Tamoltra 75/650 mg, 37,5/325 mg FC tablets.

TAMOLTRA and TAMOLTRA FORTE are indicated for the management of moderate to moderately severe pain in adults. TAMOLTRA and TAMOLTRA FORTE are not recommended for minor pain that may be treated adequately through lesser means.

Posology
TAMOLTRA: To be used in adults and children over 16 years of age.
TAMOLTRA FORTE: To be used in adults.
DO NOT EXCEED THE RECOMMENDED DOSE.
TAMOLTRA: Adults and children over the age of 16 For the management of pain, the recommended dose of TAMOLTRA is 1 or 2 tablets every 4 to 6 hours, as needed for pain relief, up to a maximum of 8 tablets per day.
TAMOLTRA FORTE: Adults The recommended dose of TAMOLTRA FORTE is 1 tablet every 4 to 6 hours as needed. The maximum total dose per day is 4 tablets. As with all analgesic medicines, a titration period of several days with gradual dose increases at the initiation of TAMOLTRA and TAMOLTRA FORTE therapy may be beneficial for some patients.
Special populations
Elderly population (65 years of age and older) No overall differences, about safety or pharmacokinetics, were noted between subjects u2265 65 years of age and younger subjects.
Renal insufficiency / dialysis In patients with renal insufficiency, the elimination of tramadol is delayed. In these patients, prolongation of the dosage intervals should be carefully considered according to the patientsu2019 requirements. For patients with creatinine clearance < 30 mL/min, the dosing interval should be increased but should not exceed 2 tablets every 12 hours.
Hepatic impairment TAMOLTRA and TAMOLTRA FORTE should not be used in patients with moderate to severe liver impairment (see section 4.3).
Paediatric population TAMOLTRA: Not indicated for use in children under the age of 16 years, as safety and efficacy have not been established.
TAMOLTRA FORTE: Not recommended in patients under 18 years old.
Method of administration
For oral use The coated tablets must be swallowed whole, with a sufficient quantity of liquid. They must not be broken or chewed. Tablets can be administered without regard to food. Missed dose: Doctors should advise patients who forget to take TAMOLTRA or TAMOLTRA FORTE to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• TAMOLTRA and TAMOLTRA FORTE are contraindicated in patients with a known hypersensitivity to tramadol, paracetamol, or other opioids such as codeine any of the other ingredients mentioned in section 6.1.
• TAMOLTRA and TAMOLTRA FORTE are also contraindicated in cases of moderate to severe liver function impairment and in acute intoxication with alcohol.
• TAMOLTRA and TAMOLTRA FORTE are contraindicated in combination with hypnotic substances or centrally acting analgesics, opioids, or psychotropic medicines.
• TAMOLTRA and TAMOLTRA FORTE should not be administered to patients receiving monoamine oxidase inhibitors (MAOIs) or within two weeks of their withdrawal.
• TAMOLTRA and TAMOLTRA FORTE must not be used for the narcotic withdrawal treatment.
• TAMOLTRA and TAMOLTRA FORTE should not be administered to patients with respiratory depression, especially in the presence of cyanosis and excessive bronchial secretions.
• TAMOLTRA and TAMOLTRA FORTE should not be given to patients with increased intracranial pressure or central nervous system depression due to head injury or cerebral disease.
• TAMOLTRA and TAMOLTRA FORTE can cause seizures (convulsions), hence it should not be used in patients with epilepsy or seizures of any cause (see section 4.4).

TAMOLTRA and TAMOLTRA FORTE contain paracetamol which may be fatal in overdose. 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.
u2022 dosages in excess of those recommended may cause severe liver damage. Patients suffering from liver or kidney disease should only take paracetamol containing products under medical supervision.
u2022 TAMOLTRA and TAMOLTRA FORTE should not be used concurrently with any other medicines containing tramadol or paracetamol.
u2022 TAMOLTRA and TAMOLTRA FORTE are not recommended in severe renal insufficiency (creatinine clearance <10 mL/mm).
u2022 TAMOLTRA and TAMOLTRA FORTE should not be used in patients with severe hepatic impairment (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.
u2022 TAMOLTRA and TAMOLTRA FORTE is not recommended for use in patients with severe respiratory insufficiency.
u2022 TAMOLTRA and TAMOLTRA FORTE are not suitable as a substitute for opioid dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.
u2022 concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended (see section 4.5).
u2022 caution should be exercised in using TAMOLTRA and TAMOLTRA FORTE in patients with impaired renal function and patients who are in shock. In patients with cranial trauma, biliary tract disorders, events of reduced consciousness for unknown reasons, respiratory disorders and patients suffering from emotional disturbances or depression or using alcohol in excess, or with an increased intracranial pressure, TAMOLTRA and TAMOLTRA FORTE should be taken with extreme caution.
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 re-uptake inhibitors, MAO-inhibitors, and neuroleptics (see section 4.3). 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 (see section 4.3). Patients known to suffer from cerebral convulsions should be carefully monitored during treatment with tramadol.
Anaphylactic reactions
Patients with a history of anaphylactic reactions to codeine and other opioids may be at increased risk and should therefore not receive TAMOLTRA or TAMOLTRA FORTE. Serious and rarely fatal anaphylactic reactions have been reported in patients receiving therapy with tramadol. Patients should be advised to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction.
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 medicine, 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.
Even at labelled dosage regimens, individuals who are ultra-rapid metabolisers may have life-threatening or fatal respiratory depression or experience signs of toxicity such as extreme sleepiness, confusion, shallow breathing, small pupils, nausea, vomiting, constipation, and lack of appetite (see section 4.9).

Concomitant use is contraindicated with:
Monoamine oxidase (MAO) Inhibitors
u2022 risk of serotonergic syndrome: diarrhoea, tachycardia, hyperhidrosis, trembling, confusional state, even coma and noradrenergic effects (see section 4.8). In cases 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 medicinal products 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 4.2), tricyclic antidepressants and mirtazapine may cause serotonin toxicity.
u2022 serotonin syndrome is likely when one of the following is observed:
uf0a7 spontaneous clonus
uf0a7 inducible or ocular clonus with agitation or diaphoresis
uf0a7 tremor and hyperreflexia
uf0a7 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:
uf0a7 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 concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, quinidine, and amitriptyline may inhibit the metabolism of tramadol.
Changes of tramadol in serum concentration have been seen with concomitant administration with cimetidine. Therefore, patients receiving chronic therapy with cimetidine should not alter the dosage regimen of TAMOLTRA and TAMOLTRA FORTE treatment.
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. TAMOLTRA and TAMOLTRA FORTE should be used cautiously, and patients should be monitored carefully.
The absorption of paracetamol may be enhanced by metoclopramide and reduced by cholestyramine.
u2022 ondansetron increased the requirement of tramadol in patients with post-operative pain.

Safe use in pregnancy and lactation has not been established.
Pregnancy
TAMOLTRA and TAMOLTRA FORTE is not recommended for pregnant mothers because tramadol has been shown to cross the placenta. Data regarding paracetamol: Epidemiological studies in human pregnancy have shown no teratogenic 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 contractility. In neonates it may induce changes in the respiratory rate which 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
TAMOLTRA and TAMOLTRA FORTE should not be used during breast feeding. Data regarding 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 medicines containing only paracetamol. Data regarding 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.
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. TAMOLTRA and TAMOLTRA FORTE can impair cognitive function and can affect a patient's ability to drive safely. When prescribing this medicine, patients should be told that TAMOLTRA and TAMOLTRA FORTE is likely to affect your ability to drive. Patients should be told to not drive until they know how TAMOLTRA and TAMOLTRA FORTE affects them.

a) Summary of the safety profile
The most frequently reported undesirable effects of the paracetamol /tramadol combination in clinical trials were gastrointestinal and central nervous system effects. Nausea, dizziness, and somnolence were observed in more than 10 % of patients.
b) Tabulated summary of adverse reactions
Side effects for TAMOLTRA AND TAMOLTRA FORTE
Tramadol and Paracetamol:
System Organ Class Frequency Side effects
Blood and lymphatic system disorders Less frequent Anaemia
Immune system disorders Frequency unknown Fixed eruption*
Metabolism and nutrition disorders Frequency unknown Hypoglycaemia, hyponatraemia*/syndrome of inappropriate antidiuretic hormone*
Psychiatric disorders Frequent Less frequent Confusional state, mood altered, anxiety, nervousness, euphoric mood), sleep disorders, anorexia, insomnia, nervousness Depression, hallucinations, depersonalisation, nightmares, delirium, drug dependence, drug abuse, impotence, amnesia, emotional liability, unusual thought processes, suicidal tendency
Nervous system disorders Frequent Less frequent Dizziness, somnolence, headache, trembling Involuntary muscular contractions, paraesthesia, ataxia, convulsions, syncope, speech disorders, hypertonia, migraine, aggravated migraine, stupor, vertigo
Eye disorders Less frequent Vision blurred, miosis, mydriasis, abnormal vision
Ear and labyrinth disorders Less frequent Tinnitus
Cardiac disorders Less frequent Palpitations, tachycardia, dysrhythmia
Vascular disorders Less frequent Hypertension, aggravated hypertension, hot flushes, hypotension, orthostatic hypotension
Respiratory, thoracic, and mediastinal disorders Less frequent Dyspnoea
Gastrointestinal disorders Frequent Less frequent Nausea, vomiting, constipation, dry mouth, diarrhoea, abdominal pain, dyspepsia, flatulence Dysphagia, melaena, tongue oedema
Hepatobiliary disorders Less frequent Liver test abnormalities, hepatitis
Skin and subcutaneous tissue disorders Frequent Less frequent Hyperhidrosis, pruritus Dermal reactions (e.g., rash, urticaria)
Renal and urinary disorders Less frequent Albuminuria, micturition disorders (dysuria and urinary retention), oliguria, renal colic, renal failure, sterile pyuria
General disorders and administrative site conditions Less frequent Chills, chest pain, asthenia, fatigue, decreased weight, withdrawal syndrome
Investigations Less frequent Transaminases increased, hypothrombinaemia, elevated creatinine
*Post marketing
Tramadol:
System Organ Class Frequency Side effects
Blood and lymphatic system disorders Frequency unknown Elevated creatinine and rare alterations of warfarin effect, including elevation of prothrombin times*, hyponatraemia*
Immune system disorders Less frequent Allergic reactions with respiratory symptoms (e.g., dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis
Metabolism and nutrition disorders Less frequent Frequency unknown Changes in appetite, motor weakness, weight loss Hypoglycaemia*
Psychiatric disorders Less frequent 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)
Nervous system disorders Frequency unknown Cognitive dysfunction, Serotonin syndrome
Cardiac disorders Less frequent Bradycardia
Vascular disorders Less frequent Postural hypotension, collapse
Respiratory, thoracic and mediastinal disorders Less frequent Frequency unknown Respiratory depression Worsening of asthma has been reported though a causal relationship has not been established, hiccups
Gastrointestinal disorders Less frequent Increased risk of abdominal pain, including pancreatitis*
Hepatobiliary disorders Less frequent Hepatitis
Skin and subcutaneous tissue disorders Frequency unknown Stevens Johnson Syndrome* /TENS*
General disorders and administrative site conditions Frequency unknown Drug withdrawal syndrome (with symptoms including agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor, gastrointestinal symptoms, panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus, and unusual CNS symptoms)
*Post marketing
Paracetamol 1. hypersensitivity, including skin rash, may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis 2. 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 3. cases of serious skin reactions have been reported. 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.

Signs and symptoms: 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.
Paracetamol
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 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.
Management of overdose:
Tramadol
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/ barbiturates). Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Treatment of acute intoxication with TAMOLTRA and TAMOLTRA FORTE 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.
Treatment for paracetamol overdosage
Although evidence is limited it is recommended that any adult person who have ingested 5 u2013 10 g or more of paracetamol (or child who has had more than 140 mg/kg) within the preceding 4 hours should have the stomach emptied by gastric lavage (emesis may be adequate for children) and a single dose of 50 g activated charcoal given via the lavage tube. Ingestion of amounts of paracetamol smaller than this requires treatment in patients susceptible to paracetamol poisoning. In patients who are stuperose or comatose, endotracheal tubing should precede gastric lavage in order to avoid aspiration. N-acetylcysteine should be administered to all cases of suspected overdose as soon as possible, preferably within eight hours of overdosage, 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 overdose 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. Further treatment is symptomatic and supportive.