This information is intended for use by health professionals

1. Name of the medicinal product

Brimisol PR 100 mg Prolonged-Release Tablet

2. Qualitative and quantitative composition

Each prolonged-release tablet contains 100mg Tramadol Hydrochloride

Excipients: Each prolonged-release tablet contains 36.0 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Prolonged-Release Tablet

(PR tablet)

White to off white, round, biconvex, film coated tablets with “100” embossed on one side and “BL” on 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, Brimisol PR 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.

For doses not practicable with this strength, other strengths of this medicinal product are available.

Children

Brimisol PR is not suitable for children below the age of 12 years.

Geriatric patients

A dose adjustment is not usually necessary in elderly 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 Insufficiency

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 patients requirements.

In cases of severe renal and/or severe hepatic insufficiency Brimisol PR 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

Brimisol PR is contraindicated

- In hypersensitivity to tramadol or any of the excipients listed in section 6.1

- In acute intoxication with alcohol, hypnotics, analgesics, opioids, or 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 concomitant treatment with linezolid ( see section 4.5)

- In patients with epilepsy not adequately controlled by treatment,

- For use in narcotic withdrawal treatment

Tramadol must not be administered during breast feeding if long term treatment, i.e. if it is necessary for more than 2 to 3 days (see section 4.6).

4.4 Special warnings and precautions for use

Consumption of alcohol is not recommended during treatment with tramadol.

Concomitant treatment with carbamazepine is not recommended (see section 4.5).

Brimisol PR 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 impairment of hepatic or renal function, and in diabetic patients because of the occurrence of hypoglycemia with tramadol..

In patients sensitive to opiates the product 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 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 be only 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. At therapeutic doses, withdrawl symptoms have been reported with a frequency of 1 in 8,000 while reports of dependence and abuse have been less frequent. Because of the potential for dependence or withdrawl to occur, the clinical need for continued analgesia should be reviewed regularly. In patients with a tendency to drug abuse or dependence, treatment with Brimisol PR 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.

Important information regarding the ingredients of this medicine

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

4.5 Interaction with other medicinal products and other forms of interaction

Brimisol PR should not be combined with selective or nonselective MAO inhibitors. Serotonin Syndrome (diarrhoea, tachycardia, sweating, tremor, confusion and coma) may develop (see section 4.3).

Linezolid: Treatment experience with non-selective MAOI indicates a risk of development of Serotonin Syndrome: diarrhoea, tachycardia, sweating, tremor, confusion and coma.

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 Brimisol PR.

Concomitant medication not recommended during treatment with tramadol

- Mixed agonist-antagonists (buprenorphine, nalbuphine and pentazocine): Concomitant treatment with tramadol is not recommended because theoretically, this could reduce the analgesic effects of the pure agonist due to competitive blocking of receptors, resulting in the risk of occurrence of withdrawal symptoms.

- Alcohol: Alcohol increases the sedative effect of opioid analgesics. The resulting drowsiness can be dangerous while driving or operating machinery. Alcoholic beverages and medicinal products containing alcohol should not be consumed during treatment with tramadol (see section 4.7).

- Naltrexone: Use of tramadol with naltrexone may reduce the analgesic effect. If necessary the analgesic dose can be increased.

Concomitant medication to be used with care during tramadol treatment

- Other morphine derivatives (including antitussives and substitution treatments) benzodiazepines, barbiturates: Major risk of respiratory depression, can be fatal in case of overdose.

- Other CNS depressants: Opioid analgesics, barbiturates, benzodiazepines, sedative antidepressants, sedative H1 antihistamines, anxiolytics other than benzodiazepines, hypnotics, neuroleptics, centrally acting antihypertensives, thalidomide, baclophene: Increased risk of central nervous system depression. The resulting impaired reaction time can make driving and operating machinery dangerous.

Concomitant administration of Brimisol PR 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 re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic anti-depressants, anti-psychotics and other seizure threshold lowering medicinal products ( such as bupropion, mirtazapine, tetrahydrocannabinol) to cause convulsions (see section 4.4).

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.

Venlafaxine: Risk of convulsions and/or Serotonin Syndrome.

