Consumer medicine information

Tramadol SR Generichealth

Tramadol hydrochloride

BRAND INFORMATION

Brand name

Tramadol SR Generichealth

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tramadol SR Generichealth.

SUMMARY CMI

Tramadol SR Generichealth

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

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

1. Why am I taking Tramadol SR Generichealth?

Tramadol SR Generichealth contains the active ingredient tramadol hydrochloride. It is used to relieve severe pain.

For more information, see Section 1. Why am I taking Tramadol SR Generichealth? in the full CMI.

2. What should I know before I take Tramadol SR Generichealth?

Do not take if you have ever had an allergic reaction to tramadol hydrochloride, other opioids 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 Tramadol SR Generichealth? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tramadol SR Generichealth 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 Tramadol SR Generichealth?

  • Swallow the tablets whole with a glass of water.
  • Discuss with your doctor the correct dose for you. Do not take more than four of the 100 mg tablets per day or two of the 150 mg or of the 200 mg tablets per day.

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

5. What should I know while taking Tramadol SR Generichealth?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking this medicine.
  • Remind your doctor if you are allergic to tramadol, opioids or any of the ingredients in this medicine or if you have had any problems with drug or alcohol dependence.
  • If you become pregnant or plan to breast-feed while taking this medicine, tell your doctor immediately.
  • If you are about started any new medicine, tell your doctor or pharmacist that you are taking this medicine.
  • If your pain is not as severe or if your pain is not helped or gets worse, talk to your doctor.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.
  • If you have to have any blood tests tell your doctor you are taking this medicine.
Things you should not do
  • Do not stop taking this medicine or change the dosage without discussing this with your doctor.
  • Do not give this medicine to anyone else, or use it to treat any other complaints.
Driving or using machines
  • Be careful when driving or operating machinery until you know how this medicine affects you.
Drinking alcohol
  • Drinking alcohol while taking this medicine can cause drowsiness, coma or death.
  • Do not drink alcohol while using this medicine.
Looking after your medicine
  • Keep your tablets in the pack until it is time to take them.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while taking Tramadol SR Generichealth? in the full CMI.

6. Are there any side effects?

Common side effects are dizziness, sedation, fatigue, headache, constipation, nausea or vomiting, sweating or dry mouth, cramps, sleep apnoea. Serious side effects are 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 or convulsions, coma, stupor, personality changes. Tell your doctor if you have extreme fatigue, lack of appetite, severe abdominal pain, nausea, vomiting or low blood pressure. 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

Tramadol SR Generichealth should only be used 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

Tramadol SR Generichealth 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

Tramadol SR Generichealth 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 Tramadol SR Generichealth 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 using Tramadol SR Generichealth

Using Tramadol SR Generichealth 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 using Tramadol SR Generichealth



FULL CMI

Tramadol SR Generichealth

Active ingredient(s): tramadol hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tramadol SR Generichealth. You should also speak to your doctor orpharmacist if you would like further information or if you have any concerns or questions about using Tramadol SR Generichealth.

Where to find information in this leaflet:

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

1. Why am I taking Tramadol SR Generichealth?

Tramadol SR Generichealth contains the active ingredient tramadol hydrochloride.

Tramadol SR Generichealth is used to relieve severe pain over a long period of time. It belongs to a group of medicines called opioid analgesics (pain relievers). Tramadol SR Generichealth tablets are designed to release active medicine gradually over several hours.

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

2. What should I know before I take Tramadol SR Generichealth?

Warnings

Do not take Tramadol SR Generichealth if:

  • you are allergic to tramadol hydrochloride, any other opioid analgesics (e.g. morphine or codeine), or any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include skin rash, itching, difficulty breathing and swelling of the face (including lips, tongue, throat etc). Always check the ingredients to make sure you can take this medicine.
  • 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 a MAOI, or have taken one within the past two weeks. Examples of MAOl-containing medicines are Nardil®, Parnate®
  • 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 use Tramadol SR Generichealth after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

Addiction

You can become addicted to Tramadol SR Generichealth even if you take it exactly as prescribed.

Tramadol SR Generichealth 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 Tramadol SR Generichealth. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking Tramadol SR Generichealth suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance

Tolerance to Tramadol SR Generichealth 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.

If you are not sure whether you should start taking Tramadol SR Generichealth, talk to your doctor.

Pregnancy and breastfeeding

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

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

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

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 Tramadol SR Generichealth and affect how it works. These include:

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

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

4. How do I take this medicine?

How much to take

The recommended dosage of Tramadol SR Generichealth is either:

  • one or two Tramadol SR Generichealth 100 mg tablet(s) twice a day (morning and evening); or
  • one Tramadol SR Generichealth 150 mg or 200 mg tablet twice a day (morning and evening).

Tramadol SR Generichealth tablets allow the body to absorb the active ingredient tramadol over a long period, so that dosing need be only twice a day

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

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.

Patients over 75 years may need a reduced daily dose of Tramadol SR Generichealth compared to younger adults.

When and how to take Tramadol SR Generichealth

  • Tramadol SR Generichealth may be taken, before, with, or after food.
  • Swallow the tablets whole with a glass of water. They must NOT be chewed, crushed or dissolved. This will release all the analgesic quite quickly. Side-effects may then occur.

How long to take Tramadol SR Generichealth

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

If you forget to take Tramadol SR Generichealth

If you forget to take a dose, you can take it as soon as you remember. The next 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 it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

If you take too much Tramadol SR Generichealth

If you or someone else receives too much (overdose), and experiences 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 Tramadol SR Generichealth 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
  • Serotonin syndrome symptoms, sweating, agitation, muscle twitching, tremor, spontaneous muscle contraction, high body temperature.

If you think that you have used too much Tramadol SR Generichealth, 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. 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.

5. What should I know while taking Tramadol SR Generichealth?

Things you should do

Tell your doctor before you take Tramadol SR Generichealth if:

  • you have a known allergy to Tramadol SR Generichealth 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 affects how your kidney or liver work
    - any stomach problems
    - a severe headache or feel sick due to a head injury
    - any fits or convulsions or take medicine for epilepsy.
  • you have or have had any problems with drug or alcohol dependence.
  • you are pregnant or intend to become pregnant. Tramadol SR Generichealth is not recommended for use during pregnancy. Talk to your doctor about the risks and benefits of using Tramadol SR Generichealth during pregnancy.
  • you are breast-feeding or plan to breast-feed. Tramadol SR Generichealth is not recommended for use during breast-feeding. Talk to your doctor about the risks and benefits of using Tramadol SR Generichealth when breastfeeding.

Things you should not do

  • Do not give Tramadol SR Generichealth to anyone else, even if they have the same condition as you.
  • Do not use Tramadol SR Generichealth to treat any other complaints unless your doctor tells you to.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Tramadol SR Generichealth affects you.

Tramadol SR Generichealth 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.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol taken with Tramadol SR Generichealth may cause may result in severe drowsiness, decreased awareness, breathing problems, coma and death.

Things you must do while taking Tramadol SR Generichealth

If you become pregnant while you are taking Tramadol SR Generichealth, tell your doctor immediately.

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

If your pain is not as severe and you feel that you do not need as much Tramadol SR Generichealth 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 have to have any blood tests tell your doctor you are taking this medicine. It may affect the results of some tests.

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

Looking after your medicine

  • Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.

Follow the instructions in 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
Common
  • dizziness
  • sedation, fatigue
  • headache
  • constipation
  • nausea or vomiting
  • sweating
  • dry mouth
Less Common
  • indigestion
  • hiccups
  • changes in appetite
  • skin reactions
  • sudden onset of low blood pressure, collapse
  • muscle weakness, cramps
  • tremor
  • seizures
  • respiratory depression
  • improvement in mood
  • confusion
  • sleep disturbance, apnoea
  • blurred vision
  • difficulty in passing urine
  • Serotonin Syndrome: signs of this vary and are not specific: they may include sweating, agitation, muscle twitching, tremor, spontaneous muscle contraction, high body temperature. Serotonin Syndrome may result from interaction of tramadol with other medicines which increase serotonin effects, for example, the SSRI antidepressants.
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
  • 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
  • coma, stupor
  • personality changes
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.

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.

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

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

What Tramadol SR Generichealth contains

Active ingredient
(main ingredient)		Tramadol hydrochloride
Other ingredients
(inactive ingredients)		Calcium hydrogen phosphate dihydrate
Hyprolose
Colloidal anhydrous silica
Magnesium stearate

Do not take this medicine if you are allergic to any of these ingredients.

What Tramadol SR Generichealth looks like

Tramadol SR Generichealth 100 mg – off-white, round biconvex tablet (AUST R 194539)

Tramadol SR Generichealth 150 mg – off-white, capsule shaped tablet (AUST R 194540)

Tramadol SR Generichealth 200 mg – off-white, capsule shaped tablet (AUST R 194541)

All tablets are contained in a blister pack within a carton of 20 tablets.

Who distributes Tramadol SR Generichealth

Generic Health Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, VIC, 3128
Australia

[email protected]
Ph: +61 3 9809 7900
www.generichealth.com.au

This leaflet was prepared in October 2021.

