SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tramadol/Paracetamol 37.5 mg / 325 mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

EACH TABLET CONTAINS:

Tramadol/Paracetamol 37.5 mg / 325 mg tablets: One tablet contains 37.5 mg of tramadol hydrochloride and 325 mg of paracetamol.

3    PHARMACEUTICAL FORM

Tablets.

White, elongated, scored tablets.

The score line on a dose of 37.5 mg /325 mg is only to facilitate the breaking of the tablet for easy swallowing and not to divide it into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

TRAMADOL/PARACETAMOL tablets are indicated for the symptomatic treatment of moderate to severe pain.

The use of TRAMADOL/PARACETAMOL should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol (see also section 5.1.).

4.2    Posology and method of administration Posology:

ADULTS AND ADOLESCENTS (12 years and older).

The use of Tramadol/Paracetamol should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol.

The dose should be adjusted, to the intensity of pain and sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected.

An initial dose of two tablets of Tramadol/Paracetamol 37.5 mg / 325 mg or one tablet of Tramadol/Paracetamol 75 mg / 650 mg is recommended.

Additional doses can be taken as needed, not exceeding 8 tablets of Tramadol/Paracetamol 37.5 mg / 325 mg or 4 tablets of Tramadol/Paracetamol 75 mg / 650 mg (equivalent to 300 mg of tramadol and 2600 mg of paracetamol) per day.

The dosing interval should not be less than 6 hours.

Tramadol/Paracetamol should under no circumstances be administered for longer than is strictly necessary (see Section 4.4). If repeated use or long-term treatment with Tramadol/Paracetamol is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place (with breaks in the treatment, where possible) to assess whether continuation of the treatment is necessary.

Paediatric population

The effective and safe use of Tramadol/Paracetamol has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population.

Elderly 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 the dosage interval is to be extended according to the patient’s requirements.

The usual dosages may be used, although it should be noted that in volunteers aged over 75 years the elimination half-life of tramadol was increased by 17% following oral administration. In patients over 75 years old, it is recommended that the minimum interval between doses should not be less than 6 hours, due to the presence of tramadol.

Renal insufficiency

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 requirement.

Due to the presence of tramadol, the use of Tramadol/Paracetamol is not recommended in patients with severe renal failure (creatinine clearance < 10 ml/min). In cases of moderate renal failure (creatinine clearance between 10 and 30 ml/min), the dosing should be increased to 12-hourly intervals. As tramadol is removed only very slowly by haemodialysis or by haemofiltration, post-dialysis administration to maintain analgesia is not usually required.

Hepatic insufficiency

In patients with severe hepatic impairment Tramadol/Paracetamol should not be used (see Section 4.3). In moderate cases, prolongation the dosage interval should be carefully considered (see Section 4.4).

Method of administration:

Oral use

Tablets must be swallowed with a sufficient quantity of liquid.

For 37.5mg/ 325mg, the score line is only to facilitate the breaking of the tablet for easy swallowing.

4.3 Contraindications

-    Hypersensitivity to the active substances or to any of the excipients listed in section 6.1,

-    acute intoxication with alcohol, hypnotic drugs or centrally acting analgesics, opioids or psychotropic drugs.

INVENTED NAME> should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal (see section 4.5),

-    severe hepatic impairment

-    epilepsy not controlled by treatment (see section 4.4).

4.4 Special warnings and precautions for use

Warnings:

-    In adults and adolescents 12 years and older. The maximum dose (equivalent to 300 mg of tramadol and 2600 mg of paracetamol) of 8 tablets a day of Tramadol/Paracetamol 37.5 mg / 325 mg or 4 tablets of Tramadol/Paracetamol 75 mg / 650 mg should not be exceeded. In order to avoid inadvertent overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol (including over the counter) or tramadol hydrochloride containing products concurrently without the advice of a physician.

-    In severe renal insufficiency (creatinine clearance <10 ml/min) Tramadol/Paracetamol is not recommended.

-    In patients with severe hepatic impairment Tramadol/Paracetamol should not be used (see section 4.3). The hazards of paracetamol overdose are greater in patients with non-cirrhotic alcoholic liver disease. In moderate cases prolongation of dosage interval should be carefully considered.

-    In severe respiratory insufficiency Tramadol/Paracetamol is not recommended.

