ZAMADOL 24HR 400 MG PROLONGED-RELEASE TABLETS - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

ZAMADOL 24hr 400mg prolonged release tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 400 mg of tramadol hydrochloride

Excipients with known effect:

Each prolonged-release tablet contains 3.40 mg lactose monohydrate (see section 4.4).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Prolonged release tablet

White film coated, oval shaped tablets approximately 19 mm in length marked T 400 on one side

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

The management of moderate to severe pain.

These tablets are indicated in adults and adolescents aged 12 years and above.

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 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 <Invented name> 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). 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.

Patients transferring from immediate release tramadol formulations should have their total daily dose calculated, and start on the nearest dose in the PR tablet range.

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.

Paediatric population under 12 years of age: Not recommended in children under 12 years of age.

Method of administration

Oral administration.

These tablets should be taken at 24-hourly intervals and must be swallowed whole and not broken, crushed or chewed.

4.3 Contraindications

Hypersensitivity to tramadol or to any of the excipients of the product listed in section 6.1. 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

Opioids may cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep related hypoxemia. Opioid use may increase the risk of CSA in a dose-dependent manner in some patients. Opioids may also cause worsening of pre-existing sleep apnoea (see section 4.8). In patients who present with CSA, consider decreasing the total opioid dosage.

Tramadol should be used with caution in patients with a history of epilepsy or susceptibility to seizures; with severely impaired hepatic or renal function; in the presence of head injury; with increased intracranial pressure; with respiratory depression; in the presence of shock.

Concomitant use of Tramadol and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Tramadol concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

With the use of this product the patient may develop tolerance to the drug and require progressively higher doses to maintain pain control, and develop physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy, especially after long-term use. When a patient no longer requires therapy with tramadol, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

There is potential for abuse and development of psychological dependence [addiction] to opioid analgesics, including tramadol. Therefore, the clinical need for continued analgesic treatment should be reviewed regularly. Treatment should be for short periods and under strict medical supervision. These tablets should be used with particular care in patients with a history of alcohol and drug abuse.

Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

Epileptic seizures 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 epileptic seizures may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold, (see section 4.5).

CYP2D6 metabolism

Tramadol is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is a risk of developing side effects of opioid toxicity even at commonly prescribed doses.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases, this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:

Population African/Ethiopian African American Asian

Prevalence % 29%

3.4% to 6.5%

1.2% to 2%

3.6% to 6.5%

6.0%

1.9%

1% to 2%

Caucasian

Greek

Hungarian

Northern European

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Paediatric Population

Post-operative use in children

There have been reports in the published literature that tramadol given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life threatening adverse events. Extreme caution should be exercised when tramadol is administered to children for post-operative pain relief and should be accompanied by close monitoring for symptoms of opioid toxicity including respiratory depression.

Children with compromised respiratory function

Tramadol is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of opioid toxicity.

4.5 Interaction with other medicinal products and other forms of interaction

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4). Drugs which depress the CNS include but are not limited to: other opioids (including antitussives and substitution therapy), anxiolytics, hypnotics and sedatives (including benzodiazepines), antipsychotics, antidepressants, phenothiazines and alcohol.

Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake 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 medicines, such as selective serotonin reuptake inhibitors (SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), MAO inhibitors (see section 4.3), tricyclic antidepressants (TCAs) 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 medicines 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 half-life of tramadol, but this is not clinically relevant.

Co-administered ritonavir may increase serum concentration of tramadol resulting in tramadol toxicity.

Digoxin toxicity has occurred rarely during co-administration of digoxin and tramadol.

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.

The analgesic effect of tramadol is in part mediated by inhibition of the re-uptake of norepinephrine and enhancement of the release of serotonin (5-HT). In studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirements of tramadol in patients with postoperative pain.

4.6 Fertility, pregnancy and lactation

Pregnancy

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. Prolonged use of tramadol hydrochloride during pregnancy can result in neonatal opioid withdrawal syndrome. Therefore, tramadol 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.

Breastfeeding

Approximately 0.1% of the maternal dose of tramadol is excreted in breast milk. In the immediate postpartum period, for maternal oral daily dosage up to 400 mg, this corresponds to a mean amount of tramadol ingested by breast-fed infants of 3% of the maternal weight-adjusted dosage. For this reason tramadol should not be used during lactation or alternatively, breastfeeding should be discontinued during treatment with tramadol. Discontinuation of breastfeeding is generally not necessary following a single dose of tramadol.

Fertility

No fertility studies in humans have been conducted with tramadol.

Post marketing surveillance data does not sufficiently describe the effect of tramadol on human fertility. In animal studies, no effect on fertility has been observed with tramadol (see section 5.3).

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/…-driving-law.

4.8 Undesirable effects

The following frequency categories form the basis for classification of the undesirable effects:

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)

Paediatric population

Neonatal drug withdrawal syndrome may occur in infants born to mothers taking tramadol, however the frequency is unknown (see section 4.6).

As these tablets are made using an insoluble matrix from which the active ingredient is gradually released, the patient may notice the matrix in their faeces.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Symptoms of overdosage are typical of other opioid analgesics, and include miosis, vomiting, circulatory collapse, sedation and coma, seizures and respiratory depression which may, in severe cases, result in a fatal outcome.

Management

A patent airway must be maintained. The pure opioid antagonists such as naloxone are specific antidotes against symptoms from opioid overdose induced by tramadol, though it will not antagonize tramadol’s in­hibitory effects on MAO reuptake or serotonin releasing effects. Other supportive measures should be employed as needed. Naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam. In case of oral intake of overdose, consider activated charcoal if the patient presents within one hour of ingestion of tramadol, provided the patient's airway can be protected.

Although it may seem reasonable to assume that later administration of activated charcoal may be beneficial for prolonged-release preparations and drugs that slow gastric emptying, there is no clinical trial evidence to support this.

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: Analgesic, Other opioids. ATC code: N02AX02

Mechanism of action

Tramadol is a centrally acting analgesic. 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 contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and serotonin.

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

Absorption

Following oral administration of a single dose, tramadol is almost completely absorbed and the absolute bioavailability is approximately 70%.

Biotransformation

Tramadol is metabolised principally by CYP2D6 to the therapeutically active to O-desmethyltramadol (M1), which has been shown to have analgesic activity in rodents, and also via CYP3A4 to the N-desmethyl metabolite. These metabolites may undergo further sulfation and glucuronidation reactions. 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.

Elimination

The elimination half-life of tramadol is around 6 hours, although this is extended to around 16 hours following prolonged absorption from the tramadol prolonged-release tablet.

Tramadol and its metabolites are almost completely excreted with the urine.

Linearity/non-linearity

Frequent dosing of conventional dosage forms leads to an accumulation of plasma concentrations which is greater than would be predicted from single dose data. This is considered to be a consequence of saturation of hepatic enzymes responsible for the metabolism of tramadol. From prolonged-release formulations, as a result of the controlled delivery of tramadol, the enzymes in the liver are not subject to saturation and a linear accumulation of plasma concentrations is noted following regular once- or twice-daily dosing.

Following administration of one Zamadol 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 Zamadol 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 <Invented name> 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 Zamadol 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 Zamadol 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 Zamadol tablet 200 mg administered once-daily were in line with single dose data, confirming that the controlled delivery of tramadol from Zamadol minimises the non-linearity associated with faster-releasing 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 O-desmethyltramadol 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 Odesmethyltramadol in children under 1 year of age.

5.3 Preclinical safety data

Genotoxicity

Tramadol was non-genotoxic in a bacterial mutation test, an in vitro human lymphocyte chromosome aberration assay and the in vivo mouse micronucleus assay. However, positive genotoxic results have been reported in the literature for the mouse lymphoma assay only in the presence of metabolic activation. Overall the weight of evidence indicates that tramadol does not pose a genotoxic risk to humans.

Carcinogenicity

Oral tramadol administered daily to rats and mice for 2 years did not show carcinogenicity

Reproductive and developmental toxicity

No effects of tramadol have been observed on male or female fertility in rats. Fetal malformations occurred in a rat developmental study in the presence of maternal toxicity and mortality. No developmental effects were observed in the rat at 20 mg/kg/day when plasma concentrations of tramadol and O-desmethyltramadol were 2.1× and 2.0× the estimated mean clinical Cmax and 0.6× and 0.7× the estimated mean clinical AUCt at the maximum recommended dose of Zamadol 400 mg once daily. When female rats were treated during gestation and lactation there was increased pup mortality and decreased body weights during lactation for the offspring at maternally toxic dose levels of 60 mg/kg/day.

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

Not applicable.

6.3. Shelf life

3 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, 10, 14, 15, 20, 28, 30, 50, 56, 60 or 100 tablets).

2) Polypropylene containers with polyethylene lids (containing 2, 7, 10, 14, 15, 20, 28, 30, 50, 56, 60 or 100 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

UK

8. MARKETING AUTHORISATION NUMBER

PL 16950/0087

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

28/11/2007