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New Zealand Data Sheet
Tramal ®^ Capsules
Tramal ®^ Solution for Injection
Tramal ®^ SR Tablets
WARNINGS
Limitations of use Because of the risks associated with the use of opioids, Tramal®^ should only be used in patients for whom other treatment options, including non-opioid analgesics, are ineffective, not tolerated or otherwise inadequate to provide appropriate management of pain (see section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE ). Hazardous and harmful use Tramal®^ poses risks of hazardous and harmful use which can lead to overdose and death. Assess the patient’s risk of hazardous and harmful use before prescribing and monitor the patient regularly during treatment (see section 4.4. SPECIAL WARNINGS AND PRECAUTIONS FOR USE ). Life threatening respiratory depression Serious, life-threatening or fatal respiratory depression may occur with the use of Tramal®. Be aware of situations which increase the risk of respiratory depression, modify dosing in patients at risk and monitor patients closely, especially on initiation or following a dose increase (see section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE ). Concomitant use of benzodiazepines and other central nervous system (CNS) depressants, including alcohol Concomitant use of opioids with benzodiazepines, gabapentinoids, antihistamines, tricyclic antidepressants, antipsychotics, cannabis or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Limit dosages and durations to the minimum required; and monitor patients for signs and symptoms of respiratory depression and sedation. Caution patients not to drink alcohol while taking Tramal®^.
1. PRODUCT NAME
Tramal®^ (tramadol hydrochloride) immediate release capsules 50 mg Tramal®^ (tramadol hydrochloride) solution for injection 50 mg/mL, 100 mg/2mL Tramal®^ SR tablets (tramadol hydrochloride) sustained release tablets) 50 mg, 100 mg, 150 mg, 200 mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Tramal®^ 50 mg capsules are yellow-yellow capsules containing: 50 mg tramadol hydrochloride.
Tramal®^ 50 mg and 100 mg injections contain: tramadol hydrochloride 50 mg/mL. Tramal®^ SR sustained release tablets contain: tramadol hydrochloride in the following dose strengths: 50, 100, 150 and 200 mg.
For full list of excipients, see section 6.1 List of excipients.
Tramal®^ capsules, Tramal®^ solution for injection, and Tramal®^ SR tablets contain tramadol hydrochloride which is ( +) - cis -2-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol hydrochloride. Tramadol hydrochloride is an odourless, white to off-white crystalline powder
that is readily soluble in both water and ethanol and has a pKa of 9.41. The water/n-octanol partition coefficient is 1.35 at pH 7. It belongs to the synthetic analgesics class and has opioid-like activity, with the formula: C 16 H 25 NO 2. HCl. MW = 299.84.
The structural formula of tramadol hydrochloride is:-
The CAS Registry Number is 36282-47-0.
3. PHARMACEUTICAL FORM
Tramal®^ capsules are oblong, yellow/yellow, shiny hard gelatin capsules size 4.
Tramal®^ solution for injection is clear, colourless solution.
Tramal®^ SR 50mg sustained release tablets are pale yellow coloured, round, biconvex, film- coated tablets, engraved with "T0" on one side and Grunenthal logo on the other side.
Tramal^ SR 100 mg sustained release tablets are supplied as white, round, biconvex, film- coated tablets, engraved with"T1" on one side and the Grunenthal logo on the other side.
Tramal^ SR 150 mg sustained release tablets are supplied as pale orange-coloured, round, bi-convex, film-coated tablets, engraved with "T2" on one side and the Grunenthal logo on the other side.
Tramal^ SR 200 mg sustained release tablets are supplied as slightly brownish orange- coloured, round, bi-convex, film-coated tablets, engraved with "T3" on one side and the Grunenthal logo on the other side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Relief of moderate to severe pain.
4.2 Dose and method of administration
Dose
The dose of tramadol should be titrated to the severity of the pain and the clinical response of the individual patient. Tramadol is approved for use in adults, adolescents and children over the age of 12 years.
dose is removed by haemodialysis, dialysis patients can receive their regular dose on the day of dialysis.
Hepatic insufficiency - Tramal®^ SR should not be used in patients with severe hepatic insufficiency. In these patients, the immediate release (IR) form of oral tramadol (capsule) may be administered if appropriate. In hepatic impairment, the initial oral dose of tramadol is 50 mg of the immediate release formulation. Depending on the severity of the impairment and individual clinical response, the recommended dosage interval (4-6 hours) may require to be extended, and/or the dose level titrated as required.
Pharmaceutical compatibility Tramal®^ injection is compatible with the following intravenous fluids: 0.9% sodium chloride, 5% glucose, 4.2% sodium bicarbonate, Ringer’s solution, Ringer’s lactate solution, Dextran 40 (10%) or polygeline 3.5%.
