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ZYDOL XL 300 MG 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 XL 300 mg prolonged release tablets.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Tablets containing tramadol hydrochloride 300 mg.
For excipients, see 6.1

3

PHARMACEUTICAL FORM
Prolonged release, white, film coated tablets, marked T 300.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of moderate to severe pain.

4.2.

Posology and method of administration
ZYDOL XL tablets should be taken at 24-hourly intervals and must be swallowed
whole and not chewed.
The dose should be adjusted to the intensity of the pain and the sensitivity of the
individual patient. The lowest effective correct dose for analgesia should generally be
selected. The correct dosage per individual patient is that which controls the pain with
no or tolerable side effects for a full 24 hours. Patients transferring from immediate
release tramadol preparations should have their total daily dose calculated, and start
on the nearest dose in the ZYDOL XL range. It is recommended that patients are
slowly titrated to higher doses to minimise transient side effects. The need for
continued treatment should be assessed at regular intervals as withdrawal symptoms
and dependence have been reported. (See Section 4.4 Special warnings and
precautions for use). A total daily dose of 400 mg should not be exceeded except in
special clinical circumstances.
Adults and children over 12 years:

The usual initial dose is one 150 mg tablet daily. If pain relief is not achieved, the
dosage should be titrated upwards until pain relief is achieved.
Geriatric 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.
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.
As tramadol is only removed very slowly by haemodialysis or by haemofiltration,
post-dialysis administration to maintain analgesia is not usually necessary.
Children under 12 years:
ZYDOL XL has not been studied in children. Safety and efficacy of ZYDOL XL
have not been established and the product should not be used in children.

4.3

Contraindications
Hypersensitivity to tramadol or to any of the excipients; acute intoxication
with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic
drugs. Tramadol should not be administered to patients who are receiving
monoamine oxidase inhibitors or within two weeks of their withdrawal.
Tramadol must not be used for narcotic withdrawal treatment.

4.4

Special warnings and precautions for use
Warnings
At therapeutic doses withdrawal symptoms have been reported at a frequency
of
1 in 8,000. Reports of dependence and abuse have been less frequent.
Because of this potential the clinical need for continued analgesic treatment
should be reviewed regularly.
In patients with a tendency to drug abuse or dependence, treatment should be
for short periods and under strict medical supervision.

Tramadol is not suitable as a substitute in opiold-dependent patients. Although
it is an opioid agonist, tramadol cannot suppress morphine withdrawal
symptoms.
Precautions
Convulsions have been reported at therapeutic doses and the risk may be
increased at doses exceeding the usual upper daily dose limit. Patients with a
history of epilepsy or those susceptible to seizures should only be treated with
tramadol if there are compelling reasons. The risk of convulsions may increase
in patients taking tramadol and concomitant medication that can lower the
seizure threshold. (See Section 4.5 Interactions with other Medicaments and
other forms of Interaction).
Tramadol should be used with caution in patients with head injury, increased
intracranial pressure, severe impairment of hepatic and renal function and in
patients prone to convulsive disorders or in shock.
Care should be taken when treating patients with respiratory depression, or if
concomitant CNS depressant drugs are being administered, as the possibility
of respiratory depression cannot be excluded in these situations. At therapeutic
doses respiratory depression has infrequently been reported.

4.5.

Interaction with other medicinal products and other forms of interaction
Concurrent administration of tramadol with other centrally acting drugs, including
alcohol, may potentiate CNS depressant effects.
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 > 38ºC 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.
Simultaneous treatment with carbamazepine may shorten the analgesic effect as a
result of a reduction in serum levels of tramadol and its active metabolite.
Co-administration with cimetidine is associated with a small prolongation of the halflife of tramadol, but this is not clinically relevant.
Co-administered ritonavir may increase serum concentrations of tramadol resulting in
tramadol toxicity.
Digoxin toxicity has occurred rarely during co-administration of digoxin and
tramadol.
Other morphine derivatives (including anti-tussives, substitution treatments),
benzodiazepines, barbiturates: Increased risk of respiratory depression, that may be
fatal in overdosage.
Mixed agonists/antagonists (eg buprenorphine, nalbuphine, pentazocine); The
analgesic effect of tramadol, which is a pure agonist, may be reduced and a
withdrawal syndrome may occur.
There have been isolated reports of interaction with coumarin anticoagulants resulting
in an increased INR and so care should be taken when commencing treatment with
tramadol in patients on anticoagulants.

4.6

Pregnancy and lactation
There are no adequate data from the use of tramadol in pregnant women.
Animal studies have shown reproductive toxicity, but not teratogenic effects
(see section 5.3). Tramadol crosses the placental barrier and chronic use
during pregnancy can cause withdrawal symptoms in the new-born baby.
Therefore, it should not be used during pregnancy.
Tramadol administered before or during birth does not affect uterine
contractility. In neonates it may induce changes in respiratory rate which are
not usually clinically relevant.
During lactation very small amounts of tramadol and its metabolites
(approximately 0.1% of an intravenous dose) are found in human breast milk.
Therefore tramadol should not be administered during breast feeding.

4.7

Effects on ability to drive and use machines

Tramadol may cause drowsiness, blurred vision and dizziness which may be
enhanced by alcohol or other CNS depressants. If affected, the patient should
not 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 you have this medicine in your body over a
specified limit unless you have a defence (called the ‘statutory defence’).
This defence applies when:
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.
Please note that it is still an offence to drive if you are unfit because of the
medicine (i.e. your ability to drive is being affected).

Details regarding a new driving offence concerning driving after drugs have been taken in the
UK may be found here: https://www.gov.uk/drug-driving-law.

4.8
Undesirable effects
Metabolism
and
nutrition disorders
Not known (cannot be
estimated from the
available data)
Nervous
disorders

Hypoglycaemia

system

Very Common (>10%)
Common (1 to 10%)

Dizziness
Muzziness
Headache

Uncommon (0.1 to 1%)

Paraesthesia,

Rare (<0.1%)

Blurred vision
Hallucinations
Nightmares
Changes in mood (usually elation, occasionally
dysphoria)
Changes in activity (usually suppression, occasionally
an increase) Changes in cognitive and sensorial capacity
(eg decision behaviour, perception disorders)

Epileptiform convulsions have 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 (eg anti-depressants or anti-psychotics)

Cardiovascular
Uncommon (0.1 to 1%)

Palpitation
Tachycardia
Postural hypotension
Cardiovascular collapse

Rare (<0.1%)

Hypertension
Bradycardia

Respiratory disorders
Rare (<0.1%)

Dyspnoea
Worsening of asthma has also been reported, though a
causal relationship has not been established.
Respiratory depression. If the recommended doses are
considerably exceeded and other centrally depressant
substances are administered concomitantly, respiratory
depression may occur.

Gastro-intestinal
disorders

Nausea

Very Common (>10%)

Vomiting

Common (1 to 10%)

Dry mouth
Retching

Uncommon (0.1 to 1%)

Constipation
Gastrointestinal irritation
Anorexia

Rare (<0.1%)

Diarrhoea

Skin & appendages
Common (1 to 10%)

Sweating

Uncommon (0.1 to 1%)

Pruritus, rash, urticaria

Urogenital
Rare (<0.1%)

Micturition disorders (difficulty in passing urine and
urinary retention)

Body as a whole
Rare (<0.1%)

Muscle weakness
Flushing
Allergic reactions (eg dyspnoea,
wheezing, angioneurotic oedema)

bronchospasm,

Anaphylaxis
Dependence
Withdrawal reactions, similar to those occurring during
opiate withdrawal, may occur and include: agitation,
anxiety, nervousness, insomnia, hyperkinesia, tremor
and gastrointestinal symptoms.
Increase in liver enzyme values have been reported in a
temporal connection with the therapeutic use of
tramadol

4.9

Overdose
Symptoms of overdosage are typical of other opioid analgesics, and include
miosis, vomiting, cardiovascular collapse, sedation and coma, seizures and
respiratory depression.
Supportive measures such as maintaining the patency of the airway and
maintaining cardiovascular function should be instituted; naloxone should be
used to reverse respiratory depression; fits can be controlled with diazepam.
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.
Emptying the gastric contents is useful to remove any unabsorbed drug,
particularly when a prolonged release formulation has been taken.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Tramadol is a centrally acting analgesic (NO2A X 02). It is a non selective pure
agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu
receptor. Other mechanisms that may contribute to its analgesic effect are inhibition
of neuronal re-uptake of noradrenaline and 5HT.
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
Following oral administration of a single dose, tramadol is almost completely
absorbed and the absolute bioavailability is approximately 70%. Tramadol is
metabolised to 0-desmethyltramadol, which has been shown to have analgesic
activity in rodents. The elimination half life of tramadol is around 6 hours, although
this is extended to around 16 hours following prolonged absorption from the ZYDOL
XL tablet.
Following administration of one ZYDOL XL tablet 200 mg in the fasting state, a
mean peak plasma concentration (Cmax) of 192 ng.ml-1 was attained. This was
associated with a median tmax of 6 hours (range 4-8 hours). The availability of
tramadol from the ZYDOL XL tablet 200 mg was complete when compared with an
immediate release tramadol solution 100 mg, after dose adjustment. In the presence of
food, the availability and controlled release properties of ZYDOL XL tablets were
maintained, with no evidence of dose-dumping.
A single dose-proportionality study has confirmed a linear pharmacokinetic response
(in relation to tramadol and 0-desmethyltramadol) following administration of the 200
mg, 300 mg and 400 mg tablets. A steady state study has confirmed the dose adjusted
bioequivalence of the 150 mg and 200 mg tablets administered once-daily. This study
also confirmed that the ZYDOL XL tablet 150 mg provided an equivalent peak
concentration and extent of availability of tramadol to an immediate release capsule
50 mg administered 8-hourly. On this basis it is recommended that patients receiving
immediate release tramadol should be transferred initially to the nearest daily dose of
ZYDOL XL tablets. It may be necessary to titrate the dose thereafter.

A further steady state study has demonstrated that immediate release tramadol tablets
50 mg, administered 6-hourly, provided plasma concentrations that were greater than
would have been anticipated following administration of a single dose. This
observation is consistent with a non-linear elimination of the drug substance. In
contrast, the plasma concentrations from ZYDOL XL tablet 200 mg administered
once-daily were in tine with single dose data, confirming that the controlled delivery
of tramadol from ZYDOL XL minimises the non-linearity associated with fasterreleasing preparations. The more predictable plasma concentrations may lead to a
more manageable dose titration process.
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
Preclinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity, genotoxicity or
carcinogenic potential.
Studies in rats and rabbits have revealed no teratogenic effects. However
embryotoxicity 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
Tablet core
Hydrogenated vegetable oil
Talc
Magnesium stearate

Film coat
Lactose monohydrate
Hypromellose (E464)
Titanium dioxide (E171)
Macrogol 4000

6.2

Incompatibilities
None known.

6.3

Shelf life
Three years.

6.4

Special precautions for storage
Do not store above 30οC.

6.5

Nature and contents of container
1) Pvc blisters with aluminium backing foil (containing 2, 7,14, 28, 30,
56 or 60 tablets).
2)

Polypropylene containers with polyethylene lids (containing 2, 7,14,

28, 30, 56 or 60 tablets).
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
None.

7

MARKETING AUTHORISATION HOLDER
Napp Pharmaceuticals Ltd
Cambridge Science Park
Milton Road
Cambridge
CB4 0GW

8

MARKETING AUTHORISATION NUMBER(S)
PL 16950/0091

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/06/1999 / 14/12/2005

10

DATE OF REVISION OF THE TEXT
05/05/2017

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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