Tritace 5mg tablets

1. Name Of The Medicinal Product

Tritace 5 mg Tablets

2. Qualitative And Quantitative Composition

Tablets

Each tablet contains ramipril 5 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablets mg 5mg

Pale red oblong tablets with score-line.

Upper stamp: 5 & logo (

Lower stamp: HMP & 5

The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

- Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

• manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or

• diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:

• Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,

• Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1),

• Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started > 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Oral use.

It is recommended that TRITACE is taken each day at the same time of the day.

TRITACE can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2).

TRITACE has to be swallowed with liquid. It must not be chewed or crushed.

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with TRITACE; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with TRITACE (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with TRITACE should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of TRITACE should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

TRITACE may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

TRITACE should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of TRITACE is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg TRITACE once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg TRITACE after one or two weeks and then to 10 mg TRITACE after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria

Starting dose:

The recommended initial dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

TRITACE should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily. The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Patients with hepatic impairment (see section 5.2)

In patients with hepatic impairment, treatment with TRITACE must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg TRITACE.

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Paediatric population

The safety and efficacy of ramipril in children has not yet been established. Currently available data for TRITACE are described in sections 4.8, 5.1, 5.2 & 5.3 but no specific recommendation on posology can be made.

4.3 Contraindications

- Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)

- History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)

- Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

- Second and third trimesters of pregnancy (see sections 4.4 and 4.6)

- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

- Patients at particular risk of hypotension

- Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

- patients with severe hypertension

- patients with decompensated congestive heart failure

- patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

- patients with unilateral renal artery stenosis with a second functional kidney

- patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

- patients with liver cirrhosis and/or ascites

- patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

- Transient or persistent heart failure post MI

- Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

- Elderly patients

See section 4.2.

Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, TRITACE must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including TRITACE (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of TRITACE should be considered prior to desensitization.

Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including TRITACE. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contra-indicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of TRITACE: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of TRITACE is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to

ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Lactation

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), Tritace is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

	Common	Uncommon	Rare	Very rare	Not known
Cardiac disorders		Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral
Blood and lymphatic system disorders		Eosinophilia	White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased		Bone marrow failure, pancytopenia, haemolytic anaemia
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, ageusia, dysgeusia,	Tremor, balance disorder		Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia
Eye disorders		Visual disturbance including blurred vision	Conjunctivitis
Ear and labyrinth disorders			Hearing impaired, tinnitus
Respiratory, thoracic and mediastinal disorders	Non-productive tickling cough, bronchitis, sinusitis, dyspnoea	Bronchospasm including asthma aggravated, nasal congestion
Gastrointestinal disorders	Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting	Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth	Glossitis		Aphtous stomatitis
Renal and urinary disorders		Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased
Skin and subcutaneous tissue disorders	Rash in particular maculo-papular	Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis	Exfoliative dermatitis, urticaria, onycholysis,	Photosensitivity reaction	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia
Musculoskeletal and connective tissue disorders	Muscle spasms, myalgia	Arthralgia
Metabolism and nutrition disorders	Blood potassium increased	Anorexia, decreased appetite,			Blood sodium decreased
Vascular disorders	Hypotension, orthostatic blood pressure decreased, syncope	Flushing	Vascular stenosis, hypoperfusion, vasculitis		Raynaud's phenomenon
General disorders and administration site conditions	Chest pain, fatigue	Pyrexia	Asthenia
Immune system disorders					Anaphylactic or anaphylactoid reactions, antinuclear antibody increased
Hepatobiliary disorders		Hepatic enzymes and/or bilirubin conjugated increased,	Jaundice cholestatic, hepatocellular damage		Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).
Reproductive system and breast disorders		Transient erectile impotence, libido decreased			Gynaecomastia
Psychiatric disorders		Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence	Confusional state		Disturbance in attention

Paediatric Population

The safety of ramipril was monitored in 325 children and adolescents, aged 2-16 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

Tachycardia, nasal congestion and rhinitis, “common” (i.e.

Conjunctivitis “common” (i.e.

Tremor and urticaria “uncommon” (i.e.

The overall safety profile for ramipril in paediatric patients dose not differ significantly from the safety profile in adults.

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.

Mechanism of action

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

	Ramipril	Placebo	relative risk (95% confidence interval)	p-value
	%	%
All patients	n=4,645	N=4,652
Primary combined events	14.0	17.8	0.78 (0.70-0.86)	<0.001
Myocardial infarction	9.9	12.3	0.80 (0.70-0.90)	<0.001
Death from cardiovascular causes	6.1	8.1	0.74 (0.64-0.87)	<0.001
Stroke	3.4	4.9	0.68 (0.56-0.84)	<0.001
Secondary endpoints
Death from any cause	10.4	12.2	0.84 (0.75-0.95)	0.005
Need for Revascularisation	16.0	18.3	0.85 (0.77-0.94)	0.002
Hospitalisation for unstable angina	12.1	12.3	0.98 (0.87-1.10)	NS
Hospitalisation for heart failure	3.2	3.5	0.88 (0.70-1.10)	0.25
Complications related to diabetes	6.4	7.6

Trileptal 150 mg, 300 mg, 600 mg Film-coated tablets

1. Name Of The Medicinal Product

Trileptal^® 150 mg Film-coated Tablets

Trileptal^® 300 mg Film-coated Tablets

Trileptal^® 600 mg Film-coated Tablets

Oxcarbazepine 150mg Film-coated Tablets

Oxcarbazepine 300mg Film-coated Tablets

Oxcarbazepine 600mg Film-coated Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 150 mg, 300 mg or 600 mg oxcarbazepine.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablets.

150 mg: pale grey green, ovaloid tablets, scored on both sides. Embossed with T/D on one side and C/G on the other side.

300 mg: yellow, ovaloid tablets, scored on both sides. Embossed with TE/TE on one side and CG/CG on the other side.

600 mg: light pink, ovaloid tablets scored on both sides. Embossed with TF/TF on one side and CG/CG on the other side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical Particulars

4.1 Therapeutic Indications

Trileptal is indicated for the treatment of partial seizures with or without secondarily generalised tonic-clonic seizures.

Trileptal is indicated for use as monotherapy or adjunctive therapy in adults and in children of 6 years of age and above.

4.2 Posology And Method Of Administration

In mono- and adjunctive therapy, treatment with Trileptal is initiated with a clinically effective dose given in two divided doses. The dose may be increased depending on the clinical response of the patient. When other antiepileptic medicinal products are replaced by Trileptal, the dose of the concomitant antiepileptic medicinal product(s) should be reduced gradually on initiation of Trileptal therapy. In adjunctive therapy, as the total antiepileptic medicinal product load of the patient is increased, the dose of concomitant antiepileptic medicinal product(s) may need to be reduced and/or the Trileptal dose increased more slowly (see section 4.5).

Trileptal can be taken with or without food.

The following dosing recommendations apply to all patients, in the absence of impaired renal function (see section 5.2). Drug plasma level monitoring is not necessary to optimise Trileptal therapy.

The tablets are scored and can be broken in two halves in order to make it easier for the patient to swallow the tablet. However, the tablet cannot be divided into equal doses. For children, who cannot swallow tablets or where the required dose cannot be administered using tablets, a Trileptal oral suspension is available.

Adults

Monotherapy

Trileptal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. If clinically indicated, the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals from the starting dose to achieve the desired clinical response. Therapeutic effects are seen at doses between 600 mg/day and 2,400 mg/day.

Controlled monotherapy trials in patients not currently being treated with antiepileptic medicinal products showed 1,200 mg/day to be an effective dose; however, a dose of 2400 mg/day has been shown to be effective in more refractory patients converted from other antiepileptic medicinal products to Trileptal monotherapy.

In a controlled hospital setting, dose increases up to 2,400 mg/day have been achieved over 48 hours.

Adjunctive therapy

Trileptal should be initiated with a dose of 600 mg/day (8-10 mg/kg/day) given in 2 divided doses. If clinically indicated, the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals from the starting dose to achieve the desired clinical response. Therapeutic responses are seen at doses between 600 mg/day and 2,400 mg/day.

Daily doses from 600 to 2,400 mg/day have been shown to be effective in a controlled adjunctive therapy trial, although most patients were not able to tolerate the 2400 mg/day dose without reduction of concomitant antiepileptic medicinal products, mainly because of CNS-related adverse events. Daily doses above 2400 mg/day have not been studied systematically in clinical trials.