Method of administration
For method of administration see section 4.2 Dose and method of administration.
4.3 Contraindications
Tramadol is contraindicated in:
- individuals with known hypersensitivity to tramadol or any excipients listed in section 6.
- acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs
- all children younger than 12 years of age (see section 4.4 Special warnings and precautions for use )
- postoperative management of children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see section 4.4 Special warnings and precautions for use )
- patients who are taking MAO inhibitors or who have taken them within the last 14 days
- known hypersensitivity to opioids
- patients with uncontrolled epilepsy or epilepsy not adequately controlled by treatment.
Tramadol must not be used for narcotic withdrawal treatment.
4.4 Special warnings and precautions for use
Hazardous and harmful use Tramal®^ contains the opioid tramadol hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Tramal®^ at recommended doses. The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Tramal®. All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see section 6.4 Special precautions for storage and section 6.6 Special precautions for disposal ). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal. Patients should be advised not to share Tramal®^ with anyone else.
Respiratory depression and sedation Tramadol should be administered cautiously in patients at risk of respiratory depression. Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Tramal®^ but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times. The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma), hepatic or renal impairment (see section 4. Special warnings and precautions for use ). Opioids should be used with caution and with close monitoring in these patients (see section 4.2 Dose and method of administration ). The use of tramadol hydrochloride is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see section 4. Contraindications ).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response (see section 4.2 Dose and method of administration ).
Cases of intra-operative respiratory depression, usually with large intravenous doses of tramadol and with concurrent administration of respiratory depressants, have been reported. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see section 4.5 Interactions with other medicines and other forms of interaction).
Sleep-related breathing disorders Drugs with μ-opioid receptor agonist activity can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Use of these drugs increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Tramal®^ with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Tramal®^ concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Tramal®^.
Use of opioids in chronic (long-term) non-cancer pain (CNCP) Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics
When discontinuing Tramal®^ in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids and section 4.2 Dose and Method of Administration).
Tramadol is not recommended as a substitute in opioid-dependent patients. Although tramadol is an opiate-agonist, it cannot suppress opioid withdrawal symptoms. Animal experiments have shown that under certain circumstances the administration of tramadol may provoke a withdrawal syndrome in opioid-dependent monkeys. Because of the difficulty in assessing dependence in patients who have previously received substantial amounts of opioid medications, caution should be used in the administration of tramadol to such patients.
In patients with a tendency for drug abuse or dependence, treatment with tramadol should only be carried out for short periods under strict medical supervision.
Accidental ingestion/exposure Accidental ingestion or exposure of Tramal®^ , especially by children, can result in a fatal overdose of Tramal®^. Patients and their caregivers should be given information on safe storage and disposal of unused Tramal®^ (see section 6.4 Special precautions for storage and section 6.6 Special precautions for disposal).
Hyperalgesia Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.
Ceasing opioids Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.
Serotonin syndrome Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic agents or tramadol alone (see
sections 4.5 Interaction with other medicines and other forms of interaction, 4. Undesirable effects and 4.9 Overdose ).
If concomitant treatment with other serotonergic agents 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 (including anxiety, agitation, and confusion), autonomic instability (including diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrhoea), and neuromuscular abnormalities (including muscle rigidity, myoclonus, tremor, and hyperreflexia). 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 drugs usually brings about a rapid improvement.
Galactose intolerance Tramal®^ SR tablets contain 2.5 mg lactose monohydrate per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take this medicine.
Acute abdominal conditions The administration of tramadol may complicate the clinical assessment of patients with acute abdominal conditions.
Increased intracranial pressure or head trauma, shock or reduced levels of consciousness Tramadol should be used with caution in patients with increased intracranial pressure, head injury, shock or a reduced level of consciousness of uncertain origin. Pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol.
Seizure risk 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 daily dose limit. In addition, tramadol may increase the seizure risk in patients taking other medication that lowers the seizure threshold (see section 4.5 Interaction with other medicines and other forms of interaction ). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances.
Anaphylactoid reactions Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving tramadol. These reactions often occur following the first dose. Other reported reactions include pruritus, hives, bronchospasm and angioedema.
Intra-operative use In one study using nitrous oxide/tramadol anaesthetic technique (with only intermittent administration of enflurane “as required”), tramadol was reported to enhance intra-operative recall. Hence its use during potentially very light levels of general anaesthesia should be avoided.
