Consumer medicine information

Tramal Capsules and Injections

Tramadol hydrochloride

BRAND INFORMATION

Brand name

Tramal

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tramal Capsules and Injections.

What is in this leaflet

This leaflet answers some common questions about TRAMAL®. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TRAMAL® against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet.

You may need to read it again.

What TRAMAL® is used for

TRAMAL® is used to relieve moderate to severe pain and belongs to a group of medicines called analgesics (pain relievers).

Your doctor may have prescribed TRAMAL® for another reason. Ask your doctor why TRAMAL® has been prescribed for you.

This medicine is available only with a doctor’s prescription.

TRAMAL® is not normally addictive although some cases have been reported.

Before you use TRAMAL®

When you must not use it

Do not use TRAMAL® if:

  • you have a known allergy to TRAMAL® or any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include skin rash, itching, difficulty breathing and swelling of the face (including lips, tongue, throat etc)
  • you are taking medicine for depression containing a "monoamine oxidase inhibitor" (such as Nardil®, Parnate®), or have taken one within the past two weeks.

Do not use TRAMAL® after the expiry date printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

Do not use TRAMAL® if the packaging is torn or shows signs of tampering.

Do not give TRAMAL® to children. There is no experience with the use of TRAMAL® in children.

If you are not sure whether you should be using TRAMAL®, talk to your doctor.

Before you use it

You must tell your doctor if:

  1. you have a known allergy to TRAMAL® or any of the ingredients listed at the end of this leaflet.
  2. you are known to be sensitive to opioids.
  3. you drink alcohol every day.
  4. you have or ever had any other health problems, including:
  • any lung or breathing problems
  • sleep-related breathing disorders
  • any diseases of the kidney, liver or pancreas
  • severe stomach problems
  • a serious head injury
  • any fits or convulsions/ epilepsy.
  1. you have or have had any problems with drug or alcohol dependence.
  2. you are pregnant or intend to become pregnant. TRAMAL® is not recommended for use during pregnancy. Talk to your doctor about the risks and benefits of using TRAMAL® during pregnancy.
  3. you are breast-feeding or plan to breast-feed.TRAMAL® is not recommended for use during breast-feeding. Talk to your doctor about the risks and benefits of using TRAMAL® when breast- feeding.

If you have not told your doctor about any of the above, tell them before you use TRAMAL®.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may interfere with TRAMAL®. These include:

  • carbamazepine (eg. Tegretol®)
  • coumarin derivatives (eg.warfarin: Some brand names are Coumadin®, or Marevan®)
  • coumarin medicine for irregular or rapid heart beat
  • medicines for depression, sleeplessness or mental conditions such as selective serotonin reuptake inhibitors (SSRI’s), serotonin-noradrenaline reuptake inhibitors (SNRI’s), tricyclic anti-depressants, quinidine, phenothiazines or anti-psychotics
  • some antibiotics.

These medicines may be affected by TRAMAL®, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Other interactions not listed above may also occur.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking TRAMAL®.

How TRAMAL® is used

TRAMAL® is available as capsules (to swallow) and injections (to be given into a vein or muscle).

Your doctor will decide:

  • how you will receive TRAMAL®;
  • what dose; and
  • for how long.

TRAMAL® Injections

If you have been prescribed TRAMAL® injections, your doctor or nurse will administer them for you. Take them with you when you visit your doctor. TRAMAL® injections can be injected into a vein or a muscle.

TRAMAL® Capsules

How much to take

For moderate pain, one TRAMAL® capsule may be enough for the first dose, followed by one or two capsules two or three times a day as required.

For moderate to severe pain, two TRAMAL® capsules are usually required for the first dose, followed by one or two capsules every four to six hours as required.

Patients over 75 years of age may require a lower daily dose.

Do not take more than eight TRAMAL® capsules per day.

Follow carefully all directions given to you by your doctor and pharmacist.

These directions may differ from the information in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How to take it

TRAMAL® capsules should be swallowed whole, with water.

When to take it

You can take TRAMAL® before, with, or after food.

How long to take it

Depending on the medical condition for which you require TRAMAL®, your doctor may tell you to take it for only a day or two or longer, up to a few months or more.

If you forget to take it

If you forget to take a dose, you can take it as soon as you remember. The next dose should be taken after four or six hours, or as prescribed by your doctor.

