INTRAM PLUS Tablet

For the symptomatic treatment of moderate to severe pain.

Dosage regimen:

Adults and adolescents (12 years and older); The use of this medicine should be restricted patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol.

The dose should be individually adjusted according to intensity of pain and response of the patient.

An initial dose is 2 tablets. Additional doses can be taken as needed, not exceeding 8 tablets per day.

The dosing interval should not be less than 6 hours. This tablet should under to circumstances be administered for longer than is strictly necessary. If repeated use or long term treatment with this tablet is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place (with breaks in the treatment, where possible), to assess whether continuation of the treatment is necessary.

Children: The effective and safe use of this medicine has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population.

See the package insert about the details below:

- Elderly patients

- Renal insufficiency

- Hepatic insufficiency

See the package insert about the details below：

Concomitant use is contraindicated with:

- Non-selective MAO inhibitors.

- Selective-A MAO inhibitors.

- Selective-B MAO inhibitors.

In case of recent treatment with MAO inhibitors, a delay of 2 weeks should occur before treatment with tramadol.

Concomitant use is not recommended with:

- Alcohol

- Carbamazepine and other enzyme inducers

- Opioid agonists-antagonists (buprenorphine, nalbuphine, pentazocine)

Concomitant use with needs to be taken into consideration

- In isolated cases there have been reports of Serotonin Syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotoninergic medicines such as selective serotonin re-uptake inhibitors (SSRI) and triptans.

- Other opioid derivatives (including antitussive drugs and substitutive treatments), benzodiazepines and barbiturates

- Other central nervous system depressants, such as other opioid derivatives (including antitussive drugs and substitutive treatments), barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally-acting antihypertensive drugs, thalidomide and baclofen

- As medically appropriate, periodic evaluation of prothrombin time should be performed when Tramadol hydrochloride/ Paracetamol and warfarin like compounds

- Other drugs known to inhibit CYP3A4, such as ketoconazole and erythromycin

- Medicinal products reducing the seizure threshold, such as bupropion, serotonin reuptake inhibitor antidepressants, tricyclic antidepressants and neuroleptics

- The pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

Tramadol hydrochloride/Paracetamol should be used with caution in opioid dependent patients, or in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract disorders, in a state of shock, in an altered state of consciousness for unknown reasons, with problems affecting the respiratory centre or the respiratory function, or with an increased intracranial pressure. Paracetamol in overdosage may cause hepatic toxicity in some patients.

Al therapeutic doses, tramadol has the potential to cause withdrawal symptoms. Rarely, cases of dependence and abuse have been reported. Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal may occur.

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 during light planes of anaesthesia should be avoided.

The maximum of 8 tablets should not be exceeded in adults and adolescents 12 years and older. In order to avoid inadvertent overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol or tramadol hydrochloride containing products concurrently without the advice or a physician. In severe renal impairment (creatinine clearance <10ml/min), Tramadol hydrochloride/Paracetamol is not recommended. In patients with severe hepatic impairment Tramadol hydrochloride/Paracetamol should not be used. 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. In severe respiratory impairment, Tramadol hydrochloride/Paracetamol is not recommended. Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesic or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with Tramadol hydrochloride/Paracetamol only if there are compelling circumstances. Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper dose limit. Concomitant use of opioid antagonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended.

The most commonly reported undesirable effects during the clinical trials performed with the paracetamol/tramadol combination were nausea, dizziness and somnolence, observed in more than 10% of the patients.

Cardiac disorders:

- Uncommon: hypertension, palpitations, tachycardia, arrhythmia.

Nervous system disorders:

- Very common: dizziness, somnolence

- Common: involuntary muscular contractions, paraesthesia, tinnitus

- Rare: ataxia, convulsions.

Psychiatric disorders:

- Common: confusion, mood changes (anxiety, nervousness, euphoria), sleep disorders

- Uncommon: depression, hallucination, nightmares, amnesia

- Rare: drug dependence.

- Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

- There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.

- Hypersensitivity to tramadol, paracetamol or to any of the excipients of the medicinal product.

- Acute intoxication with alcohol, hypnotic drugs, centrally-acting analgesics, opioids or psychotropic drugs.

- To patients who are receiving monoamine oxidase inhibitors or within 2 weeks of their withdrawal

- Severe hepatic impairment

- Epilepsy not controlled by treatment.

Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is a pure non selective agonists of theμ,δandκopioid receptors with a higher affinity for theμreceptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of nonadrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Similarly, the gastro-intestinal motility it is not modified. The cardiovascular effects are generally slight. The potency of tramadol is considered to be one-tenth to one-sixth that of morphine. The precise mechanism of the analgesic properties of paracetamol is unknown and may involve central and peripheral effects.