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Grunenthal Ltd

Units 1 and 2 Stokenchurch Business Park, Ibstone Road, Stokenchurch, Buckinghamshire, HP14 3FE, UK
Medical Information Direct Line: +44 (0)870 351 8960
Medical Information e-mail: medicalinformationie@grunenthal.com


Summary of Product Characteristics last updated on medicines.ie: 19/10/2016
SPC Zydol 100mg Solution for Injection


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1. NAME OF THE MEDICINAL PRODUCT

ZYDOL 100 mg / 2 ml Solution for Injection


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ZYDOL 100 mg / 2 ml Solution for injection ampoule contains 100 mg tramadol hydrochloride in 2 ml solution, i.e. 50 mg tramadol hydrochloride per ml.

Excipient with known effect: 1 ml of solution for injection contains 0.7 mg sodium.

For the full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Solution for injection or infusion

Clear colourless, aqueous solution.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Treatment of moderate to severe pain


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4.2 Posology and method of administration

The dose 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. The total daily dose of 400 mg tramadol hydrochloride should not be exceeded, except in special clinical circumstances.

Unless otherwise prescribed, ZYDOL should be administered as follows:

Adults and adolescents above the age of 12 years

The usual dosage is 50 or 100 mg 4-6 hourly (see section 5.1).

Intravenous injections must be given slowly over 2-3 minutes. For post-operative pain, administer an initial bolus of 100 mg. During the 60 minutes following the initial bolus, further doses of 50mg may be given every 10-20 minutes, up to a total dose of 250mg including the initial bolus. Subsequent doses should be 50mg-100mg 4-6 hourly up to a total daily dose of 400mg.

Children above the age of 1 year

The recommended single dose of tramadol hydrochloride is 1 mg/kg to 2 mg/kg body weight. The total daily dose of 8 mg tramadol hydrochloride per kg body weight or 400 mg tramadol hydrochloride, whichever is lower, should not be exceeded per day..

On account of their high dosage strengths, capsules, prolonged release tablets and dispersible tablets are not intended for children below the age of 12 years

Older 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 elimination may be prolonged. Therefore, if necessary, the dosage interval is to be extended according to the patient's requirements.

Patients with 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 intervals should be carefully considered according to the patient's requirements.

Method of administration

The solution for injection is to be injected slowly or diluted in infusion solution and infused.

It can be administered by intramuscular, intravenous, subcutaneous injection or intravenous infusion.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Duration of administration

Tramadol should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with tramadol is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.


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4.3 Contraindications

ZYDOL solution for injection is contraindicated

- in hypersensitivity to the active substance or any of the excipients listed in section 6.1,

- in acute intoxication with alcohol, hypnotics, analgesics, opioids, or other psychotropic medicinal products,

- in patients who are receiving MAO inhibitors or who have taken them within the last 14 days (see section 4.5),

- in patients with epilepsy not adequately controlled by treatment,

- for use in narcotic withdrawal treatment.


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4.4 Special warnings and precautions for use

Tramadol may only be used with particular caution in opioid-dependent patients, patients with head injury, shock, a reduced level of consciousness of uncertain origin, disorders of the respiratory centre or function, increased intracranial pressure.

In patients sensitive to opiates tramadol should only be used with caution.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered (see section 4.5), or if the recommended dosage is significantly exceeded (see section 4.9) as the possibility of respiratory depression cannot be excluded in these situations.

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 (400 mg). In addition, tramadol may increase the seizure risk in patients taking other medicinal products that lowers the seizure threshold (see section 4.5). Patients with epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances.

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 with tramadol should only be carried out for short periods under strict medical supervision.

Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.


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4.5 Interaction with other medicinal products and other forms of interaction

Tramadol should not be combined with MAO inhibitors (see section 4.3).

In patients treated with MAO inhibitors in the 14 days prior to the use of the opioid pethidine, life-threatening interactions on the central nervous system, respiratory and cardiovascular function have been observed. The same interactions with MAO inhibitors cannot be ruled out during treatment with ZYDOL.

Concomitant administration of tramadol with other centrally depressant medicinal products including alcohol may potentiate the CNS effects (see section 4.8).

The results of pharmacokinetic studies have so far shown that on the concomitant or previous administration of cimetidine (enzyme inhibitor) clinically relevant interactions are unlikely to occur. Simultaneous or previous administration of carbamazepine (enzyme inducer) may reduce the analgesic effect and shorten the duration of action.

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 medicinal products (such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions.

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

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

Other active substances known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied (see section 4.8).

In a limited number of studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.


4.6 Pregnancy and lactation

Pregnancy

Animal studies with tramadol revealed at very high doses effects on organ development, ossification and neonatal mortality. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy. Therefore ZYDOL should not be used 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. Chronic use during pregnancy may lead to neonatal withdrawal symptoms.