Do not take a double dose to make up for the dose that you missed.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (tel: 131 126) or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much TRAMAL®. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too many capsules, this may result in breathing difficulty and fits or convulsions.

While you are using TRAMAL®

Things you must do

If you become pregnant while you are taking TRAMAL®, tell your doctor immediately.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking TRAMAL®.

If your pain is not severe and you feel that you do not need as much TRAMAL® as your doctor ordered, consult your doctor.

Tell your doctor if your pain gets worse. Do not take extra doses without checking with your doctor.

If you have to have any tests tell your doctor you are taking TRAMAL®. TRAMAL® may affect the results of some tests.

Things you must not do

Do not give TRAMAL® to anyone else, even if they have the same condition as you.

Do not use TRAMAL® to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how TRAMAL® affects you.

TRAMAL® may make you drowsy or dizzy.

Side effects

Check with your doctor as soon as possible if you have any problems while taking TRAMAL®, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, TRAMAL® can cause side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you.

Common side effects:

  • dizziness
  • sedation, fatigue
  • headache
  • constipation
  • nausea or vomiting
  • sweating
  • dry mouth

Less common side effects:

  • indigestion
  • changes in appetite
  • skin reactions
  • sudden onset of low blood pressure, collapse
  • muscle weakness
  • tremor
  • seizures
  • respiratory depression
  • improvement in mood
  • confusion
  • sleep disturbance
  • blurred vision
  • difficulty in passing urine

Serotonin Syndrome: signs of this vary and are not specific: they may include sweating, agitation, muscle twitching, tremor, spontaneous muscle contraction, high body temperature. Serotonin Syndrome may result from interaction of tramadol with other medicines which increase serotonin effects, for example, the SSRI antidepressants.

Tell your doctor immediately if you experience any of the following side-effects, as urgent medical treatment may be required:

  • skin rash (red spots or patches), itching, hives, skin lumps
  • swelling or puffiness of the eyelids, face or lips
  • chest tightness, wheezing or pain in the chest
  • heart palpitations, faintness or collapse
  • hallucinations
  • convulsions.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Can TRAMAL® be addictive?

When used as prescribed by your doctor, addiction to TRAMAL® is unlikely.

If you are taking TRAMAL® for a prolonged period of time, your body may become used to the medicine and mild withdrawal symptoms may occur if you suddenly stop taking the medicine.

It is important therefore to take TRAMAL® only as directed by your doctor, and do not suddenly stop taking it. Your dosage may need to be gradually reduced.

After using TRAMAL®

Storage

Keep your TRAMAL® in the pack until it is time to take them. If you take TRAMAL® out of the pack it may not keep well.

Keep it in a cool dry place where the temperature stays below 30°C. Do not store it in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least 1½ metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking TRAMAL® or it passes its expiry date, ask your pharmacist what to do with any TRAMAL® that is left over.

TRAMAL® description

What it looks like

TRAMAL® is available as capsules or injections.

Capsules:
Each capsule is - yellow in colour. They are available in packs of 10, 20, 30 or 50 capsules.

Injections:
Clear liquid contained in 1mL or 2mL glass ampoules. Available in packs of 5 ampoules.

Ingredients

Active ingredient:

TRAMAL® capsules:
contain 50 mg tramadol hydrochloride per capsule.

TRAMAL® injections:
contain tramadol hydrochloride either:

  • 50 mg in 1 mL ampoules or
  • 100 mg in 2 mL ampoules

Inactive ingredients:

TRAMAL® capsules:

  • cellulose-microcrystalline
  • magnesium stearate
  • sodium starch glycollate
  • silica-colloidal anhydrous
  • iron oxide yellow (CI 77492)
  • titanium dioxide
  • gelatin
  • Sodium lauryl sulphate

TRAMAL® injections:

  • sodium acetate
  • water for injections.

TRAMAL® capsules and injections do not contain lactose, sucrose, tartrazine or any other azo dyes.

Manufacturer/Sponsor

TRAMAL® is made in Germany and supplied in Australia by:

Seqirus Pty Ltd
ABN 26 160 735 035
63 Poplar Road
Parkville 3052 Victoria
AUSTRALIA

Date of Preparation of this Information:

August 2015

Date of Update of this Information:

30 June 2020

The Australian registration numbers are:

Injections 50mg/mL:
AUST R 64009

Injections 100mg/2mL:
AUST R 64010

Capsules 50mg:
AUST R 64011

TRAMAL® is a registered trademark of Grunenthal GmbH used by Seqirus as authorised user.