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Tramadol SR Generichealth

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Notes

Distributed by Generic Health Pty Ltd

1 Name of Medicine

Tramadol hydrochloride.

2 Qualitative and Quantitative Composition

Tramadol SR Generichealth tablets contain the active ingredient tramadol hydrochloride.
Each modified release (sustained release) tablet contains 100 mg, 150 mg, or 200 mg of tramadol hydrochloride as the active ingredient.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tramadol SR Generichealth modified (sustained) release tablets are available in the three (3) strengths as follows:

100 mg.

Off-white, round, biconvex tablets plain on both sides.

150 mg.

Off-white, capsule-shaped tablets plain on both sides.

200 mg.

Off-white, capsule-shaped tablets plain on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

The dose of tramadol should be titrated according to the severity of the pain and the clinical response of the individual patient. Tramadol is approved for use in adults and adolescents over the age of 12 years.
Tramadol SR Generichealth is contraindicated in all children younger than 12 years of age and in postoperative management of children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
The recommended dose of Tramadol SR Generichealth in adults and adolescents over the age of 12 years is 100 mg 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.
Tramadol SR Generichealth tablets are intended for oral administration.

Dosage 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 tramadol modified 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). Tramadol is not recommended in patients with severe renal impairment (creatinine clearance < 10 mL/minute).

Hepatic insufficiency.

Tramadol modified release tablets should not be used in patients with severe hepatic insufficiency (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Individuals with known hypersensitivity to tramadol or any excipients.
Acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs.
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 monoamine oxidase (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.

Tramadol SR Generichealth contains the opioid, tramadol hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Tramadol SR Generichealth 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 SR Generichealth.
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 Tramadol SR Generichealth 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 SR Generichealth 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 opioids 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, (see Section 4.2 Dose and Method of Administration), together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.
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.

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 SR Generichealth 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 SR Generichealth 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 SR Generichealth.

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.
Symptoms of withdrawal reactions from tramadol hydrochloride are similar to those occurring during opiate withdrawal and may include: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor, pyrexia, myalgia, chills and gastrointestinal symptoms. Other symptoms that have very rarely been seen with tramadol discontinuation include panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, personalization, derealization, paranoia).
When discontinuing Tramadol SR Generichealth in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).
Tramadol is not recommended as a substitute in opioid-dependent patients. Although tramadol is an opiate-agonist, it cannot suppress opioid withdrawal symptoms. Animal experiments have shown that under certain circumstances the administration of tramadol may provoke a withdrawal syndrome in opioid-dependent monkeys.
Because of the difficulty in assessing dependence in patients who have previously received substantial amounts of opioid medications, caution should be used in the administration of tramadol to such patients.
In patients with a tendency for drug abuse or dependence, treatment with tramadol should only be carried out for short periods under strict medical supervision.

Accidental ingestion/exposure.

Accidental ingestion or exposure of Tramadol SR Generichealth, especially by children, can result in a fatal overdose of tramadol hydrochloride. Patients and their caregivers should be given information on safe storage and disposal of unused Tramadol SR Generichealth (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.

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.

Acute abdominal conditions.

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

Sleep-related breathing disorders.

Drugs with mu-opioid receptor agonist activity, such as tramadol, can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Use of these drugs increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

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 medications that lower 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.

Intraoperative use.

In one study using nitrous oxide/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 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, tramadol may be used intraoperatively in the same way as other analgesic agents are routinely used.

Long-term use.

Tramadol has been studied in controlled clinical trials for periods of up to three months. In one small uncontrolled study, patients with cancer pain received a dose of tramadol 150 mg/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.

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 and 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 tramadol modified-release tablets are not recommended.
As tramadol is only removed very slowly by haemodialysis or haemofiltration, postdialysis administration to maintain analgesia is not usually necessary (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

In subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly prolonged. Patients 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 of age (see Section 4.2 Dose and Method of Administration, Dosage in the elderly; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

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

Post-operative use in children.

There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events.
Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Central nervous system 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, tranquillizers or sedative hypnotics, benzodiazepines, gabapentinoids, cannabis, tricyclic antidepressants, antipsychotics, antihistamines and centrally-active anti-emetics (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).
The combination of tramadol with mixed opiate agonists/ antagonists (e.g. buprenorphine 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 doctor to the possibility of an interaction.
Concomitant therapeutic use of tramadol and serotonergic medicines such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see Section 4.3 Contraindications), tricyclics antidepressants and mirtazapine may cause serotonin 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 the seizure threshold.

