Aceon 100mg Prolonged-Release Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Aceon 100 mg Prolonged-release Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 100 mg of tramadol hydrochloride. For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged-release tablet
Aceon 100mg tablets are off-white, round, biconvex tablets, 9.0 mm in diameter
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of moderate to severe pain.
4.2
Posology and method of administration
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 adolescents 12 years and older:
The usual initial dose is one 100mg prolonged-release 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 150mg prolonged-release tablet, twice daily or
• one 200mg prolonged-release tablet, twice daily.
The recommended doses are intended as a guideline.
Aceon Prolonged-release 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 dose used should be the lowest dose that provides pain relief. Daily doses of 400 mg active substance should not be exceeded, except in special clinical circumstances.
Under no circumstances should Aceon Prolonged-release 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:
Aceon Prolonged-release tablets are not suitable for children under the age of 12 years.
Geriatric patients
A dose adjustment is not usually necessary in elderly 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
Aceon Prolonged-release 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 (such as moclobemide), or within 2 weeks of their withdrawal.
• in patients who are suffering from inadequately controlled epilepsy
Aceon Prolonged-release Tablets must not be used for narcotic withdrawal treatment.
4.4 Special warnings and precautions for use
Aceon Prolonged-release Tablets must be used with caution in patients dependent on opioids (for example, morphine, diamorphine and codeine) , 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 medicinal product should be used cautiously.
Convulsions have been reported at recommended dose levels 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 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, psychological and physical dependence may develop.
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.
4.5 Interaction with other medicinal products and other forms of interaction
Aceon Prolonged-release tablets must not be combined with mono amino oxidase (MAO) inhibitors (see section 4.3 ). Patients taking MAO inhibitors within 14 days prior to administration of the opioid pethidine have experienced life-threatening interactions that affect the central nervous system and respiratory and cardiovascular function. It is possible that tramadol hydrochloride may cause similar interactions with MAO inhibitors.
Concomitant use of Aceon Prolonged-release tablets with other centrally acting active substances, including alcohol, may potentiate the central nervous system 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.
In a limited number of pre-and postoperative studies, administration of the antiemetic 5-HT3 antagonist ondansetron increased the need of tramadol in patients with postoperative pain.
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) and ecchymoses in some patients.
Other medicinal products with a known inhibiting effect on CYP3A4, such as ketoconazole, ritonavir and erythromycin, could inhibit the metabolism of tramadol (N-demethylation) and probably also the metabolism of the active O-demethyled metabolite. The clinical relevancy of this interaction has not been investigated. (See 4.8 Undesirable effects).
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 crosses the placenta.
Insufficient data are available to assess the safety of tramadol in pregnancy. Therefore Aceon Prolonged-release 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 maternal tramadol dose is excreted in milk. Administration of Aceon Prolonged-release Tablets is not advised while breastfeeding.
In case of a single administration of tramadol it is not usually required to interrupt breastfeeding.
4.7 Effects on ability to drive and use machines
Aceon Prolonged-release 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 not to drive or operate machinery.
4.8 Undesirable effects
The most commonly reported adverse drug reactions are nausea and dizziness, both occurring in more than 10% of patients.
Immune system disorders
Rare (>1/10000, <1/1000): Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis;
Metabolism and nutrition disorders
Rare (>1/10000, < 1/1000): changes in appetite
Not known (cannot be estimated from the available data): hypoglycaemia
Psychiatric disorders:
Rare (>1/10000, <1/1000): hallucinations, anxiety, confusion, sleep disturbances and nightmares. Psychiatric 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.
Nervous system disorders:
Very common (> 1/10): dizziness
Common (>1/100, <1/10): headache, drowsiness
Rare (>1/10000, < 1/1000): paraesthesia, tremor, epileptiform convulsions. Very rare (< 1/10000): vertigo
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).
Eye disorders:
Rare (>1/10000, <1/1000): blurred vision
Cardiac disorders:
Uncommon (>1/1000, <1/100 ): effects on cardiovascular regulation (palpitation, tachycardia). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.
Rare (>1/10000, <1/1,000): bradycardia
Vascular disorders:
Uncommon (>1/1000, <1/100): postural hypotension or cardiovascular collapse Rare (>1/10000, <1/1,000): increase in blood pressure.
Very rare (<1/10000): flushing
Respiratory, thoracic and mediastinal disorders:
Worsening of asthma has also been reported, though a causal relationship has not been established.
Rare (>1/10000, <1/1000):: Dyspnoea, respiratory depression
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.
Gastrointestinal disorders:
Very common (>1/10): vomiting, nausea Common (>1/100, <1/10): constipation, dry mouth.
Uncommon (>1/1000, <1/100): Retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating, diarrhoea).
Hepato-biliary disorders:
Very rare (<1/10000), including isolated reports of an increase in liver enzyme values has been reported after use of tramadol.
Skin and subcutaneous tissue disorders:
Common (>1/100, <1/10): sweating
Uncommon (>1/1,000, <1/100): dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal, connective tissue and bone disorders: Rare (>1/10000, <1/1000): motorial weakness
Renal and urinary disorders:
Rare (>1/10000, <1/1000): micturition disorders (difficulty in passing urine and urinary retention).
General disorders:
Common (>1/100, <1/10): fatigue
Withdrawal symptoms, similar to those that occur in association with opiate withdrawal, may manifest as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal disturbances. Other symptoms which have rarely been observed in connection with the discontinuation of tramadol treatment include: panic attacks, severe anxiety, hallucinations, paresthesia, tinnitus and unusual CNS symptoms.
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 Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, other opioids
ATC code: N02AX02
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 analgesic doses over a large range.
In addition gastrointestinal motility is less affected.
Effects on the cardiovascular system tend to be minor.
The potency of tramadol is reported to be 1/10 to 1/6 that 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 (V_d,P = 203 ± 40 l). Protein binding is about 20%.
It has been found that after administration of the 100mg Prolonged-release Tablets the maximum peak plasma concentration C_max 141 ± 40 ng/ml was reached after 4.9 hours. After administration of the 200mg Prolonged-release Tablets a C_max of 260 ± 62 ng/ml was reached after 4.8 hours. Tramadol passes the blood-brain and placental 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 C/2P 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.
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 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 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 were found. 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
On repeated oral and parenteral administration of tramadol for 6 to 26 weeks to rats and dogs, and oral administration for 12 months in dogs, there was no evidence of changes caused by the active substance in haematogical, clinico-chemical or histological investigations.
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. The fertility of male rats was not influenced.
After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate.
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 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.
Experiments have been performed on rats and mice with regard to the tumorigenic potential of tramadol.
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
Hydroxypropylcellulose
Calcium hydrogen phosphate dihydrate
Colloidal anhydrous silica.
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Cartons consisting of:
Al - PVC / PVdC blisters
Packs of 10, 20, 30, 50, 60, 100, 150 tablets.
Tablet container consisting of: Polypropylene body and closure with aluminium tagger.
Pack size: 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Brown & Burk UK Ltd 5, Marryat Close Hounslow West Middlesex
TW4 5DQ UK
8 MARKETING AUTHORISATION NUMBER(S)
UK: PL 25298/0059
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 2011-04-28
10 DATE OF REVISION OF THE TEXT
2011-04-28
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25/05/2011
10 DATE OF REVISION OF THE TEXT
04/04/2014