Consumer medicine information

Terry White Chemists Tramadol SR Twice daily sustained release tablets

Tramadol hydrochloride

BRAND INFORMATION

Brand name

Terry White Chemists Tramadol SR Twice daily sustained release tablets

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Terry White Chemists Tramadol SR Twice daily sustained release tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

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

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is Terry White Chemists Tramadol SR. It contains the active ingredient, tramadol (as tramadol hydrochloride).

It is used to relieve moderate to severe pain.

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

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

How it works

It belongs to the group of medicines called analgesics (pain relievers). The tablets are designed to release the active ingredient for pain relief gradually over several hours.

Use in children

There is not enough information to recommend the use of this medicine in children under 12 years of age.

Use in the elderly

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

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • you have recently taken large amounts of alcohol or other substances which can affect your level of consciousness
  • you are taking a medicine containing a "monoamine oxidase inhibitor" also known as MAOI, or have taken any within the past two weeks. Examples of MAOIs include selegiline, phenelzine, tranylcypromine, linezolid, methylene blue and moclobemide
  • you require treatment for withdrawal from narcotics
  • you suffer from epilepsy which is not controlled properly by any therapy
  • it has passed the expiry date (EXP) printed on the pack.
  • the packaging is torn, shows signs of tampering or it does not look quite right.
  • you have an allergy to any other medicines known as opioid analgesics, e.g. morphine or codeine
  • you have had an allergic reaction to tramadol or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body, rash, itching or hives on the skin fainting or hayfever-like symptoms.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies or sensitivities to:
  • opioids (morphine-like medicines)
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • any disorder of the kidney, liver or pancreas, including any related to alcohol intake - for example, cirrhosis of the liver
  • stomach problems
  • fits or convulsions
  • lung or breathing problems
  • a severe headache, or you are not fully conscious, have had a head injury or have been told that you are in shock or have raised intracranial pressure
  • any drug or alcohol dependence.
  1. You are currently pregnant or breastfeeding or you plan to become pregnant or breast feed.

This medicine is not recommended for use during pregnancy or labour or whilst breast feeding. Talk to your doctor about the risks and benefits of using this medicine during pregnancy or labour or when breast feeding.

  1. You have recently been vaccinated or plan to get a vaccination.
  2. You are planning to have surgery.
  3. You are currently receiving or are planning to receive dental treatment.
  4. You are taking or are planning to take any other medicines.

This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with tramadol. These include:

  • medicines used to prevent blood clots, such as warfarin and coumarin
  • buprenorphine, morphine, pethidine and pentazocine, other similar medicines used to treat pain
  • Monoamine Oxidase Inhibitors, used to treat depression or Parkinson's disease (also tell your doctor if you have taken any of these within the last 14 days)
  • carbamazepine, used to treat epilepsy (fits) and also bipolar disorder
  • sedatives and tranquilisers, used to calm you down and/or help you sleep
  • quinidine, used to modify heart rate and rhythm
  • antipsychotics and antidepressants used for treating disorders of the brain which affect the way people think, feel or act
  • phenothiazines, used as antipsychotics, and also to help stop vomiting
  • ketoconazole, an antifungal medicine
  • erythromycin, an antibiotic
  • ondansetron, a medicine used before or after operations to stop or prevent vomiting
  • anaesthetics, used during operations
  • any other medicine which may make you sleepy.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with tramadol.

You must also be careful if you drink alcohol whilst taking this medicine.

How to take this medicine

Follow carefully all directions given to you by your doctor or pharmacist. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor or pharmacist will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

The recommended dosage is either:

  • one or two 100 mg tablet(s) twice a day (morning and evening)- maximum 4 tablets per day

or

  • one 150 mg or 200 mg tablet twice a day (morning and evening) - maximum 2 tablets per day.

For some people the starting dose may be lower.

If you are over 75 you may be prescribed a lower dose, with a maximum of 300 mg in total per day.

You may also be prescribed a lower dose if you have liver problems.

If you have kidney problems your doctor may recommend a bigger time interval between doses.

If your liver or kidney problems are severe you should not take Tramadol SR.

How to take it

Swallow the tablets whole with water.

Do NOT chew, crush or dissolve them.

This will release all the active ingredient for pain relief quite quickly. Side effects may then occur.

When to take it

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

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

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

  • if you feel that you do not need as much tramadol as your doctor has prescribed for you, talk to your doctor
  • tell your doctor if your pain is not helped or gets worse. Do not take increased amounts or extra doses of tramadol unless your doctor advises you to

If you take this medicine for more than a few months your doctor will monitor you regularly.