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold lowering drugs (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.

Use with monoamine oxidase inhibitors.

Tramadol should not be used in patients who are taking MAOIs or who have taken them within the last 14 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 450 isoenzyme. Drugs that selectively inhibit that isoenzyme (quinidine, phenothiazines and antipsychotic agents) may cause increased concentrations of tramadol and decreased concentrations of M1. The clinical consequences of these potential effects have not been fully investigated.
Concomitant administration of tramadol with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol dosage regimen is recommended.
Other drugs known to inhibit the CYP3A4 isoenzyme of cytochrome P450, such as ketoconazole and erythromycin, may inhibit the metabolism of tramadol (via N-demethylation) and probably the metabolism of the active O-demethylated metabolite (M1). The clinical importance of such an interaction has not been studied.
In a limited number of studies, the pre- or post-operative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with post-operative 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. Chronic use during pregnancy may lead to neonatal withdrawal symptoms. Studies in animals using intravenous or intramuscular 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 perinatal and postnatal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg had decreased weights and pup survival was decreased early in lactation at 80 mg/kg (six to ten 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.
Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

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 infant. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour.
The effect of tramadol, if any, on the later growth, development and functional maturation of the child is unknown.
 Tramadol is not recommended during breastfeeding, because its safety in infants and newborns has not been studied. Low levels of tramadol have been detected in breast milk. Following a single intravenous dose of tramadol 100 mg, the cumulative excretion in breast milk within 16 hours postdose was tramadol 100 microgram (0.1% of the maternal dose) and M1 27 microgram.

4.7 Effects on Ability to Drive and Use Machines

Due to its sedative effect, patients should be advised to avoid driving or operating heavy machinery while 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 (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, 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

Few cases of overdose with tramadol have been reported.

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 over dosage is due to ingestion of an oral dose form, activated charcoal may reduce absorption of the drug if given within one to two 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 pre-clinical 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 six times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding. The contribution of tramadol to human analgesia, relative to M1, is unknown.
Both human and animal studies have shown that antinociception induced by tramadol is only partially antagonised by the opiate antagonist naloxone. In addition, tramadol has been shown to inhibit reuptake of noradrenaline and serotonin in vitro, as have some other opioid analgesics. These latter mechanisms may contribute independently to the overall analgesic profile of tramadol.
The analgesic effect is dose dependent, but the relationship between serum concentrations and analgesic effect varies considerably between individuals. In one study, the median serum concentration of tramadol required for effective postoperative analgesia was 300 nanogram/mL, with individual values ranging from 20 to 990 nanogram/mL.
Apart from analgesia, tramadol may produce other symptoms similar to that of opioids including dizziness, somnolence, nausea, constipation, sweating and pruritus. However, tramadol causes significantly less respiratory depression than morphine. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no clinically significant effect on heart rate, left ventricular function or cardiac index. Orthostatic changes in blood pressure have been observed.

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.

After oral administration of tramadol modified release tablets, more than 90% of tramadol is absorbed. After a single dose, the mean absolute bioavailability is approximately 70%, irrespective of the concomitant intake of food. Oral bioavailability increases to 90% after repeated administration. The difference between absorbed and bioavailable tramadol is due to first-pass metabolism (maximum 30%). See Table 2.

Distribution.

Tramadol is rapidly distributed in the body, with a volume of distribution of 2 to 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 to 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 five to seven hours and the half-life of M1 is six to eight hours. Total clearance is approximately 430 to 610 mL/minute.

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 hours (range up to 19 hours), and the mean half-life of M1 was 19 hours (range up to 36 hours). In patients with severe renal impairment (creatinine clearance < 5 mL/minute) the mean half-life of tramadol was eleven hours (range up to 20 hours), and the mean half-life of M1 was 17 hours (range up to 43 hours).

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 tests 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 excipients contained in each of the three strengths of Tramadol SR Generichealth include calcium hydrogen phosphate dihydrate, hyprolose, colloidal anhydrous silica and magnesium stearate.

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 25°C.

6.5 Nature and Contents of Container

Tramadol SR Generichealth modified-release tablets are available in PVC/aluminium blister packs of 20 tablets.

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

Tramadol hydrochloride is an odourless, white to off white crystalline powder that is readily soluble in both water and ethanol. The water/n-octanol partition coefficient is 1.35 at pH 7.

Chemical structure.


Chemical Name: (1RS, 2RS)-2-[(dimethylamino) methyl)]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.
Molecular Formula: C16H25NO2.HCl.
Molecular Weight: 299.84.

CAS number.

53611-16-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes