Tramadol/ Paracetamol

Registered South African indications:

• Pain - moderate to moderately severe

Contraindications

South African recommendations

• Hypersensitivity to tramadol, paracetamol, or any of the other ingredients
• Hypersensitivity to other opioids such as codeine
• Severe liver function impairment
• Acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic agents
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use
• Narcotic withdrawal treatment
• Respiratory depression, especially in the presence of cyanosis and excessive bronchial secretions
• Increased intracranial pressure or central nervous system depression due to head injury or cerebral disease
• Epilepsy not controlled by treatment

Recommendations in other jurisdictions

• Hypersensitivity to the active substances or to any of the excipients
• Acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic agents
• Coadministration with monoamine oxidase inhibitors or within 14 days of their use
• Severe hepatic impairment
• Epilepsy not controlled by treatment

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Respiratory insufficiency
• Intracranial trauma
• Patients prone to seizures
• Biliary tract disorders
• Shock
• Altered mental state
• Raised intracranial pressure
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May affect ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct, tab

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Pain - moderate to moderately severe

Tramadol/ Paracetamol
37.5/325 (mg)

• Oral (fct, tab): 1-2 tab, 4-6hrly as needed for pain relief; Max: 8 tab/24hrs

Tramadol/ Paracetamol
75/650 (mg)

• Oral (fct, tab): ½-1 tab, 4-6hrly as needed for pain relief; Max: 4 tab/24hrs

Tramadol/ paracetamol is not recommended for minor pain that may be treated adequately through lesser means

The recommended dose should not be exceeded

As with all analgesic medicines, a titration period of several days with gradual dose increases at the initiation of tramadol/paracetamol 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

Tramadol/paracetamol should under no circumstances be administered for longer than is strictly necessary

Tablets must be swallowed whole, with a sufficient quantity of liquid. They must not be broken or chewed

Paed. forms avail. in SA and covered in this monograph: fct, tab

Paed. dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Pain - moderate to moderately severe

Tramadol/ Paracetamol
37.5/325 (mg)
75/650 (mg)

Younger than 16 years

• Not established for use

16 years and older

• See adult dosage

Pregnancy

• Caution
• Since tramadol hydrochloride/paracetamol is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.  Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosages
• 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

• Caution; not recommended
• Since tramadol hydrochloride/paracetamol is a fixed combination of active ingredients including tramadol, it should not be used more than once during breastfeeding or alternatively, breastfeeding should be discontinued during treatment with tramadol
• Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data on paracetamol does not contraindicate it for breastfeeding by women using single-ingredient medicinal products containing only paracetamol 
• Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate postpartum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breastfed infants of 3% of the maternal weight-adjusted dosage. For this reason, tramadol should not be used during breastfeeding or alternatively, breastfeeding should be discontinued during treatment with tramadol. Discontinuation of breastfeeding is generally not necessary following a single dose of tramadol

Renal Impairment

• CrCl ≥30 ml/min: No dose adjustment recommended
• CrCl <30 mL/min:  Caution; dose adjustment recommended
  CrCl 10-30 ml/min: 1-2 tab, 12hrly; Max: 4 tab/24hrs
  CrCl <10ml/min: Use not recommended

Hepatic Impairment

South African recommendations

37.5/325 (mg)

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

75/650 (mg)

• Mild: Caution; no dose adjustment recommended
• Moderate: Caution; dose adjustment recommended
  In moderate cases prolongation of dosage interval should be carefully considered
• Severe: Contraindicated

Recommendations in other jurisdictions

• Mild to moderate: Caution; dose adjustment recommended
  In patients with hepatic impairment the elimination of tramadol is delayed. In these patients, prolongation of the dosage intervals should be carefully considered according to the patient's requirements
• Severe: Contraindicated

Elderly

• Caution; no dose adjustment recommended 
  In older people over 75 years elimination may be prolonged
  If necessary the dosage interval is to be extended according to the patient's requirements

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Prohibited - In certain sports
  Prohibited - In competition:
  Cycling (UCI)

Central Nervous System Disorders

• Dizziness
• Headache
• Somnolence
• Paraesthesia
• Amnesia
• Ataxia
• Tremor
• Involuntary muscle contractions
• Syncope
• Speech disorders
• Seizures
• Hallucinations
• Confusion
• Sleep disturbance
• Anxiety 
• Changes in mood 
• Nervousness
• Euphoric mood
• Depression
• Nightmares
• Delirium
• Drug dependence
• Motor weakness

Cardiovascular Disorders

• Palpitation
• Postural hypotension
• Bradycardia
• Collapse
• Tachycardia
• Arrhythmia
• Chest pain
• Hypertension
• Hot flushes

Respiratory Disorders

• Worsening of asthma 

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Dry mouth
• Diarrhoea 
• Abdominal pain
• Dyspepsia
• Flatulance
• Dysphagia
• Malaena

Hepatobiliary Disorders

• Increase in transaminases 

Genitourinary Disorders

• Albuminuria
• Dysuria
• Urinary retention

Endocrine and Metabolic Disorders

• Hypoglycaemia
• Changes in appetite

Skin and Subcutaneous Tissue Disorders

• Sweating
• Pruritis
• Rash
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Increased prothrombin time
• Anaphylaxis
• Hypersensitivity reactions
• Thrombocytopenia 
• Agranulocytosis
• Hypoprothrombocytopaenia

Sensory Disorders

• Blurred vision
• Miosis
• Mydriasis
• Tinnitus

• Hypnotic agents
• Centrally acting analgesics
• Opioids
• Psychotropic agents
• Monoamine oxidase inhibitors
• CYP3A4 inducers
• Central nervous system depressants
• Alcohol

None routine

Tramadol
Tramadol is a non-selective pure agonist at mu, delta and kappa opiate receptors with noradrenergic and serotonergic reuptake inhibition.

Paracetamol
Paracetamol increases the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1, COX-2, and COX-3 enzymes involved in prostaglandin synthesis. It does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects.

COMBINATION PREPARATIONS

Tramadol/ Paracetamol

Tablet 37.5mg/325mg

• Patram Fct (Ranbaxy)
• Tamoltra (Pharma Dynamics)
• Tramacet (Janssen) originator
• Tramazac Co (Zydus)
• Tramahexal Co (Zydus)
• Ultracet (Janssen) originator

Tablet 75mg/650mg

• Tamoltra Forte (Pharma Dynamics)