Published by MIMS August 2020

BRAND INFORMATION

Brand name

Tramal

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

1 Name of Medicine

Tramadol hydrochloride.

2 Qualitative and Quantitative Composition

Tramal (tramadol hydrochloride) immediate release capsules 50 mg.
Tramal (tramadol hydrochloride) solution for injection 50 mg/mL, 100 mg/2 mL.
Tramal SR (tramadol hydrochloride) sustained release tablets 50 mg, 100 mg, 150 mg and 200 mg.
Tramal oral drops (tramadol hydrochloride) immediate release, solution 100 mg/mL.
The composition of the Tramal capsules, Tramal solution for injection, Tramal SR tablets and Tramal oral drops are as follows:

Tramal 50 mg capsules.

Contain tramadol hydrochloride 50 mg. Excipients in Tramal capsules are: microcrystalline cellulose, magnesium stearate, sodium starch glycollate, anhydrous colloidal silica. Excipients in the capsule shell are: iron oxide yellow, titanium dioxide, gelatin, sodium lauryl sulphate.

Tramal 50 and 100 solution for injection.

Contain tramadol hydrochloride 50 mg/mL. Excipients are: sodium acetate, water for injections.

Tramal SR sustained release tablets.

Contain tramadol hydrochloride in the following dose strengths: 50, 100, 150 and 200 mg. Excipients are: hypromellose 105 mPa.s, anhydrous colloidal silica, 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 yellow aluminium lake (150 and 200 mg tablets only), iron oxide red (150 and 200 mg tablets only), iron oxide yellow (50 and 200 mg tablets only) and iron oxide black (200 mg tablet only).

Tramal oral drops 100 mg/mL.

Contain tramadol hydrochloride 100 mg/mL. The excipients in the oral drops include potassium sorbate, glycerol, propylene glycol, sucrose, sodium cyclamate, saccharin sodium, ethoxylated hydrogenated castor oil, mint oil (partly dementholised), aniseed flavour (87122), and purified water.

3 Pharmaceutical Form

Tramal 50 mg capsules.

Tramal 50 mg immediate release capsules is supplied as oblong, yellow/yellow, shiny hard gelatine capsules size 4.

Tramal 50 and 100 solution for injection.

Tramal 50 and Tramal 100 solution for injection are supplied as clear, colourless solution.

Tramal SR sustained release tablets.

Tramal SR 50 mg sustained release tablets are supplied as 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.

Tramal oral drops 100 mg/mL.

Tramal oral drops solution is supplied as clear, colourless to weakly yellow slightly viscous liquid, free from visible impurities.

4 Clinical Particulars

4.1 Therapeutic Indications

Tramal capsules, solution for injection and oral drops.

Tramal capsules, solution for injection and oral drops are indicated for the short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.

Tramal SR sustained release tablets.

Tramal SR is indicated for the management of severe pain where:
other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain, and
the pain is opioid-responsive, and
requires daily, continuous, long term treatment.
Tramal SR is not indicated for use in chronic non-cancer pain other than in exceptional circumstances.
Tramal SR is not indicated as an as-needed (PRN) analgesia.

4.2 Dose and Method of Administration

The dose of tramadol should be titrated according to the severity of the pain and the clinical response of the individual patient. Tramadol is approved for use in adults and adolescents over the age of 12 years. Tramal is contraindicated in all children younger than 12 years of age and in postoperative management of children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
The recommended dosage of Tramal capsules, Tramal solution for injection, Tramal SR tablets and Tramal oral drops, respectively, are as follows:

Tramal capsules.

Oral administration.

50 - 100 mg administered two or three times daily may be sufficient. Tramal 50 mg may be adequate as the initial dose for less severe pain. Otherwise, 50 - 100 mg as needed for relief, every four to six hours may be administered. For more severe pain, an initial dose of 100 mg is usually more effective.
The maximum daily dose should not exceed 400 mg per day.

Tramal solution for injection.

Parenteral administration.

Tramal injection may be administered by intravenous or intramuscular injection. Few data are available on the administration of Tramal by repeated intramuscular injection. Intravenous injections should be given slowly over 2-3 minutes.
For postoperative pain, an initial bolus of 100 mg should be administered.
Subsequent doses of 50 mg or 100 mg every four to six hours may be given, up to a total daily dose of 600 mg.
For less severe pain: 50 mg or 100 mg every four to six hours to a maximum of 400 mg per day.

