Consumer medicine information

Zydol

Tramadol hydrochloride

BRAND INFORMATION

Brand name

Zydol

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zydol.

SUMMARY CMI

Zydol™

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking Zydol™, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before taking this medicine.

1. Why am I taking Zydol™?

Zydol™ contains the active ingredient tramadol hydrochloride. Zydol™ is taken to relieve severe pain. For more information, see Section 1. Why am I taking Zydol™? in the full CMI.

2. What should I know before I take Zydol™?

Do not take if you have ever had an allergic reaction to tramadol hydrochloride, any other opioid or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take Zydol™? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Zydol™ and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take Zydol™?

  • Your doctor will tell you how much Zydol™ you should take. This will depend on your condition and whether you are taking other medicines.
  • Patients over 75 years of age may require a lower daily dose.
  • Swallow the capsules whole with a full glass of water.

More instructions can be found in Section 4. How do I take Zydol™? in the full CMI.

5. What should I know while taking Zydol™?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking Zydol™.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking Zydol™. It may affect other medicines used during surgery.
  • If you become pregnant or start to breastfeed while taking Zydol™, tell your doctor immediately.
  • If your pain lessens or gets worse, consult your doctor.
  • If you are about to have any blood tests, tell your doctor that you are taking Zydol™. It may affect the results of some tests.
Things you should not do
  • Do not take Zydol™ to treat any other complaints unless your doctor tells you to.
  • Do not give Zydol™ to anyone else, even if they have the same condition as you.
  • Do not stop taking Zydol™ or change the dosage without checking with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how Zydol™ affects you.
  • Zydol™ may cause dizziness, light-headedness, tiredness or drowsiness in some people.
Drinking alcohol
  • You must not drink alcohol while taking Zydol™.
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep capsules in the pack until it is time to take them. If you take the capsules out of the pack, they may not keep well. Store in a cool dry place where the temperature stays below 30°C.

For more information, see Section 5. What should I know while taking Zydol™? in the full CMI.

6. Are there any side effects?

Less serious side effects are dizziness, sedation, fatigue, drowsiness, dry mouth, headache, physical weakness or loss of strength, fatigue, nausea or vomiting, constipation, indigestion and stomach pain, flatulence and sweating.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING:

Limitations of use:

Zydol™ should only be taken when your doctor decides that other treatment options are not able to effectively manage your pain or you cannot tolerate them.

Hazardous and harmful use

Zydol™ poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor you regularly during treatment.

Life threatening respiratory depression

Zydol™ can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing) even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting Zydol™ and after a dose increase, if you are older, or have an existing problem with your lungs. Your doctor will monitor you and change the dose as appropriate.

Use of other medicines while taking Zydol™

Taking Zydol™ with other medicines that can make you feel drowsy such as sleeping tablets (e.g. benzodiazepines), other pain relievers, antihistamines, antidepressants, antipsychotics, gabapentinoids (e.g. gabapentin and pregabalin), cannabis and alcohol may result in severe drowsiness, decreased awareness, breathing problems, coma and death. Your doctor will minimise the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while taking Zydol™.



FULL CMI

Zydol™

Active ingredient: tramadol hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about taking Zydol™. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking Zydol™.

Where to find information in this leaflet:

1. Why am I taking Zydol™?
2. What should I know before I take Zydol™?
3. What if I am taking other medicines?
4. How do I take Zydol™?
5. What should I know while taking Zydol™?
6. Are there any side effects?
7. Product details

1. Why am I taking Zydol™?

Zydol™ contains the active ingredient tramadol hydrochloride. Tramadol hydrochloride belongs to the group of medicines called opioid analgesics (pain relievers).

Zydol™ is used to relieve severe pain.

Zydol™ is not normally addictive. However, rarely, addiction to tramadol hydrochloride has been reported.

Tramadol hydrochloride is for use in adults and children over 12 years of age. Zydol™ should not be used in children under 12 years of age or following the removal of tonsils and/or adenoids in people between 12 and 18 years of age.

2. What should I know before I take Zydol™?

Warnings

Addiction

You can become addicted to Zydol™ even if you take it exactly as prescribed. Zydol™ 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™. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking Zydol™ suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance

Tolerance to Zydol™ 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 Zydol™ for as long as your doctor tells you. If you stop taking Zydol™ suddenly, your pain may worsen and you may experience some or all 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™ 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
Zydol™, talk to your doctor.