Elderly

Adjustment of the dose is recommended in the elderly with compromised renal function (see 'Patients with renal impairment'). For patients at risk of hyponatraemia see section 4.4.

Children

In mono- and adjunctive therapy, Trileptal should be initiated with a dose of 8-10 mg/kg/day given in 2 divided doses. In adjunctive therapy, therapeutic effects were seen at a median maintenance dose of approximately 30 mg/kg/day. If clinically indicated, the dose may be increased by a maximum of 10 mg/kg/day increments at approximately weekly intervals from the starting dose, to a maximum dose of 46 mg/kg/day, to achieve the desired clinical response (see section 5.2).

Trileptal is recommended for use in children of 6 years of age and above. Safety and efficacy have been evaluated in controlled clinical trials involving approximately 230 children aged less than 6 years (down to 1 month). Trileptal is not recommended in children aged less than 6 years since safety and efficacy have not been adequately demonstrated.

All the above dosing recommendations (adults, elderly and children) are based on the doses studied in clinical trials for all age groups. However, lower initiation doses may be considered where appropriate.

Patients with hepatic impairment

No dosage adjustment is required for patients with mild to moderate hepatic impairment. Trileptal has not been studied in patients with severe hepatic impairment, therefore, caution should be exercised when dosing severely impaired patients (see section 5.2).

Patients with renal impairment

In patients with impaired renal function (creatinine clearance less than 30 ml/min) Trileptal therapy should be initiated at half the usual starting dose (300 mg/day) and increased, in at least weekly intervals, to achieve the desired clinical response (see section 5.2).

Dose escalation in renally impaired patients may require more careful observation.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Hypersensitivity

Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been received in the post-marketing period. Cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of Trileptal. If a patient develops these reactions after treatment with Trileptal, the drug should be discontinued and an alternative treatment started.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25-30 % of these patients may experience hypersensitivity reactions (e.g. severe skin reactions) with Trileptal (see section 4.8).

Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without history of hypersensitivity to carbamazepine. Such reactions can affect the skin, liver, blood and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see section 4.8). In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Trileptal should be withdrawn immediately.

Dermatological effects

Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome) and erythema multiforme, have been reported very rarely in association with Trileptal use. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. Trileptal associated cases occurred in both children and adults. The median time to onset was 19 days. Several isolated cases of recurrence of the serious skin reaction when rechallenged with Trileptal were reported. Patients who develop a skin reaction with Trileptal should be promptly evaluated and Trileptal withdrawn immediately unless the rash is clearly not drug related. In case of treatment withdrawal, consideration should be given to replacing Trileptal with other antiepileptic drug therapy to avoid withdrawal seizures. Trileptal should not be restarted in patients who discontinued treatment due to a hypersensitivity reaction (see section 4.3).

Hyponatraemia

Serum sodium levels below 125 mmol/l, usually asymptomatic and not requiring adjustment of therapy, have been observed in up to 2.7 % of Trileptal treated patients. Experience from clinical trials shows that serum sodium levels returned towards normal when the Trileptal dosage was reduced, discontinued or the patient was treated conservatively (e.g. restricted fluid intake). In patients with pre-existing renal conditions associated with low sodium or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, desmopressin) as well as NSAIDs (e.g. indometacin), serum sodium levels should be measured prior to initiating therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients. For patients on Trileptal therapy when starting on sodium-lowering medicinal products, the same approach for sodium checks should be followed. In general, if clinical symptoms suggestive of hyponatraemia occur on Trileptal therapy (see section 4.8), serum sodium measurement may be considered. Other patients may have serum sodium assessed as part of their routine laboratory studies.

All patients with cardiac insufficiency and secondary heart failure should have regular weight measurements to determine occurrence of fluid retention. In case of fluid retention or worsening of the cardiac condition, serum sodium should be checked. If hyponatraemia is observed, water restriction is an important counter-measurement. As oxcarbazepine may, very rarely, lead to impairment of cardiac conduction, patients with pre-existing conduction disturbances (e.g. atrioventricular-block, arrhythmia) should be followed carefully.

Hepatic function

Very rare cases of hepatitis have been reported, which in most of the cases resolved favourably. When a hepatic event is suspected, liver function should be evaluated and discontinuation of Trileptal should be considered.

