Tramadol Hydrochloride

Registered South African indications:

• Management of moderate to severe pain

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Acute intoxication with alcohol, hypnotics, analgesics, opioids, or other psychotropic medicines
• In patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days
• In patients with epilepsy
• For use in narcotic withdrawal treatment
• In patients with respiratory depression, or in the presence of cyanosis and excessive bronchial secretions
• In patients with increased intracranial pressure or central nervous depression due to head injury or cerebral disease
• Pregnancy
• Breastfeeding
• In post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy
• For use in children under the age of 12 years (cap, srt)

South African recommendations

Caution in the following patient groups

• Renal impairment
• Hepatic impairment
• Elderly
• Opioid-dependent patients
• Patients sensitive to opiates
• Use with caution in patients prone to convulsive disorders or in shock

Respiratory depression and sedation

• Respiratory depression may develop if other centrally depressant medicines are given concomitantly
• May result in sedation, respiratory depression, coma and death when combined with sedating agents
• Use concomitantly with sedating medicines only when alternative treatment options are not possible
• Use the lowest effective dose and shortest possible duration if combined with sedating medicines
• Monitor closely for respiratory depression and sedation
• Inform patients and caregivers about these risks
• Exceeding recommended dosage may lead to respiratory depression

Seizures

• Seizures have been reported at recommended dose levels
• Risk increases with doses exceeding the recommended limit (400mg/day)
• May increase seizure risk in patients on tricyclic antidepressants or similar compounds
• Use only if compelling in patients with epilepsy or seizure susceptibility

Sleep-related breathing disorders

• Opioids may cause central sleep apnoea (CSA) and sleep-related hypoxaemia
• Risk of CSA increases in a dose-dependent manner
• Consider reducing total opioid dose if CSA develops

Tolerance, dependence, and withdrawal

• Tolerance, as well as psychic and physical dependence, may develop, particularly after long-term use. TRAMAZAC SR has the potential to cause withdrawal symptoms, which may include agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor, and gastrointestinal symptoms. Tapering the dose gradually is recommended to prevent withdrawal symptoms when discontinuing treatment. TRAMAZAC SR is not recommended for opioid-dependent patients, or for patients with a history of drug dependence or a tendency to abuse drugs. Individuals with a current or past history or family history of substance misuse or a mental health disorder have an increased risk of dependence and abuse. Patients should be closely monitored for signs of misuse, abuse, or addiction. It should not be used in suicidal patients

CYP2D6 metabolism

• Patients who are deficient in or completely lack the liver enzyme CYP2D6 may not achieve an adequate analgesic effect. Patients who are ultra-rapid metabolizers of the CYP2D6 enzyme are at risk of developing opioid toxicity side effects, including life-threatening respiratory depression, even within the recommended dosage range
• Analgesic effect may be reduced in patients deficient in CYP2D6
• Consider alternative medication, dose reduction and/or increased monitoring in ultra-rapid metabolisers

Hyponatraemia

• Hyponatraemia has been reported with the use of tramadol, usually in patients with predisposing risk factors such as elderly patients and/or patients using concomitant medications that may cause hyponatraemia. Monitoring for signs and symptoms of hyponatraemia is recommended for these patients

Minor pain

• Tramadol should not be used for the treatment of minor pain

Mental health disorders

• Increased risk of addiction in patients with personal or family history of substance abuse or mental illness

Opioid-sensitive patients

• Use with care in patients with increased reactivity to opioids

Excipients

• Capsule (50mg): Contains less than 1 mmol sodium (23mg) per capsule; essentially “sodium-free”
• Film-coated tablet (50mg): Tramadol 50mg film-coated tablet contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine
• Tablet (50mg): Warning for phenylketonurics – contains aspartame

Effects on ability to drive and use machines

• Tramadol may cause side effects, such as somnolence and dizziness and therefore affect the ability to drive a vehicle or use machinery
• This applies particularly in conjunction with other psychotropic medicines, including alcohol
• Caution is advised before driving a vehicle or operating machinery until the effects of tramadol are known

Additional warnings for slow-release formulations

Serotonin syndrome

• Tramadol, alone or with other serotonergic medicines, may cause serotonin syndrome, which is a potentially life-threatening condition. Patients should be carefully observed when receiving concomitant treatment with other serotonergic medicines, especially during the initiation of treatment and dose escalations. If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered

Opioid-induced hyperalgesia (OIH)

• OIH is a paradoxical response to an opioid where pain perception increases despite stable or increased opioid exposure. When OIH is suspected, the dose should be reduced or tapered off, if possible

