Priadel 400mg prolonged release tablets.

Priadel 200mg prolonged release tablets.

Priadel tablets contain 400mg lithium carbonate.

Priadel 200 tablets contain 200mg lithium carbonate.

Priadel: White, circular, bi-convex tablets engraved PRIADEL on one side, scored on the other side, in a prolonged release formulation.

Priadel 200: White, scored, capsule-shaped tablets engraved P200 on one side, in a prolonged release formulation.

1. In the management of acute manic or hypomanic episodes.

2. In the management of episodes of recurrent depressive disorders where treatment with other antidepressants has been unsuccessful.

3. In the prophylaxis against bipolar affective disorders.

4. Control of aggressive behaviour or intentional self harm.

A simple treatment schedule has been evolved which except for some minor variations should be followed whether using Priadel therapeutically or prophylactically. The minor variations to this schedule depend on the elements of the illness being treated and these are described later.

1. In patients of average weight (70kg) an initial dose of 400-1,200mg of Priadel may be given as a single daily dose in the morning or on retiring. Alternatively, the dose may be divided and given morning and evening. The tablets should not be crushed or chewed. When changing between lithium preparations serum lithium levels should first be checked, then Priadel therapy commenced at a daily dose as close as possible to the dose of the other form of lithium. As bioavailability varies from product to product (particularly with regard to retard or slow release preparations) a change of product should be regarded as initiation of new treatment.

2. Four to five days after starting treatment (and never longer than one week) a blood sample should be taken for the estimation of serum lithium level.

3. The objective is to adjust the Priadel dose so as to maintain the “Target” serum lithium concentrations at 12 and 24 hours as shown in the table below.

“Target” serum lithium concentration (mmol/l)

Both strengths have break lines, therefore they can be divided accurately to provide dosage requirements as small as 100mg. Serum lithium levels should be monitored weekly until stabilisation is achieved. The serum level should not exceed 1.5 mmol/l.

4. Lithium therapy should not be initiated unless adequate facilities for routine monitoring of serum concentrations are available. Following stabilisation of serum lithium levels, the period between subsequent estimations can be increased gradually but should not normally exceed three months. Additional measurements should be made following alteration of dosage, on development of intercurrent disease, signs of manic or depressive relapse, following significant change in sodium or fluid intake, or if signs of lithium toxicity occur.

5. Whilst a high proportion of acutely ill patients may respond within three to seven days of the commencement of Priadel therapy, Priadel should be continued through any recurrence of the affective disturbance. This is important as the full prophylactic effect may not occur for 6 to 12 months after the initiation of therapy.

6. In patients who show a positive response to Priadel therapy, treatment is likely to be long term. Careful clinical appraisal of the patient should be exercised throughout medication (see precautions).

7. If lithium is to be discontinued, particularly in cases of high doses, the dose should be reduced gradually.

Prophylactic treatment of bipolar affective disorders and control of aggressive behaviour or intentional self harm: It is recommended that the described treatment schedule is followed.

Treatment of acute manic or hypomanic episodes and recurrent depressive disorders: It is likely that a higher than normal Priadel intake may be necessary during an acute phase and divided doses would be required here. The monitoring should maintain serum levels at 0.8-1.5 mmol/l until acute symptoms have been controlled. In all other details the described treatment schedule is recommended.

Elderly:

Elderly patients or those below 50kg in weight, often require lower lithium dosage to achieve therapeutic serum levels. Starting doses of 200mg to 400mg are recommended. Dosage increments of 200 to 400mg every 3 to 5 days are usual. Total daily doses of 800 to 1800mg may be necessary to achieve effective blood lithium levels of 0.8 to 1.0 mmol/l. For prophylaxis, the dosage necessary to reach a blood lithium level of 0.4 to 0.8 mmol/l is generally in the range of 600 to 1200 mg/day.

Children and adolescents:

Not recommended.

• Hypersensitivity to lithium or to any of the excipients.

• Cardiac disease.

• Clinically significant renal impairment.

• Untreated hypothyroidism.

• Breast-feeding.

• Patients with low body sodium levels, including for example dehydrated patients or those on low sodium diets.

• Addison's disease.