Hematological effects

Very rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with Trileptal during post-marketing experience (see section 4.8). Discontinuation of the medicinal product should be considered if any evidence of significant bone marrow depression develops.

Suicidal behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for oxcarbazepine.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Hormonal contraceptives

Female patients of childbearing age should be warned that the concurrent use of Trileptal with hormonal contraceptives may render this type of contraceptive ineffective (see section 4.5). Additional non-hormonal forms of contraception are recommended when using Trileptal.

Alcohol

Caution should be exercised if alcohol is taken in combination with Trileptal therapy, due to a possible additive sedative effect.

Withdrawal

As with all antiepileptic medicinal products, Trileptal should be withdrawn gradually to minimise the potential of increased seizure frequency.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Enzyme induction

Oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD) are weak inducers in vitro and in vivo of the cytochrome P450 enzymes CYP3A4 and CYP3A5 responsible for the metabolism of a very large number of drugs, for example, immunosuppressants (e.g. ciclosporin, tacrolimus), oral contraceptives (see below), and some other antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products (see table below summarizing results with other antiepileptic medicinal products).

In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferases (effects on specific enzymes in this family are not known). Therefore, in vivo oxcarbazepine and MHD may have a small inducing effect on the metabolism of medicinal products which are mainly eliminated by conjugation through the UDP-glucuronyl transferases. When initiating treatment with Trileptal or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.

In case of discontinuation of Trileptal therapy, a dose reduction of the concomitant medications may be necessary and should be decided upon by clinical and/or plasma level monitoring. The induction is likely to gradually decrease over 2 to 3 weeks after discontinuation.

Hormonal contraceptives: Trileptal was shown to have an influence on the two components, ethinylestradiol (EE) and levonorgestrel (LNG), of an oral contraceptive. The mean AUC values of EE and LNG were decreased by 48-52 % and 32-52% respectively. Therefore, concurrent use of Trileptal with hormonal contraceptives may render these contraceptives ineffective (see section 4.4). Another reliable contraceptive method should be used.

Enzyme inhibition

Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when co-administering high doses of Trileptal with medicinal products that are mainly metabolised by CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased by up to 40 % when Trileptal was given at doses above 1200 mg/day (see table below summarizing results with other anticonvulsants). In this case, a reduction of co-administered phenytoin may be required (see section 4.2).

Antiepileptic medicinal products

Potential interactions between Trileptal and other antiepileptic medicinal products were assessed in clinical studies. The effect of these interactions on mean AUCs and C_min are summarised in the following table.

Summary of antiepileptic medicinal product interactions with Trileptal

Antiepileptic medicinal product	Influence of Trileptal on antiepileptic medicinal product	Influence of antiepileptic medicinal product on MHD
Co-administered	Concentration	Concentration
Carbamazepine	0 - 22 % decrease (30 % increase of carbamazepine-epoxide)	40 % decrease
Clobazam	Not studied	No influence
Felbamate	Not studied	No influence
Lamotrigine	Slight decrease*	No influence
Phenobarbitone	14 - 15 % increase	30 - 31 % decrease
Phenytoin	0 - 40 % increase	29 - 35 % decrease
Valproic acid	No influence	0 – 18 % decrease

* Preliminary results indicate that oxcarbazepine may result in lower lamotrigine concentrations, possibly of importance in children, but the interaction potential of oxcarbazepine appears lower than seen with concomitant enzyme inducing drugs (carbamazepine, phenobarbitone, and phenytoin).

Strong inducers of cytochrome P450 enzymes (i.e. carbamazepine, phenytoin and phenobarbitone) have been shown to decrease the plasma levels of MHD (29-40 %) in adults; in children 4 to 12 years of age, MHD clearance increased by approximately 35% when given one of the three enzyme-inducing antiepileptic medicinal products compared to monotherapy. Concomitant therapy of Trileptal and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache). When one or several antiepileptic medicinal products are concurrently administered with Trileptal, a careful dose adjustment and/or plasma level monitoring may be considered on a case by case basis, notably in paediatric patients treated concomitantly with lamotrigine.

No autoinduction has been observed with Trileptal.

Other medicinal product interactions

Cimetidine, erythromycin, viloxazine, warfarin and dextropropoxyphene had no effect on the pharmacokinetics of MHD.