Do not take Zydol™ if:

  • you are allergic to tramadol hydrochloride, or any other opioids such as morphine or codeine, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
    Some of the symptoms of an allergic reaction may include:
    - Shortness of breath.
    - Wheezing or difficulty breathing.
    - Swelling of the face, lips, tongue or other parts of the body.
    - Rash, itching or hives on the skin.
  • you have taken large amounts of alcohol or other substances which can affect your level of consciousness. Some examples of these include hypnotics (often used to treat insomnia), analgesics or opioids (used to treat pain), psychotropic drugs (medicines that may affect mood and emotions).
  • you have epilepsy which is not well controlled.
  • you have respiratory disease or slow or shallow breathing.
  • you are taking medicine for depression containing a “monoamine oxidase inhibitor” also known as MAOI, or you have taken such a medicine within the last two weeks.
  • you are younger than 12 years old or if you are between 12 and 18 years of age and are recovering from an operation to remove your tonsils and/or adenoids.

You must tell your doctor if:

  • you have known allergy to Zydol™ or any of the ingredients listed at the end of this leaflet.
  • you are known to be sensitive to opioids.
  • you drink alcohol.
  • you have or ever had any other health problems including:
    - any lung or breathing problems
    - sleep-related breathing disorders
    - any conditions that may affect how you kidney or liver work
    - any stomach problems
    - a severe headache or feeling sick due to a head injury
    - any fits or convulsions or take medicine for epilepsy.
  • you are pregnant or intend to become pregnant.
    Zydol™ is not recommended during pregnancy. Zydol™can pass to your unborn baby when you are pregnant. Talk to your doctor about the risks and benefits of using Zydol™ during pregnancy.
  • you are breastfeeding or plan to breastfeed.
    Zydol™ is not recommended for use during breastfeeding. Talk to your doctor about the risks and benefits of taking Zydol™ when breastfeeding.

If you have not told your doctor about any of the above, tell them before you take Zydol™.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Zydol™ is not recommended for use during pregnancy. Your doctor can discuss with you the risks and benefits involved.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Zydol™ is not recommended for use during breastfeeding. Your doctor can discuss with you the risks and benefits involved.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Zydol™ and affect how it works. These include:

  • Certain medicines used to treat depression, sleeplessness or mental conditions (such as MAOIs, selective serotonin reuptake inhibitors (SSRIs), tricyclic anti-depressants, phenothiazines or anti-psychotics).
  • CNS depressants (such as alcohol, opioids, tranquillisers or sedative hypnotics).
  • Carbamazepine, a medicine mainly used to treat epilepsy.
  • Coumarin derivatives (such as warfarin).
  • Medicine for irregular or rapid heartbeat.
  • Ondansetron, a medicine used to treat nausea and vomiting.
  • Some antibiotics.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Zydol™.

4. How do I take Zydol™?

How much to take

Your doctor will tell you how many Zydol™ capsules you should take. This will depend on your condition and whether you are taking any other medicines.

An initial dose of one Zydol™ capsule may provide sufficient pain relief, followed by one or two capsules two or three times a day as required.

For more severe pain, two Zydol™ 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 Zydol™ 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 Zydol™

Swallow the capsules with a full glass of water.

When to take Zydol™

Take Zydol™ at the same time each day.

Taking Zydol™ at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take Zydol™ before, with or after food.

How long to take Zydol™

This differs between individuals depending on how severe your pain is, how you respond to this medicine and the cause of your pain. Ask your doctor for advice on how long you need to take Zydol™.

Continue taking Zydol™ for as long as your doctor tells you.

Make sure you have enough to last over weekends and holidays.

If you forget to use Zydol™

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. 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.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much Zydol™

If you think that you have taken too much Zydol™, you may need urgent medical attention.

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.

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.

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

5. What should I know while taking Zydol™?

Things you should do

If you are about to start on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

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

If your pain is not as severe and you feel that you do not need as many Zydol™ capsules as your doctor prescribed, consult your doctor.

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

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 become pregnant or start to breastfeed while taking this medicine, tell your doctor immediately.

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 your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you should not do

Do not take Zydol™ to treat any other complaints unless your doctor tells you to.

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

Do not stop taking Zydol™ or change the dosage without checking with your doctor.

If you are taking Zydol™ 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Zydol™ affects you.

Zydol™ may cause dizziness, lightheadedness, 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.

Drinking alcohol

Tell your doctor if you drink alcohol.

You must not drink alcohol while taking Zydol™.

Looking after your medicine

Keep your capsules in the pack until it is time to take them.

If you take the capsules out of the pack, they may not keep well.

Keep your capsules in a place where the temperature stays below 30°C.

Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Dizziness.
  • Sedation, fatigue.
  • Drowsiness.
  • Dry mouth.
  • Headache.
  • Physical weakness or loss of strength.
  • Fatigue.
  • Nausea or vomiting.
  • Constipation.
  • Indigestion and stomach pain.
  • Flatulence.
  • Sweating.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Indigestion.
  • Skin reactions.
  • Hiccups.
  • Sudden onset of low blood pressure, collapse.
  • Fast, slow or irregular heartbeat.
  • Hot flushes.
  • Tremors/shakes.
  • Seizures.
  • Increase in blood pressure.
  • Shortness of breath.
  • Respiratory depression.
  • Changes in appetite.
  • Changes in mood.
  • Sleep disturbances.
  • Muscle weakness.
  • Difficulty in breathing.
  • Difficulty or pain in passing urine.
  • Blurred vision.
  • Problems with speech.
  • Dilated pupils.
  • Confusion.
  • 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.
  • Low blood glucose (hypoglycaemia).
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Very serious side effects

Very serious side effectsWhat to do
  • 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.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Talk to your doctor if you experience any of the following symptoms while taking this medicine.

