ZAMADOL SR 100 MG PROLONGED-RELEASE HARD CAPSULES - summary of medicine characteristics

Zamadol SR 100 mg prolonged-release hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One capsule contains 100 mg of tramadol hydrochloride

Excipients with known effect

This product contains sucrose (18.75 mg/capsule).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged release hard capsule

The 100 mg capsules are white of about 16 mm, marked T100SR

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of moderate to severe pain.

4.2 Posology and method of administration

Posology

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.

Dosage for adults and adolescents from 12 years of age:

The usual initial dose is 50–100 mg twice daily, in the morning and in the evening.

This dose may be titrated up to 150–200 mg twice daily according to pain severity. If long-term pain treatment with tramadol hydrochloride 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.

A total oral daily dose of 400 mg should not be exceeded except in special clinical circumstances.

Paediatric population:

Zamadol SR prolonged-release hard capsules should not be used in children under 12 years of age since safety and efficacy have not been established.

Elderly patients:

A dose adjustment is usually not necessary in patients up to 75 years of age without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years of age 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 Zamadol SR prolonged-release capsules is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient’s requ­irements. Zamadol SR capsules are not recommended for patients with severe hepatic and/or renal insufficiency.

Method of administration

The capsules are intended for twice daily oral administration and can be taken independently of meal times, swallowed whole with water.

Patients who have swallowing problems:

Zamadol SR prolonged-release hard capsules can be opened, carefully, so that the pellets are deposited on a spoon. The spoon and pellets should be taken into the mouth, followed by a drink of water to rinse the mouth of all pellets. The pellets must not be chewed or crushed.

4.3 Contraindications

With hypersensitivity to the active substance tramadol hydrochloride or to any of the excipients listed in section 6.1.

With acute intoxication with hypnotics, centrally acting analgesics, opioids, psychotropic drugs or alcohol.

If monoamine oxidase inhibitors (specific drugs acting against depression) are taken concomitantly or have been taken within the last 14 days before treatment with Zamadol SR prolonged-release hard capsules

Who are suffering from uncontrolled epilepsy.

Tramadol must not be used for narcotic withdrawal treatment.

4.4 Special warnings and precautions for use

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of Zamadol SR prolonged-release hard capsules and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Zamadol SR prolonged-release hard capsules concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Risk of tolerance, dependence and withdrawal symptoms:

Tolerance, psychic and physical dependence may develop, especially after long-term use. When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In patients with a tendency to drug abuse or dependence, treatment should be for short periods under strict medical supervision. In rare cases at therapeutic doses, tramadol has the potential to cause withdrawal symptoms.

Zamadol SR prolonged-release hard capsules are not a suitable substitute in opioid dependent patients. The product does not suppress morphine withdrawal symptoms although it is an opioid agonist.

CYP2D6 metabolism

Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have 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 this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. 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)

Zamadol SR prolonged-release hard capsules should be used with prudence in patients who have shown previous hypersensitivity to opiates, and in patients with severe renal or hepatic impairment, head injury, decreased level of consciousness, increased intracranial pressure, or patients in shock or at risk of convulsions.

At recommended therapeutic doses Zamadol SR prolonged-release hard capsules are unlikely to produce clinically relevant respiratory depression. Care should however be taken when administering Zamadol SR prolonged-release hard capsules to patients with existing respiratory depression or excessive bronchial secretion and in those patients taking concomitant CNS depressant drugs.

Paediatric population

Post-operative use in children:

There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnea, led to rare, but life threatening adverse events. Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.

Children with compromised respiratory function:

Tramadol is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures.

This medicinal product contains sucrose and therefore should not be used by patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.

4.5 Interaction with other medicinal products and other forms of interaction

Patients treated with monoamine oxidase inhibitors within 14 days prior to the administration of the opioid pethidine have experienced life-threatening interactions affecting the central nervous system as well as the respiratory and circulatory centres. The possibility of similar interactions occurring between monoamine oxidase inhibitors and tramadol cannot be ruled out.

Tramadol may potentiate the CNS depressant effects of other centrally acting drugs (including alcohol) when administered concomitantly with such drugs.

