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 > 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.

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)	Hypoglycaemia
Nervous system
disorders	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%) Common (1 to 10%)	Vomiting Dry mouth Retching
Uncommon (0.1 to 1%)	Constipation Gastrointestinal irritation
Rare (<0.1%)	Anorexia Diarrhoea
Skin & appendages Common (1 to 10%) Uncommon (0.1 to 1%)	Sweating Pruritus, rash, urticaria

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

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 line with single dose data, confirming that the controlled delivery of tramadol from ZYDOL XL minimises the nonlinearity associated with faster-releasing 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^oC.

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

11/07/2014