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 take hormone supplement.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Some patients may experience withdrawal symptoms after they stop taking this medicine, such as agitation, trouble sleeping or tremors.

Tell your doctor if you experience withdrawal symptoms.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

Zydol™ is only available with a doctor's prescription.

What Zydol™ contains

Active ingredient
(main ingredient)
  • Tramadol hydrochloride
Other ingredients
(inactive ingredients)
  • Microcrystalline cellulose
  • Sodium starch glycollate
  • Colloidal anhydrous silica
  • Magnesium stearate
  • Iron oxide yellow
  • Sodium lauryl sulfate
  • Gelatin
  • Titanium dioxide
Potential allergens
  • Zydol™ may contain trace amounts of phenylalanine and sulfites.

Zydol™ does not contain lactose, sucrose, tartrazine and other azo dyes

Do not take Zydol™ if you are allergic to any of these ingredients.

What Zydol™ looks like

Zydol™ 50 mg Capsules

Zydol™Oblong, yellow/yellow, shiny hard gelatin capsules size 4 with snap fit closure. The contents consist of a fine, white to pale yellow powder.

Zydol™ is available in pack size of 20 capsules.

AUST R 80744.

Who distributes Zydol™

Arrotex Pharmaceuticals Pty Ltd
15 - 17 Chapel Street
Cremorne VIC 3121
Web: https://arrotex.com.au

Zydol™ is a trademark of Grünenthal GmbH.

This leaflet was prepared in September 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Zydol

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

1 Name of Medicine

Tramadol hydrochloride.

2 Qualitative and Quantitative Composition

Zydol 50 mg capsules contain 50 mg of the active ingredient, tramadol hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Oblong, yellow/yellow, shiny hard gelatin capsules size 4 with Snap fit closure. The contents consist of a fine, white to pale yellow powder.

4 Clinical Particulars

4.1 Therapeutic Indications

For the short-term management of severe pain where other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.

4.2 Dose and Method of Administration

The dose of Zydol should be titrated according to the severity of the pain and the clinical response of the individual patient.
The recommended dosage of Zydol in adults and adolescents over the age of 12 years is as follows.

Oral administration.

50 - 100 mg administered two or three times daily may be sufficient. Zydol 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 Zydol 100 mg is usually more effective. The maximum daily dose should not exceed 400 mg per day.

Paediatric use.

The use of Zydol 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 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.

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.

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 (4-6 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

Zydol 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.
Zydol must not be used for narcotic withdrawal treatment.

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Zydol 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 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 Zydol are administered with anaesthetic medications or alcohol, respiratory depression may result. Cases of intraoperative respiratory depression, usually with large intravenous doses of Zydol and with concurrent administration of respiratory depressants, have been reported.

Sleep-related breathing disorders.

Opioids can cause sleep-related breathing disorders including central sleep apnoea (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 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).
If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose escalations.
Symptoms of serotonin syndrome may include mental status changes (including anxiety, agitation, and confusion), autonomic instability (including diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrhoea), and neuromuscular abnormalities (including muscle rigidity, myoclonus, tremor, and hyperreflexia).
If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms. Withdrawal of the serotonergic drugs usually brings about a rapid improvement.

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 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).

Tolerance and withdrawal.

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).

Accidental ingestion/exposure.

Accidental ingestion or exposure of tramadol, especially by children, can result in a fatal overdose of tramadol. 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.

Acute abdominal conditions.

The administration of Zydol may complicate the clinical assessment of patients with acute abdominal conditions.

Increased intracranial pressure, head trauma, shock or reduced levels of consciousness.

Zydol 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 Zydol 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 Zydol.

Renal and hepatic disease.

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

Use in hepatic impairment.

Metabolism of Zydol 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. As Zydol is only removed very slowly by haemodialysis or haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Patients physically dependent on opioids.

Zydol is not recommended as a substitute in opioid dependent patients. Although Zydol is an opiate agonist, it cannot suppress opioid withdrawal symptoms. Animal experiments have shown that under certain circumstances the administration of Zydol 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 therefore be used in the administration of Zydol to such patients.
In patients with a tendency for drug abuse or dependence, treatment with Zydol should only be carried out for short periods under strict medical supervision.
Cases of dependence and abuse of Zydol have been reported rarely.

Seizure risk.

