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ZYDOL SR 50MG PROLONGED-RELEASE TABLETS

Active substance(s): TRAMADOL HYDROCHLORIDE / TRAMADOL HYDROCHLORIDE / TRAMADOL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
ZYDOL SR 50 mg prolonged-release tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 50 mg tramadol hydrochloride.
Excipient: Each prolonged-release tablet contains 2.5 mg lactose monohydrate (see
section 4.4).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged-release tablets
Pale yellow coloured, round, biconvex, film-coated tablets, marked with the
manufacturer‘s logo on one side and T0 on the other side

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 doses of 400 mg tramadol hydrochloride should not be
exceeded, except in special clinical circumstances.
Unless otherwise prescribed, ZYDOL SR should be administered as follows:

Adults and adolescents above the age of 12 years:
The usual initial dose is 50-100 mg tramadol hydrochloride twice daily, morning and
evening. If pain relief is insufficient, the dose may be titrated upwards to 150 mg or
200 mg tramadol hydrochloride twice daily (see section 5.1).
Paediatric population:
ZYDOL SR is not suitable for children below the age of 12 years.
Older peoples:
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.
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. In cases of severe renal and/or
severe hepatic insufficiency ZYDOL SR prolonged-release tablets are not
recommended.
Method of administration
The tablets are to be taken whole, not divided or chewed, with sufficient liquid,
independent of meals.

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

Contraindications
ZYDOL SR 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.

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 hydrochloride 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.
ZYDOL SR prolonged-release tablets contain lactose. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption, should not take this medicinal product.

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 SR.
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 reuptake 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

Fertility, 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 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. 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. Tramadol
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.
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.
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:

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:
o

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

o

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

o

It was not affecting your ability to drive safely

Undesirable effects
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
hypoglycaemia
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: speech disorders, paraesthesia, tremor, epileptiform convulsions, involuntary
muscle contractions, abnormal coordination, syncope.
Convulsions occurred mainly after administration of high doses of tramadol or after
concomitant treatment with medicinal products which can lower the seizure threshold
(see section 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
General disorders:

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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

5

PHARMACOLOGICAL PROPERTIES

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 re-uptake 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).

5.2

Pharmacokinetic properties
More than 90% of ZYDOL SR is absorbed after oral administration. The mean
absolute bioavailability is approximately 70 %, irrespective of the concomitant intake
of food. The difference between absorbed and non-metabolised available tramadol is
probably due to the low first-pass effect. The first-pass effect after oral administration
is a maximum of 30 %.
Tramadol has a high tissue affinity (Vd,ß = 203 ± 40 l). It has a plasma protein
binding of about 20 %.
After administration of ZYDOL SR 100 mg the peak plasma concentration Cmax
=141 ± 40 ng/ml is reached after 4.9 h; after administration of ZYDOL SR 200 mg
Cmax 260 ± 62 ng/ml is reached after 4.8 hours.
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).
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 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, eleven
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,ß (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 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. In case of impaired hepatic or renal function the half-life may be slightly
prolonged. 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.
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 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).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:
microcrystalline cellulose,
hypromellose 100 000 mPa s,
magnesium stearate,
colloidal anhydrous silica.
Film coating:
hypromellose 6 mPa s,
lactose monohydrate,
macrogol 6000,
propylene glycol,
talc,
titanium dioxide (E 171),
yellow iron oxide (E 172).

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Aluminium/Polypropylene or Aluminium/PVC/PVDC foil blisters.
Pack sizes of 10, 20, 30, 50, 60, 100, 150 (10x15) prolonged-release tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling
No special requirements.
Any unused product or waste material should be disposed of in accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Grünenthal Ltd.
Regus Lakeside House
1 Furzeground Way
Stockley Park East
Uxbridge
Middlesex
UB11 1BD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 21727/0024

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
23/02/2011

10

DATE OF REVISION OF THE TEXT
26/09/2016

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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