Consumer medicine information

Tramahexal Solution for injection

Tramadol hydrochloride

BRAND INFORMATION

Brand name

Tramahexal Solution for injection

Active ingredient

Tramadol hydrochloride

Schedule

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Tramahexal.

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 using this medicine 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 TRAMAHEXAL IS USED FOR

This medicine is used to relieve moderate to severe pain.

It contains the active ingredient tramadol hydrochloride.

Tramadol hydrochloride belongs to a 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.

This medicine is very unlikely to be addictive if given as prescribed by your doctor. However, if you are using this medicine for a long period, your body may become used to it and you may experience some symptoms of withdrawal if you stop Tramahexal suddenly. It is important that you discuss this issue with your doctor.

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

BEFORE YOU USE TRAMAHEXAL

When you must not use it

Do not use this medicine if you have an allergy to:

tramadol hydrochloride, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description
any other similar medicines known as opioid analgesics, e.g. morphine, 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 use this medicine if you have or have had any of the following medical conditions:

regularly drink large quantities of alcohol
taking medicines for depression known as monoamine oxidase inhibitors (MAOI) or have taken any within the last two weeks (e.g. Nardil, Parnate)
treatment for drug or substance dependence.

Do not use 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 using this medicine, talk to your doctor.

Before you start to use it

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

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

disorder of the kidney, liver or pancreas
stomach problems
lung or breathing problems, such as asthma
fits or convulsions/epilepsy
head injury or severe headache
drug, alcohol or substance dependence.

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

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

If you have not told your doctor about any of the above, tell him/her before you start using Tramahexal.

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 Tramahexal may interfere with each other. These include:

medicines for depression including selective serotonin reuptake inhibitors (SSRI’s) and tricyclic anti-depressants (TCA’s)
medicines for mental or psychiatric disorders including phenothiazines
medicines to help you sleep
quinidine, a medicine used to treat irregular heartbeats
carbamazepine, a medicine to treat epilepsy
coumarin derivatives (e.g. warfarin: brand names are Coumadin or Marevan)
some antibiotics.

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

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

HOW TO USE TRAMAHEXAL

Your doctor will decide what dose and how long you will receive Tramahexal. This depends on your condition and how you react to this medicine.

Tramahexal should only be given by a nurse or doctor. It can be given as an injection into your veins or your muscles.

If you use too much (overdose)

As Tramahexal is given under medical supervision, it is very unlikely that you will receive too much.

However, if you experience severe side effects after being given Tramahexal, tell your doctor or nurse immediately.

Symptoms of an overdose may include drowsiness, confusion, breathing difficulty, fits or convulsions.

WHILE YOU ARE USING TRAMAHEXAL

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given Tramahexal.

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

If you become pregnant while using this medicine, tell your doctor immediately.

Tell your doctor if you feel you do not need as much Tramahexal. Your doctor may adjust your dose.

Tell your doctor if you feel Tramahexal is not helping or your pain is worsening.

Things you must not do

Do not use Tramahexal 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 Tramahexal affects you.

This medicine may cause drowsiness, dizziness or light-headedness in some people, especially after the first dose. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are using this medicine.

If you drink alcohol, dizziness or light-headedness may be worse.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Tramahexal.

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 or drowsiness
headache
fatigue
constipation
nausea or vomiting
sweating
dry mouth
indigestion
changes in appetite.

These are the more common side effects of this medicine. Mostly, these are mild and short-lived.

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

confusion
anxiety
muscle weakness
tremor
change in mood
sleep disturbance
blurred vision
skin reactions including rash, itching hives and skin lumps
difficulty in passing urine
sudden onset of low blood pressure.

The above list includes serious 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:

swelling of the face, lips, mouth or throat which may cause difficulty in swallowing
breathing difficulties including chest tightness, chest pains and wheezing
faintness or collapse
fast or irregular heartbeats
hallucination
fits or convulsions
Serotonin Syndrome: symptoms include fever, sweating, confusion, agitation, muscle twitching, difficulty with walking and balance.

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

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

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

AFTER USING TRAMAHEXAL

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

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

Protect from light.

Do not store Tramahexal 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

Return any unused or out of date medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

Tramahexal comes in one strength:

Tramahexal 100mg/2mL - clear colourless liquid, free of particles, packaged in clear glass ampoules.

Available in boxes of 5 ampoules.

Ingredients

Active ingredient:

Tramahexal 100mg/2mL - 100mg tramadol hydrochloride in 2mL.

Inactive ingredients:

sodium acetate trihydrate
water for injection.

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

Supplier

Tramahexal is supplied in Australia by:
Sandoz Pty Ltd
ABN 60 075 449 553
Level 4, 100 Harris St
Pyrmont NSW 2009
Tel: 1800 634 500

Novartis New Zealand Ltd
Private Bag 65904 Mairangi Bay
Auckland 0754
New Zealand
Tel: 0800 354 335

This leaflet was revised in May 2011.

Australian Register Number
100mg/2mL injection: AUST R 102013

BRAND INFORMATION

Brand name

Tramahexal Solution for injection

Active ingredient

Tramadol hydrochloride

Schedule

Name of the medicine

Tramadol hydrochloride.

Excipients

Sodium acetate trihydrate, water for injection.

Description

Chemical name: (1RS, 2RS)-2- [(dimethylamino)methyl]- 1-(3-methoxyphenyl) cyclohexanol hydrochloride. Molecular formula: C₁₆H₂₅NO₂.HCl. MW: 299.84. CAS: 36282-47-0. pKa: 9.41. Tramadol is an odourless, white to off white crystalline powder that is freely soluble in water and in methanol and very slightly soluble in acetone. The water/ n-octanol partition coefficient is 1.35 at pH 7.

Pharmacology

Pharmacodynamics.

Tramadol is a centrally acting synthetic analgesic of the aminocyclohexanol group with opioid-like effects. It is not derived from natural sources, nor is it chemically related to opiates.
Although preclinical testing has not completely explained the mode of action, at least two complementary mechanisms appear applicable: binding to mu-opioid receptors and inhibition of reuptake of noradrenaline and serotonin. The opioid-like activity of tramadol derives from low affinity binding of the parent compound to mu-opioid receptors and higher affinity binding of the principal active metabolite, mono O-desmethyltramadol, denoted M1, to mu-opioid receptors. In animal models, M1 is up to 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 intramuscular injection of tramadol 50 mg, 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 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

Known hypersensitivity to tramadol or any excipients; acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic medicines; patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days; known sensitivity to opioids; 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.

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.)

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.

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 is 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).

Carcinogenesis, mutagenesis, impairment of fertility

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.
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. 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. Chronic use during pregnancy may lead to neonatal withdrawal symptoms. If tramadol were to be used during labour, it may cause respiratory depression in the newborn infant. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labour.
The effect of tramadol, if any, on the later growth, development and functional maturation of the child is unknown.

Use in lactation.

Tramadol is not recommended during breastfeeding, because its safety in infants and newborn infants 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.

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

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.
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 medicine that increases serotonin by any mechanism should alert the treating doctor to the possibility of an interaction. In isolated cases there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotonergic medicines such as selective serotonin reuptake inhibitors (SSRIs). Signs of serotonin syndrome may be, e.g. confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea. 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.

Medicines which reduce the seizure threshold.

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics and other seizure threshold lowering medicines to cause convulsions.

Use with monoamine oxidase inhibitors.

Tramadol should not be used in patients who are taking monoamine oxidase inhibitors (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 P450 isoenzyme. Medicines 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 medicines 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 preoperative or postoperative application of the antiemetic 5HT₃ antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

Adverse Effects

Adverse effects that may occur after administration of tramadol resemble those known to occur with opioids. Adverse effects were recorded in 13,802 patients from trials with different formulations of tramadol. The nature and incidence of effects (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.

Metabolism and nutrition disorders.

Rare: changes in appetite.

Psychiatric disorders.

Rare: hallucinations, confusion, sleep disturbance, anxiety nightmares.

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

Gastrointestinal disorders.

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

Hepatobiliary disorders.

Very rare: elevated liver enzymes.

Nervous system disorders.

Not known: speech disorders. Very common: dizziness. Common: autonomic nervous effects (mainly dry mouth, perspiration), headache, sedation, asthenia. Uncommon: trembling. Rare: changes in mood (usually elevation, occasionally dysphoria), paraesthesia, coordination disturbance, tremor, respiratory depression, seizures, involuntary muscle contractions, changes in activity (usually suppression, occasionally increase), changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders), syncope.

Endocrine disorders.

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

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.

Eye disorders.

Rare: visual disturbance (blurred vision). Not known: mydriasis.

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 effects, 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, delusion, personalization, derealization, paranoia).

Dosage and Administration

The dose of Tramahexal injection should be titrated according to the severity of the pain and the clinical response of the individual patient.
Tramahexal injection may be administered by intravenous or intramuscular injection. Few data are available on the administration of tramadol by repeated intramuscular injection. Intravenous injections should be given slowly over two to three minutes. For postoperative pain, an initial bolus of 100 mg should be administered. Subsequent doses of 50 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 or 100 mg every four to six hours to a maximum of 400 mg/day.

Paediatric use.

The use of Tramahexal injection 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. In cases of severe renal insufficiency tramadol is 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.

Hepatic insufficiency.

Tramahexal injection should not be used in patients with severe hepatic insufficiency.

Pharmaceutical compatibility.

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

Overdosage

Contact the Poisons Information Centre on 131 126 for advice on management of 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, so that general supportive treatment is recommended. Adequate ventilation should be maintained. Haemodialysis is not expected to be helpful because it removes only a small percentage of the administered dose. 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.

Presentation

Solution for injection (clear, colourless, free from visible particles): 50 mg/1 mL*, 100 mg/2 mL: 5's (glass ampoules in boxes).
*Not currently marketed in Australia.

Storage

Store below 25°C. Protect from light.

Poison Schedule

S4.

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Tramahexal Solution for injection

Tramadol hydrochloride

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