Two recent studies of tramadol administration during anaesthesia comprising continuous administration of isoflurane did not show clinically significant lightening of anaesthetic depth or intra-operative recall. Therefore, providing the current practice of administering
Renal disease In patients with renal insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient’s requirements. In cases of severe renal insufficiency Tramal prolonged-release tablets are not recommended. As tramadol is removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary (see section 4.2 Dose and method of administration and 5.2 Pharmacokinetic properties ).
Use in the elderly In subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly prolonged. Subjects in this age group are also expected to vary more widely in their ability to tolerate adverse drug effects. Daily doses in excess of 300 mg are not recommended in patients over 75 years.
Post-operative use in children Extreme caution should be exercised when tramadol is administered to children for post- operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.
There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events.
4.5 Interaction with other medicines and other forms of interaction
Use with Central Nervous System (CNS) Depressants -
Tramadol should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anaesthetic agents, phenothiazines, tranquilisers, sedative/hypnotics, antihistamines, centrally active anti- emetics(see section 4.4 Warnings and Precautions).
The combination of tramadol with mixed opiate agonists/antagonists (e.g. buprenorphine, pentazocine) is not advisable because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.
Use with other serotonergic agents - the presence of another drug that increases serotonin by any mechanism should alert the treating physician to the possibility of an interaction. 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 4.3 Contraindications ), tricyclic antidepressants and mirtazapine may cause serotonin toxicity.
Withdrawal of the serotonergic medicines usually brings about a rapid improvement Drug treatment depends on the nature and severity of the symptoms.
Use with coumarin derivatives - caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased international normalised ratio (INR) with major bleeding and ecchymoses in some patients.
Drugs which reduce the seizure threshold - tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors(SSRIs), serotonin- norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and
other seizure threshold lowering agents (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.
Use with MAO inhibitors - tramadol should not be used in patients who are taking MAO inhibitors or who have taken them within the last fourteen days, as tramadol inhibits the uptake of noradrenaline and serotonin (see section 4.3 Contraindications ).
Other interactions - tramadol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals.
Concomitant administration of tramadol with carbamazepine causes a significant increase in tramadol metabolism, presumably through metabolic induction by carbamazepine. Patients receiving chronic carbamazepine doses of up to 800 mg daily may require up to twice the recommended dose of tramadol.
Tramadol is metabolised to M1 by the CYP2D6 P450 isoenzyme. Drugs that selectively inhibit that isoenzyme (quinidine, phenothiazines, antipsychotic agents) may cause increased concentrations of tramadol and decreased concentrations of M1. The clinical consequences of these potential effects have not been fully investigated.
Concomitant administration of tramadol with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore no alteration of the tramadol dosage regimen is recommended.
Other drugs known to inhibit the CYP3A4 isoenzyme of cytochrome P450, such as ketoconazole and erythromycin, may inhibit the metabolism of tramadol (via N- demethylation) and probably the metabolism of the active O -demethylated metabolite (M1). The clinical importance of such an interaction has not been studied.
In a limited number of studies, the pre- or post-operative application of the antiemetic 5-HT antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.
4.6 Fertility, pregnancy and lactation
Post marketing surveillance does not suggest an adverse effect of tramadol on fertility. In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects. Published data suggest an adverse influence of tramadol in rodents on male sexual and testicular function, potentially resulting in impaired fertility.
Use in pregnancy - Category C There are no adequate and well-controlled studies with tramadol in pregnant women therefore, tramadol should not be used during pregnancy. Studies in animals using IV or IM routes of administration have not been conducted.
Tramadol has been shown to be embryotoxic and foetotoxic in mice, rats and rabbits in maternally toxic doses of 120 mg/kg in mice, or higher in rats and 75 mg/kg in rabbits, but was not teratogenic at these dose levels. No harm to the foetus due to tramadol was seen at doses that were not maternally toxic.
No drug-related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol (75 mg/kg for rats or 175 mg/kg for rabbits). Embryo and foetal toxicity consisted primarily of decreased foetal weights, skeletal ossification and increased
Uncommon: orthostatic dysregulation (postural hypotension, tendency to collapse and cardiovascular collapse)
Respiratory, thoracic and mediastinal disorders Rare: dyspnoea, respiratory depression (when the recommended doses are considerably exceeded and other respiratory depressant substances are administered concomitantly) Very rare : worsening of asthma (causality not established)
Not known: Hiccups, Central sleep apnoea syndrome
Gastrointestinal disorders Very common : nausea Common : vomiting, constipation, dry mouth Uncommon : dyspepsia, diarrhoea, abdominal pain, flatulence, urge to vomit
Metabolism and nutrition disorders Rare: changes in appetite
Cases of hyponatremia have been reported in literature.
Hepatobiliary disorders: Very rare: elevated liver enzymes
Nervous system disorders Very common : dizziness Common : autonomic nervous effects (mainly dry mouth, perspiration), headache sedation, asthenia, Uncommon : trembling Rare : speech disorders, paraesthesia, coordination disturbance, tremor, seizures, involuntary muscle contractions, syncope Not known : serotonin syndrome
Psychiatric disorders Rare: hallucinations, confusional state, sleep disturbance, delirium, anxiety, nightmares, changes in mood (usually euphoric mood, occasionally dysphoria), changes in activity (usually suppression, occasionally increase), changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders) physical dependence, withdrawal syndrome (see section 4.4 Special Warnings and Precautions for Use – Tolerance, dependence and withdrawal and ceasing opioids )
Musculoskeletal and connective tissue disorders Rare: motor system weakness
General disorders and administration site conditions: Common: fatigue
Endocrine Very rare: Syndrome of inappropriate antidiuretic hormone secretion characterised by hyponatraemia secondary to decreased free-water excretion
Cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in literature.
Skin and subcutaneous tissue disorders Common : sweating Uncommon : skin reactions, pruritus, rash
Immune system disorders Rare: shock reactions, anaphylaxis, allergic reactions
Renal and urinary disorders Rare : micturition disorders (difficulty in passing urine and urinary retention), dysuria
Eye disorders Rare: miosis, mydriasis, visual disturbance (blurred vision)
The incidence of “non-specific CNS irritation” (dizziness), “autonomic nervous effects” (perspiration), “orthostatic dysregulation (tendency to collapse and cardiovascular collapse) and tachycardia and “nausea/urge to vomit/vomiting” can be increased with rapid intravenous administration and also tends to be dose dependent. No tests of significance have been performed.
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 asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/
4.9 Overdose
Symptoms Symptoms of overdosage with tramadol are similar to those of other centrally acting analgesics (opioids) and include miosis, vomiting, cardiovascular collapse, consciousness disorders including coma, convulsions, respiratory depression and respiratory arrest. Serotonin syndrome has also been reported.
Treatment Should overdosage occur, general emergency measures should be implemented. Keep the respiratory airways open, and maintain respiration and circulation. If overdosage is due to ingestion of an oral dose form.
Activated charcoal may reduce absorption of the drug if given within 1-2 hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Naloxone will reverse respiratory depression, but not all symptoms caused by overdosage with tramadol. Convulsions occurring in mice following the administration of toxic doses of tramadol could be suppressed with barbiturates or benzodiazepines, but were increased with naloxone. If convulsions are observed, diazepam should be given intravenously. Naloxone did not change the lethality of an overdose in mice.
Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of overdosage with tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification.
Oral administration of tramadol with food does not significantly affect its rate or extent of absorption. Therefore tramadol can be administered without regard to food.
After repeated oral administration of 50 mg and 100 mg tramadol capsules at six hourly intervals, steady state is reached 30 to 36 hours after the first administration and the bioavailability is greater than 90%. The plasma concentrations at steady state exceeded by 52% and 36% those extrapolated from the single dose administration studies with 50 mg and 100 mg capsules, respectively. This can be explained by first pass metabolic saturation.
After intramuscular injection of 50mg tramadol, the bioavailability is approximately 100%, and the peak serum level is attained after 45 minutes (range 15 to 90).
After oral administration of Tramal®^ SR, more than 90% of tramadol is absorbed. After a single dose, the mean absolute bioavailability is approximately 70%, irrespective of the concomitant intake of food. Oral bioavailability increases to 90% after repeated administration. The difference between absorbed and bioavailable tramadol is due to first- pass metabolism (maximum of 30%). The administration of Tramal®^ SR every 12 hours and Tramal®^ (immediate release) every 6 hours at the same daily dose, resulted in similar peak and trough serum tramadol concentrations and total tramadol exposure for the two preparations.
Serum tramadol concentrations in young males treated with Tramal ®^ SR (mean ± sd) Single Dose 100 mg 200 mg
Steady State 100 mg q12 h 200 mg q12 h Peak (ng/mL) 142 ± 40 260 ± 113 293 ± 113 579 ± 149 Time to peak (h) 4.9 ± 0.8 4.8 ± 0.8 3.5 ± 1 3.9 ± 1. Trough (ng/mL) - - 156 ± 87 265 ± 67
Distribution Tramadol is rapidly distributed in the body, with a volume of distribution of 2 – 3 L/kg in young adults. The volume of distribution is reduced by about 25% in those aged over 75 years. Plasma protein binding is about 20% and is independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Tramadol crosses the placental and blood-brain barriers. Very small amounts of tramadol and M1 are found in breast milk (0.1% and 0.02% respectively of the administered dose).
Metabolism Tramadol is extensively metabolised after oral administration. The major metabolic pathways appear to be N - and O -demethylation and glucuronidation or sulfation in the liver. Only O -desmethyltramadol (M1) is pharmacologically active. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P450. Patients who metabolise drugs poorly via CYP2D6 may obtain reduced benefit from tramadol, due to reduced formation of M1. N -demethylation is catalysed by the CYP3A4 isoenzyme of cytochrome P450. The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite.
Excretion Tramadol and its metabolites are excreted mainly by the kidneys, with a cumulative renal excretion (tramadol and metabolites) of approximately 95%. In young adults approximately
15 – 19% of an administered dose of tramadol is excreted in the urine as unmetabolised drug. In the elderly, this increases to about 35%. Biliary excretion is of little importance. In young adults, the half-life of tramadol is 5 – 7 h and the half-life of M1 is 6 – 8 h. Total clearance is approximately 430 – 610 mL/min.
Pharmacokinetics in patients with hepatic or renal impairment Elimination of tramadol and M1 is impaired in patients with hepatic or renal impairment (see section 4.4 Special warnings and precautions for use ). In patients with hepatic impairment, the mean half-life of tramadol was found to be 13 h (range up to 19 h), and the mean half-life of M1 was 19 h (range up to 36 h). In patients with renal impairment including subjects with considerably decreased CL (^) Cr [< 5mL/min] the mean half-life of tramadol was 11 h (range up to 20 h), and the mean half-life of M1 was 17 h (range up to 43 h).
Pharmacokinetics in the elderly In the elderly (age over 75 years), the volume of distribution of tramadol is decreased by 25% and clearance is decreased by 40%. As a result, tramadol Cmax and total exposure are increased by 30% and 50%, respectively, but the half-life of tramadol is only slightly prolonged (by 15%).
5.3 Preclinical safety data
Carcinogenesis, mutagenesis and impairment of fertility Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the presence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamster cells, and bone marrow micronucleus tests in mice and Chinese hamster cells. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus tests in rat cells. Overall, the weight of evidence from these tests indicates tramadol does not possess a genotoxic risk to humans.
A slight, but statistically significant increase in two common murine tumours (pulmonary and hepatic) was observed in a mouse carcinogenicity study, particularly in aged mice dosed orally up to 30 mg/kg for approximately two years. Although the study was not conducted using the Maximum Tolerated Dose, or at exposure levels expected in clinical use, this finding is not believed to suggest risk in humans. No such findings occurred in a rat carcinogenicity study.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tramal®^ 50 mg capsules: Excipients include: cellulose-microcrystalline, magnesium stearate, sodium starch glycollate, silica-colloidal anhydrous. Excipients in the capsule shell are: iron oxide yellow (CI 77492), titanium dioxide (CI 173015), sodium lauryl sulphate and gelatine.
Tramal®^ 50 mg and 100 mg injections: Excipients are: sodium acetate, Water for Injections.
Tramal®^ SR sustained release tablets: Excipients are: hypromellose10 5 mPa.s, silica-colloidal anhydrous, magnesium stearate, microcrystalline cellulose. Excipients in the film coat are: hypromellose 6 mPa.s, lactose monohydrate, macrogol 6000, propylene glycol, purified talc, titanium dioxide, quinoline
7. MEDICINE SCHEDULE
Prescription-only Medicine
8. SPONSOR
Seqirus (NZ) Ltd PO Box 62 590 Greenlane, Auckland 1546 New Zealand Telephone: 0800 502 757
9. DATE OF FIRST APPROVAL
Tramal®^ capsules – 25/9/ Tramal®^ solution for injection – 25/9/ Tramal®^ SR 50mg – 2/11/ Tramal®^ SR 100 mg – 2/3/ Tramal®^ SR 150mg – 2/3/ Tramal®^ SR 200 mg – 2/3/
10. DATE OF REVISION OF THE TEXT
23 February 2022
Tramal®^ is a registered trademark of Grunenthal GmbH used by Seqirus as authorised user.
SUMMARY TABLE OF CHANGES Section changed Summary of new information Boxed warning added 3 Spelling and punctuation amended 4.2 Text amended to include detail on compatibility 4.4 Text amended consistent with the Australian Product Information and Medsafe requested warnings 4.5 Text amended consistent with the Australian Product Information and Medsafe requested warnings 4.6 Text added that tramadol crosses the placenta 4.7 Text on driving and using machinery added 4.8 Text amended to add and remove adverse effects 4.9 Text amended consistent with the Australian Product Information 6.1 Text amended to add lactose as an excipient of known effect
