MAXITRAM SR 50 mg prolonged-release capsule, hard

MAXITRAM SR 100 mg prolonged-release capsule, hard

MAXITRAM SR 150 mg prolonged-release capsule, hard

MAXITRAM SR 200 mg prolonged-release capsule, hard

MAXITRAM SR 50 mg prolonged-release capsules, hard: 1 prolonged-release capsule contains 50mg of tramadol hydrochloride equivalent to 43.91mg tramadol.

Excipients:

0.0038mg Methyl parahydroxybenzoate/prolonged-release capsule

0.0011mg Propyl parahydroxybenzoate/prolonged-release capsule

5.35mg Sucrose/prolonged-release capsule

MAXITRAM SR 100 mg prolonged-release capsules, hard: 1 prolonged-release capsule contains 100mg of tramadol hydrochloride equivalent to 87.82mg tramadol.

Excipients:

0.0075mg Methyl parahydroxybenzoate/prolonged-release capsule

0.0023mg Propyl parahydroxybenzoate/prolonged-release capsule

10.70mg Sucrose/prolonged-release capsule

MAXITRAM SR 150 mg prolonged-release capsules, hard: 1 prolonged-release capsule contains 150mg of tramadol hydrochloride equivalent to 131.73mg tramadol.

Excipients:

0.011mg Methyl parahydroxybenzoate/prolonged-release capsule

0.0034mg Propyl parahydroxybenzoate/prolonged-release capsule

16.05mg Sucrose/prolonged-release capsule

MAXITRAM SR 200 mg prolonged-release capsules, hard: 1 prolonged-release capsule contains 200mg of tramadol hydrochloride equivalent to 175.64mg tramadol.

Excipients:

0.015mg Methyl parahydroxybenzoate/prolonged-release capsule

0.0045mg Propyl parahydroxybenzoate/prolonged-release capsule

21.40mg Sucrose/prolonged-release capsule

For a full list of excipients, see section 6.1.

Prolonged-release capsule, hard

MAXITRAM SR 50 mg prolonged-release capsules, hard: Capsules with opaque white cap and body, containing white spherical microgranules.

MAXITRAM SR 100 mg prolonged-release capsules, hard: Capsules with opaque yellow cap and natural transparent body, containing white spherical microgranules.

MAXITRAM SR 150 mg prolonged-release capsules, hard: Capsules with opaque yellow cap and body, containing white spherical microgranules.

MAXITRAM SR 200 mg prolonged-release capsules, hard: Capsules with opaque yellow cap and opaque white body, containing white spherical microgranules.

For moderate to severe pain.

The dosage should be adjusted to the severity of the patient's pain and his/her sensitivity.

Prolonged-release capsules, hard, 50mg:

Adults and adolescents aged 12 years and over:

100-200mg tramadol hydrochloride twice daily (corresponding to 200 – 400mg of tramadol hydrochloride/day), morning and evening administration recommended. If required, other forms of administration can be used.

Prolonged-release capsules, hard, 100mg:

Adults and adolescents aged 12 years and over:

100-200mg tramadol hydrochloride twice daily (corresponding to 200 – 400mg of tramadol hydrochloride/day), morning and evening administration recommended.

Prolonged-release capsules, hard, 150mg:

Adults and adolescents aged 12 years and over:

150mg tramadol hydrochloride twice daily (corresponding to 300mg of tramadol hydrochloride/day), morning and evening administration recommended.

Prolonged-release capsules, hard, 200mg:

Adults and adolescents aged 12 years and over:

200mg tramadol hydrochloride twice daily (corresponding to 400mg of tramadol hydrochloride/day), morning and evening administration recommended.

The smallest effective analgesic dose should always be used. Daily doses of 400mg of active substance must not be exceeded, unless exceptional medical reasons require so. A minimum interval of 8 hours must be respected between administrations.

Children:

MAXITRAM SR is not suitable for use in children below 25kg body weight which in general does not allow for individualized dosage in children below 12 years of age. Consequently, a more suitable form of administration should be used.

Elderly people (over 75 years):

As a rule, dosage adjustment in elderly patients (up to 75 years of age) is not required in the absence of clinically manifest hepatic or renal insufficiency. Elimination may be prolonged in elderly patients (over 75 years of age). Consequently, dosage intervals should be prolonged according to individual needs.

Hepatic and renal insufficiency/dialysis:

MAXITRAM SR should not be administered to patients with severe hepatic and/or renal insufficiency. In less severe cases, prolongation of the dosage interval can be envisaged.

Note: The recommended dosages are indicative only. In general, the smallest effective analgesic dose should be used. For the treatment of chronic pain, a pre-established posology must be respected.

For doses not realisable/practicable with this medicinal product other strengths of this medicinal product or other pharmaceutical forms and products are available.

Method of administration

The prolonged-release capsule, hard, must be swallowed whole with sufficient liquid, irrespective of mealtimes.

MAXITRAM SR must never be used for longer than therapeutically absolutely necessary. Should prolonged pain treatment according to the nature and severity of the illness be necessary, a careful evaluation should be carried out at short regular intervals (if necessary by instituting treatment pauses) to check whether or to what extent prolonged treatment is medically necessary.

MAXITRAM SR must not be used in the following cases:

− hypersensitivity to tramadol, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or to any of the excipients;

− acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs;

− patients who are taking monoamine oxidase inhibitors or have been taking them within the previous two weeks (see section 4.5);

− epilepsy uncontrolled by treatment.

MAXITRAM SR must not be used for the treatment of opioid dependence.

MAXITRAM SR 50mg is not suitable for use in children under 25kg body weight (see also section 4.2).

This medicinal product is contraindicated in children below 12 years of age.

MAXITRAM SR should only be used following a strict benefit-risk evaluation and appropriate precautionary measures in the following cases:

− opioid-dependent patients,

− impaired consciousness of unclear aetiology, shock

− impaired respiratory centre or function,

− increased intracranial pressure, head injury, or brain disease,

− impaired liver or kidney function.

The medicinal product should be used with caution in patients showing sensitivity reactions to opiates.

Convulsions have been reported in patients taking tramadol at the recommended dosage. Increased risk may be associated with the administration of doses exceeding the recommended daily dose (400mg). Tramadol can increase the risk of convulsions if combined with other medicinal products that lower the convulsion threshold (see section 4.5). Patients with a history of epilepsy or those susceptible to convulsions should only be treated with tramadol if there are compelling circumstances.

Tramadol has a slight potential for dependence. In case of prolonged use, patients may develop tolerance, and psychic and physical dependence. At therapeutic doses, withdrawal symptoms have been reported with a frequency of 1 in 8,000. In patients with a tendency to drug abuse or drug dependence, treatment with MAXITRAM SR should only be for short periods and under strict medical supervision.

MAXITRAM SR is not suitable for use as a substitute in opioid-dependent patients. Although it is an opiate agonist, tramadol cannot suppress morphine withdrawal symptoms.

The medicinal product contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possible delayed).

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Life-threatening interactions affecting the central nervous system as well as respiratory and cardiovascular function have been observed in patients who had been treated with MAO inhibitors within 14 days prior to the administration of the opioid pethidine. The same interactions with MAXITRAM SR as with MAO inhibitors cannot be ruled out.

The concurrent administration of MAXITRAM SR with other centrally acting drugs, including alcohol, may mutually potentiate effects on the CNS.

Based on available pharmacokinetic results, no clinically relevant interactions are expected with the co-administration or previous administration of tramadol with cimetidine (enzyme inhibitor). Concurrent or previous treatment with carbamazepine (enzyme inducer) may reduce and shorten the analgesic effect.

The combination of a mixture of agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended, since there is a theoretical possibility that the analgesic effect of a pure agonist becomes decreased in such conditions.

Tramadol may induce convulsions and increase the convulsion-inducing potential of selective serotonin reuptake inhibitors, tricyclic antidepressants, anti-psychotics and other convulsion threshold-lowering drugs.

In isolated cases, a serotonin syndrome has been reported with the concurrent therapeutic use of tramadol in combination with other serotoninergic substances, such as selective serotonin reuptake inhibitors (SSRIs). Symptoms of serotonin syndrome include confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. Cessation of serotoninergic drugs generally leads to rapid improvement. Treatment depends on the nature and severity of 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.

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.

Other CYP3A4 inhibitors, such as ketoconazole and erythromycin may inhibit both the metabolism of tramadol (N-demethylation) and possibly also the metabolism of the active O-demethylated metabolites. The clinical significance of this interaction is not known.

Tramadol crosses the placenta.

Insufficient experience is available on the chronic use of tramadol during pregnancy. The repeated administration of tramadol during pregnancy can lead to increased tolerance of tramadol in the fetus and consequently to withdrawal symptoms in the new-born infant after birth. For this reason MAXITRAM SR should not be used during pregnancy.

Tramadol administered before or during birth does not affect uterine contractility. In new-born infants it may induce respiratory rate changes which normally are not clinically significant.

Tramadol is excreted in very small amounts (approx. 0.1% of an intravenous dose) in human breast milk.

For this reason tramadol should not be used during lactation. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.

MAXITRAM SR may cause drowsiness and blurred vision altering one's capacity to react, so that the ability to drive and use machines or work without a steady foothold is reduced. This applies especially at the start of treatment, when changing over to another treatment, in combination with other centrally active drugs, and particularly if combined with alcohol.

The most frequent side effects occurring during treatment with MAXITRAM SR are nausea and vertigo, which occur in more than 1 out of 10 patients.

Cardiac disorders:

Uncommon ( 1/1,000 to < 1/100): there may be effects on cardiovascular regulation (palpitations, tachycardia, faintness or cardiovascular collapse). These adverse effects may occur especially if the patient is standing upright or experiencing physical stress.

Rare ( 1/10,000 to < 1/1,000): bradycardia (reduced heart rate), elevated blood pressure.

Nervous System disorders:

Very common ( 1/10): vertigo.

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

Rare ( 1/10,000 to < 1/1,000): change in appetite, paraesthesia, trembling, respiratory depression, epileptiform seizures, involuntary muscle contractions, abnormal coordination, syncope.

Depressed respiration can occur in patients exceeding the recommended dosage or simultaneously using other CNS-depressant drugs.

Epileptiform seizures principally occurring following the use of high tramadol doses or following the concomitant use of potentially seizure-inducing or seizure-threshold lowering drugs.

Psychiatric disorders:

Rare ( 1/10,000 to < 1/1,000): hallucinations, confusion, sleep disturbance, anxiety and nightmares.

Psychic complaints, which may differ in their nature or degree of intensity (depending on the patient's personality and duration of treatment), may occur following treatment with MAXITRAM SR. Symptoms may include mood changes (mostly elation, occasionally also irritability), changes in activity (mostly reduced, occasionally increased) and alterations of cognitive and sensory performance (changes in sensory perception and recognition that can lead to errors in decision making).

Dependence can occur.

Eye disorders:

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

Respiratory disorders:

Rare ( 1/10,000 to < 1/1,000): dyspnoea

Increased difficulty in breathing and a worsening of asthma have been reported. However a causal relationship with the active substance tramadol could not be established.

Gastrointestinal disorders:

Very common ( 1/10): nausea

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

Uncommon ( 1/1,000 to < 1/100): retching, diarrhoea, gastric complaints (e.g. stomach pressure, bloating).

Skin and subcutaneous tissue disorders:

Common ( 1/100 to< 1/10): sweating

Uncommon ( 1/1,000 to < 1/100): skin manifestations (e.g. itching, rash, hot flushes).

Musculoskeletal and connective tissue disorders:

Rare ( 1/10,000 to < 1/1,000): reduced muscle strength.

Hepatobiliary disorders:

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

Renal and urinary disorders:

Rare (1/10,000 to < 1/1,000): disorders of micturition or reduced diuresis.

General disorders:

Common ( 1/100 to < 1/10): fatigue

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

The long-term use of MAXITRAM SR can lead to dependence, even if the risk is low.

Following the cessation of treatment, symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesias, tremor and gastrointestinal symptoms.

Methyl parahydroxybenzoate and propyl parahydroxybenzoate can cause hypersensitivity, even delayed hypersensitivity reactions.

Symptoms

The symptoms of tramadol poisoning are typical of other centrally active analgestics (opioids). In particular, miosis, vomiting, cardiovascular collapse, impaired conciousness and coma, convulsions and respiratory depression as well as respiratory arrest may occur.

Treatment

Depending on symptoms, treatment ordinarily consists of general emergency measures for freeing the airways (beware of aspiration!) and for maintaining breathing and cardiovascular function. Naloxone can be used as an antidote in case of respiratory depression. Naloxone has been shown to have no effect on convulsions in animal experiments. Intravenous diazepam should be used instead.

Tramadol is only slightly dialysable. For this reason, haemodialysis or haemofiltration on their own are not suitable for the treatment of acute poisoning with MAXITRAM SR.

Pharmacotherapeutic group: Analgesics, other opioids.

ATC Code: N02AX02

Tramadol is a centrally-acting opioid analgesic. It is a non-selective pure agonist at μ, δ, and κ opioid receptors with a higher affinity at the μ receptors. Other mechanisms that contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline as well as increased serotonin release.

Tramadol has an antitussive effect. In contrast to morphine, tramadol in analgesic doses has no respiratory depression effect over a wide range and no effect on gastrointestinal motility. It has only a slight effect on the cardiovascular system.

Tramadol potency is given as 1/10 to 1/6 of that for morphine.

Following oral use tramadol absorption is greater than 90%. Absolute average bioavailability is 70%, irrespective of concurrent food intake. The difference between available absorbed and unmetabolized tramadol can be explained by the fact that there is only slight first-pass metabolism. First-pass metabolism following oral administration is 30% at most.

Following oral use (100mg) in liquid form, peak plasma concentrations (C_max) after 1.2 hours are calculated to be 309 ± 90ng/ml and following a similar dose in solid oral form peak plasma concentrations (C_max) after 2 hours are 280 ± 49 ng/ml. Tramadol has high tissue affinity (Vd, β = 203 ± 40 l). Serum protein binding is approximately 20%.

Following the administration of MAXITRAM SR 100mg peak plasma concentrations (C_max) after 4.9 hours are 141 ± 40ng/ml. Following the administration of MAXITRAM SR 200mg, peak plasma concentrations (C_max) after 4.8 hours are 260 ± 62ng/ml.

Tramadol crosses the blood-brain barrier and the placenta. Very slight amounts of the drug together with its O-demethyl derivative are found in maternal milk (0.1% and 0.02% of the administered dose, respectively).

The elimination half-life (t½ β) of tramadol is about 6 hours, irrespective of the method of administration. In patients over 75 years of age, elimination half-life may be prolonged by a factor of approx. 1.4.

In humans, tramadol is essentially metabolized by N- and O-demethylation as well as by conjugation of the O-demethylation products with gluconic acid. Only O-demethyl tramadol is pharmacologically active. There are considerable quantitative interindividual variations as regards the other metabolites. 11 metabolities have been found in urine to date. According to results of animal experiments, O-demethyl tramadol exceeds the potency of the parent substance by a factor of 2 to 4. Its half-life (t½ β) (6 healthy volunteers) is 7.9 hours (ranging between 5.4 to 9.6 hours) and is similar to that of tramadol.

Inhibition of the isoenzymes CYP3A4 and/or CYP2D6 involved in the biotransformation of tramadol can influence the plasma concentration of tramadol or that of its active metabolites. No clinically relevant interactions have been reported to date.

Tramadol and its metabolites are almost completely excreted via the kidneys. Cumulative urinary excretion is 90% of the total radioactivity of the administered dose. Tramadol half-life may be slightly prolonged in patients with impaired liver or kidney function. Elimination half-lives of 13.3 ± 4.9 hours (tramadol) and of 18.5 ± 9.4 hours (O-demethyl tramadol) and in extreme cases of 22.3 and 36 hours, respectively have been determined in patients with cirrhosis of the liver. Elimination half-lives of 11 ± 3.2 hours and 16.9 ± 3 hours, and in extreme cases of 19.5 hours and 43.2 hours, respectively have been determined in patients with renal insufficiency (creatinine clearance < 5ml/min).

Tramadol at therapeutic doses shows a linear pharmacokinetic profile.

The relation between serum concentrations and analgesic effect is dose-dependent while showing significant individual variations. As a rule, serum concentrations of 100 – 300 ng/ml are effective.

Some in-vitro test systems have indicated mutagenic effects. In vivo tests have been given no indications of mutagenic effects. According to current knowledge tramadol can be classified as a non-mutagenic substance.

Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in the rat and mouse. The rat study gave no indications of substance-related increases in tumour incidence. In the mouse study, increased incidence of liver cell adenoma was observed in the males (dose-dependent, non-significant increases from 15mg/kg and an increase in lung tumours in the females of all dose groups (significant but nondose dependent increases).

In studies on reproduction toxicity tramadol dosages from 50mg/kg/day in the rat produced maternal toxic effects and led to increased neonate mortality. Delayed growth in the form of disorders of ossification and delayed vaginal and eye opening occurred in the progeny. The fertility of male rats was not impaired. Females on high doses (from 50mg/kg/day) showed a reduced gestation index.

From 125mg/kg maternal toxic effects occurred in rabbits as well as skeletal anomalies in the progeny.

Capsule contents:

Sugar spheres (maize starch and sucrose)

Macrogol 4000

Polyacylate dispersion 30% (ethyl acrylate, methyl methacrylate, nonoxynol)

Dimeticone emulsion (dimethicone, (t-octyphenoxy)polyethoxyethanol, Macrogol 600, polyethylene-sorbitan-monolaurate, sodium benzoate, propyl-4-hydroxybenzoate (E216), methyl-4-hydroxybenzoate (E218), propylene glycol, sorbic acid)

Hypromellose

Talc

Capsule Shell:

Gelatin

Titanium dioxide (E171)

Tramadol Maxitram 100, 150, 200 mg prolonged-release capsules, hard:

Gelatin

Titanium dioxide (E171)

Yellow Iron Oxide (E172)

Not applicable.

3 years

Do not store above 25°C.

Aluminium/PVC blisters

Pack sizes: 10, 20, 28, 30, 50, 56, 60, 100 prolonged-release capsules, hard.

Hospital packs: 500 prolonged-release capsules, hard

Not all pack sizes may be marketed.

No special requirements.

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK8 3GY

United Kingdom

PL 08829/0162

PL 08829/0163

PL 08829/0164

PL 08829/0165

Date of first authorisation: 50mg - 27/09/2007

Date of first authorisation: 100/150/200mg: 19/09/2007

Date of latest renewal: 12/07/2011

December 2011

POM