DOLTREX Film-coated tablet Ref.[51221] Active ingredients: Tramadol

DOLTREX 50 MG tablets may only be taken with special care in opioid dependence.

DOLTREX 50 MG tablets are not suitable for children under the age of 12 years.

DOLTREX 50 MG tablets should be used with care in patients with increased reactivity to opioids. Respiratory depression may develop if the recommended dosages are exceeded or other centrally depressant medicines are given concomitantly.

DOLTREX 50 MG tablets should not be used in the treatment of minor pain.

DOLTREX 50 MG tablets should be used with caution in patients with impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock. (see Section 4.2).

Seizures

Seizures have been reported in patients receiving DOLTREX 50 MG tablets at dosages within the recommended dosage range. The risk of seizures may be enhanced in patients exceeding the recommended dose, or in patients taking tricyclic antidepressants or other tricyclic compounds e.g. promethazine, selective serotonin reuptake inhibitors, MAO-inhibitors and neuroleptics.

Drug Abuse and Dependence

Tolerance, psychic and physical dependence of the morphine-type (µ opioid) may develop. DOLTREX 50 MG tablets have been associated with craving drug-seeking behaviour and tolerance development. Symptoms of drug withdrawal syndrome, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastro-intestinal symptoms. Other symptoms that have been seen with DOLTREX 50 MG tablets discontinuation include: panic attacks; severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation and paranoia).

DOLTREX 50 MG tablets should not be used in opioid-dependent patients. DOLTREX 50 MG tablets 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 DOLTREX 50 MG tablets are not recommended.

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.

Hyponatraemia

Hyponatraemia has been reported with the use of DOLTREX 50 MG, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications 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 DOLTREX 50 MG and appropriate treatment (e.g. fluid restriction). During DOLTREX 50 MG treatment, monitoring for signs and symptoms of hyponatraemia is recommended for patients with predisposing risk factors.

Lactose

Contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take DOLTREX 50 MG.

DOLTREX 50 MG tablets should not be combined with MAO inhibitors within 14 days of withdrawal of MAO inhibitors (see Section 4.3).

In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine, lifethreatening interactions of the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with DOLTREX 50 MG tablets.

Concomitant administration of DOLTREX 50 MG tablets with other centrally depressant medicines including alcohol may potentiate the CNS effects (see Section 4.3). Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.

DOLTREX 50 MG tablets can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, anti-psychotics and other seizure threshold lowering medicinal products (such as bupropion, mirtazapine, tetra-hydrocannabinol) to cause convulsions.

Concomitant therapeutic use of DOLTREX 50 MG tablets 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. The

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.

Caution should be exercised during concomitant treatment with DOLTREX 50 MG tablets and warfarin– like medicines due to reports of increased International Normalised Ratio (INR) with major bleeding and ecchymoses in some patients.

The inhibition of one or both types of isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite. Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active Odemethylated metabolite. The clinical importance of such an interaction has not been studied (see Section 5.1).

The antiemetic 5-HT₃ antagonist ondansetron increases the requirement of DOLTREX 50 MG tablets in patients with postoperative pain. DOLTREX 50 MG tablets may decrease the antiemetic efficacy of ondansetron.

Pregnancy

Safety during pregnancy and lactation has not been established. Therefore, DOLTREX 50 MG tablets should not be used in pregnant women. DOLTREX 50 MG crosses the placenta. Animal studies with DOLTREX 50 MG revealed effects on organ development, ossification and neonatal mortality. The administration of DOLTREX 50 MG tablets during pregnancy may lead to habituation in the unborn child. The child may experience withdrawal symptoms after birth (see Section 4.3).

Breastfeeding

DOLTREX 50 MG passes into breastmilk. Mothers on DOLTREX 50 MG tablets should not breastfeed their infants.

DOLTREX 50 MG tablets may affect reactions to the extent that driving ability and the ability to operate machinery may be impaired. This applies particularly in conjunction with other psychotropic medicines including alcohol.

Table 1. The following adverse reactions have been reported in association with DOLTREX 50 MG Tablets:

Post marketing experience

Nervous system complaints: Speech disorders.

Eye disorders: Mydriasis.

Skin and subcutaneous tissue disorders: Stevens Johnson Syndrome, Toxic Epidermal Necrolysis.

Gastrointestinal disorders: Increased risk of abdominal pain, including pancreatitis has been reported.

Frequency: rare

Cases of hyponatraemia and/or SIADH have been reported in patients taking tramadol, usually in patients with predisposing risk factors, such as the elderly or those using concomitant medications that may cause hyponatraemia.

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. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.