Respiratory disorders

• Use with caution in patients with disorders of respiratory function, including asthma

Other conditions

• Use with caution in patients with hypothyroidism, prostatic hyperplasia, hypotension, inflammatory or obstructive bowel disorders, or myasthenia gravis​​​​​​

Forms avail. in SA and covered in this monograph: IR cap, IR tab, fct, srt, prt

South African registered indications and dosages

Management of moderate to severe pain

• Oral (prt): Usual initial dose: 150mg, daily; If pain relief not achieved: Titrate upwards until pain relief is achieved; Total daily dose of 400mg should not be exceeded except in special clinical circumstances

---

The correct dosage per individual patient is that which controls the pain, with no or tolerable side effects, for a full 24 hours. Patients transferring from immediate release tramadol preparations should have their total daily dose calculated, and start on the nearest dose in the prolonged release range. It is recommended that patients are slowly titrated to higher doses to minimise transient side effects. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported

---

• Oral (srt): Usual initial dose: 100mg, twice daily, preferably in the mornings and evenings; If pain relief not adequate: Increase to 150mg or 200mg, twice daily; Dosage intervals can be adjusted to individual requirements but should be at least 8hrs. Max: 400mg/24hrs
• Oral (IR tab): Initial: 50mg; Followed by: 100mg, twice daily; The dose may be increased to 150mg or 200mg, twice daily

Moderate pain

• Oral (IR cap, fct): Initial: 50mg; Followed by: 50mg or 100mg, 4-6hrly; Max: 400mg/24hrs

Severe pain

• Oral (IR cap, fct): Initial: 100mg; Followed by: 50mg or 100mg, 4-6hrly; Max: 400mg/24hrs

---

The dosage should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected

---

Method of administration
Tramadol prolonged-release tablets should be taken at 24-hourly intervals and must be swallowed whole and not broken, crushed or chewed
Tramadol capsules, film-coated tablets and slow-release tablets are to be taken whole, not divided or chewed, with sufficient liquid, with or without meals
Tramadol tablets (dissolvable) are to be dissolved in the mouth, and not chewed. The tablets may also be dispersed in a small quantity of water

---

Duration of treatment
Under no circumstances should tramadol prolonged-release tablets be given for longer than absolutely necessary. If the nature and severity of the disease require long-term pain treatment, careful checks should be carried out initially and at regular intervals to assess efficacy and adverse events and to what extent further treatment is necessary

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

South African registered indications and dosages

Management of moderate to severe pain

Younger than 12 years

• Oral (fct): Not established for use
• Oral (prt, srt, cap): Contraindicated

Older than 12 years

• See adult dosage

Immediate release tablet

Younger than 14 years

• Not established for use

Older than 14 years

• See adult dosage

---

The capsule, slow-release tablet and prolonged release tablet are contraindicated in post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy

---

Tramadol IR tablets (dissolvable) are for use in children who are 14 years and older

Pregnancy

South African recommendations

• Contraindicated
• The safety of tramadol during pregnancy has not been established and therefore it should not be used in pregnant women
• Animal studies with tramadol revealed effects on organ development, ossification and neonatal mortality. It crosses the placenta
• Administration during pregnancy may lead to habituation in the unborn child. The child may experience withdrawal symptoms after birth

Breastfeeding

South African recommendations

• Contraindicated
• Tramadol passes into breastmilk. Mothers on tramadol should not breastfeed their infants

Fertility

South African recommendations

• Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility

South African recommendations

Film-coated tablet, prolonged release tablet, slow-release tablet, capsule

• Mild to moderate: Caution; no dose adjustment recommended
  In patients with renal insufficiency the elimination of tramadol hydrochloride is delayed. In these patients’ prolongation of the dosage intervals should be carefully considered according to the patient's requirements
• Severe: Caution; not recommended

Tablet

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  The elimination of tramadol may be prolonged. The usual initial dose should be used, but for patients with creatinine clearance < 30 ml/min, the dosage interval should be increased to 12 hours

South African recommendations

Film-coated tablet, prolonged release tablet, slow-release tablet, capsule

• Mild to moderate: Caution; no dose adjustment recommended
  In patients with hepatic insufficiency the elimination of tramadol hydrochloride is delayed. In these patients’ prolongation of the dosage intervals should be carefully considered according to the patient's requirements
• Severe: Caution; not recommended

Tablet

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  The elimination of tramadol may be prolonged. The usual initial dose should be used, but in severe hepatic impairment, the dosage interval should be increased to 12 hours

South African recommendations

• ≥ 75 years: Caution; dose adjustment recommended
  A downward adjustment of the dose and/or prolongation of the interval between doses are recommended in elderly patients

