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TRAMADOL 50 MG/ML SOLUTION FOR INJECTION/INFUSION

Active substance(s): TRAMADOL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Tramadol 50 mg/ml solution for injection/infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of solution contains 50 mg of tramadol hydrochloride.
One ampoule (2 ml) contains 100 mg of tramadol hydrochloride.
Excipients with known effect: 2 ml of solution contain 1.4 mg sodium.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Solution for injection/infusion.
Clear colourless solution, free from visible particles.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of moderate to severe pain.

4.2

Posology and method of administration
Posology
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 should not be exceeded, except in
special clinical circumstances (for example, in case of cancer pain or postoperative
severe pain).

Unless otherwise prescribed, Tramadol should be administered as follows:
Adults and adolescents above the age of 12 years
Depending on the intensity of pain, 50–100 mg of tramadol (corresponds to 1-2 ml of
Tramadol) is administered every 4–6 hours. The total daily dose of 400 mg (4
ampoules) should not be exceeded.
Elderly patients
A dose adjustment is not usually necessary in patients up to 75 years without
clinically manifest hepatic or renal insufficiency. In patients over 75 years elimination
may be prolonged. Therefore, if necessary the dosage interval is to be extended
according to individual requirements.
Renal insufficiency/dialysis and hepatic insufficiency
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.
Paediatric population
Tramadol should not be used in children under 1 year of age.
For children up to the age of 12, the single dose of tramadol is 1-2 mg per kg body
weight. The lowest effective dose for analgesia should generally be selected. The total
daily dose must not exceed the lowest of these doses – 8 mg/kg body weight or 400
mg of the active substance.
Method of administration
Intravenous (solution is to be injected slowly (1 ml (50 mg of tramadol
hydrochloride) per minute)), intramuscular or subcutaneous injection. Tramadol may
also be diluted in solution for infusion (for example, 0.9% sodium chloride or 5%
glucose solution) and infused.
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.

4.3

4.4

Contraindications
-

Hypersensitivity to the active substance and/or to any of the excipients listed in
section 6.1

-

Acute intoxication with alcohol, hypnotics, analgesics, opioids, or other
psychotropic medicinal products

-

Patients who are receiving MAO inhibitors or who have taken them
within the last 14 days (see section 4.5)

-

Patients with epilepsy not adequately controlled by treatment

-

For use in narcotic withdrawal treatment.

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 the product 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 a dose of tramadol exceeds the
recommended daily dose (400 mg). Tramadol may increase the seizure risk in
patients taking other medicinal products that lowers the seizure threshold (see section
4.5). In patients with epilepsy or those susceptible to seizures, tramadol may only be
used when absolutely necessary.
Tramadol has a low dependence potential. On long-term use, tolerance, psychic
and physical dependence may develop. Therefore, 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.
This medicinal product is not suitable as a substitute in opioid-dependent patients.
Although tramadol is an opioid agonist, it cannot suppress morphine withdrawal
symptoms.
Tramadol contains less than 1 mmol (23 mg) of sodium in one ampoule.

4.5

Interaction with other medicinal products and other forms of interaction
MAO inhibitors
Tramadol should not be used in combination 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 affecting the central nervous system,
respiratory and cardiovascular function have been observed. The same interactions
with MAO inhibitors cannot be ruled out during treatment with tramadol.
Cimetidine
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.
Carbamazepine
Simultaneous or previous administration of carbamazepine (enzyme inducer) may
reduce the analgesic effect and shorten the duration of action.
CNS-active agents
Concomitant administration of Tramadol with other centrally depressant medicinal
products including alcohol may potentiate the CNS effects (see section 4.8).
Tramadol can induce convulsions and increase the potential for selective serotonin
reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs),
tricyclic antidepressants, antipsychotics and other seizure threshold-lowering
medicinal products (such as bupropion, mirtazapine, tehrahydrocannabinol) 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 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.
Coumarin derivatives

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.
CYP3A4 inhibitors
Other active substances known to inhibit CYP3A4, such as ketoconazole and
erythromycin, might inhibit the metabolism of tramadol (N- demethylation) and
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).
Ondansetron
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

Fertility, pregnancy and lactation
Pregnancy
Animal studies with tramadol at very high doses have revealed 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, tramadol 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. Prolonged use during pregnancy may lead to neonatal withdrawal
symptoms.
Breastfeeding
During lactation about 0.1% of the maternal dose is secreted into the milk. Tramadol
is not recommended during breast-feeding period. It is not usually necessary to
interrupt breast-feeding after a single administration of tramadol.
Fertility
Post marketing surveillance does not suggest an effect of tramadol on fertility.
Animal studies did not show an effect of tramadol on fertility.

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 alcohol and other
psychotropic substances.

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:

4.8



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 and

-

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.

Undesirable effects
The side effects mentioned below are listed according to MedDRA system organ
classification. The frequencies are ranked according to the following convention: very
common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare
(≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from
the available data).
The most commonly reported adverse reactions are nausea and dizziness. These occur
in more than 10% of patients.
Immune system disorders
Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic
oedema) and anaphylaxis.
Cardiac disorders
Uncommon: effect on cardiovascular regulation (palpitations, 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: effect on cardiovascular regulation (postural hypotension or
cardiovascular collapse). These adverse reactions may occur especially on
intravenous administration and in patients who are physically stressed.
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 lowering the seizure threshold (see
sections 4.4 and 4.5).
Metabolism and nutrition disorders
Rare: changes in appetite.
Not known: hypoglycaemia.
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. These include: 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.
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.

Gastrointestinal disorders
Very common: nausea.
Common: constipation, dry mouth, vomiting.
Uncommon: retching, gastrointestinal discomfort (a feeling of pressure in the
stomach, bloating), diarrhoea.
Hepatobiliary disorders
Very rare: 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: hyperhidrosis.
Uncommon: dermal reactions (e.g. pruritus, rash, urticaria).
Musculoskeletal and connective tissue disorders
Rare: muscular weakness.
Renal and urinary disorders
Rare: micturition disorders (dysuria and urinary retention).
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 the national reporting system:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the
Google Play or Apple App Store.

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 should be taken. 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 or prolonged-release formulations.
Tramadol is minimally eliminated from the serum by haemodialysis or
haemofiltration. Therefore treatment of acute intoxication with Tramadol with
haemodialysis or haemofiltration alone is not suitable for detoxification.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: analgesics, other opioids, ATC code: N02AX02
Mechanism of action
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 to 1/6 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).

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%.
Tramadol has a high tissue affinity (Vd,β = 203 ± 40 l). It has a plasma protein binding
of about 20%.
Tramadol passes the blood-brain and placental barriers. Very small amounts of the
substance and its O-desmethyl derivative are found in the breast-milk (0.1% and
0.02% respectively of the applied dose).
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. Up to now, clinically relevant interactions have not
been reported.
Tramadol and its metabolites are almost completely excreted via the kidneys.
Cumulative urinary excretion is 90% of the total radioactivity of the administered
dose. Elimination half-life t1/2,ß is approximately 6 h, irrespective of the mode of
administration. In patients above 75 years of age it may be prolonged by a factor of
approximately 1.4. In patients with cirrhosis of the liver, elimination half-lives of 13.3
± 4.9 h (tramadol) and 18.5 ± 9.4 h (O-desmethyltramadol), in an extreme case 22.3 h
and 36 h respectively, have been determined. In patients with renal insufficiency
(creatinine clearance < 5 ml/min) the values were 11 ± 3.2 h and 16.9 ± 3 h, in an
extreme case 19.5 h and 43.2 h respectively.
In humans tramadol is mainly metabolised by means of N- and O-demethylation and
conjugation of the O-demethylation products with glucuronic acid. Only Odesmethyltramadol is pharmacologically active. There are considerable
interindividual quantitative differences between the other metabolites. So far, 11
metabolites have been found in the urine. Animal experiments have shown that Odesmethyltramadol is more potent than the parent substance by the factor 2 - 4. Its
half-life, t1/2,β (6 healthy volunteers) is 7.9 h (range 5.4 – 9.6 h) and is approximately
that of tramadol.
Tramadol has a linear pharmacokinetic profile within the therapeutic dosage range.
The relationship between serum concentrations and the analgesic effect is dosedependent, but varies considerably in isolated cases. A serum concentration of 100 –
300 ng/ml is usually effective.
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 Odesmethyltramadol 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.

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, clinicochemical 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 in rats 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 15mg/kg upwards) and an increase in pulmonary tumours in females of
all dosage groups (significant, but not dose-dependent).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium acetate trihydrate

Water for injections

6.2

Incompatibilities
Tramadol should not be mixed with solutions for injection or infusion containing
diclofenac, indomethacin, phenylbutazone, diazepam, midazolam, flunitrazepam and
glyceryl trinitrate.
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.

6.3

Shelf life
4 years.
Once ampoule has been opened, the product should be used immediately.
Chemical and physical in-use stability has been demonstrated for 48 hours at 25 °C
with 0.9% sodium chloride and 5% glucose solution.
From a microbiological point of view, unless the method of opening/dilution
precludes the risk of microbial contamination, the product should be used
immediately.
If not used immediately, in-use storage times and conditions are the responsibility of
the user.

6.4

Special precautions for storage
Do not refrigerate or freeze.
For storage conditions after dilution or first opening of the medicinal product, see
section 6.3.

6.5

Nature and contents of container
2 ml of solution in type I hydrolytic class colourless borosilicate glass ampoule with
break line or open point cut.
5 ampoules in a PVC liner.
1 liner (5 ampoules) in a cardboard box.
20 liners (100 ampoules) in a cardboard box (for hospital use).

Not all pack sizes may be marketed.

6.6

Special precautions for disposal
For single use only.
Tramadol is compatible with 0.9% sodium chloride or 5% glucose solution for
infusion.
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 Tramadol solution for injection/infusion

Concentration of diluted
solution (mg tramadol
hydrochloride/ml)
25.0 mg/ml
16.7 mg/ml
12.5 mg/ml
10.0 mg/ml
8.3 mg/ml
7.1 mg/ml
6.3 mg/ml
5.6 mg/ml
5.0 mg/ml

Tramadol 50 mg/ml solution
for
injection/infusion
+
diluent added
2 ml + 2 ml
2 ml + 4 ml
2 ml + 6 ml
2 ml + 8 ml
2 ml + 10 ml
2 ml + 12 ml
2 ml + 14 ml
2 ml + 16 ml
2 ml + 18 ml

According to your calculation, dilute the contents of Tramadol ampoule by adding a
suitable diluent, mix and administer the calculated volume of diluted solution.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
AS KALCEKS
Krustpils iela 53, Rīga, LV-1057, Latvia
Tel.: + 371 67083320

e-mail: kalceks@kalceks.lv

8

MARKETING AUTHORISATION NUMBER(S)
PL 47015/0002

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/09/2017

10

DATE OF REVISION OF THE TEXT
14/09/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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