ZYDOL XL 400 MG PROLONGED RELEASE TABLETS

Active substance: TRAMADOL HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
ZYDOL XL 400 mg prolonged release tablets.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Tablets containing tramadol hydrochloride 400 mg
For excipients, see 6.1

3

PHARMACEUTICAL FORM
Prolonged release, white, film coated tablets, marked T 400

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 opioid-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
Dizziness

Very Common (>10%)

Muzziness

Common (1 to 10%)

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,

bronchospasm,

wheezing, angioneurotic oedema)
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.

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 O-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 O-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 line 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.

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 30°C

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 16950/0092

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14 June 1999

10

DATE OF REVISION OF THE TEXT
11/07/2014

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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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