Immune System Disorders

Less frequent

• Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema)
• Anaphylaxis

Psychiatric Disorders

Less frequent

• Hallucinations
• Confusion
• Sleep disturbance
• Delirium
• Anxiety
• Nightmares
• Changes in mood (euphoria, dysphoria)
• Decreased activity
• Restlessness
• Changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders)

Nervous System Disorders

Frequent

• Dizziness
• Headache
• Somnolence

Less frequent

• Paraesthesia
• Tremor
• Epileptiform convulsions
• Involuntary muscle contractions
• Abnormal coordination
• Syncope
• Speech disorders

Not known

• Speech disorders (post-marketing)

Cardiac Disorders

Less frequent

• Palpitation
• Tachycardia
• Dysrhythmias
• Bradycardia

Vascular Disorders

Less frequent

• Postural hypotension
• Cardiovascular collapse
• Increase in blood pressure

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Respiratory depression
• Dyspnoea
• Bronchospasm

Metabolism and Nutrition Disorders

Less frequent

• Changes in appetite

Frequency not known

• Hypoglycaemia

Gastrointestinal Disorders

Frequent

• Nausea
• Vomiting
• Constipation
• Dry mouth

Less frequent

• Retching
• Gastrointestinal discomfort (a feeling of pressure in the stomach, bloating)
• Diarrhoea

Rare

• Increased risk of abdominal pain, including pancreatitis (post-marketing)

Musculoskeletal and Connective Tissue Disorders

Less frequent

• Muscular weakness

Hepatobiliary Disorders

Less frequent

• Increase in liver enzyme values

Renal and Urinary Disorders

Less frequent

• Micturition disorders (dysuria and urinary retention)

Eye Disorders

Less frequent

• Miosis
• Blurred vision

Not known

• Mydriasis (post-marketing)

Skin and Subcutaneous Tissue Disorders

Less frequent

• Hyperhidrosis
• Dermal reactions (e.g. pruritus, rash, urticaria)

Not known

• Stevens Johnson Syndrome
• Toxic epidermal necrolysis

General Disorders

Frequent

• Fatigue

Investigations

Less frequent

• Increase in blood pressure

• Monoamine oxidase (MAO) inhibitors
• Centrally depressant medicines
• Sedating medicines such as benzodiazepines or related substances
• Cimetidine
• Carbamazepine
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs)
• Tricyclic antidepressants
• Antipsychotics
• Bupropion
• Mirtazapine
• Tetrahydro-cannabinol
• Coumarin derivatives (e.g. warfarin)
• Ketoconazole
• Erythromycin
• Ondansetron

Other interactions

• Alcohol

None routine.

• Signs and symptoms of hyponatraemia
• Signs and symptoms of respiratory depression and sedation
• Signs of misuse, abuse or addiction

Tramadol hydrochloride is a centrally acting opioid analgesic. It is a non-selective pure agonist at mu (μ), delta (δ) and kappa (κ) opioid receptors with a higher affinity for the μ receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. The relationship between serum concentrations and the analgesic effect is dose-dependent, but varies considerably. Patients devoid of CYP2D6 may need higher doses of tramadol hydrochloride, to achieve adequate analgesia.

Capsule 50mg

• Austell Tramadol (Austell)
• Domadol (Unichem)
• Dolotram (Ranbaxy)
• Tramal (Janssen) originator
• Tramahexal (Sandoz)
• Tramaspen (Pharmacare)
• Tramazac (Zydus)

Tablet 50mg

• Tramagesic flashtabs (Adcock)

Slow-release tablet 100mg

• Tramal SR (Janssen) originator
• Tramahexal SR (Sandoz)
• Tramazac SR (Zydus)

Slow-release tablet 150mg

• Tramal SR (Janssen) originator
• Tramazac SR (Zydus)
• Tramahexal SR (Sandoz)

Slow-release tablet 200mg

• Tramal SR (Janssen) originator
• Tramahexal SR (Sandoz)
• Tramazac SR (Zydus)

Injection (per ml) 50mg 

• Dolotram (Ranbaxy) originator
• Domadol (Unichem)
• Nobligan (Janssen) originator
• Tramal (Janssen) originator
• Tramahexal (Sandoz)
• Tramaspen (Pharmacare)
• Tramazac (Zydus) (NON EML)

COMBINATION PREPARATIONS

Paracetamol/ Tramadol 

Tablet 325mg/37,5mg

• Tramazac Co (Zydus)
• Tramacet (Janssen) originator
• Tramahexal Co (Sandoz/Zydus)
• Ultracet (Janssen) originator