Consumer medicine information

Tramadol AN Injection

Tramadol hydrochloride

BRAND INFORMATION

Brand name

Tramadol AN Injection

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tramadol AN Injection.

What is in this leaflet

This leaflet answers some common questions about TRAMADOL AN. 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 AN against the benefits this medicine is expected to have for you.

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

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

What TRAMADOL AN is used for

TRAMADOL AN is used to relieve moderate to severe pain and belongs to a group of medicines called analgesics (pain relievers).

Your doctor may have prescribed TRAMADOL AN for another reason. Ask your doctor why TRAMADOL AN has been prescribed for you.

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

TRAMADOL AN is not normally addictive although some cases have been reported.

Before you are given TRAMADOL ACT

When you must not use it

TRAMADOL AN should not be given to you if:

  • you have a known allergy to tramadol or any of the ingredients listed at the end of this leaflet.
Some of the symptoms of an allergic reaction may include skin rash, itching, difficulty breathing and swelling of the face (including lips, tongue, throat etc)
  • you are taking medicine for depression containing a "monoamine oxidase inhibitor" (such as Nardil, Parnate), or have taken one within the past two weeks.

TRAMADOL AN should not be given to you after the expiry date printed on the pack. If the expiry date has passed, it may not work as well.

TRAMADOL AN should not be used if the packaging is torn or shows signs of tampering.

Do not give TRAMADOL AN to children. There is no experience with the use of TRAMADOL AN in children.

If you are not sure whether you should be given TRAMADOL AN, talk to your doctor.

Before you are given it

You must tell your doctor if:

  1. you have a known allergy to tramadol or any of the ingredients listed at the end of this leaflet.
  2. you are known to be sensitive to opioids.
  3. you drink alcohol every day.
  4. you have or ever had any other health problems, including:
  • any lung or breathing problems
  • any diseases of the kidney, liver or pancreas
  • severe stomach problems
  • a serious head injury
  • any fits or convulsions/ epilepsy.
  1. you have or have had any problems with drug or alcohol dependence.
  2. you are pregnant or intend to become pregnant. TRAMADOL AN is not recommended for use during pregnancy. Talk to your doctor about the risks and benefits of using TRAMADOL AN during pregnancy.
  3. you are breast-feeding or plan to breast-feed.
    TRAMADOL AN is not recommended for use during breast-feeding. Talk to your doctor about the risks and benefits of using TRAMADOL AN when breast- feeding.

If you have not told your doctor about any of the above, tell them before you are given TRAMADOL AN.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may interfere with TRAMADOL AN. These include:

  • carbamazepine (e.g. Tegretol)
  • coumarin derivatives (e.g. Warfarin: Some Brand names are Coumadin, or Marevan)
  • medicines for irregular or rapid heart beat (e.g. quinidine)
  • medicines for depression, sleeplessness or mental conditions such as selective serotonin reuptake inhibitors (SSRI's), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic anti-depressants, mirtazapine, bupropion, tetrahydrocannabinol, phenothiazines or anti-psychotics
  • some antibiotics.

These medicines may be affected by TRAMADOL AN, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Other interactions not listed above may also occur.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while you are being given TRAMADOL AN.

How TRAMADOL AN is given

TRAMADOL AN injection is given into a vein or muscle.

Your doctor will decide:

  • how you will receive TRAMADOL AN,
  • what dose and
  • how often

If you have been prescribed TRAMADOL AN injections, your doctor or nurse will administer them for you. Take them with you when you visit your doctor.

If you are given too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (tel: 131 126) or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have been given too much TRAMADOL AN. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are being given TRAMADOL AN injection.

Things you must do

If you become pregnant while you are taking TRAMADOL AN, tell your doctor immediately.

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

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

Tell your doctor if your pain gets worse.

If you have to have any tests tell your doctor you are being given TRAMADOL AN. TRAMADOL AN may affect the results of some tests.

Things you must not do

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

Do not use TRAMADOL AN to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how TRAMADOL AN affects you.

TRAMADOL AN may make you drowsy or dizzy.