The interaction between oxcarbazepine and MAOIs is theoretically possible based on a structural relationship of oxcarbazepine to tricyclic antidepressants.

Patients on tricyclic antidepressant therapy were included in clinical trials and no clinically relevant interactions have been observed.

The combination of lithium and oxcarbazepine might cause enhanced neurotoxicity.

4.6 Pregnancy And Lactation

Pregnancy

Risk related to epilepsy and antiepileptic medicinal products in general:

It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to three times greater than the rate of approximately 3% in the general population. In the treated population, an increase in malformations has been noted with polytherapy, however, the extent to which the treatment and/or the illness is responsible has not been elucidated.

Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Risk related to oxcarbazepine:

Clinical data on exposure during pregnancy are still insufficient to assess the teratogenic potential of oxcarbazepine. In animal studies, increased embryo mortality, delayed growth and malformations were observed at maternally toxic dose levels (see section 5.3).

Taking these data into consideration:

• If women receiving Trileptal become pregnant or plan to become pregnant, the use of this product should be carefully re-evaluated. Minimum effective doses should be given, and monotherapy whenever possible should be preferred at least during the first three months of pregnancy.

• Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.

• During pregnancy, an effective antiepileptic oxcarbazepine treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Monitoring and prevention:

Antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the efficacy of this supplementation is not proved, a specific antenatal diagnosis can be offered even for women with a supplementary treatment of folic acid.

Data from a limited number of women indicate that plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving Trileptal treatment during pregnancy to ensure that adequate seizure control is maintained. Determination of changes in MHD plasma concentrations should be considered. If dosages have been increased during pregnancy, postpartum MHD plasma levels may also be considered for monitoring.

In the newborn child:

Bleeding disorders in the newborn caused by antiepileptic agents have been reported. As a precaution, vitamin K₁ should be administered as a preventive measure in the last few weeks of pregnancy and to the newborn.

Lactation

Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. The effects on the infant exposed to Trileptal by this route are unknown. Therefore, Trileptal should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

The use of Trileptal has been associated with adverse reactions such as dizziness or somnolence (see section 4.8). Therefore, patients should be advised that their physical and/ or mental abilities required for operating machinery or driving a car might be impaired.

4.8 Undesirable Effects

The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue occurring in more than 10% of patients.

The undesirable effect profile by body system is based on AEs from clinical trials assessed as related to Trileptal. In addition, clinically meaningful reports on adverse experiences from named patient programs and postmarketing experience were taken into account.

Frequency estimate* :- very common: 1/10; common: 1/100 - < 1/10; uncommon: 1/1,000 - < 1 /100; rare: 1/10,000 - < 1/1,000; very rare: < 1/10,000; unknown: cannot be estimated from the available data.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Blood and lymphatic system disorders
Uncommon	leucopenia.
Very rare	thrombocytopenia.
Unknown	bone marrow depression, aplastic anemia, agranulocytosis, pancytopenia, neutropenia.
Immune system disorders
Very rare	hypersensitivity (including multi-organ hypersensitivity) characterised by features such as rash, fever. Other organs or systems may be affected such as blood and lymphatic system (e.g. eosinophilia, thrombocytopenia, leucopenia, lymphadenopathy, splenomegaly), liver (e.g. abnormal liver function tests, hepatitis), muscles and joints (e.g. joint swelling, myalgia, arthralgia), nervous system (e.g. hepatic encephalopathy), kidney (e.g. proteinuria, nephritis interstitial, renal failure), lungs (e.g. dyspnea, pulmonary oedema, asthma, bronchospasms, interstitial lung disease), angioedema.
Unknown	anaphylactic reactions.
Metabolism and nutrition disorders
Common	hyponatraemia
Very rare	hyponatraemia associated with signs and symptoms such as seizures, confusion, depressed level of consciousness, encephalopathy (see also Nervous system disorders for further undesirable effects), vision disorders (e.g. blurred vision), vomiting, nausea† .
Unknown	hypothyroidism.
Psychiatric disorders
Common	confusional state, depression, apathy, agitation (e.g. nervousness), affect lability.
Nervous system disorders
Very common	somnolence, headache, dizziness.
Common	ataxia, tremor, nystagmus, disturbance in attention, amnesia.
Eye disorders
Very common	diplopia.
Common	vision blurred, visual disturbance.
Ear and labyrinth disorders
Common	vertigo.
Cardiac disorders
Very rare	arrhythmia, atrioventricular block.
Vascular disorders
Unknown	hypertension.
Gastrointestinal disorders
Very common	nausea, vomiting.
Common	diarrhoea, constipation, abdominal pain.
Very rare	pancreatitis and/or lipase and/or amylase increase.
Hepato-biliary disorders
Very rare	hepatitis.
Skin and subcutaneous tissue disorders
Common	rash, alopecia, acne.
Uncommon	urticaria.
Very rare	angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme (see section 4.4).
Musculoskeletal, connective tissue and bone disorders
Very rare	systemic lupus erythematosus.
General disorders and administration site conditions
Very common	fatigue.
Common	asthenia.
Investigations
Uncommon	hepatic enzymes increased, blood alkaline phosphatase increased.
Unknown	decrease in T4 (with unclear clinical significance)

^* according to CIOMS III frequency classification

^†Very rarely clinically significant hyponatraemia (sodium <125 mmol/l) can develop during Trileptal use. It generally occurred during the first 3 months of treatment with Trileptal, although there were patients who first developed a serum sodium <125 mmol/l more than 1 year after initiation of therapy (see section 4.4).

4.9 Overdose

Isolated cases of overdose have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment. Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatraemia, ataxia and nystagmus. There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the medicinal product by gastric lavage and/or inactivation by administering activated charcoal should be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiepileptics

ATC code: N03A F 02

Pharmacodynamic effects

The pharmacological activity of oxcarbazepine is primarily exerted through the metabolite (MHD) (see section 5.2). The mechanism of action of oxcarbazepine and MHD is thought to be mainly based on blockade of voltage-sensitive sodium channels, thus resulting in stabilisation of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminishment of propagation of synaptic impulses. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may also contribute to the anticonvulsant effects. No significant interactions with brain neurotransmitter or modulator receptor sites were found.

Oxcarbazepine and its active metabolite (MHD), are potent and efficacious anticonvulsants in animals. They protected rodents against generalised tonic-clonic and, to a lesser degree, clonic seizures, and abolished or reduced the frequency of chronically recurring partial seizures in Rhesus monkeys with aluminum implants. No tolerance (i.e. attenuation of anticonvulsive activity) against tonic-clonic seizures was observed when mice and rats were treated daily for 5 days or 4 weeks, respectively, with oxcarbazepine or MHD.

5.2 Pharmacokinetic Properties

Absorption

Following oral administration of Trileptal, oxcarbazepine is completely absorbed and extensively metabolised to its pharmacologically active metabolite (MHD).

After single dose administration of 600 mg Trileptal to healthy male volunteers under fasted conditions, the mean C_max value of MHD was 34 μmol/l, with a corresponding median t_max of 4.5 hours.

In a mass balance study in man, only 2 % of total radioactivity in plasma was due to unchanged oxcarbazepine, approximately 70 % was due to MHD, and the remainder attributable to minor secondary metabolites which were rapidly eliminated.

Food has no effect on the rate and extent of absorption of oxcarbazepine, therefore, Trileptal can be taken with or without food.

Distribution

The apparent volume of distribution of MHD is 49 litres.

Approximately 40 % of MHD, is bound to serum proteins, predominantly to albumin. Binding was independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.

Oxcarbazepine and MHD cross the placenta. Neonatal and maternal plasma MHD concentrations were similar in one case.

Biotransformation

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of Trileptal. MHD is metabolised further by conjugation with glucuronic acid. Minor amounts (4 % of the dose) are oxidised to the pharmacologically inactive metabolite (10, 11-dihydroxy derivative, DHD).

Elimination

Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95 % of the dose appears in the urine, with less than 1 % as unchanged oxcarbazepine. Faecal excretion accounts for less than 4 % of the administered dose. Approximately 80 % of the dose is excreted in the urine either as glucuronides of MHD (49 %) or as unchanged MHD (27 %), whereas the inactive DHD accounts for approximately 3 % and conjugates of oxcarbazepine account for 13 % of the dose.

Oxcarbazepine is rapidly eliminated from the plasma with apparent half-life values between 1.3 and 2.3 hours. In contrast, the apparent plasma half-life of MHD averaged 9.3 ± 1.8 h..

Dose proportionality

Steady-state plasma concentrations of MHD are reached within 2 - 3 days in patients when Trileptal is given twice a day. At steady-state, the pharmacokinetics of MHD are linear and show dose proportionality across the dose range of 300 to 2,400 mg/day.

Special populations

Patients with hepatic impairment

The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900 mg oral dose. Mild to moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. Trileptal has not been studied in patients with severe hepatic impairment.

Patients with renal impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Trileptal is administered as a single 300 mg dose, in renally impaired patients (creatinine clearance < 30 mL/min) the elimination half-life of MHD is prolonged by 60-90 % (16 to 19 hours) with a two fold increase in AUC compared to adults with normal renal function (10 hours).

Children

The pharmacokinetics of Trileptal were evaluated in clinical trials in paediatric patients taking Trileptal in the dose range 10-60 mg/kg/day. Weight-adjusted MHD clearance deceases as age and weight increases approaching that of adults. The mean weight clearance in children 4 to 12 years of age is approximately 40% higher that that of adults. Therefore MHD exposure in these children is expected to be about two-thirds that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, weight-adjusted MHD clearance is expected to reach that of adults.

Pregnancy

Data from a limited number of women indicate that MHD plasma levels may gradually decrease throughout pregnancy (see section 4.6).

Elderly

Following administration of single (300 mg) and multiple doses (600 mg/day) of Trileptal in elderly volunteers (60 - 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30 % - 60 % higher than in younger volunteers (18 - 32 years of age). Comparisons of creatinine clearances in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance. No special dose recommendations are necessary because therapeutic doses are individually adjusted.

Gender

No gender related pharmacokinetic differences have been observed in children, adults, or the elderly.

5.3 Preclinical Safety Data

Preclinical data indicated no special hazard for humans based on repeated dose toxicity, safety pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active metabolite, monohydroxy derivative (MHD).

Evidence of nephrotoxicity was noted in repeated dose toxicity rat studies but not in dog or mice studies. As there are no reports of such changes in patients, the clinical relevance of this finding in rats remains unknown.

Immunostimulatory tests in mice showed that MHD (and to a lesser extent oxcarbazepine) can induce delayed hypersensitivity.

Animal studies revealed effects such as increases in the incidence of embryo mortality and some delay in antenatal and/or postnatal growth at maternally toxic dose levels. There was an increase in rat foetal malformations in one of the eight embryo toxicity studies, which were conducted with either oxcarbazepine or the pharmacologically active metabolite (MHD), at a dose which also showed maternal toxicity (see section 4.6).

In the carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell (rats) tumours were induced in treated animals. The occurrence of liver tumours was most likely a consequence of the induction of hepatic microsomal enzymes; an inductive effect which, although it cannot be excluded, is weak or absent in patients treated with Trileptal. Testicular tumours may have been induced by elevated luteinizing hormone concentrations. Due to the absence of such an increase in humans, these tumours are considered to be of no clinical relevance. A dose-related increase in the incidence of granular cell tumours of the female genital tract (cervix and vagina) was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels comparable with the anticipated clinical exposure. The mechanism for the development of these tumours has not been elucidated. Thus, the clinical relevance of these tumours is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

silica, colloidal anhydrous

cellulose, microcrystalline

hypromellose

crospovidone

magnesium stearate.

Tablet coating:

hypromellose

talc

titanium dioxide (E 171).

150 mg coating only:

macrogol 4000

iron oxide, yellow (E 172)

iron oxide red (E 172)

iron oxide black (E 172).

300 mg tablet coating only:

macrogol 8000

iron oxide, yellow (E 172).

600 mg coating only:

macrogol 4000

iron oxide red (E 172)

iron oxide black (E 172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

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

Blister containing 10 tablets. Blister material: PVC/PE/PVDC with aluminium foil backing.

Tablets 150 mg: blister pack of 30, 50, 100, 200 and/or 500 tablets.

Tablets 300 mg: blister pack of 30, 50, 100, 200 and/or 500 tablets.

Tablets 600 mg: blister pack of 30, 50, 100, 200 and/or 500 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Autho