-    Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

-    Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medicines that lower the seizure threshold, especially selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with Tramadol/Paracetamol only if there are compelling circumstances. 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 dose limit.

-    Concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended (see section 4.5).

Special warnings and precautions for use:

Tolerance and physical and/or psychological dependence may develop, even at therapeutic doses. The clinical need for analgesic treatment should be reviewed regularly (see section 4.2). In opioid-dependent patients and patients with a history of drug abuse or dependence, treatment should only be for a short period and under medical supervision. Tramadol/Paracetamol should be used with caution in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract disorders, in a state of shock, in an altered state of consciousness for unknown reasons, with problems affecting the respiratory centre or the respiratory function or with an increased intracranial pressure.

A paracetamol overdose can cause hepatic toxicity in some patients.

Symptoms of withdrawal reaction, similar to those occurring during opiate withdrawal may occur even at therapeutic doses and for short term treatment (see section 4.8). Withdrawal symptoms may be avoided by tapering it at the time of discontinuation especially after long treatment periods. Rarely, cases of dependence and abuse have been reported (see section 4.8).

In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intra-operative recall. Until further information is available, use of tramadol during light planes of anaesthesia should be avoided.

4.5 Interaction with other medicinal products and other forms of interaction

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and seizure threshold-lowering medicinal products (such as bupropion), mirtazapine, tetrahydrocannabinol) to cause convulsions.

Concomitant therapeutic use of tramadol and serotenergic drugs, such as selective serotonin reuptake inhibitos (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.

Concomitant use is contraindicated with:

• Non-selective MAO inhibitors

Risk of serotoninergic syndrome: diarrhoea, tachycardia, sweating, trembling, confusion, and even coma.

•    Selective-A MAO inhibitors

Extrapolation from non-selective MAO inhibitors

Risk of serotoninergic syndrome: diarrhoea, tachycardia, sweating, trembling, confusion, and even coma.

•    Selective-B MAO inhibitors

Central excitation symptoms evocative of a serotoninergic syndrome: diarrhoea, tachycardia, sweating, trembling, confusion, and even coma.

In case of recent treatment with MAO inhibitors, a delay of two weeks should occur before treatment with tramadol

Concomitant use with the following is not recommended:

•    Alcohol

Alcohol increases the sedative effect of opioid analgesics.

The effect on alertness can make driving of vehicles and the use of machines dangerous.

Avoid intake of alcoholic drinks and medicinal products containing alcohol.

•    Carbamazepine and other enzyme inducers

Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.

• Opioid agonists-antagonists (buprenorphine, nalbuphine, pentazocine)

Decrease of the analgesic effect by competitive blocking effect at the receptors, with the risk of occurrence of withdrawal syndrome.

Concomitant use which needs to be taken into consideration:

• 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 medicines such as selective serotonin reuptake inhibitors (SSRIs) and triptans. Signs of serotonin syndrome may be for example: confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea.

• Other opioid derivatives (including antitussive drugs and substitutive treatments), benzodiazepines and barbiturates.

Increased risk of respiratory depression, which can be fatal in cases of overdose.

• Other central nervous system depressants, such as other opioid derivatives (including antitussive drugs and substitutive treatments), barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally-acting antihypertensives, thalidomide, and baclofen.

These drugs can cause increased central depression. The effect on alertness can make driving of vehicles and the use of machines dangerous.

•    As medically appropriate, periodic evaluation of prothrombin time should be performed when Tramadol/Paracetamol and warfarin like compounds are administered concurrently due to the reports of increased INR.

•    Other drugs 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.

•    Medicinal products reducing the seizure threshold, such as bupropion, serotonin reuptake inhibitors, tricyclic antidepressants and neuroleptics. Concomitant use of tramadol with these drugs can increase the risk of convulsions. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

•    In a limited number of studies, the pre- or post-operative application of the antiemetic 5HT3-antagonist, ondansetron, increased the requirement for tramadol in patients with post-operative pain.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Since Tramadol/Paracetamol is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.

*    Data regarding paracetamol:

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosages.

*    Data regarding tramadol:

Tramadol should not be used during pregnancy, as there is inadequate evidence available to assess the safety of tramadol in pregnant women. Tramadol administered before or during birth, does not affect uterine contractions. In neonates, it can induce changes in the respiratory rate that are usually not clinically relevant. Long-term treatment during pregnancy may lead to withdrawal symptoms in the newborn after birth as a consequence of habituation.