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. Teratogenic effects were not observed. Tramadol crosses the placenta. There is inadequate evidence available on the safety of tramadol in human pregnancy. Therefore Brimisol PR 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. Brimisol PR 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, Brimisol PR may cause effects such as somnolence, dizziness and/or drowsiness and therefore may impair the reactions of drivers and machine operators. This applies particularly in conjunction with alcohol and other psychotropic substances.

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 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

4.8 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, increase in blood pressure

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.

Nervous system disorders:

Very common: dizziness

Common: headache, somnolence, confusion

Rare: speech disorders, paraesthesia, tremor, epileptiform convulsions, involuntary muscle contractions, abnormal coordination, syncope, changes in appetite.

Epileptiform convulsions occurred mainly after administration of high doses of tramadol or after concomitant treatment with medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).

Psychiatric disorders:

Rare: hallucinations, confusion, sleep disturbance, delirium, anxiety and nightmares. Psychic adverse reactions may occur following administration of Brimisol PR 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

Respiratory, thoracic and maediastinal 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.

Gastrointestinal disorders:

Very common: nausea

Common: vomiting, constipation, dry mouth

Uncommon: retching, gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea

Skin and subcutaneous tisuue disorders:

Common: hyperhidrosis

Uncommon: dermal reactions (e.g. pruritus, rash, urticaria)

Musculoskeletal and connective tissue disorders:

Rare: muscular/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 (difficulty in passing urine, dysuria and urinary retention)

Immune system disorders

Rare: allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema) and anaphylaxis

Metabolism and nutrition disorders:

Rare: changes in appetite

Not known: hypoglycaemia

General disorders:

Common: fatigue

Rare: Allergic reactions (for example dyspnoea, bronchospasm, wheezing, Quincke's oedema) and anaphylaxis. Withdrawal symptoms similar to those observed during withdrawal of opiates may occur, such as agitation, anxiety, nervousness, insomnia, hyperkinesias, tremor and gastro-intestinal symptoms. Other symptoms of withdrawal have also been reported, including: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and other CNS problems.

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.

Unexpected effect of overdose: serotonin syndrome has been reported in a context of overdose or abuse with tramadol

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 haemo-filtration. Therefore treatment of acute intoxication with Brimisol PR with haemodialysis or haemofiltration alone is not suitable for detoxification.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other opioids; ATC-code N 02 AX 02

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 reuptake of nor adrenaline 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 Brimisol PR 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 (V d,ß= 203 ± 40 l). It has a plasma protein binding of about 20 %.

After administration of Brimisol PR 100 mg the peak plasma concentration Cmax =141 ± 40 ng/ml is reached after 4.9 h. After administration of Brimisol PR 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 O-desmethyltramadol 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 O-desmethyltramadol 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 cases of impaired hepatic and 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 dose-dependent, 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 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 O-desmethyltramadol in children under 1 year of age.

5.3 Preclinical safety data

Preclinical data reveal no special risk for clinical use based on acute toxicity, repeated dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity studies. Animal studies have not shown any teratogenic effects, but at high doses, foetotoxicity due to maternotoxicity appeared.

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, clinico-chemical 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

For Brimisol PR 100 mg Prolonged-Release Tablet

Tablet Core:

Lactose Monohydrate

Cellulose microcrystalline

Hypromellose

Silica Colloidal Anhydrous

Magnesium Stearate

Film-coating:

Hypromellose

Macrogol 6000

Purified Talc

Titanium Dioxide (E171)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C

6.5 Nature and contents of container

White, opaque PVC/Aluminium blister packs of 30 or 60 tablets

6.6 Special precautions for disposal and other handling

None

7. Marketing authorisation holder

BRISTOL LABORATORIES LIMITED

Unit 3, Canalside, Northbridge Road

Berkhamsted, Herts, HP4 1EG

United Kingdom

8. Marketing authorisation number(s)

Brimisol PR 100 mg Prolonged-Release Tablet ; 17907/ 0134

9. Date of first authorisation/renewal of the authorisation

01/11/2011

10. Date of revision of the text

24/03/2017