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs),serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), antipsychotics and other seizure threshold-lowering drugs (such as bupropion, mirtazapine, tetrahydrocan­nabinol) to cause convulsions (see section 4.4)

Concomitant therapeutic use of tramadol and serotonergic drugs such as selective

4.7 Effects on ability to drive and use machines

Zamadol SR prolonged-release hard capsules may cause drowsiness and this effect may be potentiated by alcohol, anti-histamines and other CNS depressants. If patients are affected they should be warned not to drive or operate machinery.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

– The medicine has been prescribed to treat a medical or dental problem and

– You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

– It was not affecting your ability to drive safely

4.8 Undesirable effects

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

Immune system disorders:

Rare (> 1/10,000 to < 1/1,000): Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.

Metabolism and nutrition disorders:

Rare (> 1/10,000 to < 1/1,000): Changes in appetite.

Frequency not known (cannot be estimated from the available data): Hypoglycaemia

Psychiatric disorders:

Rare (> 1/10,000 to < 1/1,000): 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 capacity (e.g. decision behaviour, perception disorders), hallucinations, confusion, sleep disturbances and nightmares.

Prolonged administration of Zamadol SR prolonged-release hard capsules may lead to dependence (see section 4.4) Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Nervous system disorders:

Very common (> 1/10) dizziness.

Common (> 1/100 to < 1/10): headache, drowsiness.

Rare (> 1/10,000 to < 1/1,000): epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with drugs which can lower the seizure threshold or themselves induce cerebral convulsions (e.g. antidepressants or anti-psychotics, see section 4.5 „Interaction with other medicinal products and other forms of interaction“.

Paraesthesia and tremor.

Very rare (< 1/10,000): vertigo

Eye disorders:

Rare (> 1/10,000 to < 1/1,000): blurred vision.

Cardiac disorders:

Uncommon (> 1/1,000 to < 1/100): effects on cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse effects may occur especially on intravenous administration and in patients who are physically stressed.

Rare (> 1/10,000 to < 1/1,000): bradycardia, increase in blood pressure.

Vascular disorders:

Very rare (< 1/10,000): flushing.

Gastrointestinal disorders:

Very common (> 1/10): vomiting, nausea.

Common (> 1/100 to < 1/10): constipation, dry mouth.

Uncommon (> 1/1,000 to < 1/100): retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating).

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.

Skin and subcutaneous tissue disorders:

Common (> 1/100 to < 1/10): sweating.

Uncommon (> 1/1,000 to < 1/100): dermal reactions (e.g. pruritus, rash, urticaria).

Musculoskeletal, connective tissue and bone disorders:

Rare (> 1/10,000 to < 1/1,000): motorial weakness.

Renal and urinary system disorders:

Rare (> 1/10,000 to < 1/1,000): micturition disorders (difficulty in passing urine and urinary retention).

General disorders and administration site conditions:

Common (> 1/100 to < 1/10): fatigue.

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

Respiratory depression has been reported. If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5 „Interaction with other medicinal products and other forms of interaction“) respiratory depression may occur.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms of tramadol overdose include vomiting, miosis, sedation, seizures, respiratory depression and hypotension, with circulatory failure and coma. Respiratory failure may also occur. Such symptoms are typical of opioid analgesics.

Treatment of overdose requires the maintenance of the airway and cardiovascular functions. Respiratory depression may be reversed using naloxone and fits controlled with diazepam. Naloxone administration may increase the risk of seizures.

The treatment of acute overdose of tramadol using haemodialysis or haemofiltration alone is not sufficient or suitable due to the slow elimination of tramadol from the serum by these routes.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other opioids, ATC code: N02AX02

Tramadol is a centrally acting analgesic which possesses opioid agonist properties. Tramadol consists of two enantiomers, the (+)-isomer is predominantly active as an opioid with preferential activity for the u-receptor. The (-)-isomer potentiates the analgesic effect of the (+)-isomer and is active as an inhibitor of noradrenaline and serotonin-uptake thereby modifying the transmission of pain impulses.

Tramadol also has an antitussive action. At the recommended dosages, the effects of tramadol given orally on the respiratory and cardiovascular systems appear to be clinically insignificant. The potency of tramadol is reported to be 1/10 to 1/6 of morphine.

Paediatric population

Effects of enteral and parenteral administration of tramadol have been investigated in clinical trials involving more than 2000 paediatric patients ranging in age from neonate to 17 years of age. The indications for pain treatment studied in those trials included pain after surgery (mainly abdominal), after surgical tooth extractions, due to fractures, burns and traumas as well as other painful conditions likely to require analgesic treatment for at least 7 days.

At single doses of up to 2mg/kg or multiple doses of up to 8mg/kg per day (to a maximum of 400mg per day) efficacy of tramadol was found to be superior to placebo, and superior or equal to paracetamol, nalbuphine, pethidine or low dose morphine. The conducted trials confirmed the efficacy of tramadol. The safety profile of tramadol was similar in adult and paediatric patients older that 1 year (see section 4.2).

5.2 Pharmacokinetic properties

Absorption

About 90% of tramadol released from Zamadol SR prolonged-release hard capsules is absorbed after oral administration. The mean absolute bioavailability is approximately 70%, irrespective of concomitant intake of food.

The difference between absorbed and non-metabolised available tramadol is probably due to low first-pass effect. The first pass-effect after oral administration is a maximum of 30%.

Tramadol has a high tissue affinity with an apparent volume of distribution of 203 ± 40 litres after oral dosing in healthy volunteers. Protein binding is limited to 20%.

After single dose administration of Zamadol SR 50 mg prolonged-release hard capsules the peak plasma concentration Cmax 70 ± 16 ng/ml is reached after 5.3 h. After administration of Zamadol SR 100 mg prolonged-release hard capsules Cmax 137 ± 27 ng/ml is reached after 5.9 h. Following administration of Zamadol SR 200 mg prolonged-release hard capsules Cmax 294 ± 82 ng/ml is reached after 6.5 h. The reference product (Tramadol Immediate Release Capsules, given as a total dose of 200 mg tramadol hydrochloride) reached a peak concentration of Cmax 640 ± 143 ng/ml after 2.0 hours.

The relative bioavailability for the slow release formulation after single dose administration is 89% and increases to 100% after multiple dose administration in comparison to the reference product.

Tramadol passes the blood-brain and placenta barriers. Very small amounts of the substance and its O-demethyl derivative are found in the breast-milk (0.1% and 0.02% respectively of the applied dose).

Biotransformation

In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only Odesmethyltramadol 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 Odesmethyltramadol is more potent than the parent substance by the factor 2–4. Its half life t./2p (6 healthy volunteers) is 7.9 h (range 5.4–9.6 h) and is approximately that of tramadol.

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.

Elimination

Elimination of half-life t/2pis approximately 6 h, irrespective of the mode of administration. In patients above 75 years of age it may be prolonged by a factor of 1.4.

Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. 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 13.3 ± 4.9 h (tramadol) and 18.5 ± 9.4 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 11 ± 3.2 h and 16.9 ± 3 h, in an extreme case 19.5 h and 43.2 h, respectively.

Linearity

Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.

Pharmacokinetic/phar­macodynamic relationship

The relationship between serum concentrations and the analgesic effect is dosedependent, but varies considerably in isolated cases. A serum concentration of 100 –300 ng/ml is usually effective.

Paediatric population

The pharmacokinetics of tramadol and O-desmethyltramadol after single-dose and multiple-dose oral administration to subjects aged 1 year to 16 years were found to be generally similar to those in adults when adjusting for dose by body weight, but with a higher between-subject variability in children aged 8 years and below.

In children below 1 year of age, the pharmacokinetics of tramadol and Odesmethyltramadol have been investigated, but have not been fully characterized. Information from studies including this age group indicates that the formation rate of O-desmethyltramadol via CYP2D6 increases continuously in neonates, and adult levels of CYP2D6 activity are assumed to be reached at about 1 year of age. In addition, immature glucuronidation systems and immature renal function may result in slow elimination and accumulation of O-desmethyltramadol in children under 1 year of age.

5.3 Preclinical safety data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. Studies of tramadol in rats and rabbits have revealed no teratogenic effects. However, embryo toxicity was shown in the form of delayed ossification. Fertility, reproductive performance and development of offspring were unaffected.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule Contents: Sugar spheres (sucrose and maize starch), colloidal anhydrous silica, ethylcellulose, shellac, talc.

Capsule Shell: Gelatin, Titanium Dioxide (E171)

The 50 mg and 150 mg capsules also contain Iron Oxide Yellow (E172) and

Indigotine (E132).

The 200 mg capsules also contain Iron Oxide Yellow (E172)

Printing ink contains shellac, iron oxide black (E172), propylene glycol and ammonium hydroxide.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

White opaque PVC/PVDC and aluminium foil blisters. Each blister contains 10 capsules.

Each pack contains 10, 20, 30, 50, 60 or 100 capsules per pack.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Mylan Products Ltd.,

Station Close,

Potters Bar,

Herts,

EN6 1TL,

United Kingdom.

8 MARKETING AUTHORISATION NUMBER(S)

PL 46302/0150

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

15/02/2002