Consumer medicine information

Zydol SR

Tramadol hydrochloride

BRAND INFORMATION

Brand name

Zydol SR

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zydol SR.

What is in this leaflet

This leaflet answers some common questions about Zydol Sustained Release tablets. 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 Zydol SR against the benefits this medicine is expected to have for you.

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

Keep this leaflet. You may need to read it again.

What Zydol SR is used for

ZYDOL SR is used to relieve severe pain which requires daily, long term treatment. It belongs to a group of medicines called opioid analgesics (pain relievers).

ZYDOL SR tablets are designed to release active medicine gradually over several hours.

Your doctor may have prescribed ZYDOL SR for another reason. Ask your doctor why this medicine has been prescribed for you.

ZYDOL SR is available only on a doctor’s prescription.

ZYDOL SR is for use in adults and children over 12 years of age. It should not be used in children under the age of 12 years or following the removal of tonsils and/or adenoids in people under 18.

Before you use Zydol SR

When you must not use this medicine

Do not take ZYDOL SR if:

  • you have an allergy to 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 have an allergy to any other medicines known as opioid analgesics, eg. morphine or codeine
  • you have respiratory disease or slow or shallow breathing
  • you have taken large amounts of alcohol or other substances which can affect your level of consciousness. Some examples of these substances include sleeping pills, pain relievers or other psychotropic medicines (medicines that affect mood and emotions)
  • you are taking medicine for depression containing a “monoamine oxidase inhibitor” also known as MAOI, or have taken any within the past two weeks. Examples of MAOI-containing medicines are Nardil®, Parnate®
  • you have uncontrolled epilepsy or if your epilepsy is not well controlled by treatment
  • you are younger than 12 years old or if You are between 12 – 18 years of age and are recovering from an operation to remove your tonsils and/or adenoids.

Do not take ZYDOL SR if the packaging is torn or shows signs of tampering.

Do not take ZYDOL SR if any tablets look damaged or discoloured.

Do not take ZYDOL SR after the expiry date which is printed on the carton box. If you take this medicine after the expiry date has passed, it may not work as well.

If it is after the expiry date, or the packaging is damaged, return it to your phamacist for disposal.

Addiction
You can become addicted to ZYDOL SR even if you take it exactly as prescribed. ZYDOL SR may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence
As with all other opioid containing products, your body may become used to you taking ZYDOL SR. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking ZYDOL SR suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance
Tolerance to ZYDOL SR may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Withdrawal
Continue taking your medicine for as long as your doctor tells you. If you stop having this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating.

Very rarely, some patients have experienced the following withdrawal reactions:

  • panic attacks
  • severe anxiety
  • hallucinations
  • tingling or numbness (pins and needles)
  • ringing in your ears
  • confusion, delusions or paranoia.

ZYDOL SR given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

You must tell your doctor if:

  • you know you are sensitive to Zydol SR or any of the ingredients listed at the end of this leaflet
  • you know you are sensitive to opioids
  • you drink alcohol
  • you have any health problems including:
    - any lung or breathing problems
    - sleep-related breathing disorders
    - fits or convulsions, or take medicines for epilepsy
    - any condition that may affect how your kidney or liver work
    - any stomach problems
    - a severe headache or feel sick due to a head injury
  • you have, or have had, any drug or alcohol dependence problems
  • you have galactose intolerance, or lactase deficiency or glucose-galactose malabsorption
  • you are pregnant or intend to become pregnant. ZYDOL SR is not recommended for use during pregnancy. ZYDOL SR can pass to your unborn baby when you are pregnant. Talk to your doctor about the risks and benefits of using ZYDOL SR during pregnancy
  • you are breast feeding or plan to breast feed. ZYDOL SR is not recommended for use during breast feeding. Talk to your doctor about the risks and benefits of using ZYDOL SR when breast-feeding

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor or pharmacist 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 ZYDOL SR.

These include:

  • carbamazepine (eg. Tegretol®)
  • coumarin derivatives (eg. Warfarin: some Brand names are Coumadin®, or Marevan®)
  • 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 ZYDOL SR, 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 ZYDOL SR.

How to take this medicine

Carefully follow all directions given to you by your doctor or pharmacist. They may differ from the information contained in this leaflet.

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

ZYDOL SR tablets should be swallowed whole with water. They maybe taken, before, with, or after food.

ZYDOL SR tablets are only designed to work properly if swallowed whole. The tablets may release all their contents at once if broken, chewed, crushed or dissolved, which can be dangerous and cause serious problems, such as an overdose which may be fatal. Unless stated otherwise, they should be swallowed whole.

How much to take

The recommended dosage of ZYDOL SR is either:

  • two ZYDOL SR 50 tablets twice a day (morning and evening)
    OR
  • one or two ZYDOL SR 100 mg tablet(s) twice a day (morning and evening)
    OR
  • one ZYDOL SR 150 mg or 200 mg tablet twice a day (morning and evening).

As all patients respond to treatment differently, your doctor may start you on a lower dose.

Do not take more than eight of the 50 mg tablets per day.

Do not take more than four of the 100 mg tablets per day

Do not take more than two of the 150 mg or of the 200 mg tablets per day.

If you are over 75 years of age, you may require a lower daily dose of ZYDOL SR compared to younger adults.

If you forget to take it

If you forget to take one dose, take the dose when you remember. The following dose should be taken after twelve hours, or as prescribed by your doctor.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

How long to take it

This differs between individuals depending on how severe your pain is, how you respond to ZYDOL SR, and the cause of your pain. Ask your doctor for advice on how long you need to take ZYDOL SR tablets.

If you take too much (overdose)

If you or someone else receive too much (overdose), and experience one or more of the symptoms below, call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally used ZYDOL SR that was prescribed for you. If someone takes an overdose they may experience one or more of the following symptoms:

  • Slow, unusual or difficult breathing
  • Drowsiness, dizziness or unconsciousness
  • Slow or weak heartbeat
  • Nausea or vomiting
  • Convulsions or fits

If you think you or someone else may have used too much ZYDOL SR, you should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

While you are using this medicine

Things you must do

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

If your pain is not as severe and you feel that you do not need to take as many Zydol SR tablets as your doctor prescribed, consult your doctor.

Tell your doctor if your pain is not helped or gets worse. Do not take increased amounts or extra doses without checking with your doctor.

Tell any other doctors, dentists, and pharmacists who treat you, that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

Keep all of your doctor’s appointments so that your progress can be checked.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they seem to have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you. This medicine may cause dizziness, light-headedness, tiredness, drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

All medicines can cause unwanted effects, and some side-effects have been reported with ZYDOL SR. Most side-effects reported with ZYDOL SR are minor and temporary. However, some may be serious and need medical attention.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

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

The most common side-effects of ZYDOL SR are:

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

The following side-effects are less common:

  • indigestion
  • hiccups
  • changes in appetite
  • skin reactions
  • sudden onset of low blood pressure, collapse
  • muscle weakness
  • tremor
  • seizures
  • respiratory depression
  • improvement of 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, spontaneous muscle contraction, tremor, high body temperature. Serotonin Syndrome may result from interaction of tramadol with other medicines which increase serotonin effects, for example, the SSRI antidepressants.
  • low blood glucose (hypoglycaemia)

This is not a complete listing.

Occasionally, other side-effects may be experienced.

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

Talk to your doctor if you experience any of the following symptoms while taking ZYDOL SR tablets.

Extreme fatigue, lack of appetite, severe abdominal pain, nausea, vomiting or low blood pressure. This may indicate that you have adrenal insufficiency (low cortisol levels).

Adrenal insufficiency is caused by failure of the adrenal glands to produce enough or any of the hormones cortisol and aldosterone.

If you have these symptoms, contact your doctor, who will decide if you need to talk hormone supplement.

