Lithium salts.

Lithium carbonate

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.

Children and adolescents:

Not recommended.

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.

• 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. 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.

• 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.

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.

Sanofi-Aventis

(POM)

22 November 2011