SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zamadol® Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Tramadol hydrochloride 50 mg/ml of injection solution (100 mg per ampoule).

3 PHARMACEUTICAL FORM

Clear, colourless sterile solution for injection. Zamadol Injection has an osmolarity of 320-380 mOsmol, whereas normal serum is 285-290 mOsmol. Zamadol Injection therefore is slightly hypertonic.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of moderate to severe pain.

4.2 Posology and method of administration

The injection is for parenteral administration either intramuscularly, by slow intravenous injection or, when diluted in solution, by infusion or patient controlled analgesia. The dose of Zamadol Injection should be adjusted to the intensity of the pain and the sensitivity of the individual patient. The lowest effective dose for analgesia should generally be selected.

Adults:

A dose of 50 or 100 mg 4-6 hourly is usually required. Intravenous injections must be given slowly over 2-3 minutes.

In post-operative pain, an initial bolus of 100 mg is administered. For the 60 minutes following this initial bolus, 50 mg doses may be given every 10-20 minutes up to a total dose of 250 mg including the initial bolus.

Subsequent doses should be 50 or 100 mg 4-6 hourly up to a total daily dose of 600 mg.

A total parenteral daily dose of over 600 mg should not be exceeded except in special circumstances.

Elderly patients:

A dose adjustment is not usually necessary in patients up to 75 years without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years the elimination may be prolonged. Therefore, if necessary the dosage intervals should be carefully considered according to the patients requirements.

Renal insufficiency/dialysis and hepatic impairment:

In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage interval should be carefully considered according to the patient’s requirements.

•    For creatinine clearance <30 ml/min the dosing should be increased to 12 hourly intervals.

•    For creatinine clearance <10 ml/min (severe renal impairment) tramadol is not recommended.

Tramadol is removed very slowly by haemodialysis or haemofiltration and therefore post-dialysis dosing to maintain analgesia is usually unnecessary.

Children

Over 12 years: Dosage as for adults

Under 12 years: Zamadol Injection has not been studied in children. Therefore, safety and efficacy have not been established and the product should not be used in children.

4.3 Contraindications

Zamadol Injection should not be given to patients who have previously shown hypersensitivity to the active substance tramadol or to any of the excipients.

The product should not be administered to patients suffering from acute intoxication with hypnotics, centrally acting analgesics, opioids, psychotropic drugs or alcohol.

Tramadol should not be administered to patients who are receiving monoamine oxidase inhibitors or within 2 weeks of their withdrawal.

Contraindicated in patients suffering from uncontrolled epilepsy.

Tramadol must not be used for narcotic withdrawal treatment.

4.4 Special warnings and precautions for use

Warnings

Tramadol has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment should be for short periods under strict medical supervision. In rare cases at therapeutic doses, tramadol has the potential to cause withdrawal symptoms.

Zamadol Injection is not a suitable substitute in opioid dependent patients. The product does not suppress morphine withdrawal symptoms although it is an opioid agonist.

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see section 4.5).

Precautions

Zamadol Injection should be used with prudence in patients who have shown previous hypersensitivity to opiates, and in patients with severe renal or hepatic impairment, head injury, decreased level of consciousness, increased intracranial pressure, or patients in shock or at risk of convulsions.

At recommended therapeutic doses Zamadol Injection are unlikely to produce clinically relevant respiratory depression. Care should however be taken when administering Zamadol SR Capsules to patients with existing respiratory depression or excessive bronchial secretion and in those patients taking concomitant CNS depressant drugs.

4.5 Interaction with other medicinal products and other forms of interaction

Patients treated with monoamine oxidase inhibitors within 14 days prior to the administration of the opioid pethidine have experienced life-threatening interactions affecting the central nervous system as well as the respiratory and circulatory centres. The possibility of similar interactions occurring between monoamine oxidase inhibitors and tramadol cannot be ruled out.

Tramadol may potentiate the CNS depressant effects of other centrally acting drugs (including alcohol) when administered concomitantly with such drugs.

Tramadol can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs) serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), antipsychotics and other seizure threshold lowering medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions (see section 4.4).

Concomitant therapeutic use of tramadol and serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO-inhibitors (see section 4.3), tricyclic antidepressants and mirtazapine may cause serotonin toxicity. Serotonergic 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 oC and inducible or ocular clonus.

Withdrawal of the serotonergic drugs usually brings about a rapid improvement. Treatment depends on the type and severity of the symptoms.