Breastfeeding:

Since Tramadol/Paracetamol is a fixed combination of active ingredients including tramadol, it should not be ingested during breastfeeding.

*    Data on paracetamol:

Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breast feeding by women using single ingredient medicinal products containing only paracetamol.

*    Data on tramadol:

Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason, tramadol should not be used during lactation or alternatively, breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.

4.7    Effects on ability to drive and use machines

Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or other central nervous system (CNS) depressants. If affected, the patient should not drive or operate machinery.

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 or 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 undesirable effects during the clinical trials performed with the paracetamol/ tramadol combination were nausea, dizziness and somnolence, which were observed in more than 10% of the patients.

Cardiovascular system disorders:

Uncommon (> 1/1,000 to <1/100): hypertension, palpitations, tachycardia, arrhythmia.

Central and peripheral nervous system disorders:

Very common (> 1/10): dizziness, somnolence.

Common (>1/100 to <1/10): headaches, trembling.

Uncommon (>1/1,000 to <1/100): involuntary muscular contractions, paraesthesia, tinnitus.

Rare (>1/10,000 to <1/1,000): ataxia, convulsions, syncope.

Psychiatric disorders:

Common (>1/100 to <1/10): confusion, mood changes (anxiety, nervousness, euphoria), sleep disorders.

Uncommon (> 1/1,000 to <1/100): depression, hallucinations, nightmares, amnesia. Rare (>1/10,000 to <1/1,000): drug dependence.

Post-marketing surveillance:

Very rare (<1/10,000): abuse.

Vision disorders:

Rare (>1/10,000 to <1/1,000): blurred vision.

Respiratory system disorders:

Uncommon (> 1/1,000 to <1/100): dyspnoea.

Gastrointestinal disorders:

Very common (> 1/10): nausea,

Common (> 1/100 to <1/10): vomiting, constipation, dry mouth, diarrhoea, abdominal pain, dyspepsia, flatulence.

Uncommon (> 1/1,000, <1/100): dysphagia, melaena.

Liver and biliary system disorders:

Uncommon (> 1/1,000 to <1/100): hepatic transaminases increase,

Skin and appendages disorders:

Common (> 1/ 100 to <1/ 10): sweating, pruritus.

Uncommon (> 1/1,000 to <1/100): dermal reactions (e.g., rash, urticaria).

Urinary system disorders:

Uncommon (> 1/1,000 to <1/100): albuminuria, micturation disorders (dysuria and urinary retention).

General disorders:

Uncommon (> 1/1,000 to <1/100): shivers, hot flushes, thoracic pain.

Metabolism and nutrition disorders:

Unknown: hypoglycaemia

Although not been observed during clinical trials, the occurrence of the following undesirable effects related to the administration of tramadol or paracetamol cannot be excluded:

Tramadol:

•    Postural hypotension, bradycardia, collapse (tramadol).

•    Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation in prothrombin times.

•    Rare cases (>1/10,000 to <1/1,000): allergic reactions with respiratory symptoms (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.

•    Rare cases (>1/10,000 to <1/1,000): changes in appetite, motor weakness and respiratory depression.

•    Psychic side effects may occur following administration of tramadol, which vary individually in intensity and nature (depending on the 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).

•    Worsening of asthma has been reported, though a causal relationship has not been established.

•    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 if tramadol hydrochloride is discontinued abruptly include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.

Paracetamol:

•    Adverse effects of paracetamol are rare, but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias, including thrombocytopenia and agranulocytosis, but they were not necessarily causally related to paracetamol.

•    There have been several reports that suggest that paracetamol may produce hypoprothrombinaemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.

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 professional are asked to report any suspected adverse reactions via the Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard).

4.9 Overdose

Tramadol/Paracetamol is a fixed combination of active substances. In case of overdose, the symptoms may include the signs and symptoms of toxicity of tramadol and/or paracetamol or of both these active ingredients.

Symptoms of an overdose from tramadol:

In principle, on intoxication with tramadol, symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include, in particular, miosis, vomiting, cardiovascular collapse, consciousness disorders including coma, convulsions and respiratory depression, including respiratory arrest.

Symptoms of overdose from paracetamol:

An overdose is of particular concern in young children. Symptoms of paracetamol overdosage in the first 24 hours, are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion.

Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmia and pancreatitis have been reported.

Liver damage is possible in adults who have taken 7.5-10 g or more of paracetamol. It is considered that excessive quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested) become irreversibly bound to liver tissue.

Emergency treatment:

-    Transfer immediately to a specialised unit.

-    Maintain respiratory and circulatory functions.

-    Prior to starting treatment, a blood sample should be taken as soon as possible after overdose, in order to measure the plasma concentration of paracetamol and tramadol and in order to perform hepatic tests.

-    Perform hepatic tests at the start (of the overdose) and repeat every 24 hours. An increase in hepatic enzymes (ASAT, ALAT) is usually observed, which normalizes after one or two weeks.

-    Empty the stomach by causing the patient to vomit (when the patient is conscious) by irritation or gastric lavage.

-    Supportive measures, such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted. Naloxone should be used to reverse respiratory depression; fits may be controlled with diazepam.

-    Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore, treatment with of acute intoxication with Tramadol/Paracetamol with haemodialysis or haemofiltration alone is not suitable for detoxification.

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any adult or adolescent who had ingested around 7.5 g or more of paracetamol in the preceding 4 hours, or any child taking 150 mg/kg of paracetamol in the preceding 4 hours, should undergo gastric lavage.

Paracetamol concentrations in blood should be measured more than 4 hours after an overdose, in order to be able to assess the risk of developing liver damage (via the paracetamol overdose nomogram). Administration of oral methionine or intravenous N-acetyl cysteine (NAC), which may have a beneficial effect up to at least 48 hours after the overdose. Administration of intravenous NAC is most beneficial when initiated within 8 hours of overdose ingestion. However, NAC should still be given if the time to presentation is greater than 8 hours after overdose and continued for a full course of therapy. NAC treatment should be started immediately when a massive overdose is suspected. General supportive measures must be available.

Irrespective of the reported quantity of paracetamol ingested, the antidote for paracetamol, NAC, should be administered orally or intravenously, as quickly as possible, if possible, within 8 hours following the overdose.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Tramadol, combinations.

ATC code: N02A X 52 ANALGESICS

Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is a pure, non-selective agonist of the p, 5 and k opioid receptors, with a higher affinity for p receptors. Other mechanisms that contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.

Tramadol causes an antitussive effect. Unlike morphine, a broad range of analgesic doses of tramadol has no respiratory depressive effect. Similarly, gastro-intestinal motility is not modified. Cardiovascular effects are generally slight. The potency of tramadol is considered to be one tenth to one sixth that of morphine.

The exact mechanism of the analgesic properties of paracetamol is unknown and may involve central and peripheral effects.

Tramadol/Paracetamol is positioned as a Class II analgesic on the WHO pain ladder and should be utilised accordingly by physicians.

5.2 Pharmacokinetic properties

Tramadol is administered as a racemic and both the [-] and [+] forms of tramadol and its metabolite, M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life is longer) than that of paracetamol.

After a single oral administration of a tablet of tramadol/paracetamol (37.5 mg/325 mg), peak plasma concentrations of 64.3/55.5 ng/ml [(+)-tramadol/(-)-tramadol] and

4.2 pg/ml (paracetamol) are reached after 1.8 h [(+) tramadol/(-)-tramadol] and 0.9 h (paracetamol), respectively. The mean elimination half-lives t1/2 are 5.1/4.7 h [(+)-tramadol/(-)-tramadol] and 2.5 h (paracetamol).

During pharmacokinetic studies performed on healthy volunteers, after single and repeated oral administrations of Tramadol/Paracetamol, no significant clinical changes were seen in the kinetic parameters of each active ingredient compared to the parameters of the active ingredients used alone.

Absorption:

Racemic tramadol is absorbed readily and almost completely after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75%. After repeated administration, the bioavailability increases and reaches approximately 90%.

After the administration of Tramadol/Paracetamol, the oral absorption of paracetamol is rapid and nearly complete, and takes place mainly in the small intestine. Peak plasma concentrations of paracetamol are reached in one hour and are not modified by concomitant administration of tramadol.

Oral administration of Tramadol/Paracetamol with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol; therefore, Tramadol/Paracetamolcan be taken independently of meal times.

Distribution:

Tramadol has a high tissue affinity (VdJ3=203 ± 40 l). Plasma protein binding is 20%.

Paracetamol appears to be widely distributed throughout most body tissues, except fat. Its apparent volume of distribution is about 0.9 l/kg. A relatively small portion (~ 20%) of paracetamol binds to plasma proteins.

Metabolism:

Tramadol is metabolised extensively after oral administration. About 30% of the dose is excreted, unchanged, in urine as unchanged drug, while 60% is excreted as metabolites.

Tramadol is metabolised through O-demethylation (catalysed by the enzyme CYP2D6) of the metabolite M1, and through N-demethylation (catalysed by CYP3A) of the metabolite M2. M1 is also metabolised by N-demethylation and by conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours. The metabolite, M1, has analgesic properties and is more potent than the parent drug. The plasma concentrations of M1 are several fold lower than those of tramadol, and the contribution to the clinical effect is unlikely to change with multiple doses.

Paracetamol is principally metabolised mainly in the liver through two major hepatic routes: glucuronidation and sulphation. The latter route can be rapidly saturated at doses that are higher than the therapeutic dose. A small fraction (less than 4%) is metabolised by the cytochrome, P450, to an active intermediate product (N-acetyl benzoquinoneimine), which, under normal conditions of use, is readily detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, in cases of massive overdose, the quantity of this metabolite is increased.

Elimination:

Tramadol and its metabolites are cleared mainly by the kidneys. The half-life of paracetamol is about 2 to 3 hours in adults. It is shorter in children and slightly longer in newborns and cirrhotic patients. Paracetamol is mainly eliminated by the dose-dependent formation of glucoro-conjugated and sulpho-conjugated derivatives. Less than 9% of paracetamol is excreted, unchanged, in urine. In renal insufficiency, the half-life of both compounds is prolonged.

5.3 Preclinical safety data

No preclinical study has been performed with the fixed combination (tramadol and paracetamol) to evaluate its carcinogenic or mutagenic effects or its effects on fertility.

No teratogenic effect that can be attributed to this medicine has been observed in the progeny of rats treated orally with the combination of tramadol/paracetamol.

The combination tramadol/paracetamol has been proven to be embryotoxic and foetotoxic in the rat at materno-toxic dose (50/434 mg/kg of tramadol/paracetamol), i.e., 8.3 times the maximum therapeutic dose in man. No teratogenic effect has been observed at this dose. The toxicity to the embryo and the foetus results in a decreased foetal weight and an increase in supernumerary ribs. Lower doses causing less severe effects on materno-toxic effect (10/87 and 25/217 mg/kg tramadol/paracetamol) did not result in toxic effects in the embryo or the foetus.

Results of standard mutagenicity tests did not reveal a potential genotoxic risk for tramadol in man.

The results of carcinogenicity tests do not suggest a potential risk of tramadol in man.

Animal studies with tramadol revealed, at very high doses, effects on organ development, ossification and neonatal mortality associated with maternotoxicity. Fertility reproductive performance and development of offspring were unaffected. Tramadol crosses the placenta. No effect on fertility has been observed after oral administration of tramadol up to doses of 50 mg/kg in the male rat and 75 mg/kg in the female rat.

Extensive investigations showed no evidence of a relevant genotoxic risk of paracetamol at therapeutic (i.e., non-toxic) doses.

Long-term studies in rats and mice yielded no evidence of relevant tumorigenic effects at non-hepatotoxic dosages of paracetamol.

Animal studies and extensive human experience to date yield no evidence of reproductive toxicity.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Povidone (E1201), magnesium stearate (E572), anhydrous colloidal silica, sodium starch glycolate (type A) and pregelatinised maize starch.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

Tramadol/Paracetamol tablets are packed in aluminium-polyethylene strips or aluminium/ PVC-PVDC blisters.

Tramadol/Paracetamol 37.5 mg / 325 mg tablets: Packs contain 2, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 tablets.

6.6    Special precautions for disposal

The disposal of any unused drug and all materials that come into contact with it will be performed according to local regulations (or such can be returned to the pharmacy).

7    MARKETING AUTHORISATION HOLDER

Aspire Pharma Ltd Bellamy House Winton Road Petersfield Hampshire GU32 3HA UK

8    MARKETING AUTHORISATION NUMBER(S)

PL35533/0042

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/02/2016

10    DATE OF REVISION OF THE TEXT

02/08/2016