Side effects

Check with your doctor as soon as possible if you have any problems while you are being given TRAMADOL AN, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines, TRAMADOL AN can cause side effects. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

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

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

Common side effects:

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

Less common side effects:

  • indigestion
  • changes in appetite
  • skin reactions
  • sudden onset of low blood pressure, collapse
  • muscle weakness
  • tremor
  • seizures
  • respiratory depression
  • changes in mood
  • confusion
  • sleep disturbance
  • blurred vision
  • difficulty in passing urine

Serotonin Syndrome: signs of this vary and are not specific: they may include fever, sweating, confusion, agitation, diarrhoea, muscle twitching, difficulty with walking and balance. Serotonin Syndrome may result from interaction of tramadol with other medicines which increase serotonin effects, for example, the SSRI antidepressants.

Tell your doctor immediately if you experience any of the following side-effects, as urgent medical treatment may be required:

  • skin rash (red spots or patches), itching, hives, skin lumps
  • swelling or puffiness of the eyelids, face or lips
  • chest tightness, wheezing or pain in the chest
  • heart palpitations, faintness or collapse
  • hallucinations
  • convulsions.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Can TRAMADOL AN be addictive?

When given as prescribed by your doctor, addiction to TRAMADOL AN is unlikely.

If you are given TRAMADOL AN 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 use tramadol only as directed by your doctor, and do not suddenly stop taking it. Your dosage may need to be gradually reduced.

Tell your doctor if you are worried about addiction.

After using TRAMADOL AN

Storage

Keep your TRAMADOL AN in the pack until it is time for it to be given to you. If you take TRAMADOL AN out of the pack it may not keep well.

Keep it in a cool dry place where the temperature stays below 30º C. Do not store it in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least 1 1/2 metres above the ground is a good place to store medicines.

Disposal

If your TRAMADOL AN passes its expiry date or you no longer need it, ask your pharmacist what to do with any TRAMADOL AN that is left over.

TRAMADOL AN description

What it looks like

TRAMADOL AN is available as an injection solution containing tramadol hydrochloride 100mg/2mL.

It is a clear to slightly yellow coloured liquid contained in 2mL glass ampoules. Available in packs of 5 ampoules.

Ingredients

Active ingredient:

tramadol hydrochloride 100 mg in 2 mL ampoules

Inactive ingredients:

  • sodium acetate
  • water for injections.

TRAMADOL AN does not contain lactose, sucrose, tartrazine or any other azo dyes.

Sponsor

Juno Pharmaceuticals Pty Ltd
42 Kelso St
Cremorne VIC 3121

Date of Preparation:

08 October 2019

Registration Number:

TRAMADOL AN Injection 100mg/2mL:

AUST R 202840

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Tramadol AN Injection

Active ingredient

Tramadol hydrochloride

Schedule

S4

 

1 Name of Medicine

Tramadol hydrochloride.

2 Qualitative and Quantitative Composition

Tramadol hydrochloride is an odourless, white to off-white crystalline powder that is freely soluble in both water and methanol and has a pKa of 9.41. The water/n-octanol partition coefficient is 1.35 at pH 7. It belongs to the synthetic analgesics class and has opioid-like activity.
Tramadol AN solution for injection contains tramadol hydrochloride 100 mg/2 mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tramadol AN solution for injection is a transparent, colourless or slightly yellowish solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Relief of moderate to severe pain.

4.2 Dose and Method of Administration

The dose of tramadol hydrochloride 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 dosage of tramadol hydrochloride solution for injection is as follows:

Tramadol AN solution for injection.

Parenteral administration.

Tramadol AN injection may be administered by intravenous or intramuscular injection. Few data are available on the administration of tramadol hydrochloride by repeated intramuscular injection. Intravenous injections should be given slowly over 2-3 minutes.
For postoperative pain, an initial bolus of 100 mg should be administered.
Subsequent doses of 50 mg or 100 mg every four to six hours may be given, up to a total daily dose of 600 mg.
For less severe pain: 50 mg or 100 mg every four to six hours to a maximum of 400 mg per day.

Paediatric use.

The use of tramadol is not recommended as safety and efficacy in children 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. 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, Use in renal impairment).

Hepatic insufficiency.

Depending on the severity of impairment and individual clinical response, the recommended dosage interval (4 to 6 hours) may require to be extended, and/or the dose level titrated as required (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

4.3 Contraindications

Tramadol is contraindicated in:
individuals with known hypersensitivity to tramadol or any excipients;
acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs;
patients who are receiving MAO inhibitors or who have taken them within the last 14 days;
known sensitivity to opioids;
patients with uncontrolled epilepsy or epilepsy not adequately controlled by treatment.
Tramadol must not be used for narcotic withdrawal treatment.

4.4 Special Warnings and Precautions for Use

General.