Administration of Zamadol Injection together with carbamazepine results in markedly decreased serum concentrations of tramadol which may reduce analgesic effectiveness and shorten the duration of action.

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

The combination of mixed agonists/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol is not recommended because it is theoretically possible that the analgesic effect of a pure agonist is attenuated under these circumstances.

There is no interaction with food.

4.6 Pregnancy and lactation

Zamadol Injection should not be used throughout pregnancy as there is inadequate evidence available to assess the safety of tramadol in pregnant women. Tramadol - administered before or during birth - does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant.

Lactation

Zamadol Injection should not be administered during breast feeding as tramadol and its metabolites have been detected in breast milk. 0.1% of the dose administered to the mother may be excreted in milk.

4.7 Effects on ability to drive and use machines

Zamadol Injection may cause drowsiness and this effect may be potentiated by alcohol and other CNS depressants. If patients are affected they should be warned not to drive or operate machinery.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if:

-    The medicine has been prescribed to treat a medical or dental problem,

-    You have taken it according to the instructions given by the prescriber and in the information provided with the medicine, and

-    It was not affecting your ability to drive safely

4.8 Undesirable effects

The most commonly reported adverse drug reactions are nausea and dizziness, both occurring in more than 10% of patients.

Immune system disorders:

Rare (>1/10,000, <1/1,000): Allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis.

Metabolism and nutrition disorders:

Rare (>1/10,000, <1/1,000): Changes in appetite.

Frequency not known (cannot be estimated from the available data): hypoglycaemia

Psychiatric disorders:

Rare (>1/10,000, <1/1,000): psychic side-effects may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood (usually elation, occasionally dysphoria), changes in activity (usually suppression, occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour, perception disorders), hallucinations, confusion, sleep disturbances and nightmares.

Prolonged administration of Zamadol Injection may lead to dependence (see section 4.4) Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms.

Nervous system disorders:

Very common (>1/10) dizziness

Common (>1/100, <1/10): headache, drowsiness.

Rare (>1/10,000, <1/1,000): epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with drugs which can lower the seizure threshold or themselves induce cerebral convulsions (e.g. antidepressants or anti-psychotics, see section 4.5 "Interaction with other medicinal products and other forms of interaction".

Paraesthesia and tremor.

Very rare (<1/10,000): vertigo

Eye disorders:

Rare (>1/10,000, <1/1,000): blurred vision.

Cardiac disorders:

Uncommon (>1/1,000, <1/100): effects on cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse effects may occur especially on intravenous administration and in patients who are physically stressed.

Rare (>1/10,000, <1/1,000): bradycardia, increase in blood pressure.

Vascular disorders:

Very rare (<1/10,000): flushing.

Respiratory disorders:

Worsening of asthma has also been reported, though a causal relationship has not been established.

Respiratory depression has been reported. If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5 "Interaction with other medicinal products and other forms of interaction") respiratory depression may occur.

Gastrointestinal disorders:

Very common (>1/10): vomiting, nausea.

Common (>1/100, <1/10): constipation, dry mouth

Uncommon (>1/1,000, <1/100): retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating).

Hepato-biliary disorders:

In a few isolated cases an increase in liver enzyme values has been reported in a temporal connection with the therapeutic use of tramadol.

Skin and subcutaneous tissue disorders:

Common (>1/100, <1/10): sweating.

Uncommon (>1/1,000, <1/100): dermal reactions (e.g. pruritus, rash, urticaria).

Musculoskeletal, connective tissue and bone disorders:

Rare (>1/10,000, <1/1,000): motorial weakness.

Renal and urinary system disorders:

Rare (>1/10,000, <1/1,000): micturition disorders (difficulty in passing urine and urinary retention).

General disorders:

Common (>1/100, <1/10): fatigue.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms of tramadol overdose include vomiting, miosis, sedation, seizures, respiratory depression and hypotension, with circulatory failure and coma. Respiratory failure may also occur. Such symptoms are typical of opioid analgesics.

Treatment of overdose requires the maintenance of the airway and cardiovascular functions. Respiratory depression may be reversed using naloxone and fits controlled with diazepam. Naloxone administration may increase the risk of seizures.

The treatment of acute overdose of tramadol using haemodialysis or haemofiltration alone is not sufficient or suitable due to the slow elimination of tramadol from the serum by these routes.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Analgesic, ATC code: N02AX02

Tramadol is a centrally acting analgesic which possesses opioid agonist properties. Tramadol consists of two enantiomers, the (+)-isomer is predominantly active as an opioid with preferential activity for the p-receptor. The (-)-isomer potentiates the analgesic effect of the (+)-isomer and is active as an inhibitor of noradrenaline and serotonin uptake thereby modifying the transmission of pain impulses.