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.

Storage and Disposal

Storage

Keep it in the pack until it is time to take them. If you take Zydol SR 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. Protect from light.

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 Zydol SR or it passes its expiry date, ask your pharmacist what to do with any Zydol SR that is left over.

Do not use this medicine after the expiry date.

Zydol SR description

What it looks like

50mg tablets- pale yellow round tablets imprinted with GRUNENTHAL logo on one side and engraved with “T0” on the other side.

100mg tablets- white round tablets imprinted with GRUNENTHAL logo on one side and engraved with “T1” on the other side.

150mg tablets- pale orange tablets imprinted with GRUNENTHAL logo on one side and engraved with “T2” on the other side.

200mg tablets- slightly brownish-orange coloured tablets imprinted with GRUNENTHAL logo on one side and engraved with “T3” on the other side.

All strengths are available in packs 20 or 60 tablets

Ingredients

This Active ingredient:

ZYDOL SR 50- 50 mg tramadol hydrochloride.

ZYDOL SR 100- 100 mg tramadol hydrochloride

ZYDOL SR 150- 150 mg tramadol hydrochloride

ZYDOL SR 200- 200 mg tramadol hydrochloride

Inactive ingredients:

  • hypromellose
  • colloidal anhydrous silica
  • microcrystalline cellulose
  • magnesium stearate
  • lactose monohydrate
  • macrogol 6000
  • propylene glycol
  • purified talc
  • titanium dioxide
  • quinoline yellow aluminium lake (150 and 200 mg tablets)
  • iron oxide red (150 and 200 mg tablets)
  • iron oxide yellow (50 and 200 mg tablets)
  • iron oxide black (200 mg tablets).

Sponsor

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
Australia

AUST R: 121849 Tablets 50mg
AUST R: 80724 Tablets 100mg
AUST R: 80726 Tablets 150mg
AUST R: 80725 Tablets 200mg

Zydol™ is a trademark of Grunenthal GmbH.

This leaflet was prepared in
August 2023

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Zydol SR

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

1 Name of Medicine

Tramadol hydrochloride.

2 Qualitative and Quantitative Composition

Zydol SR sustained release tablets contain tramadol hydrochloride in the following dose strengths: 50, 100, 150 and 200 mg.

Excipients with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zydol SR 50 mg tablets: Pale yellow coloured, round, biconvex, film-coated modified release tablets. Engraved on one side with "T0" and with the Grunenthal logo on the other side.
Zydol SR 100 mg tablets: White, round, biconvex, film-coated modified release tablets approximately 10 mm in diameter. Engraved on one side with "T1" and with the Grunenthal logo on the other side.
Zydol SR 150 mg tablets: Pale orange coloured, round, biconvex, film-coated modified release tablets approximately 10 mm in diameter. Engraved on one side with "T2" and with the Grunenthal logo on the other side.
Zydol SR 200 mg tablets: Slightly brownish-orange coloured, round, biconvex, film-coated modified release tablets approximately 10 mm in diameter. Engraved on one side with "T3" and with the Grunenthal logo on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Zydol 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.
Zydol SR is not indicated for use in chronic non-cancer pain other than in exceptional circumstances.
Zydol SR is not indicated as an as-needed (PRN) analgesia.

4.2 Dose and Method of Administration

The dose of Zydol SR should be titrated according to the severity of the pain and the clinical response of the individual patient. The recommended dose of Zydol 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.

Paediatric use.

Tramadol 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).

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.

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 Zydol 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.

Zydol 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).

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.

Zydol SR contains the opioid tramadol hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Tramadol 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 tramadol.
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 Zydol SR 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 tramadol, 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.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

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 Section 4.5; Section 4.8; Section 4.9).
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.

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 tramadol 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 tramadol 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 tramadol.