Tramal SR tablets.

Oral administration.

The recommended dose of Tramal SR in adults and adolescents over the age of 12 years is 100 to 200 mg twice daily, preferably morning and evening.
For initial titration therapy, a lower starting dose may be appropriate for some patients.
The tablets are to be taken whole, not divided or chewed, with sufficient liquid, irrespective of food intake.
The maximum daily dose should not exceed 400 mg per day.

Tramal oral drops.

Tramal is contraindicated in all children younger than 12 years of age and in postoperative management of children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

Oral administration.

The recommended dose of Tramal oral drops in adults and adolescents over the age of 12 years is a single dose of 20 drops of Tramal oral drops (see Table 1). This provides 50 mg of tramadol hydrochloride. If there is no pain relief after 30 to 60 minutes, a second dose of 20 drops of Tramal oral drops can be taken. Depending on the pain, the analgesic effect lasts for 4 to 6 hours.
For more severe pain, the recommended dose of Tramal oral drops in adults and adolescents over the age of 12 years is a single dose of 40 drops of Tramal oral drops. This provides 100 mg of tramadol hydrochloride.
The maximum daily dose should not exceed a total of 160 drops (that is 8 x 20 drops or 4 x 40 drops). This maximum daily dose provides 400 mg tramadol hydrochloride.

Renal insufficiency.

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. Since only 7% of an administered dose is removed by haemodialysis, dialysis patients can receive their regular dose on the day of dialysis (see Section 4.4 Special Warnings and Precautions for Use).

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 impairment and individual clinical response, the recommended dosage interval (4 to 6 hours) may require to be extended, and/or the dose level titrated as required (see Section 4.4 Special Warnings and Precautions for Use).

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%.

4.3 Contraindications

Tramadol is contraindicated in:
individuals with known hypersensitivity to tramadol or any excipients;
acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs;
patients with severe respiratory disease, acute respiratory disease and respiratory depression;
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 receiving MAO inhibitors or who have taken them within the last 14 days;
known sensitivity 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; 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.

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 4.4 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 4.3 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).
When large doses of tramadol are administered with anaesthetic medications or alcohol, respiratory depression may result. Cases of intra-operative respiratory depression, usually with large intravenous doses of tramadol and with concurrent administration of respiratory depressants, have been reported.

Sleep-related breathing disorders.

Drugs with mu-opioid receptor agonist activity, such as tramadol, 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 in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient’s condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid. Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
Symptoms of withdrawal reactions from tramadol hydrochloride are similar to those occurring during opiate withdrawal and may include: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor, pyrexia, myalgia, chills and gastrointestinal symptoms. Other symptoms that have very rarely been seen with tramadol discontinuation include panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, personalization, derealization, paranoia).
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; see 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 tramadol hydrochloride. Patients and their caregivers should be given information on safe storage and disposal of unused Tramal (see Section 6.4 Special Precautions for Storage; 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.

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 consult a physician before use.

Fructose intolerance.

Tramal oral drops contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency 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, 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 Interactions with Other Medicines and Other Forms of Interactions). 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 planes 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 continuous, potent (volatile or intravenous) anaesthetic agent is followed, tramadol may be used intra-operatively in the same way as other analgesic agents are routinely used.

Long-term use.

Tramadol has been studied in controlled clinical trials for periods of up to three months. In one small uncontrolled study, patients with cancer pain received a dose of 150 mg tramadol per day for up to six months. Beyond six months no clinical studies investigating the safety and efficacy of tramadol are available. When tramadol treatment of pain is required long-term, careful and regular monitoring should be carried out to establish whether, and to what extent, ongoing treatment is necessary.

CYP2D6 metabolism.

Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses.
General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, miosis, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised in Table 2:

Renal and hepatic disease.

With the prolonged half-life in these conditions, achievement of steady state is delayed, so that it may take several days for elevated plasma concentrations to develop (see Use in hepatic impairment, Use in renal impairment).

Use in hepatic impairment.

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosage reduction is recommended (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

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 only 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; Section 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 (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The use of tramadol hydrochloride is contraindicated in all children younger than 12 years of age and in postoperative management of children younger than 18 years of age following tonsillectomy and/or adenoidectomy.

Post-operative use in children.

