Analgesics

Tramadol hydrochloride

One Zydol 50mg capsule contains 50mg tramadol hydrochloride

Green/pale yellow hard gelatine capsules for oral administration, imprinted with Grünenthal logo.

Treatment of moderate to severe pain.

The dose should be adjusted to the intensity of the pain and the sensitivity of the individual patient.

Unless otherwise prescribed, Zydol should be administered as follows:

Adults and Children aged 12 years and over

Oral administration

Acute Pain: An initial dose of 100mg is usually necessary. This can be followed by doses of 50 or 100mg not more frequently than 4 hourly, and duration of therapy should be matched to clinical need.

Pain Associated with Chronic Conditions: Use an initial dose of 50mg and then titrate dose according to pain severity. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported.

The lowest analgesically effective dose should generally be selected. Daily doses of 400 mg active substance should not be exceeded, except in special clinical circumstances.

The capsules are to be taken whole, not divided or chewed, with sufficient liquid, independent of meals.

Zydol should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Zydol 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.

Children

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

Geriatric patients

The usual dosages may be used although it should be noted that in volunteers aged over 75 years the elimination half-life of tramadol was increased by 17% following oral administration.

Renal Insufficiency/Dialysis and Hepatic Insufficiency

The elimination of tramadol may be prolonged. The usual initial dosage should be used. For patients with creatinine clearance <30ml/min, the dosage interval should be increased to 12 hours. Tramadol is not recommended for patients with severe renal impairment (creatinine clearance <10ml/min). As tramadol is only removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary.

Hepatic impairment

The elimination of tramadol may be prolonged. The usual initial dosage should be used but in severe hepatic impairment the dosage interval should be increased to 12 hours.

Not recommended.

The usual dosages may be used although it should be noted that in volunteers aged over 75 years the elimination half-life of tramadol was increased by 17% following oral administration.

Zydol is contraindicated

- in hypersensitivity to tramadol or any of the excipients,

- in acute intoxication with alcohol, hypnotics, analgesics, opioids, or psychotropic medicinal products,

- in patients who are receiving MAO inhibitors or who have taken them within the last 14 days,

- in patients with epilepsy not adequately controlled by treatment,

- for use in narcotic withdrawal treatment.

Zydol may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure.

In patients sensitive to opiates the product 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 , or if the recommended dosage is significantly exceeded as the possibility of respiratory depression cannot be excluded in these situations.

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 increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold. 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 with Zydol should only be carried out for short periods 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.

Zydol 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 interactions with MAO inhibitors cannot be ruled out during treatment with Zydol.

Concomitant administration of Zydol with other centrally depressant medicinal products including alcohol may potentiate the CNS effects.

The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur. Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.

The combination with mixed agonist/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable, because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.

Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors, tricyclic anti-depressants, anti-psychotics and other seizure threshold lowering medicinal products to cause convulsions.

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 inhibitors (SSRIs) or with MAO inhibitors. Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. 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 coumarin derivatives (e.g. warfarin) due to reports of increased INR with major bleeding and ecchymoses in some patients.

Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the 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 ondansetron increased the requirement of tramadol in patients with postoperative pain.

The most commonly reported adverse reactions are nausea and dizziness, both occurring in more than 10 % of patients.

Cardiovascular disorders:

uncommon (1/1000, <1/100): 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 (1/10000, <1/1000): bradycardia, increase in blood pressure

Nervous system disorders:

very common (1/10): dizziness

common (1/100, <1/10): headache, somnolence

rare (1/10000, <1/1000): changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope.

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 (1/10000, <1/1000): hallucinations, confusion, sleep disturbance, anxiety and nightmares. Psychic adverse reactions may occur following administration of Zydol 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 behaviour, perception disorders). Dependence may occur.

Eye disorders:

rare (1/10000, <1/1000): blurred vision

Respiratory disorders:

rare (1/10000, <1/1000):dyspnoea

Worsening of asthma has been reported, though a causal relationship has not been established.

Gastrointestinal disorders:

very common (1/10): nausea

common (1/100, <1/10): vomiting, constipation, dry mouth

uncommon (1/1000, <1/100): retching; gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea

Skin and subcutaneous disorders:

common (1/100, <1/10): sweating

uncommon (1/1000, <1/100):dermal reactions (e.g. pruritus, rash, urticaria)

Musculoskeletal disorders:

rare (1/10000, <1/1000): 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 (1/10000, <1/1000): micturition disorders (difficulty in passing urine, dysuria and urinary retention)

General disorders:

common (1/100, <1/10): fatigue

rare (1/10000, <1/1000): 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

Grunenthal Ltd

(POM)

12 August 2009