Consumer medicine information

Tramadol Sandoz Capsules

Tramadol hydrochloride

BRAND INFORMATION

Brand name

Tramadol Sandoz

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tramadol Sandoz Capsules.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TRAMADOL SANDOZ against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may need to read it again.

What TRAMADOL SANDOZ is used for

TRAMADOL SANDOZ is used to relieve moderate to severe pain. It belongs to the group of medicines called analgesics (pain relievers).

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

TRAMADOL SANDOZ capsules are not usually addictive. However, rarely, addiction to tramadol has been reported.

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

Before you take TRAMADOL SANDOZ

When you must not take it

Do not take TRAMADOL SANDOZ if you have an allergy to:

  • any medicine containing tramadol hydrochloride.
  • any of the ingredients listed at the end of this leaflet.
  • any other medicines known as opioid analgesics, e.g. morphine or codeine.

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

Do not take this medicine if you

  • have taken large amounts of alcohol or other substances which can affect your level of consciousness.
  • are taking medicine for depression containing a “monoamine oxidase inhibitor” also known as MAOI, or have taken any within the past two weeks. Examples of MAOI- containing medicines are Nardil, Parnate.
  • are having treatment for withdrawal from narcotics.
  • have epilepsy that is not under control

Do not give this medicine to a child under the age of 12 years. Safety and effectiveness in children younger than 12 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are known to be sensitive to opioids.

Tell your doctor if you drink alcohol everyday.

Tell your doctor if you have or have had any of the following medical conditions:

  • any lung or breathing problems
  • fits or convulsions/epilepsy
  • any disorder of the kidney, liver or pancreas
  • any stomach problems
  • severe headaches or have had a head injury
  • you have, or have had, any drug or alcohol dependence
  • you have galactose intolerance, or lactase deficiency or glucose- galactose malabsorption
  • Sleep related breathing disorders

Tell your doctor if you think you may require long term use of TRAMADOL SANDOZ.

You may require careful monitoring.

Tell your doctor if you are pregnant or plan to become pregnant. TRAMADOL SANDOZ is not recommended for use during pregnancy.

Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breast feeding or plan to breast feed. TRAMADOL SANDOZ is not recommended for use during breast feeding. Your doctor can discuss with you the risks and benefits involved.

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

Taking other medicines

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

Some medicines and TRAMADOL SANDOZ may interfere with each other. These include:

  • carbamazepine (e.g. Tegretol®)
  • coumarin derivatives (e.g. Warfarin: some Brand names are Coumadin®, or Marevan®)
  • coumarin medicine for irregular or rapid heart beat
  • medicines for depression (mirtazapine), tricyclic anti-depressants (e.g. Sinequan, Allegron), selective serotonin reuptake inhibitors (SSRI’s) (e.g. Prozac, Zoloft), serotonin noradrenaline reuptake inhibitors (SNRI’s) (e.g. Efexor, Cymbalta), MAOI (e.g. Nardil, Parnate), bupropion (Zyban)
  • medicines for sleeplessness (e.g. Temaze)
  • quinidine, medicine used to treat abnormal heart rhythms
  • anti-psychotics or phenothiazines (e.g. Risperdal, Clozaril)
  • medicines for pain (e.g. tetrahydrocannabinol, buprenorphine (Subutex), pentazocine
  • medicines for seizures (carbamazepine, eg. Tegretol)
  • some antibiotics
  • ketoconazole, an antifungal medicine.

These medicines may be affected by TRAMADOL SANDOZ or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Other interactions not listed above may also occur.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take TRAMADOL SANDOZ

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

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

How much to take

For moderate pain, one TRAMADOL SANDOZ capsule may be enough for the first dose, followed by one or two capsules eight to twelve hours a day as required.

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

As all patients respond to treatment differently, your doctor may prescribe a lower dose, particularly if you have any medical conditions.

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

Patients over 75 years may need a reduced daily dose of TRAMADOL SANDOZ compared to younger adults.

How to take it

Swallow the capsules whole with a full glass of water.

When to take it

TRAMADOL SANDOZ may be taken, before, with, or after food.

How long to take it

Continue taking your medicine for as long as your doctor tells you. This differs between individuals depending on how severe your pain is, how you respond to TRAMADOL SANDOZ, and the cause of your pain.