Tramadol also has an antitussive action. At the recommended dosages, the effects of tramadol given orally on the respiratory and cardiovascular systems appear to be clinically insignificant. The potency of tramadol is reported to be 1/10 to 1/6 of morphine.

5.2 Pharmacokinetic properties

a) General

The mean absolute bioavailability after intramuscular administration was found to be 100%.

The distribution of tramadol following intravenous administration is rapid and in two phases with different half-lives of 0.31 ± 0.17 hours (initial rapid phase) and 1.7 ± 0.4 hours (slower phase) respectively.

After intravenous administration of 100 mg tramadol, the serum concentration was 613 ± 221 ng/ml at 15 minutes post dosing and 409 ± 79 ng/ml at 2 hours post dosing. Tramadol has a high tissue affinity with an apparent volume of distribution of 203 L after intravenous dosing in healthy volunteers.

Tramadol undergoes hepatic metabolism with approximately 85% of an intravenous dose being metabolised in young healthy volunteers.

In humans tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active. There are considerable interindividual quantitative differences between the other metabolites. So far, eleven metabolites have been found in the urine. Animal experiments have shown that O-desmethyltramadol is more potent than the parent substance by the factor 2 - 4. Its half life t/p (6 healthy volunteers) is 7.9 h (range 5.4 - 9.6 h) and is approximately that of tramadol.

The inhibition of one or both P450 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism of tramadol, may affect the plasma concentration of tramadol or its active metabolite. The clinical consequences of such interactions are not known.

Tramadol is essentially excreted via the kidneys. The mean elimination halflife of tramadol following intravenous administration is 5-6 hours. Total clearance of tramadol was 28.0 L/h following intravenous administration.

b) Characteristics in patients

Effect of age: Tramadol pharmacokinetics show little age-dependence in volunteers up to the age of 75 years. In volunteers aged over 75 years, the terminal elimination half-life was 7.0 ± 1.6 h compared to 6.0 ± 1.5 h in young volunteers after oral administration.

Effect of hepatic or renal impairment: As both tramadol and its pharmacologically active metabolite, O-demethyl tramadol, are eliminated both metabolically and renally, the terminal half-life of elimination (t/) may be prolonged in patients with hepatic or renal dysfunction. However, the increase in t/ is relatively small if either excretory organ is functioning normally. In liver cirrhosis patients, the mean t/ of tramadol was 13.3 ± 4.9 hours. In patients with renal failure (creatinine clearance <5 mL/min) the t/ of tramadol was 11.0 ± 3.2 hours and that of Ml was 16.9 ± 3.0 hours. Extreme values observed to date are 22.3 hours (tramadol) and 36.0 hours (Ml) in liver cirrhosis patients and 19.5 hours (tramadol) and 43.2 hours (M1) in renal failure patients.

5.3 Preclinical safety data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. Studies of tramadol in rats and rabbits have revealed no teratogenic effects. However, embryo toxicity was shown in the form of delayed ossification. Fertility, reproductive performance and development of offspring were unaffected.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium acetate

Water for injection

Nitrogen (insert head space gas)

6.2 Incompatibilities

Precipitation will occur if Zamadol Injection is mixed in the same syringe with injections of diazepam, diclofenac sodium, indomethacin, midazolam and piroxicam.

6.3    Shelf life

2 years

6.4    Special precautions for storage

No special requirements.

6.5 Nature and contents of container

A colourless glass ampoule containing 2 ml of injection solution. Ampoules are contained in a pre-fabricated blister strip, (5 ampoules per strip) which is enclosed in a cardboard outer carton. Cartons contain either 5 or 10 ampoules.

6.6 Special precautions for disposal

Zamadol Injection is physically and chemically compatible for up to 24 hours with the following infusion solutions:

Ringer-Lactate solution 5% Glucose

The prepared infusion solution should be made immediately before use.

7. MARKETING AUTHORISATION HOLDER

Meda Pharmaceuticals Ltd Skyway House Parsonage Road Takeley

Bishop’s Stortford CM22 6PU

8    MARKETING AUTHORISATION NUMBER(S)

PL 15142/0118

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/02/2002 / 26/05/2005

11/07/2014