• When considering Priadel therapy, it is necessary to ascertain whether patients are receiving lithium in any other form. If so, check serum levels before proceeding.

• Before beginning a lithium treatment:

− it is important to ensure that renal function is normal.

− cardiac function should be assessed.

− thyroid function should be evaluated. Patients should be euthyroid before initiation of lithium therapy.

• Renal, cardiac and thyroid functions should be re-assessed periodically.

• The possibility of hypothyroidism and renal dysfunction arising during prolonged treatment should be borne in mind and periodic assessments made.

• Patients receiving long term lithium therapy should be warned by the physician and be given clear instructions regarding the symptoms of impending intoxication (see 4.9 Overdose). They should be warned of the urgency of immediate action should these symptoms appear, and also of the need to maintain a constant and adequate salt and water intake. Treatment should be discontinued immediately on the first signs of toxicity (see 4.9 Overdose).

• Patients should be warned to report if polyuria or polydipsia develop. Episodes of nausea, vomiting, diarrhoea, fluid deprivation (e.g. excessive sweating), and/or other conditions leading to salt/water depletion should also be reported. Drugs likely to upset electrolyte balance such as diuretics (including severe dieting) should also be reported. Indeed, sodium depletion increases the plasma lithium concentration (due to competitive reabsorption at the renal level). In these cases, lithium dosage should be closely monitored and reduction of dosage may be necessary.

• Caution should be exercised to ensure that diet and fluid intake are normal in order to maintain a stable electrolyte balance. This may be of special importance in very hot weather or work environment. Infectious diseases including colds, influenza, gastro-enteritis and urinary infections may alter fluid balance and thus affect serum lithium levels. Treatment should be discontinued during any intercurrent infection and should only be reinstituted after the patient's physical health has returned to normal.

• Elderly patients are particularly liable to lithium toxicity. Use with care as lithium excretion may also be reduced. They may exhibit adverse reactions at serum levels ordinarily tolerated by younger patients.

Interactions which increase lithium concentrations:

If one of the following drugs is initiated, lithium dosage should either be adjusted or concomitant treatment stopped, as appropriate:

• Metronidazole.

• Non-steroidal anti-inflammatory drugs (monitor serum lithium concentrations more frequently if NSAID therapy is initiated or discontinued).

• ACE inhibitors.

• Diuretics (thiazides show a paradoxical antidiuretics effect resulting in possible water retention and lithium intoxication). If a thiazide diuretic has to be prescribed for a lithium-treated patient, lithium dosage should first be reduced and the patient re-stabilised with frequent monitoring. Similar precautions should be exercised on diuretic withdrawal.

• Other drugs affecting electrolyte balance, e.g. steroids, may alter lithium excretion and should therefore be avoided.

• Tetracyclines.

Interactions which decrease serum lithium concentrations:

• Xanthines (theophylline, caffeine).

• Sodium bicarbonate containing products.

• Diuretics (osmotic and carbonic anhydrase inhibitors).

• Urea.

Interactions causing neurotoxicity:

• Neuroleptics (particularly haloperidol at higher dosages), flupentixol, diazepam, thioridazine, fluphenazine, chlorpromazine and clozapine may lead in rare cases to neurotoxicity in the form of confusion, disorientation, lethargy, tremor, extra-pyramidal symptoms and myoclonus.

• Methyldopa.

• Selective Serotonin Re-uptake Inhibitors (e.g. fluvoxamine and fluoxetine) as this combination may precipitate a serotoninergic syndrome, which justifies immediate discontinuation of treatment.

• Calcium channel blockers may lead to a risk of neurotoxicity in the form of ataxia, confusion and somnolence, reversible after discontinuation of the drug. Lithium concentrations may be increased.

• Carbamazepine may lead to dizziness, somnolence, confusion and cerebellar symptoms.

Lithium may prolong the effects of neuromuscular blocking agents. There have been reports of interaction between lithium and phenytoin, indometacin and other prostaglandin-synthetase inhibitors.

4.6.1 Pregnancy

Lithium therapy should not be used during pregnancy, especially during the first trimester, unless considered essential. There is epidemiological evidence that it may be harmful to the foetus in human pregnancy. Lithium crosses the placental barrier. In animal studies lithium has been reported to interfere with fertility, gestation and foetal development. An increase in cardiac and other abnormalities, especially Ebstein anomaly, are reported. Therefore, a pre-natal diagnosis such as ultrasound and electrocardiogram examination is strongly recommended. In certain cases where a severe risk to the patient could exist if treatment were stopped, lithium has been continued during pregnancy.

If it is considered essential to maintain lithium treatment during pregnancy, serum lithium levels should be closely monitored and measured frequently since renal function changes gradually during pregnancy and suddenly at parturition. Dosage adjustments are required. It is recommended that lithium be discontinued shortly before delivery and reinitiated a few days post-partum.

Neonates may show signs of lithium toxicity necessitating fluid therapy in the neonatal period. Neonates born with low serum lithium concentrations may have a flaccid appearance that returns to normal without any treatment.

4.6.2 Women of child-bearing potential

It is advisable that women treated with lithium should adopt adequate contraceptive methods. In case of a planned pregnancy, it is strongly recommended to discontinue lithium therapy.

4.6.3 Lactation

Since adequate human data on use during lactation, adequate animal reproduction studies are not available and as lithium is secreted in breast milk, bottle-feeding is recommended (see section 4.3 Contra-indications).

As lithium may cause disturbances of the CNS, patients should be warned of the possible hazards when driving or operating machinery.

Side effects are usually related to serum lithium concentration and are less common in patients with plasma lithium concentrations below 1.0 mmol/l.

Initial therapy: fine tremor of the hands, polyuria and thirst may occur.

Body as a whole: muscle weakness, peripheral oedema.

Cardiovascular: cardiac arrhythmia (NOS), mainly bradycardia, sinus node dysfunction, peripheral circulatory collapse, hypotension, oedema, ECG changes such as reversible flattening or inversion of T-waves and QT prolongation, cardiomyopathy.

CNS: ataxia, hyperactive deep tendon reflexes, extrapyramidal symptoms, seizures, slurred speech, dizziness, nystagmus, stupor, coma, pseudotumor cerebri, myasthenia gravis, vertigo, giddiness, dazed feeling, memory impairment.

Dermatology: alopecia, acne, folliculitis, pruritus, aggravation or occurrence of psoriasis, allergic rashes, acneiform eruptions, papular skin disorders, cutaneous ulcers.

Endocrine: euthyroid goitre, hypothyroidism, hyperthyroidism and thyrotoxicosis. Lithium-induced hypothyroidism may be managed successfully with concurrent levothyroxine. Hypercalcaemia, hypermagnesaemia, hyperparathyroidism have been reported.

Gastrointestinal: anorexia, nausea, vomiting, diarrhoea, excessive salivation, dry mouth, abdominal discomfort, taste disorder, gastritis.

Haematological: leucocytosis.

Metabolic and Nutrional: weight gain, hyperglycaemia.

Renal: polydipsia and/or polyuria, symptoms of nephrogenic diabetes insipidus, histological renal changes with interstitial fibrosis after long term treatment.

High serum concentrations of lithium including episodes of acute lithium toxicity may aggravate these changes. The minimum clinically effective dose of lithium should always be used. In patients who develop polyuria and/or polydipsia, renal function should be monitored, e.g. with measurement of blood urea, serum creatinine and urinary protein levels in addition to the routine serum lithium assessment.

Reproductive: sexual dysfunction.

Senses: dysgeusia, blurred vision, scotomata.

Rare cases of nephrotic syndrome, speech disorder, confusion, impaired consciousness, myoclonus and abnormal reflex have been reported.

If any of the above symptoms appear, treatment should be stopped immediately and arrangements made for serum lithium measurement.

In patients with a raised lithium concentration, the risk of toxicity is greater in those with the following underlying medical conditions: hypertension, diabetes, congestive heart failure, chronic renal failure, schizophrenia, Addison's disease.

Acute

A single acute overdose usually carries low risk and patients tend to show mild symptoms only, irrespective of their serum lithium concentration. However more severe symptoms may occur after a delay if lithium elimination is reduced because of renal impairment, particularly if a slow-release preparation has been taken. The fatal dose, in a single overdose, is probably over 5g.

If an acute overdose has been taken by a patient on chronic lithium therapy, this can lead to serious toxicity occurring even after a modest overdose as the extravascular tissues are already saturated with lithium.

Chronic

Lithium toxicity can also occur in chronic accumulation for the following reasons: Acute or chronic overdosage; dehydration e.g. due to intercurrent illness, deteriorating renal function, drug interactions, most commonly involving a thiazide diuretic or a non-steroidal anti-inflammatory drug (NSAID).

Symptoms

The onset of symptoms may be delayed, with peak effects not occurring for as long as 24 hours, especially in patients who are not receiving chronic lithium therapy or following the use of a sustained release preparation.

Mild: Nausea, diarrhoea, blurred vision, polyuria, light headedness, fine resting tremor, muscular weakness and drowsiness.

Moderate: Increasing confusion, blackouts, fasciculation and increased deep tendon reflexes, myoclonic twitches and jerks, choreoathetoid movements, urinary or faecal incontinence, increasing restlessness followed by stupor. Hypernatraemia.

Severe: Coma, convulsions, cerebellar signs, cardiac dysrythmias including sinoatrial block, sinus and junctional bradycardia and first degree heart block. Hypotension or rarely hypertension, circulatory collapse and renal failure.

Management

There is no specific antidote to lithium poisoning. In the event of accumulation, lithium should be stopped and serum estimation should be carried out every 6 hours. Under no circumstances should a diuretic be used. Osmotic diuresis (mannitol or urea infusion) or alkalinisation of the urine (sodium lactate or sodium bicarbonate infusion) should be initiated. All patients should be observed for a minimum of 24 hours. ECG should be monitored in symptomatic patients. Steps should be taken to correct hypotension.

Consider gastric lavage for non-sustained-release preparations if more than 4 g has been ingested by an adult within 1 hour or definite ingestion of a significant amount by a child. Slow-release tablets do not disintegrate in the stomach and most are too large to pass up a lavage tube. Gut decontamination is not useful for chronic accumulation. Activated charcoal does not adsorb lithium.

Peritoneal or haemodialysis should be instituted promptly if there is deterioration in the patient's condition (e.g. marked neurological or cardiac features), if the serum lithium level is over 4.0 mmol/l, in an acute overdose (not in addition to chronic use), if there is a deterioration in the patient's condition, or if the serum lithium concentration is not falling at a rate corresponding to a half-life of under 30 hours. This should be continued until there is no lithium in the serum or dialysis fluid. Serum lithium levels should be monitored for at least a further week to take account of any possible rebound in serum lithium levels as a result of delayed diffusion from the body tissues.

In cases of acute on chronic overdose or in cases of chronic lithium toxicity if the lithium concentration is>4.0 mmol/l, discuss with your local poisons service.

Clinical improvement generally takes longer than reduction of serum lithium concentrations regardless of the method used.

The mode of action of lithium is still not fully understood. However, lithium modifies the production and turnover of certain neurotransmitters, particularly serotonin, and it may also block dopamine receptors.

It modifies concentrations of some electrolytes, particularly calcium and magnesium, and it may reduce thyroid activity.

Lithium has a half life of about 24-hours although this increases to about 36-hours in the elderly due to a progressive decrease in renal lithium clearance with age. Lithium is 95% eliminated in the urine. Time to peak serum level for prolonged release Priadel tablets is about 2 hours and approximately 90% bioavailability would be expected.

Nothing of therapeutic relevance.

Priadel contains Glycerol distearate, mannitol, acacia spray dried, sodium laurilsulfate, magnesium stearate, maize starch and sodium starch glycolate (Type A).

Priadel 200 contains Glycerol monostearate, glycerol distearate, mannitol, acacia spray dried, sodium laurilsulfate, magnesium stearate, maize starch and sodium starch glycolate (Type A).

None stated

Three years.

Do not store above 25ºC. Store in the original package to protect from moisture.

Pack sizes:

Priadel: Blister packs 100

Priadel 200: Blister packs 100

Not applicable

sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

Priadel: 04425/0325

Priadel 200: 04425/0322

27^th January 2009

27^th January 2009

POM