4.5       Interactions with other medicinal products and other forms of interaction

Serum lithium levels may be increased if one of the following drugs is co-administered. When appropriate, either lithium dosage should be adjusted or concomitant treatment stopped.

·        Thiazide diuretics may reduce lithium renal clearance, potentially leading to lithium intoxication. If a thiazide diuretic has to be used, lithium dosage should first be reduced. Loop diuretics seem less likely to increase lithium levels.

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

·        Non-steroidal anti-inflammatory drugs (NSAIDs) including cyclo-oxygenase (COX) 2 inhibitors

·        Angiotensin-converting enzyme (ACE) inhibitors

·        Angiotensin II receptor antagonists

·        Metronidazole may reduce lithium renal clearance

·        Tetracyclines

Serum lithium levels may be decreased due to an increase in lithium renal clearance in case of concomitant administration of one of the following drugs:

·        Osmotic diuretics and carbonic anhydrase inhibitors

·        Xanthine (theophylline, caffeine)

·        Sodium bicarbonate

Co-administration of the following drugs may increase the risk of neurotoxicity:

·        Calcium channel blockers may lead to a risk of neurotoxicity with symptoms such as ataxia, confusion and somnolence. Lithium concentrations may be increased.

·        Antipsychotic drugs such as haloperidol, thioridazine, fluphenazine, chlorpromazine and clozapine may lead in rare cases to neurotoxicity with symptoms such as confusion, disorientation, lethargy, tremor, extra-pyramidal symptoms and myoclonus. Increased lithium levels were present in some of the reported cases. Discontinuation of both drugs is recommended at the first signs of neurotoxicity.

·        Carbamazepine may lead to dizziness, somnolence, confusion and cerebellar symptoms such as ataxia.

·        Methyldopa

·        Triptan derivatives and/or serotoninergic antidepressants such as SSRIs (such as fluoxatine and fluvoxamine) may result in occurrence of serotonin syndrome, which requires immediate treatment discontinuation.

Seritonin syndrome: The Serotonin Syndrome is a potentially life-threatening adverse drug reaction, which is caused by an excess in serotonin (e.g. from overdose or concomitant  use of serotonergic drugs), necessitating hospitalisation or even causing death. Symptoms may include:

-         Mental status change (agitation, confusion, hypomania, eventually coma);

-         Neuromuscular abnormalities (myoclonus, tremor, hyperreflexia, rigidity, akathisia);

-         Autonomic hyperactivity (hypo or hypertension, tachycardia, shivering, hyperthermia, diaphoresis);

-         Gastrointestinal symptoms (diarrhoea).

Strict adherence to the recommended doses is an essential factor for the prevention of the occurrence of this syndrome.

·         Caution is advised if lithium is co-administered with other drugs that prolong the QT interval (see also Section 6 and Section 11) e.g. Class IA (e.g. quinidine, disopyramide) or Class III (e.g. amiodarone) antiarrhythmic agents, cisapride, antibiotics such as erythromycin, antipsychotics such as thioridazine or amisulpride. This list is not exhaustive.

·        Caution is advised if lithium is co-administered with drugs that lower the epileptic threshold (see section 4.4), e.g. antidepressants such as SSRIs, tricyclic antidepressants, antipsychotics, anaesthetics, theophylline. This list is not comprehensive.

Neonates may show signs of lithium toxicity necessitating fluid therapy in the neonatal period, including symptoms such as lethargy, flaccid muscle tone, or hypotonia. Neonates born with low serum lithium concentrations may have a flaccid appearance that returns to normal without any treatment.Careful clinical observation of the neonate exposed to lithium during pregnancy is recommended and lithium levels may need to be monitored as necessary.

4.6.1        Women of child-bearing potential

Women of childbearing potential should use effective contraceptive methods during treatment with lithium.

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.

4.6.2        Lactation

Lithium is secreted in breast milk, and there have been reports of neonates showing signs of lithium toxicity (see section 4.6.1). Therefore lithium should not be used during breast feeding (see section 4.3). A decision should be made whether to discontinue lithium therapy or to discontinue breast feeding, taking into account the importance of the drug to the mother and the importance of breast feeding to the infant. Therefore, bottle-feeding is recommended (see section 4.3 Contraindications).

4.8       Undesirable effects

Side effects are usually related to serum lithium concentration and are less common in patients with plasma lithium concentrations infrequent at levels below 1.0 mmol/l. The adverse reactions usually subside with a temporary reduction or discontinuation of the lithium treatment. Mild gastrointestinal effects such as nausea, a general discomfort and vertigo, may occur initially, but frequently disappear after the first few days of lithium administration. Fine hand tremors, polyuria and mild thirst may persist.

DermatologySkin and subcutaneous tissue disorders: acne, aggravation or occurrence of psoriasis, allergic rashes, alopecia, cutaneous ulcers.

Musculoskeleta and connective tissue disordersl: muscle weakness

Central nNervous system disorders: tremor especially fine hand tremors, vertigo, speech disorderdysarthria, impaired consciousness, myoclonyus, and abnormal reflexes, convulsions (see section 4.4 & section 4.5), benign intracranial hypertension (see section 4.4), extrapyramidal disorders have been reported.  Memory impairment may occur during long term use.

Gastrointestinal disorders: abdominal discomfort, taste disorder, nausea, vomiting, diarrhoea, salivary hypersecretion, dry mouth.

Endocrine disorders: long term adverse effects may include thyroid function disturbances such as euthyroid goitre and/or hypothyroidism. Rarely hyperthyroidism may also occur. Lithium-induced hypothyroidism may be managed successfully with concurrent levothyroxine. Hypercalcaemia, hypermagnesaemia, hyperparathyroidism have been reported.

Metabolic and Nutritional disorders: Weight increase.

CardiovascularCardiac disorders: QT prolongation, sometimes associated with ventricular tachycardia or torsades de points, which may result in ventricular fibrillation or cardiac arrest and sudden death. Other cardiac arrhythmia mainly bradycardia, sinus node dysfunction, ECG changes such as reversible flattening or inversion of T-waves, AV block,.  Ccardiomyopathy.

HaematologicalBlood and lymphatic disorders: leucocytosis

Renal and urinary disorders: polydipsia and/or polyuria, and nephrogenic diabetes insipidus have been reported (see section 4.4). This is usually due to lithium blocking the effect of ADH and is reversible on lithium withdrawal.

However, lLong term treatment with lithium may also result in permanent changes in kidney histology and impairment of renal function.

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.

Rare cCases of nephrotic syndrome have been reported.

Psychiatric disorders: Confusion.