SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Tramadol Hydrochloride 50mg Effervescent Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each Effervescent tablet contains 50mg Tramadol hydrochloride

Excipients with known effect: Each effervescent tablet contains 75mg lactose (as lactose monohydrate) and approximately 214mg sodium (see section 4.4)

3    PHARMACEUTICAL FORM

Effervescent tablets

Round, biplane white or off-white tablets of approximate diameter of 17.818.3mm with bevel-edges both sides

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Management (treatment and prevention) of moderate to severe pain.

4.2    Posology and method of administration

Posology

Dosage and administration:

As with all analgesic drugs, the dose of Tramadol Hydrochloride 50mg Effervescent Tablets should be adjusted according 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 aged 12 years and over:

Depending upon the severity of the pain, the initial dose is 50 or 100mg followed by 50 or 100mg not more frequently than 4 hourly. For acute pain an initial dose of 100mg is usually necessary. For pain associated with chronic conditions an initial dose of 50mg is advised. Treatment periods should usually be limited and intermittent. Treatment should be given only where there exists a medical need. A total oral daily dose of more than 400mg is not usually required.

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.

It should be noted that in volunteers aged over 75 years the elimination halflife Tramadol was increase by 17% following oral administration.

Renal insufficiency / renal dialysis/ 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.

For patients with creatinine clearance <30 ml/min, the dosage interval should be increased to 12 hours. Tramadol is not recommended for patients with severe renal impairment (creatinine clearance <10 ml/min).

In severe hepatic impairment the dosage interval should be increase to 12 hours.

Paediatric population:

Not recommended for children under 12 years of age.

Method of administration

Dissolve effervescent tablets in a glass of water prior to intake.

4.3 Contraindications

Tramadol Hydrochloride is contraindicated : o in hypersensitivity to the active substance or to any of the excipients listed in section 6.1 o in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids of psychotropic drugs o in common with other opioid analgesics it should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal

o in patients with epilepsy not adequately controlled by treatment o for use in narcotic withdrawal treatment

o in patients with the hereditary metabolic disease phenylketonuria. The medicinal product contains the sweetener aspartame

4.4 Special warnings and precautions for use

Warnings:

Tramadol Hydrochloride 50mg Effervescent Tablets has been shown to have a low potential to cause physical dependence On long-term use tolerance, psychic and physical dependence may develop, however cases of abuse and dependence have occurred. For this reason the clinical need for continued analgesic treatment should be carried out for short periods under strict medical supervision and reviewed regularly.

Tramadol Hydrochloride 50mg Effervescent Tablets is not suitable as a substitute in opioid dependent patients. Although it is an opioid agonist, Tramadol Hydrochloride 50mg Effervescent Tablets cannot suppress morphine withdrawal symptoms.

In patients sensitive to opiates the product should only be used with caution. Precautions for use:

Tramadol Hydrochloride 50mg Effervescent Tablets should be used with particular caution in patients with head injury, opioid-dependent patients, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure, severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock.

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. At therapeutic doses respiratory depression has infrequently been reported.

Convulsions have been reported in patient receiving tramadol at therapeutic doses and the risk may be increased at doses exceeding the recommended upper daily dose limit (400 mg). Patients with a history of epilepsy or susceptibility to seizures should be treated with Tramadol Hydrochloride 50mg Effervescent Tablets only if there are compelling reasons to do so.

In addition the risk of convulsions may increase in patients taking Tramadol Hydrochloride 50mg Effervescent Tablets and concomitant medication that can lower the seizure threshold (see section 4.5).

In one study use of Tramadol Hydrochloride 50mg Effervescent Tablets during general anaesthesia with enflurane and nitrous oxide was reported to enhance intraoperative recall. Until further information is available use of Tramadol Hydrochloride 50mg Effervescent Tablets during light planes of general anaesthesia should be avoided.

Each tablet contains approximately 214mg sodium. This should be borne in mind when using Tramadol Hydrochloride 50mg Effervescent Tablets in patients on a low sodium diet.

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Tramadol should 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.

Concomitant administration of Tramadol Hydrochloride 50mg Effervescent Tablets with other centrally acting drugs including alcohol may potentiate CNS depressant effects (see section 4.8).

The results of pharmacokinetic studies have so far shown that on the Simultaneous administration or previous administration with cimetidine (enzyme inhibitor) is associated with clinically insignificant changes in serum concentrations of tramadol. Therefore no alteration of the Tramadol Hydrochloride 50mg Effervescent Tablets dosage regimen is recommended for patients receiving chronic cimetidine therapy.

Simultaneous or previous administration of carbamazepine (enzyme inducer) markedly decreases serum concentrations of tramadol to an extent that a decrease in analgesic effectiveness and a shorter duration of action may occur. There is a theoretical possibility that tramadol could interact with lithium and 5HT and noradrenaline potentiating ant-depressants due to their respective mechanisms of action. There have been no reports of this potential interaction.

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.

Quinidine has been reported to increase the Cmax and AUC of tramadol approximately 25%. However, these increases fell within the normal therapeutic range for tramadol and no dosage adjustment is required.

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.

In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotoninergic medicinal products such as selective serotonin re-uptake inhibitors (SSRIs) or with MAO inhibitors. Signs of serotonin syndrome may be for example confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. Withdrawal of the serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the 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.

4.6 Fertility, Pregnancy and lactation

Pregnancy:

Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality. Animal studies (rats and rabbits, exposure to tramadol up to 7 times that expected in man) have not revealed teratogenic effects and minimal embryotoxicity (delayed ossification). Fertility, reproductive performance and development of offspring were unaffected. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy therefore Tramadol Hydrochloride 50mg Effervescent Tablets 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.

