Temrez 37,5 mg; 325 mg FC tablets.

TEMREZ 37.5/325 is indicated for the management of moderate to moderately-severe pain in adults. TEMREZ 37.5/325 is not recommended for minor pain that may be treated adequately through lesser means.

Posology
To be used in adults and children over 16 years of age. DO NOT EXCEED THE RECOMMENDED DOSE.
Adults
For the management of pain, the recommended dose of TEMREZ 37.5/325 is 1 or 2 tablets every 4 to 6 hours as needed for pain relief up to a maximum of 8 tablets per day. As with all analgesic medicines, a titration period of several days with gradual dose increases at the initiation of TEMREZ 37.5/325 therapy may be beneficial for some patients. Clinical studies with tramadol in patients with moderate to moderately severe chronic pain indicate that the tolerability of tramadol can be improved by starting tramadol at a low dose with gradual upward dose titration to reach doses that provide sufficient pain relief.
Special populations
Renal impairment: For patients with creatinine clearance < 30 mL/min, the dosing interval of TEMREZ 37.5/325 should be increased not to exceed 2 tablets every 12 hours.
Method of administration
For oral use. Tablets must be swallowed whole, with a sufficient quantity of liquid. They must not be broken or chewed.

• TEMREZ 37.5/325 is contraindicated in patients with a known hypersensitivity to tramadol, paracetamol, or any of the other ingredients mentioned in section 6.1 or other opioids such as codeine.
• TEMREZ 37.5/325 is also contraindicated in cases of severe liver function impairment and in acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic medicines.
• TEMREZ 37.5/325 should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.
• TEMREZ 37.5/325 must not be used for narcotic withdrawal treatment.
• TEMREZ 37.5/325 should not be given to patients with respiratory depression especially in the presence of cyanosis and excessive bronchial secretions.
• TEMREZ 37.5/325 should not be given to patients with increased intracranial pressure or central nervous system depression due to head injury or cerebral disease.
• TEMREZ 37.5/325 is contraindicated in epilepsy not controlled by treatment.

The maximum dose of 8 tablets of Tramadol hydrochloride/Paracetamol 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 medical practitioner. (See section 4.9)
In the event of overdosage or suspected overdose and notwithstanding the fact that the person may be asymptomatic, the nearest doctor, hospital or Poison Centre must be contacted immediately. Dosages in excess of those recommended may cause severe liver damage. Patients suffering from liver or kidney disease should take paracetamol containing medicines under medical supervision.
Tramadol may only be taken with special care in opioid dependence, reduced level of consciousness of uncertain origin, disorders of the respiratory function and increased intracranial pressure.
Seizures: Seizures have been reported in patients receiving tramadol at dosages within the recommended dosage range. The risk of seizures is enhanced in patients exceeding the recommended dose, or in patients taking tricyclic anti-depressants or other tricyclic compounds e.g. promethazine, selective serotonin reuptake inhibitors, MAO-inhibitors and neuroleptics. The risk of seizures may also be increased in patients with epilepsy, with a history of seizures or in patients with a recognised risk for seizures e.g. drug and alcohol withdrawal, intracranial infections, head trauma, metabolic disorders and naloxone administration with tramadol overdose. Patients known to suffer from cerebral convulsions should be carefully monitored during treatment with tramadol.
CYP2D6 ultra-rapid metabolism of tramadol: Patients who are CYP2D6 ultra-rapid metabolisers may convert tramadol to its active metabolite (M1) more rapidly and completely than other patients. This rapid conversion may lead to higher than expected serum M1 levels which could lead to an increased risk of respiratory depression. Alternative medication, dose reduction and/or increased monitoring for signs of tramadol overdose, such as respiratory depression is recommended in patients known to be CYP2D6 ultra-rapid metabolisers.
Drug Abuse and Dependence: Tramadol has a dependence potential and tolerance, psychic and physical dependence of the morphine-type (u03bc opioid) may develop with long-term use. The medicine has been associated with craving, drug-seeking behaviour and tolerance development. Cases of abuse and dependence on tramadol have been reported. Tramadol should not be used in opioid-dependent patients. Tramadol can reinstate physical dependence in patients that have been previously dependent or chronically using other opioids. In patients with a tendency to drug abuse, a history of drug dependence or who are chronically using opioids, treatment with tramadol is not recommended.
Withdrawal: Withdrawal symptoms may occur if TEMREZ 37.5/325 is discontinued abruptly. Panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus, and unusual CNS symptoms have also been reported with abrupt discontinuation of tramadol hydrochloride. Clinical experience suggests that withdrawal symptoms may be relieved by tapering the medicine.
Severe cutaneous adverse reactions (SCARs): Severe cutaneous adverse reactions (SCARs) such as toxic epidermal necrolysis (TEN), Steven-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), eosinophilia and systemic (DRESS)/Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE) have been reported in patients treated with paracetamol containing medicines. If a patient develops SCAR, treatment with TEMREZ 37.5/325 must immediately be discontinued and appropriate treatment instituted.
Precautions u2013 general: Do not co-administer TEMREZ 37.5/325 with other tramadol or paracetamol containing medicines.
Use with alcohol: TEMREZ 37.5/325 should not be taken with alcohol containing beverages.
Use with CNS depressants: The administration of TEMREZ 37.5/325 concurrently with central nervous system (CNS) depressants such as alcohol, opioids, anaesthetic agents, phenothiazines, tranquilisers or sedative hypnotics is likely to intensify and prolong CNS effects.
Use in renal disease: TEMREZ 37.5/325 should be used with caution in patients with impaired renal function and in patients prone to convulsive disorders or in shock.
Hyponatraemia: Hyponatraemia has been reported with the use of TEMREZ 37.5/325, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medicines that may cause hyponatraemia. This hyponatraemia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of TEMREZ 37.5/325 and appropriate treatment (e.g. fluid restriction). During TEMREZ 37.5/325 treatment, monitoring for signs and symptoms of hyponatraemia is recommended for patients with predisposing risk factors.
Sleep-related breathing disorders: Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Concomitant use is contraindicated with:
Monoamine oxidase (MAO) Inhibitors
u2022 Risk of serotonergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma. In case of recent treatment with MAO inhibitors, a delay of two weeks should occur before treatment with tramadol.
Concomitant use is not recommended with:
Alcohol
u2022 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 of medicines containing alcohol.
Carbamazepine and other enzyme inducers
u2022 Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.
Opioid agonists-antagonists (buprenorphine, nalbuphine, pentazocine)
u2022 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:
u2022 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 medicines (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.
u2022 Concomitant therapeutic use of tramadol and serotonergic medicines such as selective serotonin re-uptake inhibitors (SSRIs) serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin toxicity.
u2022 Serotonin syndrome is likely when one of the following is observed:
u2022 Spontaneous clonus
u2022 Inducible or ocular clonus with agitation or diaphoresis
u2022 Tremor and hyperreflexia
u2022 Hypertonia and body temperature > 38 u00b0C and inducible or ocular clonus.
Withdrawal of the serotonergic medicines usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.
u2022 Other opioid derivatives (including antitussive medicines and substitutive treatments). Increased risk of respiratory depression which can be fatal in cases of overdose.
u2022 Other central nervous system depressants, such as other opioid derivatives (including antitussive medicines and substitutive treatments), other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally-acting antihypertensive medicines, thalidomide and baclofen. These medicines can cause increased central depression. The effect on alertness can make driving of vehicles and the use of machines dangerous.
u2022 Sedating medicines such as benzodiazepines or related substances:
u2022 The concomitant use of opioids with sedative medicines such as benzodiazepines or related medicines increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effects. The dose and duration of the concomitant use should be limited (see section 4.4).
u2022 As medically appropriate, periodic evaluation of prothrombin time should be performed when tramadol hydrochloride/paracetamol and warfarin-like compounds are administered concurrently due to reports of increased INR.
u2022 Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
u2022 Concomitant administration of diflunisal and paracetamol produces a 50 % increase in paracetamol plasma levels in normal volunteers. TEMREZ 37.5/325 should be used cautiously and patients should be monitored carefully.
u2022 Concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, quinidine and amitriptyline may inhibit the metabolism of TEMREZ 37.5/325.
u2022 Ondansetron increased the requirement of tramadol in patients with post-operative pain.

Safe use in pregnancy and lactation has not been established. TEMREZ 37.5/325 is not recommended for pregnant mothers because tramadol has been shown to cross the placenta.
Fertility
Post marketing surveillance does not suggest an effect of tramadol on fertility.

Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery. TEMREZ 37.5/325 can impair cognitive function and can affect a patient's ability to drive safely. When prescribing this medicine, patients should be told that TEMREZ 37.5/325 is likely to affect your ability to drive. Patients should be told to not drive until they know how TEMREZ 37.5/325 affects them.

Tabulated list of adverse reactions
System Organ Class Adverse reaction Frequency
Metabolism and nutrition disorders Hypoglycaemia Frequency unknown
Psychiatric disorders Confusional state, mood altered, anxiety, nervousness, euphoric mood, sleep disorders, anorexia Frequent
Depression, hallucinations, depersonalisation, nightmares, delirium, drug dependence, drug abuse, impotence Less frequent
Nervous system disorders Dizziness, somnolence, headache, trembling Frequent
Involuntary muscular contractions, paraesthesia, amnesia, ataxia, convulsions, syncope, speech disorders Less frequent
Eye disorders Vision blurred, miosis, mydriasis Less frequent
Ear and labyrinth disorders: Tinnitus Less frequent
Blood disorders Anaemia Less frequent
Cardiac disorders Palpitations, tachycardia, dysrhythmia Less frequent
Gastro-intestinal disorders: Nausea, vomiting, constipation, dry mouth, diarrhoea, abdominal pain, dyspepsia, flatulence Frequent
Dysphagia, melaena Less frequent
General disorders and administration site conditions Chills, chest pain, asthenia, fatigue, decreased weight Less frequent
Investigations: Transaminases increased Less frequent
Renal and urinary disorders Albuminuria, micturition disorders (dysuria and urinary retention), oliguria Less frequent
Respiratory, thoracic and mediastinal disorders Dyspnoea Less frequent
Skin and subcutaneous tissue disorder Hyperhidrosis, pruritus Frequent
Dermal reactions (e.g. rash, urticaria). Less frequent
Vascular disorders: hypertension, aggravated hypertension, hot flush, hypotension Less frequent: Post-marketing experience Gastro-intestinal disorders: Increased risk of abdominal pain, including pancreatitis Frequency unknown
Skin and subcutaneous tissue disorders Severe cutaneous adverse reactions (SCARs) such as toxic epidermal necrolysis (TEN), Steven-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), eosinophilia and systemic (DRESS)/Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE) Frequency unknown
Although not observed during clinical trials, the occurrence of the following undesirable effects known to be related to the administration of tramadol or paracetamol cannot be excluded: Tramadol u2022 Postural hypotension, bradycardia, collapse (tramadol). u2022 Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times. u2022 Cases of less frequent: allergic reactions with respiratory symptoms (e.g. dyspnoea, bronchospasm, wheezing, angioedema) and anaphylaxis. u2022 Less frequent: Changes in appetite, motor weakness, and respiratory depression. u2022 Psychic side-effects may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood, (usually euphoric mood occasionally dysphoria), changes in activity (usually suppression occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour perception disorders). u2022 Worsening of asthma has been reported though a causal relationship has not been established. u2022 Symptoms of drug withdrawal syndrome, similar to those occurring during opiate withdrawal may occur as follows: Agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have been seen if tramadol hydrochloride is discontinued abruptly include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms. Paracetamol u2022 Hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis. u2022 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. u2022 Cases of serious skin reactions have been reported.

The clinical presentation of overdosage may include the signs and symptoms of tramadol toxicity, paracetamol toxicity or both.
Tramadol
The initial symptoms of tramadol overdosage may include respiratory depression and/or seizures. Primary attention should be given to maintaining adequate ventilation along with general supportive treatment. While naloxone will reverse some, but not all symptoms caused by overdosage, the risk of seizures is also increased with naloxone administration. Treatment of restlessness and / or convulsions is symptomatic and supportive (benzodiazepines I barbiturates). Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Treatment of acute intoxication with TEMREZ 37.5/325 with haemodialysis or haemofiltration alone is therefore not suitable for detoxification.
Paracetamol
Prompt treatment is essential. In the event of an overdosage, consult a medical practitioner immediately, or take the person to a hospital directly. A delay in starting treatment may mean that antidote is given too late to be effective. Evidence of liver damage is often delayed until after the time for effective treatment has lapsed. Susceptibility to paracetamol toxicity is increased in patients who have taken repeated high doses (greater than 5 -10 g/day) of paracetamol for several days, in chronic alcoholism, chronic liver disease, AIDS, malnutrition, and with the use of drugs that induce liver microsomal oxidation such as barbiturates, isoniazid, rifampicin, phenytoin and carbamazepine. Symptoms of paracetamol overdosage in the first 24 hours include pallor, nausea, vomiting, anorexia and possibly abdominal pain. Mild symptoms during the first two days of acute poisoning do not reflect the potential seriousness of the overdosage. Liver damage may become apparent 12 to 48 hours or later after ingestion, initially by elevation of the serum transaminase and lactic dehydrogenase activity, increased serum bilirubin concentration and prolongation of the prothrombin time. Liver damage may lead to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage.
Abnormalities of glucose metabolism and metabolic acidosis may occur. Cardiac dysrhythmias have been reported.
Treatment for paracetamol overdosage: N-acetylcysteine should be administered to all cases of suspected overdose as soon as possible preferably within eight hours of overdosage, although treatment up to 36 hours after ingestion may still be of benefit, especially if more than 150 mg/kg of paracetamol was taken. An initial dose of 150 mg/kg N-acetylcysteine in 200 mL dextrose injection given intravenously over 15 minutes, followed by an infusion of 50 mg/kg in 500 mL dextrose injection over the next four hours, and then 100 mg/kg in 1000 mL dextrose injection over the next sixteen hours. The volume of intravenous fluid should be modified for children. Although the oral formulation is not the treatment of choice, 140 mg/kg dissolved in water may be administered initially, followed by 70 mg/kg every four hours for seventeen doses. A plasma paracetamol level should be determined four hours after ingestion in all cases of suspected overdosage. Levels done before four hours, unless high may be misleading. Patients at risk of liver damage, and hence requiring continued treatment with N-acetylcysteine, can be identified according to their plasma paracetamol level. The plasma paracetamol level can be plotted against time since ingestion in the nomogram. Those whose plasma paracetamol levels are above the u201cnormal treatment lineu201d, should continue N-acetylcysteine treatment with 100 mg/kg IV over sixteen hours repeatedly until recovery. Patients with increased susceptibility to liver damage as identified above, should continue treatment if concentrations are above the u201chigh risk treatment lineu201d. Prothrombin index correlates best with survival. Monitor all patients with significant ingestions for at least ninety six hours.