Summary of Product Characteristics Part IB1 Tramadol HCl Disphar druppels 100 mg/ml, oral drops Page 1 of 7

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1 Tramadol HCl Disphar druppels 100 mg/ml, oral drops Page 1 of 7 1. NAME OF THE MEDICINAL PRODUCT Tramadol HCl Disphar druppels 100 mg/ml, oral drops 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 1 ml solution contains 100 mg tramadol hydrochloride For excipients see 6.1 List of Excipients. 3. PHARMACEUTICAL FORM Oral drops, solution. Clear, colourless or yellowish solution. 4. CLINICAL PARTICULARS 4.1. Therapeutic indications Treatment of moderate to severe pain Posology and method of administration As with all analgesic drugs, the dose of tramadol should be adjusted according to the severity of the pain and the sensitivity of the individual patient. The duration of the analgesic effect is dependent on pain intensity and lasts between 4 to 8 hours. Treatment should be limited and intermittent, as dependency may occur during tramadol use. The benefit of prolonged administration should be reviewed to ensure a balance against the risk of dependency (see 4.4, Special warnings and precautions for use; and 4.8, Undesirable effects). The maximal daily dose of 400 mg should not be exceeded. Adults, adolescents and children aged 12 years and over The usual single dose is 50 to 100 mg tramadol hydrochloride, 3 to 4 times a day (20 40 drops Tramadol HCl Disphar druppels 100 mg/ml, oral drops). When this does not give sufficient pain relief, the dose should be increased gradually until sufficient pain relief is obtained. Elderly For patients aged below 75 years with normal renal and hepatic function the dose of adults should be used. The elimination-half-life of tramadol may be increased in patients aged over 75 years. In these cases the dose-interval should be prolonged individually. Patients with renal or hepatic impairment The elimination half-life of tramadol may be prolonged in these patient populations. When single doses are used for relief of acute pain dose adjustment is not required. Tramadol is contraindicated in patients with serious renal impairment (creatinine clearance < 10 ml/min.) and/or serious hepatic impairment. In patients with hepatic or renal impairment (creatinine clearance < 30 ml/min.) a prolonged dose interval may be required. However, when the dose is increased gradually, these patients should be monitored carefully. Dialysis: As tramadol is only removed very slowly by haemodialysis or haemofiltration, postdialysis administration to maintain analgesia is not usually necessary.

2 Tramadol HCl Disphar druppels 100 mg/ml, oral drops Page 2 of 7 Children, toddlers and infants aged below 12 years Children, toddlers and infants aged between 1 and 12 years may receive a single dose of 1 2 mg tramadol hydrochloride per kg body weight 3 to 4 times a day, with a maximal dose of 8 mg/kg/day. The table below gives characteristic examples for the concerned ages (1 drop Tramadol HCl Disphar 100 mg/ml contains approximately 2.5 mg tramadol hydrochloride): Age Body weight Number of drops 1 year 3 years 6 years 9 years 11 years 10 kg 15 kg 20 kg 30 kg 45 kg Posology The drops should be swallowed with sufficient liquid or on sugar, independent of the meal Contraindications Hypersensitivity towards tramadol or any of the excipients. Acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol should not be administered to patients receiving monoamine oxidase (MAO) inhibitors or within two weeks of their withdrawal. Tramadol should not be used during narcotic detoxicification therapy. Severe hepatic impairment. Severe renal impairment (creatinine clearance < 10 ml/min) Special warnings and precautions for use Warnings At therapeutic doses withdrawal symptoms have been reported at a reporting frequency of 1 in 8,000. In therapeutic doses tramadol may cause physical dependence (see 4.8 undesirable effects). Reports of dependence and abuse have been less frequent. Because of this potential the clinical need for continued analgesic treatment should be reviewed regularly. In patients with a tendency to drug abuse or dependence, treatment should be used for short periods and under strict medical supervision. Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms. Precautions Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit (400 mg tramadol). 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 section 4.5 Interactions with other medicaments and other forms of Interactions).

3 Tramadol HCl Disphar druppels 100 mg/ml, oral drops Page 3 of 7 Tramadol should be used with caution in patients with head injury, increased intracranial pressure, and in patients prone to convulsive disorders or in shock. Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses respiratory depression has infrequently been reported Interaction with other medicinal products and other forms of interaction Tramadol should not be combined with MAO inhibitors (see 4.3, Contraindications). Concomitant administration of tramadol with other CNS depressant drugs including alcohol may potentiate CNS undesirable effects. Simultaneous administration of carbamazepine (an enzyme inducer) markedly decreases serum concentrations of tramadol and this decreases the analgesic effectiveness and duration of action. Concommitant administration of tramadol and cimetidine is associated with a little prolongation of tramadol half-life, nut this is not clinically relevant. The combination with mixed agonist/antagonist (such as buprenorfin, nalbufin, pentazocin) and tramadol is not recommended as the analgesic effect of a pure agonist may be reduced under these conditions. Tramadol may induce convulsions and increase the potential for both selective serotonin reuptake inhibitors (fluoxetine, paroxetine, fluvaxomine) and tricyclic antidepressants, antipsychotics and other agents that reduce the convulsion threshold to cause convulsions (see 4.4, Special warnings and precautions for use and 5.2, Pharmacokinetic properties). Co-administered ritonavir may increase serum concentrations of tramadol resulting in tramadol toxicity. Caution should be used during concomitant treatment with tramadol and coumarin derivates (such as warfarin) because of reports of increased INR and ecchymosis in some patients. The mechanism of this interaction is unknown Pregnancy and lactation Pregnancy There is insufficient data about the use of tramadol in human pregnancy to assess possible harmful effects. Animal studies have not revealed any embryotoxic effect, except at maternally toxic doses. The use of Tramadol HCl Disphar druppels 100 mg/ml, oral drops during pregnancy is not recommended, unless strictly required. Lactation Tramadol and its metabolites are found in small amounts in human breast milk. The use of Tramadol HCl Disphar druppels 100 mg/ml, oral drops during the period of breast feeding is not recommended. However, after a single administration of Tramadol HCl Disphar druppels 100 mg/ml, oral drops it is not necessary to interrupt breast feeding Effects on ability to drive and use machines Tramadol may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. The patient should not drive or operate machinery when drowsiness occurs Undesirable effects The most commonly reported adverse drug reactions are nausea and dizziness, both occurring in more than 10 % of patients. The frequencies in the table below are defined as follows:

4 Tramadol HCl Disphar druppels 100 mg/ml, oral drops Page 4 of 7 Very common: > 1/10 ; common: > 1/100, <1/10 ; uncommon: > 1/1000, <1/100 ; rare > 1/10.000, <1/1000 ; very rare : < 1/10.000, including reports of isolated cases. Gastrointestinal disorders: Very common Nausea. Common Vomiting, constipation, dry mouth. Uncommon Retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating). Rare Changes of appetite. Cardiac disorders: Uncommon Palpitations, tachycardia. These adverse effects may occur especially on intravenous administration and in patients who are physically stressed. Rare Bradycardia. Vascular disorders: Uncommon Orthostatic hypotension, cardiovascular collapse. These adverse effects may occur especially on intravenous administration and in patients who are physically stressed. Rare Elevated blood pressure Nervous system disorders: Very common Dizziness Common Headache, muzziness. Rare Respiratory depression, paresthesia, tremor. Respiratory depression may occur when the recommended doses are markedly exceeded of when other CNS depressants are administered simultaneously (see 4.5, Interaction with other medicinal products and other forms of interaction). Epileptoform convulsions have occurred predominantly after concomitant administration of agents that reduce the convulsion threshold or that cause cerebral convulsions by themselves (such as antidepressants or antipsychotics, see 4.5 Interaction with other medicinal products and other forms of interaction). Psychiatric disorders: Rare Psychic side-effects, hallucinations, confusion, sleep disturbance and nightmares. Psychic side-effects may occur following administration of tramadol, which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial ability (e.g. decision behaviour, perception disorders). Very rare Dependence, abuse and withdrawal symptoms may occur. Symptoms of such reactions may be: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms and the majority is identical to the symptoms occurring after opiate withdrawal. Eye disorders: Rare Blurred vision. Respiratory, thoracic and mediastinal disorders: Worsening of asthma has been reported, though a causal relationship has not been established.

5 Tramadol HCl Disphar druppels 100 mg/ml, oral drops Page 5 of 7 Skin and subcutaneous tissue disorders: Common Sweating. Uncommon Skin reactions (pruritus, rash, urticaria). Musculoskeletal and connective tissue disorders: Rare Motoric muscle weakness. Hepatobiliary disorders: Very rare Increases in liver enzyme values in a temporal connection with the therapeutic use of tramadol. Renal and urinary disorders: Rare micturition disorders (difficulty in passing urine and urinary retention). General disorders and administration site conditions: Rare Allergic reactions (dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis. 4.9 Overdosage Symptoms of overdosage are, like those for other opioid analgesics, miosis, vomiting, cardiovascular collapse, sedation and coma, seizures and respiratory depression. Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted. Naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam. Tramadol is minimally eliminated from the serum by haemodialysis. Therefore treatment of acute intoxication with tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification. To empty the stomach vomiting should be induced (when the patient is conscious) or gastric lavage. Removal of the stomach content is useful to remove unabsorbed substance, especially when a formulation with regulated release has been taken. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group : opioid analgesics ATC code : N 02 AX 02 Tramadol is a centrally acting analgesic. It is a non selective pure agonist at µ-, δ- en κ-opioid receptors with a higher affinity for the µ-receptor. Other mechanisms which may contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenalin and serotonin. 5.2 Pharmacokinetic properties Absorption After oral administration, tramadol is almost completely absorbed and the mean absolute bioavailability is approximately 70%. The difference between absorbed and available drug is caused by a low first-pass metabolism. This is not more than 30% after oral administration.

