Dolotram Plus 37,5 mg AND 325 mg FC tablets.

DOLOTRAM PLUS is indicated for the management of moderate to moderately severe pain in adults. DOLOTRAM PLUS 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 DOLOTRAM PLUS 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 DOLOTRAM PLUS therapy may be beneficial for some patients. Clinical studies with tramadol in patients with moderate to moderately severe chronic pain indicated that the tolerability of tramadol can be improved by starting at a lower dose with gradual upward titration to reach doses that provide sufficient pain relief.
Special populations:
Renal impairment: In patients with creatinine clearance < 30 mL/min, the dosing interval of DOLOTRAM PLUS should be increased not to exceed 2 tablets every 12 hours.
Hepatic impairment: The use of DOLOTRAM PLUS in patients with moderate to severe hepatic impairment is contraindicated.
Method of administration: For oral use. Tablets must be swallowed whole, with a sufficient quantity of liquid. They must not be broken or chewed.

• DOLOTRAM PLUS 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.
• DOLOTRAM PLUS is also contraindicated in cases of moderate to severe liver function impairment (hepatic impairment) and in acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic medicines.
• DOLOTRAM PLUS should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.
• DOLOTRAM PLUS must not be used for narcotic withdrawal treatment.
• DOLOTRAM PLUS should not be given to patients with respiratory depression especially in the presence of cyanosis and excessive bronchial secretions.
• DOLOTRAM PLUS should not be given to patients with increased intracranial pressure or central nervous system depression due to head injury or cerebral disease.
• DOLOTRAM PLUS is contraindicated in epilepsy not controlled by treatment.

DOLOTRAM PLUS contains 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. The maximum dose of 8 tablets of DOLOTRAM PLUS 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). Dosages in excess of those recommended may cause severe liver damage. Patients suffering from liver or kidney disease should take paracetamol-containing products 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 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.
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.
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.
Caution should be exercised in patients with a personal or family history of mental health disorders as tramadol in DOLOTRAM PLUS has an increased risk for addiction and abuse.
Care is advised in the administration of DOLOTRAM PLUS to patients with moderate to severe hepatic impairment.
Withdrawal symptoms may occur if DOLOTRAM PLUS 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); exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and eosinophilia and systemic (DRESS)/Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE) have been reported in patients receiving paracetamol. Patients should be informed about the signs of serious skin reactions, and if a patient develops SCARs, treatment with DOLOTRAM PLUS must immediately be discontinued and appropriate treatment instituted.
Precautions u2013 general: Do not co-administer DOLOTRAM PLUS with other tramadol or paracetamol containing products.
Use with alcohol: DOLOTRAM PLUS should not be taken with alcohol containing beverages.
Use with CNS depressants: The administration of DOLOTRAM PLUS concurrently with central nervous system (CNS) depressants such as alcohol, opioids, anaesthetic medicines, phenothiazines, tranquilisers or sedative hypnotics is likely to intensify and prolong CNS effects.
Use in renal disease: DOLOTRAM PLUS should be used with caution in patients with impaired renal function and in patients prone to convulsive disorders or in shock. Care is advised in the administration of DOLOTRAM PLUS to patients with severe renal impairment.
Hyponatraemia has been reported with the use of DOLOTRAM PLUS 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 DOLOTRAM PLUS and appropriate treatment (e.g. fluid restriction). During DOLOTRAM PLUS treatment, monitoring for signs and symptoms of hyponatraemia is recommended for patients with predisposing risk factors.
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.
Excipient warning: DOLOTRAM PLUS contains less than 1 mmol sodium per tablet, that is to say essentially u2018sodium-freeu2019.

Concomitant use is contraindicated with:
Monoamine oxidase (MAO) inhibitors: 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: 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: Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.
Warfarin and anticoagulants: The paracetamol effect in DOLOTRAM PLUS. Concurrent, chronic, high-dose administration of DOLOTRAM PLUS may increase the anticoagulant effect. As medically appropriate, periodic evaluation of prothrombin time should be performed DOLOTRAM PLUS and warfarin-like compounds are administered concurrently due to reports of increased INR.
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:
Tramadol in DOLOTRAM PLUS 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 serotonergic medicines such as selective serotonin reuptake inhibitors (SSRIs) serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.2), tricyclic antidepressants and mirtazapine may cause serotonin toxicity.
Hepatotoxic medicines: Increased risk of hepatotoxicity.
Enzyme-inducing medicines: Increased risk of hepatotoxicity and possible decrease in therapeutic effect of DOLOTRAM PLUS.
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 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.
Other opioid derivatives (including antitussive medicines and substitutive treatments) increased the risk of respiratory depression, which can be fatal in cases of overdose.
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.
Sedating medicinal products such as benzodiazepines or related substances: 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).
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. Concomitant administration of diflunisal and paracetamol produces a 50 % increase in paracetamol plasma levels in normal volunteers. DOLOTRAM PLUS should be used cautiously and patients should be monitored carefully. Concomitant administration with inhibitors of CYP2D6 such as fluoxetine, paroxetine, quinidine and amitriptyline may inhibit the metabolism of DOLOTRAM PLUS. Ondansetron increased the requirement of tramadol in patients with post-operative pain.

Safe use in pregnancy and lactation has not been established. DOLOTRAM PLUS 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. DOLOTRAM PLUS can impair cognitive function and can affect a patient's ability to drive safely. When prescribing this medicine, patients should be advised that DOLOTRAM PLUS is likely to affect your ability to drive. Patients should be advised not to drive until they know how DOLOTRAM PLUS affects them.

Tabulated list of adverse reactions
System organ class Adverse reaction Frequency
Metabolism and nutrition disorders hypoglycaemia Frequency unknown
Psychiatric disorders medicines dependence Frequency unknown
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 , meleana 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 disorders hyperhidrosis, pruritus frequent
dermal reactions (e.g. rash, urticaria), Less frequent
Vascular disorders: hypertension, aggravated hypertension, hot flush, hypotension Less frequent
Post marketing experience: The following post-marketing experiences have been reported :
System organ class Adverse reaction Frequency
Gastro-intestinal disorders Increased risk of abdominal pain, including pancreatitis has been reported Less frequent
Skin and subcutaneous tissue disorders Erythema, flushing, acute generalised exanthematous, pustulosis Toxic epidermal necrolysis Stevens-Johnson syndrome Risk of Fixed drug eruptions (FDE) Risk of Drug-induced hypersensitivity syndrome (DIHS) Less frequent
Renal and urinary disorders Uncommon: albuminuria, micturition disorders (dysuria and urinary retention) Less frequent
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:

• Postural hypotension, bradycardia, collapse (tramadol).
• Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.
• Cases of less frequent: allergic reactions with respiratory symptoms (e.g. dyspnoea, bronchospasm, wheezing, angioedema) and anaphylaxis.
• Less frequent: 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 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).
• Worsening of asthma has been reported though a causal relationship has not been established.
• 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.

• Hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis.
• 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.
• 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/ barbiturates). Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Treatment of acute intoxication with DOLOTRAM PLUS 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 u2013 10 g/day) of paracetamol for several days, in chronic alcoholism, chronic liver disease, AIDS, malnutrition, and with the use of medicine 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 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 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.