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 nonpharmacological 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.
When discontinuing Zydol SR 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).
Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: 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, personalisation, derealisation, paranoia).
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 tramadol, especially by children, can result in a fatal overdose of Zydol SR. Patients and their caregivers should be given information on safe storage and disposal of unused tramadol (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.

Zydol SR tablets contain 2.5 mg lactose 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, 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 an inhaled nitrous oxide/parenteral tramadol anaesthetic technique (with only intermittent administration of enflurane 'as required'), tramadol was reported to enhance intraoperative recall. Hence its use during potentially very light planes of general anaesthesia should be avoided.
Two recent studies of parenteral tramadol administration during anaesthesia comprising continuous administration of isoflurane did not show clinically significant lightening of anaesthetic depth or intraoperative recall. Therefore, providing the current practice of administering continuous, potent (volatile or intravenous) anaesthetic agent is followed, parenteral tramadol may be used intraoperatively in the same way as other analgesic agents are routinely used.

Note.

A parenteral formulation of Zydol is not available.

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.

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 or prolongation of the dosage intervals should be carefully considered according to the patient's requirements (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 Zydol prolonged-release tablets are not recommended (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
As tramadol is removed only very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually 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 1.

Adrenal insufficiency.

Opioid analgesics may occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include e.g. severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite, and weight loss.

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 4.2 Dose and Method of Administration, Use in the elderly; Section 5.2 Pharmacokinetic Properties.

Paediatric use.

The use of tramadol is contraindicated in children 12 years and under 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, sedatives, 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 and 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), tricyclic antidepressants and mirtazapine, may cause serotonin syndrome (see Section 4.4; Section 4.8).
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 medicinal products (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 post-operative 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 post-natal 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. Tramadol crosses the placenta.

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 breast feeding, 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. Even when taken according to instructions, tramadol may cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators. This applies particularly in conjunction with other psychotropic substances, particularly alcohol.

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 = > 1/1000 and < 1/100; rare = > 1/10,000 and < 1/1000; 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.
Cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in literature.

Metabolism and nutrition disorders.

Rare: changes in appetite.
Not known: hypoglycaemia.
Cases of hyponatremia have been reported in literature.

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 (eg decision behaviour, perception disorders), physical dependence, withdrawal syndrome (see Section 4.4 Special Warnings and Precautions for Use, Tolerance, dependence and withdrawal, Ceasing opioids).

Nervous system disorders.

Very common: dizziness.
Common: autonomic nervous effects (mainly dry mouth, perspiration), headache, sedation, asthenia.
Uncommon: trembling.
Rare: speech disorders, changes in mood (usually elevation, occasionally dysphoria) paraesthesia, coordination disturbance, tremor, seizures, involuntary muscle contractions, syncope.
Not known: serotonin syndrome.

Eye disorders.

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

Cardiac disorders.

Uncommon: tachycardia, flushing, palpitations.
Rare: bradycardia.

Vascular disorders.

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.

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. 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 medicine 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 its mode of action is not completely understood, from animal tests at least two complementary mechanisms appear applicable: binding to mu-opioid receptors and inhibition of re-uptake 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 re-uptake 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 post-operative 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.

More than 90% of tramadol is absorbed after oral administration of Zydol SR. 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 Zydol SR every 12 hours and Zydol (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 2.

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

The excipient composition of Zydol SR preparations is as follows: hypromellose, colloidal anhydrous silica, magnesium stearate, microcrystalline cellulose. Excipients in the film coat are: hypromellose, 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).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

Store below 30°C. Protect from light.

6.5 Nature and Contents of Container

Zydol SR 50 mg, 100 mg, 150 mg and 200 mg tablets - packs of 20 and 60.
Blister packs are made from PP/Al or PVC/PVDC/Al material.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Zydol SR preparations contain tramadol hydrochloride which is (1RS, 2RS)-2- [(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride. It belongs to the synthetic analgesics class and has opioid-like activity, 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.
The structural formula of tramadol hydrochloride is:

CAS number.

36282-47-0.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes