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1. Maneo 100 Mg Prolonged-Release Tablets
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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Maneo 100 mg Prolonged-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Prolonged-release tablet contains 100 mg of tramadol hydrochloride

Excipient with known effect:

Each tablet contains 0.2 mg of lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

Maneo 100 mg Prolonged-release tablets: White to off white, round, biconvex beveled edge, film coated tablet debossed with “M” on one side and “TM1” 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. Unless otherwise prescribed, Maneo should be administered as follows:

Adults and adolescents above the age of 12 years:

The usual initial dose is 50 to 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.

Dependent upon the needs of the patient, subsequent doses may be administered earlier than 12 hours, but must not be administered earlier than 8 hours after the previous dose. Under no circumstances should more than two doses be taken in any one 24 hour period.

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

The lowest analgesically effective dose should generally be selected. Daily doses of 400 mg tramadol hydrochloride should not be exceeded, except in special clinical circumstances.

Maneo tablets should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with tramadol hydrochloride 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.

Paediatric population

Maneo tablets are 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 Impairment

In patients with renal and/or hepatic insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage interval should be carefully considered according to the patient’s requirements. In cases of severe renal and/or severe hepatic insufficiency Maneo tablets are not recommended.

Method of administration For oral use.

The tablets are to be taken whole, not divided or chewed, with sufficient liquid, independent of meals.

4.3 Contraindications

Maneo tablets are contraindicated:

•    in hypersensitivity to the active substance or to any of the excipients listed in section 6.1,

•    in acute intoxication with alcohol, hypnotics, analgesics, opioids, or other psychotropic medicinal products,

•    in patients who are receiving MAOIs (monoamine oxidase inhibitors) or who have taken them within the last 14 days (see section 4.5),

•    in patients with epilepsy not adequately controlled by treatment,

•    for use in narcotic withdrawal treatment.

4.4 Special warnings and precautions for use

Tramadol hydrochloride 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, patients with moderate to severe impaired liver or kidney function.

In patients sensitive to opiates the product should only be used with caution.

Maneo tablets should not be used in combination with alcohol.

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 hydrochloride at the recommended dose levels. The risk may be increased when doses of tramadol hydrochloride exceed the recommended upper daily dose limit (400 mg). In addition, tramadol hydrochloride 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 hydrochloride if there are compelling circumstances.

Tramadol hydrochloride has a low dependence potential. On long-term use tolerance, psychic and physical dependence may develop. In patients with a tendency to drug abuse or dependence, treatment with tramadol hydrochloride should only be carried out for short periods under strict medical supervision.

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

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

Tramadol hydrochloride should not be combined with MAOIs (see section 4.3).

In patients treated with MAOIs 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 MAOIs cannot be ruled out during treatment with Maneo tablets.

Concomitant administration of tramadol hydrochloride 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.

The combination with mixed agonist/antagonists (e.g. buprenorphine, nalbuphine, pentazocine) and tramadol hydrochloride is not advisable, because the analgesic effect of a pure agonist may be theoretically reduced in such circumstances.

Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, anti-psychotics 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 serotoninergic medicinal products usually brings about a rapid improvement. Treatment depends on the nature and severity of the symptoms.

Caution should be exercised during concomitant treatment with tramadol hydrochloride 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 hydrochloride in patients with postoperative pain.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of tramadol hydrochloride in pregnant women.

Studies in animals have shown reproductive toxicity. 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 (see section 5.3).

Maneo tablets are not recommended during pregnancy.

Tramadol hydrochloride - when 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

Tramadol hydrochloride has been identified in breastfed newborns/infants of treated women. During lactation about 0.1% of the maternal dose is secreted into the milk.

There is insufficient information on the effects of tramadol hydrochloride in newboms/infants. After a single administration of tramadol it is not usually necessary to interrupt breast-feeding.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Maneo tablets therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Post marketing surveillance does not suggest an effect of tramadol hydrochloride on fertility. Animal studies did not show an effect of tramadol hydrochloride on fertility.

4.7 Effects on ability to drive and use machines

Even when taken according to instructions, tramadol hydrochloride may cause effects such as somnolence and dizziness 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 used in the table below are according to the following convention:

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) and Very rare (<1/10,000),

Not known (cannot be estimated from the available data)

System Organ Class	Frequency	Adverse drug reactions
Immune system disorders	Rare	Anaphylaxis, allergic reactions (e.g. dyspnoea, bronchospasm, wheezing, angioneurotic oedema)

Metabolism and	Rare	Changes in appetite
nutrition disorders	Not known	Hypoglycaemia.
Psychiatric disorders	Rare	Hallucinations, confusion, sleep disturbance, delirium, anxiety and nightmares.
		Psychic adverse reactions may occur following administration of tramadol hydrochloride 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). Dependence may occur.
		Symptoms of withdrawal reactions, 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 hydrochloride discontinuation include: panic attacks, severe anxiety, hallucinations, paraesthesias, tinnitus and unusual CNS symptoms (i.e. confusion, delusions, depersonalisation, derealisation, paranoia).
Nervous system	Very	Dizziness
disorders	common
	Common	Headache, somnolence
	Rare	Paraesthesia, tremor, epileptiform convulsions*, involuntary muscle contractions, abnormal coordination, syncope, speech disorders
Eye disorders	Rare	Miosis, blurred vision, mydriasis
Cardiac disorders	Uncommon	Cardiovascular regulation (palpitation, tachycardia, postural hypotension or cardiovascular collapse). These adverse reactions may occur especially on intravenous administration and in patients who are physically stressed.
	Rare	Bradycardia, increase in blood pressure
Respiratory, thoracic and mediastinal	Rare	Respiratory depression*, dyspnoea
disorders	Not known	Worsening of asthma has been reported, though a causal relationship has not been established.
Gastrointestinal	Very	Nausea
disorders	common
	Common	Vomiting, constipation, dry mouth

	Uncommon	Retching; gastrointestinal irritation (a feeling of pressure in the stomach, bloating), diarrhoea
Hepatobiliary disorders	Very rare	Increase liver enzyme values
Skin and subcutaneous tissue disorders	Common Uncommon	Hyperhidrosis Dermal reactions (e.g. pruritus, rash, urticaria)
Musculoskeletal and connective tissue disorders	Rare	Muscle weakness
Renal and urinary disorders	Rare	Micturition disorders (difficulty in passing urine, dysuria and urinary retention)
General disorders and administration site conditions	Common	Fatigue

*    If the recommended doses are considerably exceeded and other centrally depressant

substances are administered concomitantly (see section 4.5), respiratory depression may occur. Epileptiform convulsions occurred mainly after administration of high doses of tramadol hydrochloride or after concomitant treatment with medicinal products which can lower the seizure threshold (see sections 4.4 and 4.5).

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 hydrochloride 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.

Treatment

The general emergency measures apply. Protect the airway, 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 with oral formulations, gastrointestinal decontamination with activated charcoal or by gastric lavage is only recommended within 2 hours after tramadol hydrochloride intake. Gastrointestinal decontamination at a later time point may be useful in case of intoxication with exceptionally large quantities or prolonged-release formulations.

Tramadol hydrocloride is minimally eliminated from the serum by haemodialysis or haemo-filtration. Therefore treatment of acute intoxication with Maneo tablets with haemodialysis or haemofiltration alone is not suitable for detoxification

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, other opioids, ATC code N02AX02 Mechanism of action

Tramadol hydrochloride is a centrally acting opioid analgesic. It is a non-selective pure agonist at p, 8 and k opioid receptors with a higher affinity for the p receptor. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release.

Tramadol hydrochloride 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.

5.2 Pharmacokinetic properties

Absorption

More than 90% of tramadol hydrochloride 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 hydrochloride is probably due to the low first-pass effect. The first-pass effect after oral administration is a maximum of 30 %.

After administration of tramadol hydrochloride 100 mg prolonged-release tablets the peak plasma concentration C_max =141 ± 40 ng/ml is reached after 4.9 h. After administration of tramadol hydrochloride 200 mg prolonged- release tablets C_max 260 ± 62 ng/ml is reached after 4.8 hours.

Distribution

Tramadol hydrochloride has a high tissue affinity (V d,B= 203 ± 40 l). It has a plasma protein binding of about 20 %.

Tramadol hydrochloride 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).

Biotransformation

Elimination half-life ti_/2,B 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 hydrocloride 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 ti/2,fl (6 healthy volunteers) is 7.9 h (range 5.4 - 9.6 h) and is approximately that of tramadol hydrochloride.

The inhibition of one or both types of the isoenzymes CYP3A4 and CYP2D6 involved in the biotransformation of tramadol hydrochloride may affect the plasma concentration of tramadol or its active metabolite. Up to now, clinically relevant interactions have not been reported.

Elimination

Tramadol hydrochloride 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.

Linearitv/non-linearitv

Tramadol hydrochloride 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.

5.3 Preclinical safety data

On repeated oral and parenteral administration of tramadol hydrochloride 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 hydrochloride 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)

6.1 List of excipients

Cellulose, microcrystalline Hypromellose Silica, colloidal anhydrous Magnesium stearate

Film-coating: Hypromellose (E464) Lactose monohydrate Talc (E553 b)

Macrogol

Propylene glycol (E1520) Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable

6.3    Shelflife

For Al/OPA/PVC/Al blisters 2 years

For HDPE bottles and Al/PVC/PE/PVDC blisters 3 years

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

HDPE Bottles with polypropylene child-resistant closures containing 100 prolonged-release tablets.

HDPE Bottles with polypropylene screw-cap closures containing 500 and 1000 prolonged-release tablets (Dispensing package).

Al/OPA/PVC/Al and Al/PVC/PE/PVDC blisters in cardboard cartons containing 10, 20, 20x1, 28, 30, 50, 56, 60, 60x1, 90 and 100 prolonged-release tablets.

Not all pack sizes may be marketed.