Breast-feeding:

Tramadol and its metabolites are found in small amounts in human breast milk. An infant could ingest 0.1% of the dose given to the mother. Tramadol Hydrochloride 50mg Effervescent Tablets should not be administered during breast feeding. After a single administration of tramadol it is not usually necessary to interrupt breast-feeding.

Fertility

Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.

4.7 Effects on ability to drive and use machines

Even when taken according to instructions, Tramadol Hydrochloride 50mg Effervescent Tablets may cause drowsiness and dizziness and therefore may impair the reactions of drivers and machine operators, this effect may be potentiated by alcohol and other CNS depressants or psychotropic substances. 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:

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.

The frequencies are defined as follows:

Very common: >1/10

Common: >1/100, <1/10

Uncommon: >1/1000, <1/100

Rare: >1/10 000, <1/1000

Very rare: <1/10 000

Not known: cannot be estimated from the available data

Cardiovascular disorders:

uncommon: 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 Nervous system disorders

Tiredness, drowsiness, which in most instances followed intravenous use, have been rarely reported.

very common: dizziness common: headache, somnolence

rare: changes in appetite, paraesthesia, tremor, respiratory depression, epileptiform convulsions, involuntary muscle contractions, abnormal coordination and 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 disorder:

rare: hallucinations, confusion, sleep disturbance , anxiety and nightmares. Psychic adverse reactions may occur following administration of tramadol which vary individually I 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: blurred vision, miosis, mydriasis

Respiratory disorders: rare :dyspnoea

Worsening of asthma has 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), diarrhea

Skin and subcutaneous disorders: common: sweating

uncommon:dermal reactions (e.g. pruritus, rash, urticaria)

Musculoskeletal disorders: rare: 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: micturition disorders (difficulty in passing urine, dysuria and urinary retention)

Metabolism and nutrition disorders: not known: hypoglycaemia

General disorders: common: fatigue

rare: 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 (i.e. confusion, delusions, personalization, derealisation, paranoia).

Physical dependence:

Abuse and withdrawal reactions include agitation , anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Other adverse events:

Diaphoresis has been reported Flushing have been rarely reported. Cases of blood dyscrasias have been rarely observed during treatment with tramadol, but causality has not been established.

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of overdosage:

In principle, on intoxication with tramadol Symptoms of overdosage and typical of other centrally acting (opioid) analgesics to be expected, and these include in particular, miosis, vomiting, cardiovascular collapse, sedation and consciousness disorders up to coma, seizures and respiratory depression up to respiratory arrest.

Therapeutic measures in overdosage:

Supportive and general emergency measures such as keep open the respiratory tract (aspiration!), maintain respiration, the patency of the airway and maintaining cardiovascular function should be instituted. Depending on the symptoms, naloxone should be used to reverse respiratory depression. In animal experiments, naloxone had no effect on convulsions, in such cases fits can be controlled with diazepam given intravenously.

In case of intoxication orally, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities.

Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with Tramadol Hydrochloride Effervescent Tablets 50mg with haemodialysis or haemofiltration alone is not suitable for detoxification.

5.1 Pharmacodynamic properties

Tramadol Hydrochloride 50mg Effervescent Tablets is a cantrally acting analgesic. It is non selective pure agonist at mu, delta and kappa opioid with a higher affinity for the mu receptor. Other mechanisms which may contribute to its analgesic effect are inhibitor of neuronal reuptake of noradrenaline and enhancement of serotonin release.

5.2 Pharmacokinetic properties

The half life of the terminal elimination phase (t_1/2B) was 6.0 + h in young volunteers. Tramadol pharmacokinetics show little age dependence in volunteers up to the age of 75 years. In volunteers aged over 75 years, t_1/2B was 7.0 + 1.6 on oral administration. Since tramadol is eliminated both metabolically and renally, the terminal half-life t_1/2B may be prolonged in impaired hepatic or renal function. However, the increase in the t_1/2B values is relatively if at least one of these organs is functioning normally. In patients with liver cirrhosis t_1/2B tramadol was a mean of 13.3 +4.9 h; inpatients with renal insufficiency (creatinine clearance <5 ml/min) it was 11.0 +3.2 h.

5.3 Preclinical safety data

In single and repeat-dose toxicity studies (rodents and dogs) exposure to tramadol 10 times that expected in man is required before toxicity (hepatotoxicity) is observed. 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. Symptoms of toxicity are typical of opioids and include restlessness, salivation, ataxia, vomiting, tremor, reduced weight gain, dyspnoea and convulsions. 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.

Exposure to tramadol (<that expected in man) in lifetime toxicity studies in rodents did not reveal any evidence of carcinogenic hazard, and a battery of in-vitro and in vivo mutagenicity tests were negative. 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.

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.

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, nonsignificant 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

Citric acid

Sodium hydrogen carbonate

Lactose monohydrate

Sodium sulfate

Sodium carbonate

Povidone

Sodium cyclamate

Aspartame

Macrogol

Orange Flavouring

Simethicone emulsion

Water

Isopropanol

6.2 Incompatibilities

Not applicable

6.3    Shelf life

5 years

6.4    Special precautions for storage

Do not store 25°C. Keep the container tightly closed.

6.5    Nature and contents of container

Polypropylene tube with polyethylene stopper containing silica gel as desiccant.

Contents: 10, 20,30 or 100 effervescent tablets Not all packs sizes may be marketed.

6.6    Special precautions for disposal

Dissolve effervescent tablets in a glass of water prior to intake.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Limited 3 Howard Road Eaton Socon St Neots

Cambridgeshire PE198ET UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 11311/0531

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/03/2009

10    DATE OF REVISION OF THE TEXT

25/08/2015