Breast-feeding

During lactation about 0.1 % of the maternal dose is secreted into the milk. ZYDOL is not recommended during breast-feeding. After a single administration of tramadol it is not usually necessary to interrupt breast- feeding.

Fertility

Post marketing surveillance does not suggest an effect of tramadol on fertility. Animal studies did not show an effect of tramadol on fertility.


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4.7 Effects on ability to drive and use machines

Even when taken according to instructions, tramadol may cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators. This applies particularly in conjunction with other psychotropic substances, particularly alcohol.


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4.8 Undesirable effects

Rapid intravenous administration may be associated with a higher incidence of adverse effects and therefore should be avoided.

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

The frequencies are defined as follows:

Very common: ≥1/10

Common: ≥1/100, <1/10

Uncommon: ≥1/1000, <1/100

Rare: ≥1/10 000, <1/1000

Very rare: <1/10 000

Not known: cannot be estimated from the available data

Cardiac disorders:

Uncommon: cardiovascular regulation (palpitation, tachycardia). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.

Rare: bradycardia

Investigations:

Rare: increase in blood pressure

Vascular disorders:

Uncommon: cardiovascular regulation (postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.

Metabolism and nutrition disorders:

Rare: changes in appetite

Respiratory, thoracic and mediastinal disorders:

Rare: respiratory depression, dyspnoea

If the recommended doses are considerably exceeded and other centrally depressant substances are administered concomitantly (see section 4.5), respiratory depression may occur.

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

Nervous system disorders:

Very common: dizziness

Common: headache, somnolence

Rare: paraesthesia, tremor, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope, speech disorders.

Convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).

Psychiatric disorders:

Rare: hallucinations, confusion, sleep disturbance, delirium, anxiety and nightmares. Psychic adverse reactions may occur following administration of tramadol, which vary individually in intensity and nature (depending on personality and duration of treatment). 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). Drug dependence may occur. Symptoms of drug withdrawal syndrome, similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor 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, depersonalisation, derealisation, paranoia)

Eye disorders:

Rare: miosis, mydriasis, blurred vision

Gastrointestinal disorders:

Very common: nausea

Common: constipation, dry mouth, vomiting

Uncommon: retching, gastrointestinal discomfort (a feeling of pressure in the stomach, bloating), diarrhoea

Skin and subcutaneous tissue disorders:

Common: hyperhidrosis

Uncommon: dermal reactions (e.g. pruritus, rash, urticaria)

Musculoskeletal and connective tissue disorders:

Rare: motorial weakness

Hepatobiliary 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.

Renal and urinary disorders:

Rare: micturition disorders (dysuria and urinary retention)

Immune system disorders:

Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis

Metabolism and nutrition disorders:

Not known: hypoglycaemia

General disorders and administration site conditions:

Common: 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie


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4.9 Overdose

Symptoms

In principle, on intoxication with tramadol symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.

Treatment

The general emergency measures apply. Keep open the respiratory tract (aspiration!), maintain respiration and circulation depending on the symptoms. The antidote for respiratory depression is naloxone. In animal experiments naloxone had no effect on convulsions. In such cases diazepam should be given intravenously.

In case of intoxication orally, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities.

Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with ZYDOL with haemodialysis or haemofiltration alone is not suitable for detoxification.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other opioids; ATC code: N02 AX02

Tramadol is a centrally acting opioid analgesic. It is a non selective pure agonist at μ, δ and κ opioid receptors with a higher affinity for the μ receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.

Tramadol has an antitussive effect. In contrast to morphine, analgesic doses of tramadol over a wide range have no respiratory depressant effect. Also gastrointestinal motility is less affected. Effects on the cardiovascular system tend to be slight. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth) that 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 2 mg/kg or multiple doses of up to 8 mg/kg per day (to a maximum of 400 mg 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 than 1 year (see section 4.2).


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5.2 Pharmacokinetic properties

After intramuscular administration in humans, tramadol is absorbed rapidly and completely: the mean peak serum concentration (Cmax) is reached after 45 minutes and bioavailability is almost 100%.

The half-life of the terminal elimination phase (t½β) was 6.0 ± 1.5 h in young volunteers. Tramadol pharmacokinetics show little age dependence, the minimal changes being therapeutically irrelevant. In patients above the age of 65 years, the t½β was 6.5 ± 1.7 h on oral administration. In volunteers aged over 75 years, t½β was 7.0 ± 1.6 h on oral administration.

Since tramadol is eliminated both metabolically and renally, the terminal half-life t½β may be prolonged in impaired hepatic or renal function. However, the increase in the t½β values is relatively low if at least one of these organs is functioning normally. In patients with liver cirrhosis t½β, tramadol was a mean of 13.3 ± 4.9 h; in patients with renal insufficiency (creatinine clearance < 5ml/min) it was 11.0 ± 3.2 h.

Paediatric population

The pharmacokinetics of tramadol and O-desmethyltramadol after single-dose and multiple-dose 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 O-desmethyltramadol in children under 1 year of age.


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5.3 Preclinical safety data

On repeated oral and parenteral administration of tramadol for 6 - 26 weeks in rats and dogs and oral administration for 12 months in dogs haematological, clinico-chemical and histological investigations showed no evidence of any substance-related changes. Central nervous manifestations only occurred after high doses considerably above the therapeutic range: restlessness, salivation, convulsions, and reduced weight gain. Rats and dogs tolerated oral doses of 20 mg/kg and 10 mg/kg body weight respectively, and dogs rectal doses of 20 mg/kg body weight without any reactions.

In rats tramadol dosages from 50 mg/kg/day upwards caused toxic effects in dams and raised neonate mortality. In the offspring retardation occurred in the form of ossification disorders and delayed vaginal and eye opening. Male fertility was not affected. After higher doses (from 50 mg/kg/day upwards) females exhibited a reduced pregnancy rate. In rabbits there were toxic effects in dams from 125 mg/kg upwards and skeletal anomalies in the offspring.

In some in-vitro test systems there was evidence of mutagenic effects. In-vivo studies showed no such effects. According to knowledge gained so far, tramadol can be classified as non-mutagenic.

Studies on the tumorigenic potential of tramadol hydrochloride have been carried out in rats and mice. The study in rats showed no evidence of any substance-related increase in the incidence of tumours. In the study in mice there was an increased incidence of liver cell adenomas in male animals (a dose-dependent, non-significant increase from 15 mg/kg upwards) and an increase in pulmonary tumours in females of all dosage groups (significant, but not dose-dependent).


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

water for injection

sodium acetate


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6.2 Incompatibilities

ZYDOL solution for injection has proved to be incompatible (immiscible) with solutions for injection of diazepam, diclofenac, indometacin, phenylbutazone, midazolam, piroxicam and isoxicam.


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6.3 Shelf life

5 years.

Once opened, Zydol should be used immediately and any unused portions should be discarded.


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6.4 Special precautions for storage

Do not store above 30°C

Store in the original container.


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6.5 Nature and contents of container

ZYDOL solution for injection is supplied in boxes of 5 clear Type I glass ampoules, each ampoule containing 2ml of tramadol hydrochloride.


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6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused product or waste material should be disposed of in accordance with local requirements.

Instructions for handling

Calculation of injection volume

1) Calculate the total dose of tramadol hydrochloride (mg) required: bodyweight (kg) x dosage (mg/kg)

2) Calculate the volume (ml) of diluted solution to be injected: divide the total dose (mg) by an appropriate concentration of diluted solution (mg/ml; see table below).

Table: Dilution of ZYDOL solution for injection

ZYDOL 50mg solution for injection + diluent added

ZYDOL 100mg solution for injection + diluent added

Concentration of diluted solution for injection (mg tramadol hydrochloride/ml)

1 ml + 1 ml

2 ml + 2 ml

25.0 mg/ml

1 ml + 2 ml

2 ml + 4 ml

16.7 mg/ml

1 ml + 3 ml

2 ml + 6 ml

12.5 mg/ml

1 ml + 4 ml

2 ml + 8 ml

10.0 mg/ml

1 ml + 5 ml

2 ml + 10 ml

8.3 mg/ml

1 ml + 6 ml

2 ml + 12 ml

7.1 mg/ml

1 ml + 7 ml

2 ml + 14 ml

6.3 mg/ml

1 ml + 8 ml

2 ml + 16 ml

5.6 mg/ml

1 ml + 9 ml

2 ml + 18 ml

5.0 mg/ml

According to your calculation, dilute the contents of ZYDOL ampoule by adding a suitable diluent, mix and administer the calculated volume of diluted solution. Discard the excess solution for injection.

ZYDOL solution for injection is physically and chemically compatible for up to 24 hours with 4.2% sodium bicarbonate and Ringer's solution and for up to 5 days with the following infusion solutions.

0.9% sodium chloride

0.18% sodium chloride and 4% glucose

sodium lactate compound

5% glucose

Haemaccel


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7. MARKETING AUTHORISATION HOLDER

Grünenthal Ltd.,

Regus Lakeside House

1 Furzeground Way

Stockley Park East

Uxbridge

Middlesex UB11 1BD

United Kingdom


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8. MARKETING AUTHORISATION NUMBER(S)

PA 1189/1/4


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:  

16th April 1993

Date of last renewal:  

22nd May 2008


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10. DATE OF REVISION OF THE TEXT

October 2016



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Active Ingredients

 
   Tramadol Hydrochloride