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.
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.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Use with 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, tranquillisers, sedative, hypnotics, benzodiazepines, gabapentinoids, cannabis, tricyclic antidepressants, antipsychotics, antihistamines and centrally-active anti-emetics (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants including alcohol).
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 reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see Section 4.3 Contraindications), tricyclics antidepressants and mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely when one of the following is observed:
spontaneous clonus;
inducible or ocular clonus with agitation or diaphoresis;
tremor and hyper-reflexia;
hypertonia and body temperature > 38°C and inducible or ocular clonus.
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 reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold lowering drugs (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 serum 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 postoperative application of the antiemetic 5HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effects on fertility in rats were observed for tramadol at oral dose levels of up to 50 mg/kg/day.
(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 at 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 supernumerary ribs at maternally toxic dose levels. Transient delays in development or behavioural parameters were also seen in pups from rat dams allowed to deliver. Embryo and foetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit.
In peri- and postnatal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg had decreased weights and pup survival was decreased early in lactation at 80 mg/kg (6-10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels.

Labour and delivery.

Tramadol should not be used in pregnant women prior to or during labour unless the potential benefits outweigh the risks, because safe use in pregnancy has not been established. Chronic use during pregnancy may lead to neonatal withdrawal symptoms. If tramadol were to be used during labour, it may cause respiratory depression in the newborn. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour.
The effect of tramadol, if any, on the later growth, development and functional maturation of the child is unknown.
Tramadol is not recommended during breastfeeding, because its safety in infants and newborns has not been studied. Low levels of tramadol have been detected in breast milk. Following a single intravenous 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 microgram of tramadol (0.1% of the maternal dose) and 27 microgram of M1.

4.7 Effects on Ability to Drive and Use Machines

Due to its sedative effect, patients should be advised to avoid driving or operating machinery whilst taking tramadol.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions that may occur after administration of tramadol resemble those known to occur with opioids. Adverse reactions were recorded in 13,802 patients from trials with different formulations of tramadol. The nature and incidence of reactions (in CIOMS format where very common ≥ 1/10; common ≥ 1/100 and < 1/10; uncommon ≥ 1/1,000 and < 1/100; rare ≥ 1/10,000 and < 1/1,000; and very rare < 1/10,000) were as follows:

Immune system disorders.

Rare: shock reactions, anaphylaxis, allergic reactions.

Endocrine disorders.

Very rare: syndrome of inappropriate antidiuretic hormone secretion characterised by hyponatraemia secondary to decreased free water excretion.

Metabolism and nutrition disorders.

Rare: changes in appetite.

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).

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.

Eye disorders.

Rare: miosis, mydriasis, visual disturbance (blurred vision).

Cardiac disorders.

Uncommon: tachycardia, flushing.
Rare: bradycardia.

Vascular disorders.

Uncommon: orthostatic dysregulation (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).

Gastrointestinal disorders.

Very common: nausea.
Common: vomiting, constipation.
Uncommon: dyspepsia, diarrhoea, abdominal pain, flatulence, urge to vomit.

Hepatobiliary disorders.

Very rare: elevated liver enzymes.

Skin and subcutaneous tissue disorders.

Common: sweating.
Uncommon: skin reactions, pruritus, rash.

Musculoskeletal and connective tissue disorders.

Rare: motor system weakness.

Renal and urinary disorders.

Rare: micturition disorders (difficulty in passing urine and urinary retention), dysuria.

General disorders and administration site conditions.

Common: fatigue.

Investigations.

Rare: increase in blood pressure.
The incidence of "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 suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

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.