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 intra-operative 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 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 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 intra-operative 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 intra-operative recall. Therefore, providing the current practice of administering continuous, potent (volatile or intravenous) anaesthetic agent is followed, tramadol may be used intra-operatively 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. 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.

Use in hepatic impairment.

With the prolonged half-life in hepatic disease, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.
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).

Use in renal impairment.

With the prolonged half-life in renal disease, achievement of steady-state is delayed, so that it may take several days for elevated plasma concentrations to develop.
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, post-dialysis administration to maintain analgesia is not usually necessary.

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. For dosage information, see Section 4.2 Dose and Method of Administration.

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Use with CNS depressants.

Tramadol should be used with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anaesthetic agents, phenothiazines, tranquillisers or sedative hypnotics.
The combination of tramadol with mixed opiate agonists/antagonists (e.g. buprenorphine, pentazocine) is not advisable because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.

Use with other serotonergic agents.

The presence of another drug that increases serotonin by any mechanism should alert the treating physician to the possibility of an interaction. Concomitant therapeutic use of tramadol and serotonergic medicines such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see Section 4.3 Contraindications), tricyclic antidepressants and mirtazapine may cause serotonin 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 re-uptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other seizure threshold-lowering drugs (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.

Use with MAO inhibitors.

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

Other interactions.

Tramadol does not appear to induce its own metabolism in humans, since observed maximal serum concentrations after multiple oral doses are higher than expected based on single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in animals. Concomitant administration of tramadol with carbamazepine causes a significant increase in tramadol metabolism, presumably through metabolic induction by carbamazepine. Patients receiving chronic carbamazepine doses of up to 800 mg daily may require up to twice the recommended dose of tramadol.
Tramadol is metabolised to M1 by the CYP2D6 P450 isoenzyme. Drugs that selectively inhibit that isoenzyme (quinidine, phenothiazines, antipsychotic agents) may cause increased concentrations of tramadol and decreased concentrations of M1. The clinical consequences of these potential effects have not been fully investigated.
Concomitant administration of tramadol with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. Therefore no alteration of the tramadol dosage regimen is recommended.
Other drugs known to inhibit the CYP3A4 isoenzyme of cytochrome P450, such as ketoconazole and erythromycin, may inhibit the metabolism of tramadol (via N-demethylation) and probably the metabolism of the active O-demethylated metabolite (M1). The clinical importance of such an interaction has not been studied.
In a limited number of studies, the pre- or post-operative application of the antiemetic 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.
Studies in animals using IV or IM routes of administration have not been conducted. Tramadol has been shown to be embryotoxic and foetotoxic in mice, rats and rabbits at maternally toxic doses of 120 mg/kg in mice, or higher in rats and 75 mg/kg in rabbits, but was not teratogenic at these dose levels. No harm to the foetus due to tramadol was seen at doses that were not maternally toxic. No drug-related teratogenic effects were observed in progeny of mice, rats or rabbits treated with tramadol (75 mg/kg for rats or 175 mg/kg for rabbits).
Embryo and foetal toxicity consisted primarily of decreased foetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in development or behavioural parameters were also seen in pups from rat dams allowed to deliver. Embryo and foetal lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme maternal toxicity in the rabbit.
In peri- and post-natal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg had decreased weights and pup survival was decreased early in lactation at 80 mg/kg (6 - 10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels.

Labour and delivery.

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

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions that may occur after administration of tramadol resemble those known to occur with opioids. Adverse reactions were recorded in 13,802 patients from trials with different formulations of tramadol. The nature and incidence of reactions (in CIOMS format where very common = > 1/10; common = > 1/100 and < 1/10; uncommon = > 1/1000 and < 1/100; rare = > 1/10,000 and < 1/1000; and very rare = < 1/10,000) were as follows:

Immune system disorders.

Rare: shock reactions, anaphylaxis, allergic reactions.

Endocrine disorders.

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

Metabolism and nutrition disorders.

Rare: changes in appetite.

Psychiatric disorders.

Rare: hallucinations, confusion, 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, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, personalization, derealisation, paranoia).