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

If you forget to take it

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

Do not take a double dose to make up for missed doses.

This may increase the chance of unwanted side effects.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much tramadol, you may have constricted pupils, go into shock, vomit, have problems breathing, become unconscious, and/or suffer fits (convulsions).

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you plan to have any vaccinations or immunisations
  • you become pregnant or plan to breastfeed (tell your doctor immediately)
  • you are about to have any blood tests
  • you are going to have surgery.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking tramadol.

Things you must not do

Do not:

  • give this medicine to anyone else, even if their symptoms seem similar to yours
  • take your medicine to treat any other complaints unless your doctor or pharmacist tells you to
  • stop taking your medicine, or change the dosage, without checking with your doctor.

Things to be careful of

Avoid or be especially careful driving or operating machinery or doing anything else that requires concentration and good reflexes; tramadol can cause drowsiness, dizziness or fatigue in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Avoid drinking large quantities of alcohol, as this may make you feel even more sleepy, and may also increase the chance of liver problems.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking tramadol or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

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

This list includes the more common side effects. Mostly, these are mild:

  • dizziness
  • feeling sleepy, tired or weak
  • headache
  • constipation, diarrhoea
  • wind, indigestion, feeling or being sick
  • sweating
  • dry mouth
  • flushing
  • dilated pupils
  • feeling faint or dizzy when standing up (due to lowered blood pressure)
  • changes in appetite

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

These may be serious side effects. You may need medical attention. Most of these side effects are rare.

  • mild skin reactions or itching
  • sudden increase or decrease in blood pressure
  • muscle weakness, feeling uncoordinated
  • trembling, twitching
  • tingling sensation (pins and needles),
  • problems speaking
  • feeling "high"
  • hallucinations (seeing, feeling or hearing things that are not there)
  • feeling spaced out, confused or unable to make proper decisions
  • problems sleeping, nightmares
  • blurred vision
  • difficulty or pain when passing urine, or passing less urine than usual
  • Serotonin Syndrome: signs of this vary and are not specific. They may include sudden fever, sweating, confusion, hallucinations, loss of coordination, agitation, diarrhoea, muscle twitching, sudden jerking movements, overactive reflexes, difficulty with walking and balance, fast heart beat, sweating, muscle spasm, racing thoughts, restlessness. Serotonin Syndrome may result from interaction of tramadol with other medicines which increase serotonin effects, for example, the SSRI antidepressants.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and are usually very rare. You may need urgent medical attention or hospitalisation.

  • chest tightness, wheezing or pain in the chest
  • faster or slower heart rate, palpitations, fainting or collapse
  • convulsions (fits)
  • problems breathing or asthma getting worse

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to tramadol, stop taking this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hayfever-like symptoms

Withdrawal Symptoms

If you are taking this medicine for a long while, your body may become used to tramadol and mild withdrawal symptoms may occur if you suddenly stop taking it. For example, you may become agitated, shaky, hyperactive, anxious, or nervous, have problems sleeping, and/or suffer fever, muscle pain or chills.

Very rarely, people have had panic attacks, severe anxiety, hallucinations, tingling sensation (pins and needles), ringing in the ears, confusion, delusions, paranoia, or a feeling of being spaced out or apart from everything.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, 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 or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What Terry White Chemists Tramadol SR looks like

100 mg tablets
Off-white, round, biconvex tablets

150 mg tablets
Off-white, capsule-shaped tablets

200 mg tablets
Off-white, capsule-shaped tablets

Contained in blister packs in cartons of 20 tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 100 mg, 150 mg or 200 mg of tramadol as the active ingredient.

It also contains the following inactive ingredients:

  • Calcium hydrogen phosphate
  • Hydroxypropylcellulose
  • Colloidal anhydrous silica
  • Magnesium stearate

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

Terry White Chemists Tramadol SR 100mg tablets
Blister packs
AUST R 154401.

Terry White Chemists Tramadol SR 150mg tablets
Blister packs
AUST R 154402.

Terry White Chemists Tramadol SR 200mg tablets
Blister packs
AUST R 154403.

Sponsor

Southern Cross Pharma Pty Ltd
56 Illabunda Drive
Malua Bay, NSW, 2536

Distributor

Symbion Pharmacy Services Pty Ltd
48-58 Overseas Drive
Noble Park North, VIC 3174
Australia

Terry White Chemists is a registered trade mark of Symbion Pharmacy Services Pty Ltd.

This leaflet was last updated in:
November 2010.

BRAND INFORMATION

Brand name

Terry White Chemists Tramadol SR Twice daily sustained release tablets

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Name of the medicine

Tramadol hydrochloride.

Excipients.

Calcium hydrogen phosphate, hyprolose, anhydrous colloidal silica and magnesium stearate.

Description

Chemical name: (1RS,2RS)-2-[(dimethylamino)methyl)]-1- (3-methoxyphenyl)cyclohexanol hydrochloride. Molecular formula: C16H25NO2.HCl. MW: 299.84. CAS: 53611-16-8. 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.

Pharmacology

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.

Pharmacodynamics.

Although the mode of action is not completely understood, 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.

Pharmacokinetics.

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 1.)

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 Precautions). 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%).

Indications

Relief of moderate to severe pain.

Contraindications

Individuals with known hypersensitivity to tramadol or any excipients; acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs; 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.

Precautions

Acute abdominal conditions.

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

Respiratory depression.

Tramadol should be administered cautiously in patients at risk of respiratory depression. 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.

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.

Patients physically dependent on opioids.

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 therefore 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. Cases of dependence and abuse of tramadol have been reported rarely.

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 Interactions with Other Medicines). 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.

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 Impaired renal function and Impaired hepatic function, below.)

Impaired renal function.

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 prolonged 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.

Impaired hepatic function.

Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In cirrhotic patients, dosage reduction is recommended (see Dosage and Administration).

Effects on fertility.

No effects on fertility in rats were observed for tramadol at oral dose levels of up to 50 mg/kg/day.

Use in pregnancy.

(Category C)
There are no adequate and well controlled studies with tramadol in pregnant women, therefore tramadol should not be used during pregnancy. Studies in animals using intravenous or intramuscular routes of administration have not been conducted.
Tramadol has been shown to be embryotoxic and fetotoxic 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 fetus 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 fetal toxicity consisted primarily of decreased fetal 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 fetal 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.

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. 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.

Use in lactation.

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.

Use in children.

The use of tramadol is not recommended as safety and efficacy in children 12 years and under have not been established.

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.

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.

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.

Effect on ability to drive or operate machinery.

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

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.
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 Contraindications), tricyclics antidepressants and mirtazapine may cause serotonin toxicity. Serotonin syndrome is likely when one of the following is observed.
Spontaneous clonus.
Inducible or ocular clonus with agitation or diaphoresis.
Tremor and hyper-reflexia.
Hypertonia and body temperature > 38°C and inducible or ocular clonus. Withdrawal of the serotonergic medicines usually brings about a rapid improvement. Drug treatment depends on the nature and severity of the symptoms.

Use with coumarin derivatives.

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

Drugs which reduce the seizure threshold.

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

Use with 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 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 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, 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 preoperative or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

Adverse 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.

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.

Drug abuse and dependence.

Although tramadol can produce drug dependence of the mu-opioid type (like codeine or dextropropoxyphene) and potentially may be abused, there has been little evidence of abuse in clinical experience to date. In clinical trials, tramadol produced some effects similar to an opioid, and at supratherapeutic doses was recognised as an opioid in subjective/ behavioural studies.
Part of the activity of tramadol is thought to be derived from its active metabolite, which is responsible for some delay in onset of activity and some extension of the duration of mu-opioid activity. Delayed mu-opioid activity is believed to reduce a drug's abuse liability.

Tolerance and withdrawal.

Tolerance development has been reported to be relatively mild. Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor, pyrexia, myalgia, chills and gastrointestinal symptoms. Other symptoms that have very rarely been seen with tramadol discontinuation include panic attacks, severe anxiety, hallucinations, paraesthesiae, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation, paranoia).

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

Paediatric use.

The use of Tramadol SR is not recommended as safety and efficacy in children over the age of 12 years have not been established.

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 SR prolonged release tablets are not recommended.
Since only 7% of an administered dose is removed by haemodialysis, dialysis patients can receive their regular dose on the day of dialysis. Tramadol is not recommended in patients with severe renal impairment (creatinine clearance < 10 mL/minute).

Hepatic insufficiency.

Tramadol SR should not be used in patients with severe hepatic insufficiency.

Overdosage

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 overdosage is due to ingestion of a sustained release oral dose form of tramadol, emptying the stomach by gastric lavage should be considered because of the possibility of ongoing release in the stomach. 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. 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.
Contact the Poisons Information Centre on 131 126 for advice on the management of overdose.

Presentation

Modified (sustained) release tablets (off white), 100 mg (round, biconvex; AUST R 154401), 150 mg (capsule shaped; AUST R 154402), 200 mg (capsule shaped; AUST R 154403): 20's (blister packs in carton).

Storage

Store below 25°C.

Poison Schedule

S4.