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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Tramadol is a centrally acting synthetic analgesic of the aminocyclohexanol group with opioid-like effects. It is not derived from natural sources, nor is it chemically related to opiates. Although preclinical testing has not completely explained the mode of action, at least two complementary mechanisms appear applicable: binding to mu-opioid receptors and inhibition of reuptake of noradrenaline and serotonin. The opioid-like activity of tramadol derives from low affinity binding of the parent compound to mu-opioid receptors and higher affinity binding of the principal active metabolite, mono O-desmethyltramadol, denoted M1, to mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding. The contribution of tramadol to human analgesia, relative to M1, is unknown.
Both human and animal studies have shown that antinociception induced by tramadol is only partially antagonised by the opiate antagonist naloxone. In addition, tramadol has been shown to inhibit reuptake of noradrenaline and serotonin in vitro, as have some other opioid analgesics. These latter mechanisms may contribute independently to the overall analgesic profile of tramadol.
The analgesic effect is dose dependent, but the relationship between serum concentrations and analgesic effect varies considerably between individuals. In one study, the median serum concentration of tramadol required for effective postoperative analgesia was 300 nanogram/mL, with individual values ranging from 20 to 990 nanogram/mL.
Apart from analgesia, tramadol may produce other symptoms similar to that of opioids including: dizziness, somnolence, nausea, constipation, sweating and pruritus. However, tramadol causes significantly less respiratory depression than morphine. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no clinically significant effect on heart rate, left ventricular function or cardiac index. Orthostatic changes in blood pressure have been observed.
Part of the activity of tramadol is thought to be derived from its active metabolite, which is responsible for some delay in onset of activity and some extension of the duration of mu-opioid activity. Delayed mu-opioid activity is believed to reduce a drug’s abuse liability.
Tolerance development has been reported to be relatively mild.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Tramadol is administered as a mixture of two stereoisomers; the following information refers to the combined concentration of both isomers.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.

Absorption.

Tramadol is rapidly and almost completely absorbed after oral administration of 50 mg capsules following a mean absorption delay (t0) of approximately 30 minutes. The absorption half-life (t1/2) is 23 ± 11 minutes.
After oral administration of two 50 mg capsules, the mean absolute bioavailability (fabs) is 68-72% and the peak serum level (Cmax) is reached two hours (range one to three) after administration. The mean peak plasma concentration (Cmax) is approximately 280 nanogram/mL after oral administration of two capsules. At this time, the mean serum concentration after intravenous injection is 1.46 times higher, amounting to approximately 410 nanogram/mL. 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 50 mg 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 30%).
The administration of Tramal SR every 12 hours and Tramal (immediate release) every 6 hours at the same total daily dose resulted in similar peak and trough serum tramadol concentrations and total tramadol exposure for the two preparations. See Table 3.

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 microgram/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Tramadol crosses both the placenta and the blood brain barrier. 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 a considerably decreased ClCr [< 5 mL/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%) (see Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

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 mouse and Chinese hamster cells. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and the micronucleus tests in rat cells. Overall, the weight of evidence from these tests indicates tramadol does not possess a genotoxic risk to humans.

Carcinogenicity.

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

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Tramal solution for injection is incompatible with injection solutions containing diclofenac, indomethacin, phenylbutazone, diazepam, flunitrazepam, glyceryl trinitrate or midazolam.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tramal capsules, Tramal solution for injection, Tramal SR 50, 100, 150 and 200 tablets and Tramal oral drops should be stored below 30°C.
Tramal oral drops - discard 12 months after opening.

6.5 Nature and Contents of Container

Tramal 50 mg capsules.

Tramal 50 mg immediate release capsules are packed in PVC/PVDC/Al or PVC/PE/PVDC/Al blister packs of 6, 10, 20, 30 and 50 capsules.

Tramal 50 and 100 solution for injection.

Tramal 50, solution for injection are packed in Type 1 clear glass ampoule pack containing 5 ampoules of 1 mL each.
Tramal 100, solution for injection are packed in Type 1 clear glass ampoule pack containing 5 ampoules of 2 mL each.

Tramal SR sustained release tablets.

Tramal SR 50 mg, 100 mg, 150 mg and 200 mg sustained release tablets are packed in PVC/PVDC/Al or PP/Al blister.
Tramal SR 50 mg, 100 mg are available in pack size of 4, 20 and 60 tablets.
Tramal SR 150 mg and 200 mg are available in pack size of 20 and 60 tablets.

Tramal oral drops 100 mg/mL.

Tramal oral drops, solution are available in bottle sizes of 10 mL with dropper device.
Tramal oral drops, solution are packed in amber Type III glass bottle with PP child-resistant cap with a dropper.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Tramal capsules, Tramal solution for injection, Tramal SR tablets and Tramal oral drops contain tramadol hydrochloride which is (1RS, 2RS)-2- [(dimethylamino)methyl]-1- (3-methoxyphenyl) cyclohexanol hydrochloride, with the formula: C16H25NO2.HCl. MW = 299.84.
Tramadol hydrochloride is an odourless, white to off white crystalline powder that is readily soluble in both water and methanol 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.

Chemical structure.


CAS number.

The CAS registry number is 36282-47-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes