Tramadol Hydrochloride 50mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Tramadol Hydrochloride 50mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 50mg tramadol hydrochloride.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Yellow/green hard gelatin capsule
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
As an analgesic. Tramadol Hydrochloride 50mg Capsules are indicated for the treatment of moderate to severe pain.
4.2 Posology and method of administration
Capsules should be swallowed whole with sufficient liquid. Capsules’ intake is independent of meals.
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
Adults and children, 12 years and over:
Dependent upon pain severity, the initial dose is 50mg or 100mg; with subsequent doses of either 50mg or 100mg, depending upon clinical need, every four to six hours.
In acute pain, an initial dose of 100mg is usually required. Chronic pain usually requires an initial dose of 50mg and then titrations according to pain severity.
Treatment should be limited and intermittent and given only when clinically required.
The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported.
The total daily oral dose should not exceed 400mg, except in special clinical circumstances.
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.
Children less than 12 years of age:
Not recommended.
4.3 Contraindications
Contraindicated in patients who are:
• hypersensitive to tramadol or to any of the excipients
• acutely intoxicated with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs
• receiving, or have received in the preceding fourteen days, monoamine oxidase inhibitors.
• for use in narcotic withdrawal treatment.
Tramadol Hydrochloride 50mg Capsules may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure.
In patients sensitive to opiates the product should only be used with caution.
Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered (see section 4.5), or if the recommended dosage is significantly exceeded (see section 4.9) as the possibility of respiratory depression cannot be excluded in these situations.
Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400 mg).
In addition, tramadol may increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold (see section 4.5). Patients with epilepsy or those susceptible to seizures should be only treated with tramadol if there are compelling circumstances.
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 with Tramadol Hydrochloride 50 mg Capsules should only be carried out for short periods under strict medical supervision.
Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
4.5 Interaction with other medicinal products and other forms of interaction
Tramadol Hydrochloride 50mg Capsules not be combined with MAO inhibitors (see section 4.3).
In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine, life-threatening interactions on the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with Tramadol Hydrochloride 50mg Capsules.
Concomitant administration of Tramadol Hydrochloride 50mg Capsules with other centrally depressant medicinal products including alcohol may potentiate the CNS effects (see section 4.8).
The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur. Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.
The combination with mixed agonist/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not advisable, because the analgesic effect of a pure agonist may be theoretically reduced in such 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 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.
Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied (see section 4.8).
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.
When administered with coumarin anticoagulants interaction results in an increased INR according to isolated reports. Care should be taken when commencing treatment with tramadol in patients on anticoagulants.
Pregnancy:
Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality. Teratogenic effects were not observed. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy. Therefore Tramadol Hydrochloride 50mg Capsules should not be used in pregnant women. 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. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.
Lactation:
During lactation about 0.1 % of the maternal dose is secreted into the milk. Tramadol Hydrochloride 50mg Capsules are not recommended during breastfeeding. After a single administration of tramadol it is not usually necessary to interrupt breast-feeding.
4.7 Effects on ability to drive and use machines
Tramadol Hydrochloride 50mg Capsules may cause drowsiness, this effect can be potentiated by alcohol and other CNS depressants; patients must be warned not to drive or operate machinery if affected.
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 reactions are nausea and dizziness, both occurring in more than 10 % of patients.
Cardiovascular disorders:
uncommon (± 1/1000, <1/100): 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
Nervous system disorders:
very common (±1/10): dizziness
common (±1/100, <1/10): headache, somnolence
rare (±1/10000, <1/1000): 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 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 medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).
Psychiatric disorders:
rare (±1/10000, <1/1000): hallucinations, confusion, sleep disturbance, anxiety and nightmares. Psychic adverse reactions may occur following administration of Tramadol Hydrochloride 50mg Capsules which vary individually in intensity and nature (depending on personality and duration of treatment). 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). Dependence may occur.
Eye disorders:
rare (±1/10000, <1/1000): blurred vision Respiratory disorders:
rare (±1/10000, < 1/1000): dyspnoea
Worsening of asthma has been reported, though a causal relationship has not been established.
Gastrointestinal disorders:
very common (± I 10): 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), diarrhoea
Skin and subcutaneous disorders:
common (±1/100, <1/10): sweating
uncommon (t 1/1000, <1/100):dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal disorders:
rare (± 1/10000, <1/1000): motorial weakness
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.
Renal and urinary disorders:
rare (± 1/10000, <1/1000) : micturition disorders (difficulty in passing urine, dysuria and urinary retention)
General disorders:
common (±1/100, <1/10): fatigue
rare (±1/10000, <1/1000): allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis; Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen with tramadol discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms.
Symptoms: Typical of opioid analgesics, including vomiting, cardiovascular collapse, miosis, seizures, respiratory depression, sedation and coma.
Treatment: Institution of supportive measures to maintain patency of the airway and the cardiovascular function. Respiratory depression may be reversed by the administration of Naloxone; administration of Diazepam can be used to control fits.
Haemodialysis/haemofiltration leads to minimal serum elimination of tramadol, thus it is not suitable as a sole treatment for detoxification.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics ATC code: N02AX02
Tramadol Hydrochloride 50mg Capsules is a centrally acting analgesic, with non-selective agonist properties for the mu, delta and kappa opioid receptors, it shows a higher affinity for the mu receptor. Supplementary actions, apparently playing a part in analgesic efficacy, are the inhibition of neuronal reuptake of noradrenaline and the enhancement of serotonin release.
Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Also gastrointestinal motility is less affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth) that of morphine.
5.2 Pharmacokinetic properties
After oral administration, tramadol is almost completely absorbed. Mean absolute bioavailability is approximately 70% following a single dose and increases to approximately 90% at steady state. Plasma protein binding of tramadol is approximately 20%. Approximately 90% is excreted via the kidneys with the remaining 10% excreted in the faeces.
The pharmacokinetic profile of tramadol is linear within the therapeutic dosage range.
The elimination half life of tramadol, in healthy young volunteers, is reported as 5.1h to 5.9h; it shows little age dependency although with increasing age there is a trend to increasing half life. In patients with impaired hepatic function (cirrhosis of the liver), the terminal half life increases by a factor of two to three times; similarly in patients with impaired renal function (creatinine clearance between 5 to 80ml/min), the terminal half life increases by a factor of one and a half to two times the normal.
Tramadol is metabolized by the cytochrome P450 isoenzyme CYP2D6. It undergoes biotransformation to a number of metabolites mainly by means of N and O demethylation. O desmethyl tramadol appear to be the most pharmacologically active metabolite showing analgesic activity in rodents. As humans excrete a higher percentage of unchanged tramadol than animals it is believed that the contribution made by this metabolite to analgesic activity is likely to be less in humans than animals. In human the plasma concentration of this metabolite is about 25% that of unchanged tramadol.
Since tramadol is eliminated both metabolically and renally, the terminal halflife t1/2P tramadol was a mean of 13.3 + 4.9.
5.3 Preclinical safety data
On repeated oral and parenteral administration of tramadol for 6 - 26 weeks in rats and dogs and oral administration for 12 months in dogs haematological, clinico-chemical and histological investigations showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses considerably above the therapeutic range: restlessness, salivation, convulsions, and reduced weight gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.
In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams and raised neonate mortality. In the offspring retardation occurred in the form of ossification disorders and delayed vaginal and eye opening. Male fertility was not affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the offspring.
In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies showed no such effects. According to knowledge gained so far, tramadol can be classified as non-mutagenic.
Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dose-dependent)
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tramadol Hydrochloride 50mg Capsules capsules also contain; Croscarmellose sodium Povidone (polyvinylpyrrolidone)
Microcrystalline cellulose Silicon dioxide Magnesium stearate Gelatin
Titanium dioxide Iron oxide yellow Quinoline yellow Brilliant blue FD&C No. 1.
6.2 Incompatibilities
None known.
6.3 Shelf life
4 Years
6.4 Special precautions for storage
Tramadol Hydrochloride 50mg Capsules capsules should be stored below 25oC , in the original package, to protect from moisture and light.
Tramadol Hydrochloride 50mg Capsules are presented in combination aluminium/polyvinylchloride blister packs of 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Morningside Healthcare Ltd 115 Narborough Road Leicester LE3 0PA United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 20117/0086
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
DATE OF REVISION OF THE TEXT
10
05/08/2014