ZAMADOL INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Zamadol® Injection

3   PHARMACEUTICAL FORM

4   CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of moderate to severe pain.

4.2 Posology and method of administration

Posology

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.

Dosage for adults and adolescents from 12 years of age:

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 of age without clinically manifest hepatic or renal insufficiency. In elderly patients over 75 years of age 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.

Dosage for paediatric 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.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with tramadol in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Method of administration

The solution for injection is to be injected intravenously, intramuscularly, or subcutaneously. Intravenous administration is to be given slowly (1 ml of solution for injection, equivalent to 50 mg of tramadol hydrochloride, per minute).

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

Serotonin syndrome

Serotonin syndrome, a potentially life-threatening condition, has been reported in patients receiving tramadol in combination with other serotonergic agents or tramadol alone (see sections 4.5, 4.8 and 4.9).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose escalations.

Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular abnormalities and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms. Withdrawal of the serotonergic drugs usually brings about a rapid improvement.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of Zamadol Injection and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Zamadol Injection concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dosedependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with tramadol.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

CYP2D6 metabolism:

Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:

Hungarian

1.9%

1% to 2%

Northern European

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit (400 mg). The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold (see section 4.5). Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons.

Adrenal insufficiency

Opioid analgesics may occasionally cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of acute or chronic adrenal insufficiency may include e.g. severe abdominal pain, nausea and vomiting, low blood pressure, extreme fatigue, decreased appetite, and weight loss.

Paediatric population

Post-operative use in children

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

Children with compromised respiratory function

Tramadol is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, i.e. essentially “sodium-free”.

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 Injections are unlikely to produce clinically relevant respiratory depression. Care should however be taken when administering Zamadol Injection 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.

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

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 syndrome, a potentially life-threatening condition (see sections 4.4 and 4.8).

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 Fertility, pregnancy and lactation

Pregnancy

Zamadol Injection should not be used during pregnancy as there is inadequate evidence available to assess the safety of tramadol in pregnant women.

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available. Tramadol – administered before or during birth – does not affect uterine contractility.

Breast-feeding

Approximately 0.1% of the maternal dose of tramadol may be secreted in breast milk. In the immediate post-partum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason, administration to nursing women is not recommended as tramadol may cause respiratory depression in the infant. Alternatively, breast-feeding should be discontinued during treatment with tramadol. Discontinuation of breast-feeding is generally not necessary following a single dose of tramadol.

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.

Frequency unknown: Prolonged administration of Zamadol Injection may lead to drug dependence (see section 4.4 ).

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

Not known: Serotonin syndrome

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.

Respiratory, thoracic and mediastinal disorders

Frequency unknown: Hiccups

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

Uncommon (>1/1,000, <1/100): drug withdrawal syndrome

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

Serotonin syndrome has also been reported.

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.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

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 g-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.

Paediatric population

Effects of enteral and parenteral administration of tramadol have been investigated in clinical trials involving more than 2000 paediatric patients ranging in age from neonate to 17 years of age. The indications for pain treatment studied in those trials included pain after surgery (mainly abdominal), after surgical tooth extractions, due to fractures, burns and traumas as well as other painful conditions likely to require analgesic treatment for at least 7 days.

At single doses of up to 2mg/kg or multiple doses of up to 8mg/kg per day (to a maximum of 400mg per day) efficacy of tramadol was found to be superior to placebo, and superior or equal to paracetamol, nalbuphine, pethidine or low dose morphine. The conducted trials confirmed the efficacy of tramadol. The safety profile of tramadol was similar in adult and paediatric patients older that 1 year (see section 4.2).

5.2 Pharmacokinetic propertiesa) 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-desmthyltramadol 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 cytochrome P450 isoenzymes, CYP3A4 and CYP2D6 involved in the biotransformation of tramadol, may affect the plasma concentration of tramadol or its active metabolite.

Tramadol is essentially excreted via the kidneys. The mean elimination half-life 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.

Paediatric population

The pharmacokinetics of tramadol and O-desmethyltramadol after single-dose and multipledose oral administration to subjects aged 1 year to 16 years were found to be generally similar to those in adults when adjusting for dose by body weight, but with a higher between-subject variability in children aged 8 years and below.

In children below 1 year of age, the pharmacokinetics of tramadol and O-desmethyltramadol have been investigated, but have not been fully characterized. Information from studies including this age group indicates that the formation rate of O-desmethyltramadol via CYP2D6 increases continuously in neonates, and adult levels of CYP2D6 activity are assumed to be reached at about 1 year of age. In addition, immature glucuronidation systems and immature renal function may result in slow elimination and accumulation of Odesmethyltramadol in children under 1 year of age.

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 (f/2) 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 f/2 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 (M1) 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

Mylan Products Ltd.,

Station Close,

Potters Bar,

Herts,

EN6 1TL,

United Kingdom.