Marol 100mg Prolonged-Release Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Marol 100mg Prolonged-release tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Marol Tablets are prolonged release tablet containing 100 mg of Tramadol hydrochloride.
For excipients, see section 6.1
3 PHARMACEUTICAL FORM
Prolonged release tablet.
Marol 100 mg tablets are off white, round biconvex tablets, 9.1 mm diameter
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of moderate to severe pain.
4.2 Posology and method of administration
Route of Administration
Oral use
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, Marol tablets should be given as follows:
Adults and adolescents older than 12 years:
The usual initial dose is one 100mg tablet, twice daily, in the morning and evening.
Dependent upon the needs of the patient, subsequent doses may be administered earlier than 12 hours, but must not be administered earlier than 8 hours after the previous dose.
If the painkilling is insufficient, the dose may be increased to: one 150mg tablet, twice daily or one 200mg tablet, twice daily.
Marol tablets should be swallowed completely, without breaking or chewing, independent of meals, with sufficient liquid.
The dose used should be the lowest dose that provides pain relief. A daily dose of 400 mg of tramadol is usually sufficient, except in special clinical circumstances.
Under no circumstances should Marol tablets be used for longer than absolutely necessary.
If long-term pain treatment with Marol 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
Marol Tablets are not suitable for children under the age of 12 years.
Geriatric patients
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
Renal insufficiency/dialysis and hepatic impairment
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
Marol tablets should 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 drugs.
- in patients receiving MAO-inhibitors, or within 2 weeks of their withdrawal. Marol tablets should not be used for narcotic withdrawal treatment.
4.4 Special warnings and precautions for use
Marol Tablets should 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 opioids the medicine 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 of convulsions may increase in patients taking tramadol and concomitant medication 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. 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 product does not suppress morphine withdrawal symptoms although it is an opioid agonist.
4.5 Interaction with other medicinal products and other forms of interaction
Tramadol /MAO - inhibitors
Marol tablets should not be combined with MAO-inhibitors (see section 4.3).
Tramadol / Other centrally acting active substances
In concomitant use of Marol tablets and other centrally acting drugs, including alcohol, a potentiation of CNS effects should be taken into consideration (See section 4.8).
Tramadol / Enzyme inhibitor / inducer
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 inducer) may reduce the analgesic effectiveness and shorten the duration of the action.
Tramadol /Mixed opioid agonists / antagonists
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 / Seizure threshold lowering drugs
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.
Tramadol / Serotonergic agents
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.
Tramadol / Coumarin derivatives
Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased INR and ecchymoses in some patients.
Tramadol / CYP3A4 Inhibitors
Other medicinal products with a known inhibiting effect on CYP3A4, such as ketoconazole and erythromycin, 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 section 4.8).
4.6 Pregnancy and lactation
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 Marol tablets should 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 Marol 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
Marol tablets may cause drowsiness and patients should be warned not to drive or use machinery if affected. This is especially applicable in combination with other psychotropic drugs.
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:
o The medicine has been prescribed to treat a medical or dental problem and
o You have taken it according to the instructions given by the
prescriber and in the information provided with the medicine and
o 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.
Cardiac disorders:
Uncommon (>= 0.1 % - < 1%): 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 (>= 0.01 % - <0.1%): bradycardia, increase in blood pressure.
Nervous system disorders:
Very common (>= 10%): dizziness Common (>= -1 -10%): headache, drowsiness
Rare>= 0.01 % - < 0.1%): changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions.
If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section) respiratory depression may occur.
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 (see sections 4.4 and 4.5)
Psychiatric disorders:
Rare (>= 0.01 % - 0.1%): hallucinations, confusion, sleep disturbances and nightmares. Psychic side-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).
Eye disorders:
Rare (>= 0.01 % - <0.1%): blurred vision Respiratory disorders:
Worsening of asthma has also been reported, though a causal relationship has not been established.
Gastrointestinal disorders:
Very common (>= 10%): nausea
Common (>= 1% -10%): vomiting, constipation, dry mouth.
Uncommon (>= 0.1 % - <1%): Retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating).
Skin and subcutaneous tissue disorders:
Common (>= 1 % - 10%): sweating
Uncommon (>= 0.1 % - <1%): dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal disorders:
Rare (>= 0.01 % - < 0.1%): motorial weakness Hepato-biliary disorders:
In a few isolated cases (<= 0.01 %) an increase in liver enzyme values has been reported after use of tramadol.
Renal and urinary system disorders:
Rare (>= 0.01 % - < 0.1%) : micturition disorders (difficulty in passing urine and urinary retention).
Immune system disorders:
Rare (>= 0.01 % - <0.1%): Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis;
General disorders:
Symptoms which occur on withdrawal, identical to withdrawal symptoms in opioids, may be: agitation, anxiety, nervousness, sleep disorders, hyperkinesia, tremor and gastro intestinal symptoms.
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. Emptying of the stomach by means of vomiting (patient to be conscious) or by means of pumping the stomach. The antidote for respiratory depression is nalaxone. In animal tests naloxone proved to be ineffective against convulsions. In that case diazepam should be administered intravenously.
Tramadol is only minimally removed from plasma using haemodialysis, haemofiltration or haemoperfusion. 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
ATC code N 02 AX 02: Pharmacotherapeutic group: Analgesics, other opioids
Tramadol is a centrally acting opioid analgesic. It is a non-selective, complete agonist of p-, 8- 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 serotonin.
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
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 (Vdj = 203 ± 40 l). Protein binding is about 20%.
After administration of tramadol 100mg prolonged release tablets the maximum peak plasma concentration Cmax 141 ± 40 ng/ml is reached after 4.9 hours. After administration of tramadol 200mg prolonged release tablets a Cmax 260 ± 62 ng/ml is reached after 4.8 hours.
Tramadol passes the blood-brain and placenta barrier. 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).
Elimination of half-life t'Ypis 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. 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 t^P (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 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.
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 substance in haematological, 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 resp 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 mortality in new born rats. In young rats development disorders occurred as ossification 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 skeletal anomalies in the offspring.
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 it is unclear whether tramadol possesses mutagenic potential.
Experiments have been performed on rats and mice with regard to the tumourigenic 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 incidence of liver - cell adenomas in males (depending on the dose, with an insignificant increase as of 15 mg/kg) and an increased chance of lung tumours in females in all dose selections (significant, but not dose dependent) was found.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium hydrogen phosphate dihydrate (E341), Hydroxypropylcellulose (E463),
Colloidal anhydrous silica (E551),
Magnesium stearate (E470b).
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Al / clear PVC blisters in carton boxes in packs of 10, 20, 30, 50, 60, 90, 100, 120, and 180 tablets.
Al / opaque PVC blisters in carton boxes in packs of 10, 20, 30, 50, 60, 90, 100, 120, and 180 tablets.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Morningside Healthcare Limited
115 Narborough Road
Leicester
LE30PA
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20117/0045
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22/02/2008
10 DATE OF REVISION OF THE TEXT
09/07/2014