Convulsions have been reported in patients receiving Zydol at the recommended dose levels. The risk may be increased when doses of Zydol exceed the recommended upper daily dose limit. In addition, Zydol 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 Zydol if there are compelling circumstances.

Anaphylactoid reactions.

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving Zydol. These reactions often occur following the first dose. Other reported reactions include pruritus, hives, bronchospasm and angioedema.

Intraoperative 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.

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.)

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.

Zydol should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anaesthetic agents, phenothiazines, tranquillisers or 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 or other CNS depressants, including alcohol).
The combination of Zydol with mixed opiate agonists/ antagonists (e.g. buprenorphine or 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 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
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 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 drugs (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.

Use with MAO inhibitors.

Zydol should not be used in patients who are taking MAO inhibitors or who have taken them within the last fourteen days, as Zydol inhibits the uptake of noradrenaline and serotonin (see Section 4.3 Contraindications).

Other interactions.

Zydol does not appear to induce its own metabolism in humans, since observed maximal plasma concentrations after multiple oral doses are higher than expected based on single dose data. Zydol is a mild inducer of selected drug metabolism pathways measured in animals.
Concomitant administration of Zydol with carbamazepine causes a significant increase in Zydol 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 Zydol.
Zydol is metabolised to M1 by the CYP2D6 P450 isoenzyme. Drugs that selectively inhibit that isoenzyme (quinidine, phenothiazines and antipsychotic agents) may cause increased concentrations of Zydol and decreased concentrations of M1. The clinical consequences of these potential effects have not been fully investigated.
Concomitant administration of Zydol with cimetidine does not result in clinically significant changes in Zydol pharmacokinetics. Therefore no alteration of the Zydol 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 Zydol (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, Zydol should not be used during pregnancy. Studies in animals using IV or IM routes of administration have not been conducted.
Tramadol has been shown to be embryotoxic and foetotoxic in mice, rats and rabbits in maternally toxic doses of 120 mg/kg in mice, or higher in rats and 75 mg/kg in rabbits, but was not teratogenic at these dose levels. No harm to the foetus due to tramadol was seen at doses that were not maternally toxic.
No drug-related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol (75 mg/kg for rats or 175 mg/kg for rabbits). Embryo and foetal toxicity consisted primarily of decreased foetal weights, skeletal ossification and increased 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.

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

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 Zydol. 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 to human analgesia of tramadol relative to M1 is unknown.
Several animal tests 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. Onset of analgesia in humans is evident within one hour after oral administration reaching a peak in approximately two to three hours.
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 Zydol 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

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.

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. Although not confirmed in humans, tramadol has been shown in rats to cross the blood brain barrier.
Tramadol crosses the placenta. Very small amounts of tramadol and M1 are found in the breast milk (0.1% and 0.02%, respectively, of the administered dose).

Metabolism.

Tramadol is extensively metabolised after oral administration. Approximately 15 - 19% of the dose is excreted in the urine as unchanged drug. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Only 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%. The proportion of drug excreted in the urine as unchanged tramadol is greater in elderly subjects (34.9% of an oral dose) than in young subjects (13.6%). Total clearance is approximately 430-610 mL/min.
Biliary excretion was shown to be of little importance. In a study of cholecystectomised patients, the cumulative biliary excretion of unchanged tramadol proved to be 240 times lower than its renal excretion and this relationship was 1/390 and 1/70 for the M1 and M1-conjugated metabolites, respectively.
The half-life of tramadol is in the order of 5-7 hours in young adults, with relatively modest coefficients of variation. Following repeated administration, the increase in bioavailability is accompanied by an increase in renal excretion.
The half-life of M1 corresponds approximately to that of unchanged tramadol (6-8 hours).
Excretion is impaired in patients with renal or hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use). In patients with hepatic impairment, the half-life of tramadol has been found to be 13 hours.

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 hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and the micronucleus tests in rats. Overall, the weight of evidence from these tests indicates Zydol 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 (dosing orally up to 30 mg/kg for approximately two years, although the study was not done with the maximum tolerated dose or at exposure levels expected from 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 excipients in Zydol capsules are: microcrystalline cellulose, magnesium stearate, sodium starch glycollate, colloidal silica anhydrous. The excipients in the capsule shell are: iron oxide yellow, titanium dioxide, gelatin and sodium lauryl sulfate.

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

PVC/PE/PVDC with Al foil and PVC/PVDC with Al blister packs of 6, 8, 10 and 20 capsules.

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

Chemical structure.

Zydol contains tramadol hydrochloride known chemically as (±)-cis-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol hydrochloride with the formula: C16H25NO2.HCl.
Tramadol is an odourless, white to off white crystalline powder that is readily soluble in both water and ethanol and has a pKa of 9.41. The water/ n-octanol partition coefficient is 1.35 at pH 7.
MW = 299.84.
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