TAMOLTRA Film coated tablet Ref.[115184] Active ingredients: Paracetamol Tramadol

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.

• 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.
• TAMOLTRA and TAMOLTRA FORTE should not be used concurrently with any other medicines containing tramadol or paracetamol.
• TAMOLTRA and TAMOLTRA FORTE are not recommended in severe renal insufficiency (creatinine clearance <10 mL/mm).
• 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.
• TAMOLTRA and TAMOLTRA FORTE is not recommended for use in patients with severe respiratory insufficiency.
• 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.
• concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended (see section 4.5).
• 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).

Drug abuse and dependence

Tramadol has a dependence potential and tolerance, psychic and physical dependence of the morphine-type (μ 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 patients who are chronically using opioids, treatment with tramadol is not recommended.

There is an increased risk of addiction in patients with a personal or family history of substance abuse or mental health disorders.

TAMOLTRA and TAMOLTRA FORTE should not be given to patients who are suicidal or prone to addiction.

Withdrawal

Withdrawal symptoms may occur if TAMOLTRA and TAMOLTRA FORTE 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.

Gradual tapering, using TAMOLTRA and TAMOLTRA FORTE, is preferred wherever possible, although in some cases it may be necessary to change to a different opioid because of ease of use, duration of action and ability to taper the dose. Clonidine may help to suppress some of the symptoms of abrupt opioid withdrawal, such as anxiety, insomnia, and muscle ache.

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 SCARs, treatment with TAMOLTRA and TAMOLTRA FORTE must immediately be discontinued, and appropriate treatment instituted.

Hyponatraemia

Hyponatraemia has been reported with the use of TAMOLTRA and TAMOLTRA FORTE, 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 TAMOLTRA and TAMOLTRA FORTE and appropriate treatment (e.g., fluid restriction). During treatment, monitoring for signs and symptoms of hyponatraemia is recommended for patients with predisposing risk factors.

Use with general anaesthetics

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, as in TAMOLTRA and TAMOLTRA FORTE, during light planes of anaesthesia should be avoided.

Use with CNS depressants

The administration of TAMOLTRA and TAMOLTRA FORTE 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 including profound sedation and respiratory depression.

TAMOLTRA and TAMOLTRA FORTE should be used with caution and in reduced dosages when administered to patients receiving CNS depressants (see section 4.5).

Serotonin syndrome

Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol, as in TAMOLTRA and TAMOLTRA FORTE, in combination with other serotonergic medicines or tramadol alone (see sections 4.5, 4.8 and 4.9).

If concomitant treatment with other serotonergic medicines is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose escalations.

Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms. Withdrawal of the serotonergic

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 or stopping the total opioid dosage.

Precautions – general

Do not co-administer TAMOLTRA and TAMOLTRA FORTE with other tramadol or paracetamol containing products.

Use with alcohol

TAMOLTRA and TAMOLTRA FORTE should not be taken with alcohol containing beverages.

Use in renal disease

TAMOLTRA and TAMOLTRA FORTE should be used with caution in patients with impaired renal function and in patients prone to convulsive disorders or in shock.

Paediatric population

TAMOLTRA and TAMOLTRA FORTE are not indicated for use in children and adolescents under the age of 16 (see sections 4.1 and 4.2).

Concomitant use is contraindicated with

Monoamine oxidase (MAO) Inhibitors

• 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

• 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.

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 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
• 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.
• 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 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 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 medicines 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).
• 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.
• 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
• 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. 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
• 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 TAMOLRA 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:

^* Post marketing

Tramadol:

^* 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.

^* Post marketing

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

An email can be sent directly to the company, pharmacovigilance@pharmadynamics.co.za to ensure safety of the product.

Not applicable.