Ask your doctor for advice on how long you need to take TRAMADOL SANDOZ capsules.

If you forget to take it

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

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

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.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much TRAMADOL SANDOZ. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include decrease in breathing and fits or convulsions.

While you are using TRAMADOL SANDOZ

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking TRAMADOL SANDOZ.

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

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

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

If you 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.

Things you must not do

Do not take TRAMADOL SANDOZ to treat any other complaints unless your doctor tells you to.

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

Things to be careful of

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

Ask your doctor for advice about whether it is safe for you to drive or operate machinery while taking TRAMADOL SANDOZ.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking TRAMADOL SANDOZ.

This medicine helps most people with moderate to severe pain, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

Tell your doctor or pharmacist if you notice any of the following and they worry you:

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

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • indigestion
  • changes in appetite
  • skin reactions
  • jaundice (yellowing of the skin), swelling in the legs
  • sudden onset of low blood pressure, collapse
  • muscle weakness
  • tremor
  • seizures
  • respiratory depression
  • improvement or changes in mood or behaviour
  • confusion, delirium, anxiety
  • change in sensations such as pricking or tingling
  • sleep disturbance
  • changes in activity, co-ordination or speech
  • blurred vision or changes to the eye
  • slow or fast heart beat
  • difficulty in passing urine
  • Serotonin Syndrome: signs of this vary and are not specific; they may include sweating, agitation, muscle twitching, spontaneous muscle contraction, tremor, high body temperature. Serotonin Syndrome may result from interaction of tramadol with other medicines which increase serotonin effects, for example, the SSRI antidepressants.

The above list includes less common side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • 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
  • shortness of breath, difficulty breathing
  • heart palpitations, faintness or collapse
  • hallucinations
  • convulsions

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

When used as prescribed by your doctor, addiction to TRAMADOL SANDOZ is very unlikely.

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

It is important therefore to take TRAMADOL SANDOZ only as directed by your doctor.

After using TRAMADOL SANDOZ

Storage

Keep your capsules tablets 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 cool dry place where the temperature stays below 25°C.

Do not store TRAMADOL SANDOZ or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

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

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

TRAMADOL SANDOZ 50 mg – capsules with a yellow body and a green cap.

Available in blister packs of 20 capsules.

Ingredients

Active ingredient:

  • tramadol hydrochloride

Inactive ingredients:

  • croscarmellose sodium
  • povidone
  • microcrystalline cellulose
  • colloidal anhydrous silica
  • magnesium stearate
  • gelatin
  • titanium dioxide
  • quinoline yellow
  • iron oxide yellow
  • brilliant blue FCF.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Distributor

TRAMADOL SANDOZ is distributed in Australia by:

Sandoz Pty Ltd
54 Waterloo Road
Macquarie Park, NSW 2113

This leaflet was prepared in April 2020.

TRAMADOL SANDOZ 50 mg: AUST R 141240

TRAMADOL SANDOZ_cmi\0320/21

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Tramadol Sandoz

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Notes

Distributed by Sandoz Pty Ltd

1 Name of Medicine

Tramadol hydrochloride.

2 Qualitative and Quantitative Composition

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

3 Pharmaceutical Form

Green - yellow hard gelatin capsules containing tramadol hydrochloride 50 mg.

4 Clinical Particulars

4.1 Therapeutic Indications

Tramadol Sandoz is indicated for the short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.

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 Sandoz 50 mg capsules is approved for use in adults and adolescents over the age of 12 years. Tramadol Sandoz 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).

Oral administration.

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

Use in the elderly.

In subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly prolonged. Subjects in this age group are also expected to vary more widely in their ability to tolerate adverse drug effects. Daily doses in excess of 300 mg are not recommended in patients over 75 years.

Renal insufficiency.

In patients with renal insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements. 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. Depending on the severity of impairment and individual clinical response, the recommended dosage interval (4 to 6 hours) may need to be extended, and/or the dose level titrated as required (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Tramadol is contraindicated in:
individuals with known hypersensitivity to tramadol or any excipients;
acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs;
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 Sandoz contains the opioid tramadol hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Tramadol Sandoz 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 Sandoz.
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 Sandoz 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 Sandoz 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). 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 intraoperative respiratory depression, usually with large intravenous doses of tramadol and with concurrent administration of respiratory depressants, have been reported.

Sleep-related breathing disorders.

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

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of Tramadol Sandoz 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 [Product] 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 Sandoz.

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 Sandoz 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).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Tramadol Sandoz, especially by children, can result in a fatal overdose of [opioid]. Patients and their caregivers should be given information on safe storage and disposal of unused Tramadol Sandoz (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 tramadol may complicate the clinical assessment of patients with acute abdominal conditions.

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

Tramadol should be used with caution in patients with increased intracranial pressure, head injury, shock or a reduced level of consciousness of uncertain origin. Pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for an adverse drug reaction when evaluating altered mental status in these patients if they are receiving tramadol.

Seizure risk.

Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit. In addition, tramadol may increase the seizure risk in patients taking other medication that lowers the seizure threshold (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances.

Anaphylactoid reactions.

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

Intra-operative use.

In one study using nitrous oxide/ tramadol anaesthetic technique (with only intermittent administration of enflurane 'as required'), tramadol was reported to enhance 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 150 mg tramadol per day for up to six months. No clinical studies investigating the safety and efficacy of tramadol beyond six months 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.

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 (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. As tramadol is removed only 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. Subjects in this age group are also expected to vary more widely in their ability to tolerate adverse drug effects. Daily doses in excess of 300 mg are not recommended in patients over 75 years (see Section 4.2 Dose and Method of Administration, Use in the elderly; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

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

Post-operative use in children.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Use with 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, tranquillisers 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, pentazocine) is not advisable because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.

Use with other serotonergic agents.

The presence of another drug that increases serotonin by any mechanism should alert the treating physician to the possibility of an interaction. Concomitant therapeutic use of tramadol and serotonergic medicines such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see Section 4.3 Contraindications), tricyclics antidepressants and mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely when one of the following is observed: spontaneous clonus, inducible or ocular clonus with agitation or diaphoresis, tremor and hyperreflexia, hypertonia and body temperature > 38°C and inducible or ocular clonus.
Withdrawal of the serotonergic medicines usually brings about a rapid improvement. Drug treatment depends on the nature and severity of the symptoms.

Use with coumarin derivatives.

Caution should be exercised during concomitant treatment with tramadol and coumarin derivatives (e.g. warfarin) due to reports of increased international normalised ratio (INR) with major bleeding and ecchymoses in some patients.

Drugs which reduce the seizure threshold.

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

Use with 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 P450 isoenzyme. Drugs that selectively inhibit that isoenzyme (quinidine, phenothiazines, antipsychotic agents) may cause increased concentrations of tramadol and decreased concentrations of M1. The clinical consequences of these potential effects have not been fully investigated.
Concomitant administration of tramadol with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore, no alteration of the tramadol dosage regimen is recommended.
Other drugs known to inhibit the CYP3A4 isoenzyme of cytochrome P450, e.g. ketoconazole and erythromycin, may inhibit the metabolism of tramadol (via N-demethylation) and probably the metabolism of the active O-demethylated metabolite (M1). The clinical importance of such an interaction has not been studied.
In a limited number of studies, the pre or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effects on fertility in rats were observed for tramadol at oral dose levels of up to 50 mg/kg/day.
(Category C)
There are no adequate and well controlled studies with tramadol in pregnant women, therefore, tramadol should not be used during pregnancy.
Tramadol has been shown to be embryotoxic and foetotoxic in mice, rats and rabbits at maternally toxic doses of 120 mg/kg in mice, or higher in rats and 75 mg/kg in rabbits, but was not teratogenic at these dose levels. No harm to the foetus due to tramadol was seen at doses that were not maternally toxic.
No drug related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol (75 mg/kg for rats or 175 mg/kg for rabbits). Embryo and foetal toxicity consisted primarily of decreased foetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in development or behavioural parameters were also seen in pups from rat dams allowed to deliver. Embryo and foetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit.
In peri and postnatal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg had decreased weights and pup survival was decreased early in lactation at 80 mg/kg (6 to 10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels.

Labour and delivery.

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

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

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

Immune system disorders.

Rare: shock reactions, anaphylaxis, allergic reactions.

Endocrine disorders.

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

Metabolism and nutrition disorders.

Rare: changes in appetite.

Psychiatric disorders.

Rare: hallucinations, confusional state, sleep disturbance, delirium, anxiety, nightmares, changes in mood (usually euphoric mood, occasionally dysphoria), changes in activity (usually suppression, occasionally increase), changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders).

Nervous system disorders.

Very common: dizziness.
Common: autonomic nervous effects (mainly dry mouth, perspiration), headache, sedation, asthenia.
Uncommon: trembling.
Rare: speech disorders, paraesthesia, coordination disturbance, tremor, seizures, involuntary muscle contractions, syncope.

Eye disorders.

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

Cardiac disorders.

Uncommon: tachycardia, flushing.
Rare: bradycardia.

Vascular disorders.

Uncommon: orthostatic dysregulation (tendency to collapse and cardiovascular collapse).

Respiratory, thoracic and mediastinal disorders.

Rare: dyspnoea, respiratory depression (when the recommended doses are considerably exceeded and other respiratory depressant substances are administered concomitantly).
Very rare: worsening of asthma (causality not established).

Gastrointestinal disorders.

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

Hepatobiliary disorders.

Very rare: elevated liver enzymes.

Skin and subcutaneous tissue disorders.

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

Musculoskeletal and connective tissue disorders.

Rare: motor system weakness.

Renal and urinary disorders.

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

General disorders and administration site conditions.

Common: fatigue.

Investigations.

Rare: increase in blood pressure.
The incidence of "CNS irritation" (dizziness), "autonomic nervous effects" (perspiration), "orthostatic dysregulation" (tendency to collapse and cardiovascular collapse) and tachycardia and "nausea/ urge to vomit/ vomiting" can be increased with rapid intravenous administration and also tends to be dose dependent. No tests of significance have been performed.

Reporting suspected adverse effects.

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

4.9 Overdose

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.

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-desmethyl tramadol, 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.

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 to 72% and the peak serum level (Cmax) is reached two hours (range: one to three hours) after administration. The mean peak plasma concentration (Cmax) is approximately 280 nanogram/mL after oral administration of two capsules. 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 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% those extrapolated from the single dose administration studies with 50 mg capsules. This can be explained by first-pass metabolic saturation.

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 concentrations 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 breastmilk (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-desmethyl tramadol (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/min.

Pharmacokinetics in patients with hepatic or renal impairment.

Elimination of tramadol and M1 is impaired in patients with hepatic or renal impairment (see Section 4.4 Special Warnings and Precautions for Use). In patients with hepatic impairment, the mean half-life of tramadol was found to be 13 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/min) the mean half-life of tramadol was 11 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 test in Chinese hamster cells, and bone marrow micronucleus tests in mouse and Chinese hamster cells. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and the micronucleus tests in rat cells. Overall, the weight of evidence from these tests indicates tramadol does not possess a genotoxic risk to humans.

Carcinogenicity.

A slight, but statistically significant increase in two common murine tumours (pulmonary and hepatic) was observed in a mouse carcinogenicity study, particularly in aged mice dosed orally up to 30 mg/kg for approximately two years. Although the study was not conducted using the maximum tolerated dose, or at exposure levels expected in clinical use, this finding is not believed to suggest risk in humans. No such findings occurred in a rat carcinogenicity study.

6 Pharmaceutical Particulars

6.1 List of Excipients

The excipients contained in the product include croscarmellose sodium, povidone, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate, gelatin, titanium dioxide, quinoline yellow, iron oxide yellow, brilliant blue FCF.

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

Tramadol Sandoz 50 mg capsules should be stored below 25°C, and protected from light and moisture. If ambient temperatures above 30°C and/or high humidity are likely to be experienced during ongoing storage, a cool, dry place should be sought to keep this medicine.

6.5 Nature and Contents of Container

Blister packs of 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

The chemical name of tramadol hydrochloride is (1RS,2RS)-2- [(dimethylamino) methyl)]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.
Molecular formula: C16H25NO2.HCl. MW: 299.84.
Tramadol hydrochloride is an odourless, white to off white crystalline powder that is readily soluble in both water and ethanol and has a pKa of 9.41. The water/ n-octanol partition coefficient is 1.35 at pH 7.

Chemical structure.

The chemical structure of tramadol hydrochloride is:

CAS number.

36282-47-0.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes