Treatment of moderately severe to severe pain.

Posology

The dosage should be adjusted to the intensity of pain and the patient’s individual sensitivity. In general, the lowest dose sufficient for analgesia should be selected. Daily doses of 400 mg active substance should not be exceeded, unless there are special medical circumstances (e.g. for tumour pain and severe post-operative pain).

 

Unless otherwise prescribed, Tramal capsules should be dosed as follows:

 

Adults and adolescents over 12 years of age

Mode of administration	Single dose	Maximum daily dose
Tramal capsules	50 to 100 mg every 4 to 6 hours (1 to 2 hard capsules) (See Section 5.1)	400 mg   (up to 8 hard capsules)

 

 

 

 

If no sufficient analgesia occurs within 30 to 60 minutes following single-dose administration of 50 mg tramadol hydrochloride, a second single dose of 50 mg can be given.

If the demand is likely to be higher for severe pain, the higher single dose of Tramal capsules (100 mg tramadol hydrochloride) can be administered as the initial dose.

Depending on the pain, the effect lasts for 4 to 6 hours. For the treatment of severe post-operative pain, even higher doses may be required in the first few hours on an on-demand basis. Requirements over 24 hours are generally no higher than with normal administration.

 

Paediatric patients

Tramal capsules are not suitable for children below 12 years of age.

 

Geriatric patients

As a general rule, no dose adjustment is required in patients up to 75 years of age without clinically manifest hepatic or renal insufficiency. Elimination may be delayed in elderly patients over 75 years of age. Therefore, the dosing interval must, if necessary, be prolonged according to the patient’s need.

 

Hepatic and renal insufficiency/dialysis

In patients with hepatic and/or renal insufficiency, the elimination of tramadol is delayed. In these patients, consideration should be given to prolonging the dosing interval according to individual need.

 

 

Note

 

 

The recommended dosages are guideline values. For the treatment of chronic pain, Tramal capsules should be administered according to a fixed schedule.

 

 

Method of administration

The capsules are to be taken whole, with sufficient liquid, independently of meals.

 

Duration of use

Under no circumstances should Tramal capsules be used for longer than therapeutically absolutely necessary. If, depending on the nature and severity of the disease, longer-term analgesic treatment with Tramal capsules appears necessary, careful and regular checks should be made (if necessary, by inserting breaks in treatment) to establish whether and to what extent there is still a medical need.

 

Tramal capsules must not be used • in cases of hypersensitivity to tramadol or to any of the excipients listed in section 6.1 • in cases of acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic agents • in patients receiving MAO inhibitors or having used them within the last 14 days (see section 4.5) • in patients whose epilepsy cannot be adequately controlled by treatment • for drug replacement therapy

Tramal capsules must only be used with particular caution in cases of opioid dependence, head injury, shock, impaired consciousness of uncertain origin, disorders of the respiratory centre or respiratory function and in conditions with increased intracranial pressure.

In patients sensitive to opiates, the product should only be used with caution.

 

 

 

 

In patients with respiratory depression, or if CNS depressants are co-administered (see section 4.5), or if the recommended maximum daily dose is significantly exceeded (see section 4.9), treatment should be administered with caution, as the possibility of respiratory depression under these circumstances cannot be excluded.

 

Seizures have been reported with tramadol ingestion at the recommended dosage. There may be an increased risk when administering dosages that exceed the recommended maximum daily dose

(400 mg). Tramadol can increase the risk of seizures when medicinal products that lower the seizure threshold are co-administered (see section 4.5). Patients suffering from epilepsy or susceptible to seizures should be treated with tramadol only in compelling, exceptional cases.

 

CYP2D6-mediated metabolism

Tramadol is metabolised by the hepatic enzyme CYP2D6. If a patient has a deficiency in this enzyme or this enzyme is completely absent in the patient, it may not be possible to achieve a sufficient analgesic effect. It is estimated that up to 7% of the Caucasian population has this deficiency.

However, if the patient is an ultra-rapid metaboliser, there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases, symptoms of circulatory and respiratory depression can occur, which can be life-threatening and, in very rare cases, even fatal.

Estimates for the prevalence of ultra-rapid metabolisers in different populations are summarised below:

 

 

Population African/Ethiopian Afro-American Asian

Caucasian Greek Hungarian North European

 

Prevalence in % 29%

3.4% to 6.5%

1.2% to 2%

3.6% to 6.5%

6.0%

1.9%

1% to 2%

 

 

Postoperative use in children

It has been reported in the published literature that post-operative tramadol in children following tonsillectomy and/or adenoidectomy for obstructive sleep apnoea has led to rare but life-threatening adverse events. When Tramadol is administered to children for postoperative pain relief, extreme caution should be exercised and close monitoring should be provided for symptoms of opioid toxicity, including respiratory depression.

 

Children with impaired respiratory function

Tramadol is not recommended for use in children whose respiratory function may be impaired, including in neuromuscular disorders, severe cardiac or respiratory disease, upper respiratory or pulmonary infections, multiple trauma or extensive surgical procedures. These factors can lead to a worsening of the symptoms of opioid toxicity.

 

Tolerance, as well as mental and physical dependence, may develop, especially after prolonged use. Therefore, in patients with a tendency for drug abuse or dependence, treatment with Tramal capsules should only be administered over the short term and under very strict medical supervision.

 

 

 

 

If tramadol therapy is no longer required by a patient, it may be advisable to gradually taper the dose to prevent withdrawal symptoms.

 

Tramadol is not suitable as a drug substitute in opioid dependence. Although tramadol is an opiate agonist, it cannot suppress morphine withdrawal symptoms.

 

Tramal capsules must not be combined with MAO inhibitors (see section 4.3).

 

In patients treated with MAO inhibitors within 14 days prior to administration of pethidine (an opioid), life-threatening interactions have been seen, affecting the central nervous system and respiratory/circulatory function. These same interactions with MAO inhibitors cannot be excluded when treating with Tramal capsules.

 

Concomitant administration of Tramal capsules with other centrally depressant medicinal products, including alcohol, may potentiate the CNS effects (see section 4.8).

 

Concomitant or prior administration of cimetidine (an enzyme inhibitor) is unlikely to cause clinically relevant interactions, based on the pharmacokinetic results available. Concomitant or prior administration of carbamazepine (an enzyme inducer) may reduce the analgesic effect and shorten the duration of action.

 

Tramadol can induce convulsions and increase the seizure-inducing potential of selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants, neuroleptics and other medicinal products that lower the seizure threshold (such as bupropion, mirtazapine and tetrahydrocannabinol).

 

Concomitant therapy with tramadol and serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine can cause serotonin syndrome. Serotonin syndrome is likely when one of the following symptoms or groups of symptoms is observed:

·   spontaneous clonus

·   inducible or ocular clonus with agitation or diaphoresis

·   tremor and hyperreflexia

·   muscular hypertonia and body temperature > 38°C and inducible or ocular clonus

 

In general, discontinuation of the serotonergic agents usually brings about a rapid improvement. Corrective measures depend on the nature and severity of the symptoms.

 

Caution is advised when co-administering tramadol and coumarin derivatives (e.g. warfarin), as increased INR values with major bleeding and ecchymoses have been observed in some patients.

 

Other active substances that inhibit CYP3A4, such as ketoconazole and erythromycin, may inhibit both the metabolism of tramadol (N-demethylation) and possibly that of the active O-demethylated metabolite. The clinical significance of this interaction is not known (see section 4.8).

 

In a limited number of studies, pre- and postoperative administration of ondansetron, an antiemetic 5- HT3 antagonist, increased the need for tramadol in patients with postoperative pain.

Pregnancy

At very high doses, animal studies with tramadol showed effects on organ development, bone growth and the mortality rate in neonates. No teratogenic effects were observed. Tramadol crosses the placenta. There is insufficient evidence regarding the safety of tramadol in human pregnancy. Tramal capsules should therefore not be administered to pregnant women.

Tramadol does not affect uterine contractility, either before or during childbirth. In neonates, it can lead to changes in the respiratory rate, but these are generally not clinically relevant. Chronic use during pregnancy can lead to withdrawal symptoms in the neonate.

 

Breast-feeding

Approximately 0.1% of the tramadol dose administered to the mother is excreted in breast milk. In the immediate postpartum period for a maternal oral dose of up to 400 mg, this corresponds to a mean amount of tramadol absorbed by breast-fed infants of 3% of the maternal dosage adjusted to body weight. Tramadol should not be used during breast-feeding. Alternatively, breast-feeding should be withheld during treatment with tramadol. After a single dose of tramadol, it is generally not necessary to stop breast-feeding.

 

Fertility

Postmarketing observations do not provide evidence of any effect of tramadol on fertility. Animal studies have shown no effect of tramadol on fertility.

 

 

Even when used as directed, Tramal capsules can cause effects such as drowsiness and dizziness and may therefore alter responsiveness to such an extent that the ability to drive or use machines is impaired. This particularly applies in interaction with alcohol and other psychotropic agents.

The following frequencies are used for the evaluation of undesirable effects: Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1,000 to < 1/100) Rare (≥ 1/10,000 to < 1/1,000) Very rare (< 1/10,000)

Not known (cannot be estimated from the available data).

 

Nausea and dizziness are the most common undesirable effects, both occurring in more than 10% of patients.

 

Immune system disorders

Rare:                                                     allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioedema) and anaphylaxis.

 

Cardiac disorders

 

 

 

 

Uncommon:                                           effect on circulatory regulation (palpitations, tachycardia). In particular, these adverse reactions can occur with intravenous administration and in patients under physical stress.

Rare:                                                     bradycardia.

 

Investigations

Rare:                                                     increased blood pressure.

 

Vascular disorders

Uncommon:                                           effect on circulatory regulation (orthostatic hypotension or circulatory collapse). In particular, these adverse reactions can occur with intravenous administration and in patients under physical stress.

Nervous system disorders

Very common:                                       dizziness.

Common:                                               headache, drowsiness.

Rare: paraesthesia, tremor, involuntary muscle twitches, coordination disorders, syncope, speech disorders

Seizures have mainly occurred after high tramadol dosages or after concomitant use of medicinal products that can lower the seizure threshold (see sections 4.4 and 4.5).

 

Metabolism and nutrition disorders

Rare:                                                     changes in appetite.

Not known:                                            hypoglycaemia.

 

Psychiatric disorders

Rare:                                                     hallucinations, confusion, sleep disorders, delirium, anxiety and nightmares.

Various psychiatric adverse reactions can occur following administration of Tramal capsules, which vary individually in intensity and nature (depending on personality and duration of treatment). These include mood changes (mostly elated mood, occasionally dysphoria), changes in activity (mostly suppression; occasionally an increase) and changes in cognitive and sensory performance (e.g. decision-making behaviour, perception disorders).

Drug dependence may develop. The following symptoms of a drug withdrawal syndrome similar to that with opiates may occur: agitation, anxiety, nervousness, sleep disorders, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms observed in very rare cases upon discontinuation of tramadol include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms (e.g. confusion, delusion, depersonalisation, derealisation, paranoia).

Eye disorders

Rare:                                                     miosis, blurred vision, mydriasis.

 

 

 

 

 

Respiratory, thoracic and mediastinal disorders

Rare:                                                     respiratory depression, dyspnoea.

Respiratory depression can occur if the recommended dosages are significantly exceeded and when other CNS depressants are co-administered (see section 4.5).

Exacerbation of asthma has been reported. However, no causal relationship could be established.

 

Gastrointestinal disorders

Very common:                                       nausea.

Common:                                               vomiting, constipation, dry mouth.

Uncommon:                                           retching, gastrointestinal discomfort (e.g. gastric pressure, bloated sensation), diarrhoea.

 

Hepatobiliary disorders

In a few isolated cases, elevated liver enzyme levels have been reported in temporal association with the therapeutic use of tramadol.

 

Skin and subcutaneous tissue disorders

Common:                                               hyperhidrosis.

Uncommon:                                           skin reactions (e.g. pruritus, erythema, urticaria).

 

Musculoskeletal and connective tissue disorders

Rare:                                                     motor weakness.

 

Renal and urinary disorders

Rare:                                                     micturition disorders (dysuria and urinary retention).

 

General disorders and administration site conditions Common:                                               exhaustion.

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the

 

Bundesinstitut für Arzneimittel und Medizinprodukte [Federal Institute for Drugs and Medical Devices] Abt. Pharmakovigilanz

Kurt-Georg-Kiesinger Allee 3

53175 Bonn, Germany Website: http://www.bfarm.de

 

Symptoms

Basically, symptoms similar to those with other centrally acting analgesics (opioids) can be expected in cases of intoxication with tramadol. In particular, the following can be anticipated: miosis, vomiting, circulatory collapse, impaired consciousness and even comatose state, seizures and respiratory depression to the point of respiratory paralysis.

 

Therapy

General rules for emergencies apply. Maintain airway patency (caution: aspiration) and respiratory/circulatory function, depending on the symptoms. Give naloxone as an antidote for respiratory depression. In animal studies, naloxone had no effect against seizures. In such cases, diazepam should be administered intravenously.

In case of oral intoxication, 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.

Tramadol is eliminated from the serum to a minor extent by haemodialysis and haemofiltration. For this reason, haemodialysis or haemofiltration alone are not suitable for the treatment of acute intoxication with Tramal capsules.

1.1       Pharmacotherapeutic group: other opioids. ATC code: N 02 AX 02: analgesics

Tramadol is a centrally acting opioid analgesic. It is a non-selective pure agonist for µ-, d- and k- opioid receptors with greater affinity to µ-receptors. Other mechanisms contributing to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.

 

Tramadol has an antitussive effect. Unlike morphine, tramadol has no respiratory depressant effect at analgesic doses over a wide range. Gastrointestinal motility is likewise less affected. Effects on the cardiovascular system tend to be minor. The potency of tramadol is stated to be ¹/₁₀ (one tenth) to

1/₆ (one sixth) that of morphine.

 

Paediatric population

 

The effects of enteral and parenteral administration of tramadol were examined in clinical studies with more than 2000 paediatric patients aged from neonates to 17 years. The indications for analgesia investigated in these studies were postoperative pain (particularly abdominal), pain after surgical tooth extraction, as a result of fractures, burns and trauma, as well as other painful conditions expected to make analgesic treatment necessary for 7 days.

 

In single doses of up to 2 mg/kg or multiple doses of up to 8 mg/kg daily (up to a maximum of 400 mg per day), the efficacy of tramadol was superior compared to placebo and greater or equal to paracetamol, nalbuphine, pethidine or low-dosed morphine. The studies conducted confirmed the efficacy of tramadol. The safety profile of tramadol was similar in adults and paediatric patients over  1 year of age (see section 4.2).

More than 90% of tramadol is absorbed after oral administration. The mean absolute bioavailability is approximately 70%, irrespective of concomitant food intake. The difference between absorbed and non-metabolised available tramadol is probably due to the first-pass effect. The first-pass effect after oral administration is a maximum of 30%.

 

After oral administration of 100 mg tramadol in liquid form, the peak plasma concentration C_max after

1.2 hours is calculated to be 309 ± 90 ng/mL. After oral administration of the same dose in solid form, C_max after 2 hours is 280 ± 49 ng/mL.

 

Tramadol has a high tissue affinity (V_d,ß = 203 ± 40 L). Serum protein binding is approximately 20%.

 

Tramadol crosses the blood-brain barrier and placenta. It is found in very small amounts in breast milk together with its O-desmethyl derivative (0.1% and 0.02% of the administered dose, respectively).

 

Inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6, which are involved in the biotransformation of tramadol, may affect the plasma concentration of tramadol or its active metabolite.

 

Tramadol and its metabolites are almost entirely excreted via the renal route. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. The elimination half-life t_½,ß is about 6 hours, irrespective of the method of administration. In patients over 75 years of age, it may be prolonged by a factor of about 1.4. If hepatic and renal function is impaired, a slight prolongation of half-lives must be anticipated. In patients with liver cirrhosis, elimination half-lives of 13.3 ±

4.9 hours (tramadol) and 18.5 ± 9.4 hours (O-desmethyltramadol) have been determined; in extreme cases, 22.3 hours and 36 hours, respectively. In patients with renal insufficiency (creatinine clearance

< 5 mL/min), the values were 11 ± 3.2 hours and 16.9 ± 3 hours, respectively; in extreme cases,

19.5 hours and 43.2 hours, respectively.

In humans, tramadol is mainly metabolised by N- and O-demethylation, as well as by 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. To date, 11 metabolites have been found in the urine. Based on animal studies, O-desmethyltramadol is more potent than the parent substance by a factor of 2 to 4. Its half-life t_½,ß (6 healthy subjects) is

7.9 hours (range: 5.4 to 9.6 hours) and is approximately that of tramadol.

 

Tramadol shows a linear pharmacokinetic profile within the therapeutic dose range.

The relationship between serum concentrations and analgesic effect is dose-dependent, but varies considerably in individual cases. A serum concentration of 100 to 300 ng/mL is usually effective.

 

Paediatric population

 

The pharmacokinetics of tramadol and O-desmethyltramadol after single and multiple oral dose administration in patients aged from 1 to 16 years was generally similar to that in adults when the dosage was adjusted in relation to body weight, but with a higher interindividual variability in children aged 8 years and under.

 

 

 

 

In children below 1 year of age, the pharmacokinetics of tramadol and O-desmethyltramadol have been investigated but have not yet been completely characterised. Information from studies including this age group indicates that the rate of formation of O-desmethyltramadol via CYP2D6 increases continuously in neonates and the level of CYP2D6 activity of adults is reached at about the age of

1 year. Moreover, an immature glucuronidation system and renal function may result in slowed elimination and accumulation of O-desmethyltramadol in children below 1 year of age.

Upon repeated oral and parenteral administration of tramadol over 6 to 26 weeks in rats and dogs, as well as orally over 12 months in dogs, the haematological, clinical/chemical and histological studies showed no indication of substance-related changes. Central nervous-related phenomena occurred only after high doses far exceeding the therapeutic dose: akathisia, salivation, seizures and reduced weight gain. Oral doses of 20 mg/kg and 10 mg/kg body weight were tolerated without reactions in rats and dogs, respectively, as were rectal doses of 20 mg/kg body weight in dogs.

 

In rats, tramadol dosages from 50 mg/kg per day caused toxic effects in dams and increased neonatal mortality. In the offspring, retardation occurred in the form of ossification disorders, as well as delayed vaginal and eye opening. The fertility of male and female rats was not adversely affected. In rabbits, toxic effects occurred in dams and skeletal anomalies in the progeny at doses of 125 mg/kg or more.

 

Indications of mutagenic effects were seen in some in vitro test systems. In vivo studies revealed no indications of a mutagenic effect. Based on the data available, tramadol can be classified as a non- mutagenic substance.

 

Studies on the tumorigenic potential of tramadol hydrochloride were conducted in rats and mice. The study in rats showed no indications of any increase in substance-related tumour incidence. In the study on mice, an increased incidence of hepatocellular adenomas in male animals (a dose-dependent, non- significant increase at 15 mg/kg or more) was observed, as well as an increase in pulmonary tumours among female animals in all dose groups (a significant, but non-dose-dependent increase).

  Capsule contents: microcrystalline cellulose sodium starch glycolate (type A) colloidal anhydrous silica magnesium stearate

 

Capsule shell: gelatin

yellow iron oxide (E 172) titanium dioxide (E 171) sodium lauryl sulphate

Not applicable

36 months.

Do not store above 30 °C.

PP/aluminium foil blister or PVC/PVDC/aluminium foil blisters or PVC/aluminium foil blisters. Pack sizes of 10, 30 or 50 hard capsules.

Hospital pack with 150 (10 x 15) hard capsules.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.