Larapam 100mg Sr Tablets
1. NAME OF THE MEDICINAL PRODUCT
Larapam 100mg SR Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 100 mg tramadol hydrochloride.
For the full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Prolonged-release tablet.
Larapam 100mg SR Tablets are round, off white tablets.
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.
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.
Paediatric population
Larapam SR is not suitable for children under the age of 12 years.
Older people
A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years elimination may be prolonged. Therefore, if necessary the dosage interval is to be extended according to the patient's requirements.
Method of administration
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.
In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements.
4.3 Contraindications
Larapam SR Tablets must not be used in:
- hypersensitivity to the active substance or any of the excipients listed in 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.
4.4 Special warnings and precautions for use
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 product 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 products 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.
There are three case reports of hyponatraemia in the current safety surveillance of Tramadol, which indicate the possibility of serious electrolyte disturbance after start of treatment with Tramadol.
There are some cases of hyponatraemia reported in relation to Tramadol use post-marketing, which indicates the possibility of serious electrolyte disturbance after start of treatment with Tramadol.
4.5 Interaction with other medicinal products and other forms of interaction
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).
Currently available pharmacokinetic data indicate that clinically relevant interactions are unlikely during concomitant and after previous use of cimetidine (enzyme inhibitor).
The concomitant or prior use of carbamazepine (enzyme inducer) 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 can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.
Concomitant therapeutic use of tramadol and serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely when one of the following is observed:
• Spontaneous clonus
• Inducible or ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature > 38 °C and inducible or ocular clonus.
Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.
Caution must be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased international normalisation ratio (INR) with major bleeding and ecchymoses in some patients.
Other substances that inhibit CYP3A4, such as ketoconazole and erythromycin, may
suppress the metabolism of tramadol (N-demethylation) and possibly also that of the active O-demethylated
metabolites. The clinical relevance of this interaction is not known.
The analgesic effect of tramadol is in part mediated by inhibition of the re - uptake of norepinephrine and enhancement of the release of serotonin (5 - HT). In studies the pre-or postoperative application of the antiemetic 5HT3-antagonist ondansetron resulted in an increase of tramadol consumption in patients suffering from post-operative pain.
4.6 Fertility, pregnancy and lactation
Pregnancy
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.
Breast-feeding
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.
4.7. Effects on ability to drive and use machines
Larapam SR Tablets may cause dizziness and/or drowsiness, and therefore, even when used according to 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 not to drive or operate machinery.
4.8 Undesirable effects
Undesirable effects reported are listed according to the following frequency: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data) .
Metabolism and nutrition disorders:
Unknown: hypoglycaemia
Cardiac disorders:
Uncommon: 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: bradycardia, increase in blood pressure.
Very rare: flushing
Nervous system disorders:
Very common: dizziness Common: headache, drowsiness
Rare: 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 active substances are administered concomitantly (see section 4.5) 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: vertigo.
Psychiatric disorders:
Rare: hallucinations, confusion, sleep disturbances, anxiety 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.
Eye disorders:
Rare: blurred vision
Respiratory, thoracic and mediastinal disorders:
Rare: dyspnoea
Worsening of asthma has also been reported, though a causal relationship has not been established.
Gastrointestinal disorders:
Very common: nausea
Common: vomiting, constipation, dry mouth.
Uncommon: Retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea
Skin and subcutaneous tissue disorders:
Common: sweating
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal, connective tissue and bone disorders:
Rare: motorial weakness
Hepato-biliary disorders:
Very rare: including isolated reports of an increase in liver enzyme values
Renal and urinary system disorders:
Rare: micturition disorders (difficulty in passing urine, dysuria and urinary retention)
Immune system disorders:
Rare: Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis
General disorders:
Common: fatigue
Frequency not known: hyponatraemia
Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesias, tremor and gastrointestinal symptoms.
Other symptoms of withdrawal have also been reported, including: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and other CNS problems.
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 (www.mhra.gov.uk/yellowcard).
4.9 Overdose
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.
Emptying of the stomach by means of vomiting (patient to be conscious) or by means of pumping the stomach. Gastric lavage can be considered, if the ingestion of overdose is very recent. This must not delay the (repeated) administration of activated charcoal to prevent the
absorption of tramadol.
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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, other opioids ATC code N 02 AX 02:
Mechanism of action
Tramadol is a centrally acting opioid analgesic.
It is a non-selective, complete agonist of p-, 5- and K-opioid receptors with a higher affinity for p-receptors. Other mechanisms contributing to the analgesic effect are the inhibition of the neural noradrenalin reuptake and an enhanced release of serotonine.
Clinical efficacy and safety 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
5.2 Pharmacokinetic properties
Absorption
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^p = 203 ± 40 l). Protein binding is about 20%.
After administration of Larapam 100mg SR Tablets the maximum peak plasma concentration Cmax 141 ± 40 ng/ml is reached after 4.9 hours. After administration of Larapam 200mg SR Tablets a Cmax 260 ± 62 ng/ml is reached after 4.8 hours.
Distribution
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).
Biotransformation
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 TAP (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 cytochrome P450 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 halflife 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.
Elimination
Elimination of half-life TAP is 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.
Linearity
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.
5.3 Preclinical safety data
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 respectively 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 cannot 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.
6.1 List of excipients
Calcium hydrogen phosphate dihydrate
Hyprolose
Silica, colloidal anhydrous magnesium stearate
6.2. Incompatibilities
Not applicable.
6.3. Shelf life
36 months.
6.4. Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
10, 20, 30, 50, 60, 100 and 100x1 (unit-dose) tablets in PVC/Aluminium blister packs
- PVC transparent, colourless
- PVC white, opaque
- Aluminium 20 pm
- Aluminium 9 pm
Not all pack-sizes may be marketed.
6.6. Instructions for use and handling
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Sandoz Limited Frimley Business Park,
Frimley,
Camberley,
Surrey,
GU16 7SR.
United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 04416/0596
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
26/08/2009
10
DATE OF REVISION OF THE TEXT
08/02/2014