 x 50 capsules Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements 7

Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Nycomed Danmark A/S Langebjerg 1, P.O. Box 88 DK-4000 Roskilde Denmark 8. MARKETING AUTHORISATION NUMBER(S) 18099 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17 June 1998 10. DATE OF REVISION OF THE TEXT MM/YYYY09/2012 8