Larapam 200mg SR Tablets

Each prolonged-release tablet contains 200 mg tramadol hydrochloride.

For excipients, see section 6.1

Prolonged-release tablet.

Larapam 200mg SR Tablets are capsule shaped, off white tablets

Treatment of moderate to severe pain.

The dose should be adjusted to the severity of the pain and the individual clinical response of the patient.

Unless otherwise prescribed, Larapam SR Tablets should be given as follows:

Adults and adolescents older than 12 years:

The usual initial dose is one Larapam 100mg SR Tablet, twice daily, in the morning and evening. The dosage interval must not be less than 8 hours.

If the pain relief is insufficient, the dose may be increased to:

one Larapam 150mg SR Tablet, twice daily or

one Larapam 200mg SR Tablet, twice daily.

Larapam SR Tablets should be swallowed whole without breaking or chewing, with a sufficient amount of liquid. The tablets can be taken with or without food.

The recommended doses are intended as a guideline.

The dose used should be the lowest dose that provides pain relief. A daily dose of 400 mg active substance is usually sufficient, except in special clinical circumstances.

Under no circumstances should Larapam SR Tablets be used for longer than absolutely necessary.

If long-term pain treatment with tramadol 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

Larapam SR Tablets are not suitable for children under the age of 12 years.

Elderly

As a rule adjustment of the dose, in elderly patients (up to 75 years) without any clinical manifestations of hepatic or renal impairment , is not necessary.

In older patients (above 75 years) the elimination may be delayed. In which case the dose interval should be prolonged.

Renal impairment, dialysis and hepatic impairment

In patients with serious renal or hepatic impairment the use of Larapam SR Tablets are not recommended. In moderate cases, an adjustment of the dosage interval may be considered.

Larapam SR Tablets must not be used in:

- hypersensitivity to tramadol, or any excipients in the tablet (see section 6.1),

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

- in patients receiving MAO-inhibitors, or within 2 weeks of their withdrawal.

- in patients who are suffering from uncontrolled epilepsy.

Larapam SR Tablets must not be used for narcotic withdrawal treatment.

Larapam SR Tablets must be used with caution in patients dependent on opioids, patients suffering head injuries, shock, decreased level of consciousness of unknown origin, disturbances of the respiratory centre or function, or increased intracranial pressure.

In patients sensitive for opiods the medicinal products should be used cautiously.

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit (400 mg).

The risk on convulsions may increase in patients taking tramadol and concomitant medicinal product that can lower the seizure threshold. (see section 4.5. ). Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons.

Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. At therapeutic doses withdrawal symptoms have been reported at a frequency of 1 in 8,000. 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 for short periods under strict medical supervision

Tramadol is not a suitable substitute in opioid dependent patients. The medicinal product does not suppress morphine withdrawal symptoms although it is an opioid agonist.

Larapam SR Tablets must not be combined with mono amino oxidase (MAO)-inhibitors (see section 4.3 ).

In concomitant use of Larapam SR Tablets and other centrally acting active substances, including alcohol, a potentiation of central nervous system (CNS) effects has to be taken into consideration ( See section 4.8 ).

The results of pharmacokinetic research, so far, showed that no interactions need to be expected in concomitant or prior use of cimetidine (enzyme inhibitor).

The concomitant or prior use of carbamazepine (enzyme inductor) may reduce the analgesic effectiveness and shorten the duration of the action.

The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended because it is theoretically possible that the analgesic effect of a pure agonist is attenuated under these circumstances.

Tramadol may induce convulsions and may increase the potential for selective serotonin re-uptake inhibitors, tricyclic antidepressants, anti-psychotics and other seizure threshold lowering active substances to cause convulsions.

Isolated cases of serotonergic syndrome have been reported with the therapeutic use of tramadol in combination with other serotonergic agents such as selective serotonin re-uptake inhibitors (SSRIs). Serotonergic syndrome can be manifested by symptoms such as confusion, restlessness, fever, sweating, ataxia, hyperreflexia, myoclonia and diarrhoea. Withdrawal of the serotonergic agent produces a rapid improvement. It depends on the nature and severity of symptoms whether medicinal treatment is to be considered.

Caution must be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased international normalisation ratio (INR) and ecchymoses in some patients.

Other medicinal products with a known inhibiting effect on CYP3A4, such as ketoconazole and erythromycine, could inhibit the metabolism of tramadol (N-demethylation) and probably also the metabolism of the active O-demethyl-metabolite. The clinical relevancy of this interaction has not been investigated. (See 4.8 Undesirable effects).

Animal tests with very large concentrations of tramadol showed effects on the development of the organs, bone formation and mortality of the neonate.

Teratogenic effects have not been found. Tramadol passes the placenta. Insufficient data are available to assess the safety of tramadol in pregnant women.

Therefore Larapam SR Tablets must not be used during pregnancy.

Tramadol – administered before or during birth – does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant.

When breastfeeding about 0.1 % of the tramadol dose administered is excreted in milk. Administration of Larapam SR Tablets is not advised while breastfeeding.

In case of a once only administration of tramadol it is usually not required to discontinue breastfeeding.

Larapam SR Tablets may cause dizziness and/or drowsiness, and therefore, even when used according the directions, can influence the ability to drive and use machines. This effect may be potentiated by alcohol, at the beginning of treatment, when switching the active substance, and on concomitant use of other CNS-depressant or anti-histamines. If patients are affected they should be warned no to drive or operate machinery.

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

Cardiac disorders:

Uncommon (>1/1000, <1/100): effects on 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.

Very rare (<0.01%): flushing

Nervous system disorders:

Very common (>1/10): dizziness

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

Rare (>1/10000, < 1/1000): changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions.

If the recommended doses are considerably exceeded and other centrally depressant active substances are administered concomitantly (see section 4.5 "Interaction with other medicinal products and other forms of interaction") respiratory depression may occur.

Epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with active substances which can lower the seizure threshold or themselves induce cerebral convulsions ( see section 4.4 and 4.5 ).

Very rare (<1/10000): vertigo.

Psychiatric disorders:

Rare (>1/10,000, <1/1,000): hallucinations, confusion, sleep distubances and nightmares. Psychic undesirable effects may 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). Tramadol can cause dependence. Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesias, tremor and gastrointestinal symptoms.

Eye disorders:

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

Respiratory , thoracic and mediastinal disorders:

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

Gastrointestinal disorders:

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

Skin and subcutaneous tissue disorders:

Common (>1/100, <1/10): sweating

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

Musculoskeletal , connective tissue and bone disorders:

Rare (>1/10000, <1/1000): motorial weakness

Hepato-biliary disorders:

Very rare (<1/10000), including isolated reports of an increase in liver enzyme values has been reported after use of tramadol.

Renal and urinary system disorders:

Rare (>1/10000, <1/1000): micturition disorders (difficulty in passing urine and urinary retention).

Immune system disorders:

Rare (>1/10000, <1/1000):Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis;

General disorders:

Common (>1/100, <1/10): fatigue

Symptoms

In tramadol intoxication, in principle, the same symptoms occur as for all other central acting analgesics (opioids). In particular, these include miosis, vomiting, cardiovascular collapse, narrowing of consciousness leading to coma, convulsions, respiratory depression leading to respiratory failure.

Treatment

General emergency measures are applicable.

Maintenance of the airway (aspiration), maintenance of respiration and cardiovascular circulation depending on the symptoms.

In addition activated charcoal can be administered. The antidote for respiratory depression is naloxon.

In animal tests naloxon proved to be ineffective against convulsions.

In that case diazepam should be administered intravenously.

Tramadol is only minimally removed from plasma using haemodialysis or haemofiltration.

Therefore treatment of acute overdose of tramadol using haemodialysis or haemofiltration alone is not a suitable way of detoxification.

Pharmacotherapeutic group: Analgesics, other opioids

ATC code N 02 AX 02:

Tramadol is a centrally acting opioid analgesic.

It is a non-selective, complete agonist of μ-, δ- and κ-opioid receptors with a higher affinity for μ-receptors. Other mechanisms contributing to the analgesic effect are the inhibition of the neural noradrenalin reuptake and an enhanced release of serotonine.

Tramadol has an antitussive action.

Contrary to morphine tramadol does not suppress respiration in analgetic doses over a large range.

In addition gastrointestinal motility is not influenced.

The action on the cardiovascular system seems too minor.

The potency of tramadol is reported to be 1/10 to 1/6 of morphine

More than 90% of tramadol 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 (V_d,β = 203 ± 40 l). Protein binding is about 20%.

After administration of Larapam 100mg SR Tablets the maximum peak plasma concentration C_max 141 ± 40 ng/ml is reached after 4.9 hours. After administration of Larapam 200mg SR Tablets a C_max 260 ± 62 ng/ml is reached after 4.8 hours.

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

Elimination of half-life t½βis 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.

In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. The enzymes involved in the metabolism of tramadol are the cytochrome P450 isoenzymes, CYP3A4 and CYP2D6. Only O-desmethyltramadol 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 O-desmethyltramadol is more potent than the parent substance by the factor 2-4. Its half life t½β (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 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite. The clinical consequences of any such interactions are not known.

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 or 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.

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

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

In repeated oral and parenteral administration of tramadol during 6 to 26 weeks to rats and dogs, as also during 12 months to dogs, there are no indications for changes caused by the active substance in haematogical, clinical-chemical and histological experiments.

Only after high doses, far above the therapeutic doses, central symptoms occurred: restlessness, salivation, convulsion, reduced increase in weight.

Rats and dogs tolerate the oral dose of 20 mg/kg respectivly 10 mg/kg bodyweight, dogs also tolerate 20 mg/kg bodyweight, rectally administered.

Tramadol doses as from 50 mg/kg/day cause intoxication of the mother, in rats, and result in an increased morbidity in new born rats.

In young rats development disorders occurred as oscification disturbances, delayed opening of the vagina and eyes.

The fertility of male rats was not influenced.

However the percentage of females with young reduced after high dosages (as of 50 mg/kg/day).

In rabbits, toxic effects occurred as of 125 mg/kg in the mother and skeleton disorders in the young.

In some in-vitro test systems there is report on mutagenic effects.

In in-vivo experiments there was no indication for mutagenic effects.

On the basis of the knowledge available up till now tramadol can be classified as a non mutagenic substance.

Experiments have been performed on rats and mice with regard to the oncogenic potential of tramadol.

From tests in rats it could not be shown that the substance increases the chance of tumours.

In tests in mice an increased chance on hepatic-cell adenoms in males (depending on the dose, with an insignificant increase as of 15 mg/ml) and an increased chance of lung tumours in females in all dose selections (significant, but dose independent) was found.

Calcium hydrogen phosphate dihydrate (E341),

hydroxypropylcellulose (E463),

Silica, colloidal anhydrous (E551),

magnesium stearate (E470b).

Not applicable.

3 years

Do not store above 25°C.

10, 20, 30, 50, 60, 100x1 (unit-dose) tablets in PVC/Aluminium blister packs

- PVC transparent, colourless

- PVC white, opaque

- Aluminium 20 μm

- Aluminium 9 μm

No special requirements.

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

PL 04416/0598

29^th October 2004

11/2010