6 Tramadol HCl Disphar druppels 100 mg/ml, oral drops Page 6 of 7 Distribution The data suggest an effective distribution and tight tissue binding as the volume of distribution is larger than the volume of the body. Protein binding was 4% - 20%. Biotransformation Hepatic CYP2D6 appears the main responsible for the formation of O-desmethyl-tramadol, while the formation of N-desmethyl-tramadol is catalysed by CYP2D6 and CYP3A4. Conjugation of the O-demethylation products with glucuronic acid may occur. Only O-desmethyl-tramadol is pharmacologically active. Approximately 5 10 % of the Caucasian population has a slow metabolism and a reduced CYP2D6 enzyme activity. Serum concentrations of tramadol are higher in slow metabolisers compared with fast metabolisers, while O-desmethyltramadol concentrations are lower. Inhibition of one or both isoenzyme types CYP3A4 (such as for instance by ketokonazol, erythromycine) and CYP2D6 (such as for instance by fluoxetine, paroxetine, quinidine, ritonavir) involved in the biotransformation of tramadol, may affect the plasma concentrations of tramadol or its active metabolites. The same is true for enzyme inducers (such as for instance rifampicine, fenytoin). Up till now no clinically relevant interactions have been reported. Elimination Tramadol and its metabolites are almost completely excreted via the kidneys. 90% of the total radio-label of an administered dose is excreted via the kidneys. Irrespective of the method of administration, the terminal half-life (t ½β ) is about 6 hours. The half-life of O-desmethyl-tramadol is comparable to that of tramadol. The half-life may be prolonged by a factor 1.4 in patients with an impaired hepatic and renal function. In patients with serious organ failure (for instance liver cirrhosis, creatinine clearance < 5 ml/min) a 2 to 3 fold prolongation of the elimination half-life is observed. Linearity/non-linearity Tramadol shows a linear pharmacokinetic profile in the therapeutic dose range. The relation between serum concentrations and analgesic affect is dose dependent, with large differences for each individual case however. A serum concentration of ng/ml is generally effective. 5.3 Preclinical safety data During repeated oral and parenteral administration of tramadol for 6 to 26 weeks to rats and dogs and for 12 months to dogs, based on haematological, clinical-chemical and histological examination no indications for substance induced changes have been found. Only after high dosages, that exceeded the therapeutical dose to a large extent, the following symptoms occurred: restlessness, salivation, convulsion, reduced weight increase. Without any reaction rats and dogs tolerated oral doses of 20 mg/kg resp. 10 mg/kg body weight, and dogs also 20 mg/kg body weight rectally administered. Tramadol dosages from 50 mg/kg/day caused in rats intoxication of the mother and resulted in increased mortality of new born rats. The development of young rats was impaired: impairment of ossification and delayed opening of the vagina and eyes. The fertility of male rats was not influenced. However, the percentage of pregnant females decreased after high dosages (from 50 mg/kg per day). In rabbits toxic effects in the mother and skeletal changes in the infants occurred from 125 mg/kg.

7 Tramadol HCl Disphar druppels 100 mg/ml, oral drops Page 7 of 7 Mutagenic effects were found in some in vitro test systems. No indications for a mutagenic effect were found in in vivo tests. Based on the current available knowledge tramadol may be classified as a non-mutagenic substance. The oncological potential of tramadolhydrochloride has been studied in rats and mice. The rat studies did not demonstrate that the substance increases the risk of tumours. The mice studies demonstrated an increased risk for hepatic cell adenomas in male mice (dose dependent, with a nonsignificant increase from 15 mg/kg) and an increasing number of lung tumours in female mice of all dose groups (significant, but independent of the dose). 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Saccharose, saccharin sodium, potassium sorbate (E202), polysorbate 20, anise oil, peppermint oil, water. 6.2 Incompatibilities Not applicable. 6.3 Shelf-life 3 years. 6.4 Special precautions for storage No special storage temperature. 6.5 Nature and contents of container Brown glass (type III) bottle with a dropper and a child proof screw cap. Pack containing 1, 3 or 5 bottles. Not all pack sizes may be marketed. 6.6 Instructions for use and handling No particularities. 7. MARKETING AUTHORISATION HOLDER 8. MARKETING AUTHORISATION NUMBER 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT