Zeridame Sr 200mg Prolonged Release Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zeridame SR 200mg Prolonged Release Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One prolonged-release tablet contains 200mg tramadol hydrochloride.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged-release tablet.
Zeridame SR 200mg Prolonged Release Tablets are off white, capsule shaped tablets 17.1 mm long.
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.
For doses not realisable / practicable with this medicinal product, other strengths of this medicinal product are available.
Unless otherwise prescribed, Zeridame SR Prolonged Release Tablets should be given as follows:
Adults and adolescents older than 12 years:
The usual initial dose is 100mg, 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. Under no circumstances should more than two doses be taken in any one 24 hour period.
If the painkilling is insufficient, the dose may be increased to:
150mg, twice daily or 200mg, twice daily.
The smallest effective analgesic dose should always be used. Daily doses of 400 mg of active substance must not be exceeded, unless exceptional medical reasons require so.
Under no circumstances should Zeridame SR 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.
Paediatric population
Zeridame SR is 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.
Method of administration
Zeridame SR Prolonged Release Tablets should be swallowed completely, without breaking or chewing, independent of meals, with sufficient liquid.
4.3 Contraindications
- Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1
- acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs.
- patients receiving MAO - inhibitors, or within 2 weeks of their withdrawal.
- patients with epilepsy not adequately controlled by treatment
- opioid withdrawal treatment.
4.4 Special warnings and precautions for use
Zeridame SR should only be used following a strict benefit - risk evaluation and appropriate precautionary measures in the following cases: 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, patients with moderate to severe impaired liver or kidney function.
Zeridame SR should not be used in combination with alcohol.
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 on 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.
Fatal cases of unintended overdose are reported to be related with the use of other psycho-active medicines or substances including alcohol. Tramadol should be prescribed with care in alcoholics and users of other psycho-active drugs.
After long term treatment (> 3 months) of analgesics with use every second day or more frequently, headache may develop or aggravate. Cases of medication overuse headache (MOH - medication-overuse headache) have been reported following not registered use of Tramadol in the treatment of tension or cluster headache or migraine. Headache caused by overuse of analgesics should not be treated by increasing the dose. In such cases the use of analgesics should be discontinued in consultation with a doctor.
4.5 Interaction with other medicinal products and other forms of interaction
MAO - inhibitors
Zeridame SR should not be combined with MAO-inhibitors (see section 4.3). Life threatening interactions affecting the central nervous system as well as respiratory and cardiovascular function have been observed in patients who have been treated with MAO inhibitors within 14 days prior to the administration of the opioid pethidine. The same interactions with Zeridame SR as with MAO inhibitors cannot be ruled out.
Other centrally acting active substances
In concomitant use of Zeridame SR and other centrally acting drugs, including alcohol, a potentiation of CNS effects should be taken into consideration (See section 4.8).
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.
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.
Serotonergic agents /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.
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.
Coumarin derivatives
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.
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).
Ondansetron
The analgesic effect of Tramadol is in part mediated by inhibition of the reuptake of norepinephrine and enhancement of the release of serotonin (5-HT). In studies the pre - or postoperative application of the antiemetic 5 - HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative 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 crosses the placenta, insufficient experience is available on the chronic use of tramadol during pregnancy. The repeated administration of tramadol during pregnancy can lead to increased tolerance of tramadol in the foetus and consequently to withdrawal symptoms in the new borne infant after birth, as a consequence of habituation.
Therefore Zeridame SR 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.
Breast-feeding
When breastfeeding about 0.1 % of the tramadol dose administered is excreted in milk. Administration of Zeridame SR 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
Zeridame SR has minor or moderate influence on the ability to drive and use machines. It may cause drowsiness and blurred vision. This is especially applicable in combination with other psychotropic drugs, and alcohol. Ambulant patients should 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:
- The medicine has been prescribed to treat a medical or dental problem and
- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
- 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).
Not known: speech disorders
Psychiatric disorders:
Rare ( 1/10000, <1/1000): hallucinations, confusion, sleep disturbance, anxiety and nightmares.
Psychic adverse reactions may occur following administration of Tramadol 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 ( 1/10): 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 ( 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)
Metabolism and nutrition disorder:
Not known: Hypoglycaemia
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.
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. Consideration should also be given to the administration of activated charcoal, if necessary via the stomach pump tube. Depending how long has elapsed from ingestion, administration of a suitable laxative to speed up elimination should be considered. In the event that the patient’s consciousness is reduced, intubation prior to performing these procedures is essential.
The antidote for respiratory depression is naloxone.
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. Administration of a suitable laxative may help to speed up elimination of unabsorbed tramadol, if administered early after overdose.
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, partial 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 noradrenaline reuptake, and an enhanced release of serotonin.
Pharmacodynamic effects / Clinical efficacy and safety Tramadol has an antitussive action.
Contrary to morphine tramadol does not suppress respiration in analgetic doses over a large range.
The action on the cardiovascular system is minimal.
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 %.
Distribution
Tramadol has a high tissue affinity (Vd,p = 203 ± 40 l). Protein binding is about 20 %.
After administration of Tramadol 100 mg SR Tablets the maximum peak plasma concentration Cmax 141 ± 40 ng / ml is reached after 4.9 hours. After administration of Tramadol 200 mg SR 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).
Biotransformation
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/2p (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.
Elimination
Elimination of half-life t/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.
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.
Linearity
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
Pharmacokinetic / pharmacodynamics relationship
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 newborn 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 tumuorigenic 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
3 years
PP / PE tablet container: 6 months after opening
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
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, 180, and 500 tablets.
Al / opaque PVC child resistant blisters in carton boxes in packs of 10, 20, 30, 50, 60, 90, 100, 120, 180, and 500 tablets.
Polypropylene tablet container with polyethylene tamper evident closure containing 10, 20, 30, 50, 60, 90, 100, 120, 180, and 500 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No Special Requirements
7 MARKETING AUTHORISATION HOLDER
Actavis Group PTC ehf. Reykjavikurvegi 76-78 220 HafnarfjorQur Iceland
8 MARKETING AUTHORISATION NUMBER(S)
PL 30306/0724
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27/10/2008
10 DATE OF REVISION OF THE TEXT
23/09/2015