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 http://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.
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 Poison 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 re-uptake of noradrenaline and serotonin. The opioid-like activity of tramadol derives from low affinity binding of the parent compound to mu-opioid receptors and higher affinity binding of the principal active metabolite, mono O-desmethyltramadol, denoted M1, to mu-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in mu-opioid binding. The contribution of tramadol to human analgesia, relative to M1, is unknown.
Both human and animal studies have shown that antinociception induced by tramadol is only partially antagonised by the opiate antagonist naloxone. In addition, tramadol has been shown to inhibit re-uptake of noradrenaline and serotonin in vitro, as have some other opioid analgesics. These latter mechanisms may contribute independently to the overall analgesic profile of tramadol.
The analgesic effect is dose dependent, but the relationship between serum concentrations and analgesic effect varies considerably between individuals. In one study, the median serum concentration of tramadol required for effective post-operative analgesia was 300 nanogram/mL, with individual values ranging from 20 to 990 nanogram/mL.
Apart from analgesia, tramadol may produce other symptoms similar to that of opioids including: dizziness, somnolence, nausea, constipation, sweating and pruritus. However, tramadol causes significantly less respiratory depression than morphine. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no clinically significant effect on heart rate, left ventricular function or cardiac index. Orthostatic changes in blood pressure have been observed.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Tramadol is administered as a mixture of two stereoisomers; the following information refers to the combined concentration of both isomers.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.

Absorption.

After intramuscular injection of 50 mg tramadol, the bioavailability is approximately 100%, and the peak serum level is attained after 45 minutes (range 15 to 90).

Distribution.

Tramadol is rapidly distributed in the body, with a volume of distribution of 2 - 3 L/kg in young adults. The volume of distribution is reduced by about 25% in those aged over 75 years. Plasma protein binding is about 20% and is independent of concentration up to 10 microgram/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Tramadol crosses both the placenta and the blood-brain barrier. Very small amounts of tramadol and M1 are found in breast-milk (0.1% and 0.02% respectively of the administered dose).

Metabolism.

Tramadol is extensively metabolised after oral administration. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. Only O-desmethyltramadol (M1) is pharmacologically active. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P450. Patients who metabolise drugs poorly via CYP2D6 may obtain reduced benefit from tramadol, due to reduced formation of M1. N-demethylation is catalysed by the CYP3A4 isoenzyme of cytochrome P450. The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol may affect the plasma concentration of tramadol or its active metabolite.

Excretion.

Tramadol and its metabolites are excreted mainly by the kidneys, with a cumulative renal excretion (tramadol and metabolites) of approximately 95%. In young adults approximately 15 - 19% of an administered dose of tramadol is excreted in the urine as unmetabolised drug. In the elderly, this increases to about 35%. Biliary excretion is of little importance. In young adults, the half-life of tramadol is 5 - 7 h and the half-life of M1 is 6 - 8 h. Total clearance is approximately 430 - 610 mL/min.

Pharmacokinetics in patients with hepatic or renal impairment.

Elimination of tramadol and M1 is impaired in patients with hepatic or renal impairment (see Section 4.4 Special Warnings and Precautions for Use). In patients with hepatic impairment, the mean half-life of tramadol was found to be 13 h (range up to 19 h), and the mean half-life of M1 was 19 h (range up to 36 h). In patients with renal impairment including subjects with a considerably decreased CLCr [< 5 mL/min] the mean half-life of tramadol was 11 h (range up to 20 h), and the mean half-life of M1 was 17 h (range up to 43 h).

Pharmacokinetics in the elderly.

In the elderly (age over 75 years), the volume of distribution of tramadol is decreased by 25% and clearance is decreased by 40%. As a result, tramadol Cmax and total exposure are increased by 30% and 50%, respectively, but the half-life of tramadol is only slightly prolonged (by 15%).

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 are sodium acetate and water for injections.

6.2 Incompatibilities

Tramadol AN solution for injection is incompatible with injection solutions containing diclofenac, indomethacin, phenylbutazone, diazepam, flunitrazepam, glyceryl trinitrate or midazolam. Tramadol AN injection is compatible with the following intravenous fluids: 0.9% sodium chloride, 5% glucose, 4.2% sodium bicarbonate, Ringer's solution, Ringer's lactate solution, Dextran 40 (10%) or polygeline 3.5%.

6.3 Shelf Life

3 years.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from light.

6.5 Nature and Contents of Container

Tramadol AN solution for injection contains tramadol hydrochloride 100 mg/2 mL.

Pack size.

Available in packs of 5, Type 1 glass ampoules of 2 mL each.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical name: (1RS, 2RS) -2-[(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.

Chemical structure.


CAS number.

36282-47-0.
Molecular weight: 299.84.
Molecular formula: C16H25NO2.HCl.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes