Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK
Do not use in patients with a history of hypersensitivity to lithium or to any of the excipients listed in section 6.1, severe renal insufficiency, cardiovascular insufficiency and untreated hypothyroidism.
Lithium should not be given to patients with low body sodium levels, including, for example, dehydrated patients, those on low sodium diets, those with Addison’s disease, those with Brugada syndrome or family history of Brugada syndrome.
Do not use in patients who are breastfeeding.
When considering Li-Liquid therapy, it is necessary to ascertain whether patients are receiving lithium in any other form. If so, check serum levels before proceeding.
The minimum clinically effective dose of lithium should always be used (see Section 4.2). Clear instructions regarding the symptoms of impending toxicity should be given by the physician to patients receiving long-term lithium therapy (see Section 4.9). 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. At the first sign of toxicity, the patient should consult a physician and lithium levels should be checked. Treatment should be discontinued immediately on the first signs of toxicity (see Section 4.9).
Before starting treatment with lithium, renal function, cardiac function and thyroid function should be evaluated. Patients should be euthyroid before initiation of lithium therapy. Lithium therapy is contraindicated in patients with severe renal insufficiency or cardiac insufficiency (see Section 4.3).
Renal, cardiac and thyroid functions should be re-assessed regularly during treatment with lithium.
For monitoring recommendations of lithium serum levels see Section 4.2.
Since lithium is primarily excreted via the renal route, significant accumulation of lithium may occur in patients with renal insufficiency. Therefore, if patients with mild or moderate renal impairment are being treated with lithium, serum lithium levels should be closely monitored (see Section 4.2) and the dose should be adjusted accordingly. If very regular and close monitoring of serum lithium levels and plasma creatinine levels is not possible, lithium should not be prescribed in this population. Lithium is contraindicated in patients with severe renal insufficiency (see Section 4.3).
The possibility of hypothyroidism and renal dysfunction arising during prolonged treatment should be borne in mind and periodic assessments made.
Patients should be warned to report if polyuria or polydipsia develop. In patients who develop polyuria and/or polydipsia (see Section 4.8), renal function should be monitored in addition to the routine serum lithium assessment.
Cases of microcysts, oncocytomas and collecting duct renal carcinoma have been reported in patients with severe renal impairment who received lithium for more than 10 years (see Section 4.8).
If episodes of nausea, vomiting, diarrhoea, excessive sweating, and/or other conditions leading to salt/water depletion (including severe dieting) occur, lithium dosage should be closely monitored and dosage adjustments made as necessary. Drugs likely to upset electrolyte balance such as diuretics should also be reported. Indeed, sodium depletion increases the lithium plasma 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 discontinuation should be considered during any intercurrent infection.
The risk of convulsions may be increased in case of co-administration of lithium with drugs that lower the epileptic threshold, or in epileptic patients (see sections 4.5 and 4.8).
There have been case reports of benign intracranial hypertension (see Section 4.8). Patients should be warned to report persistent headache and/or visual disturbances.
As a precautionary measure, lithium should be avoided in patients with congenital long QT syndrome, and caution should be exercised in patients with risk factors such as QT interval prolongation (e.g. uncorrected hypokalaemia, bradycardia), and in patients concomitantly treated with drugs that are known to prolong the QT interval (see Sections 4.5 and 4.8).
Lithium may unmask or aggravate Brugada syndrome, a hereditary disease of the cardiac sodium channel with characteristic electrocardiographic changes (right bundle branch block and ST segment elevation in right precordial leads), which may lead to cardiac arrest or sudden death. Lithium should not be administered to patients with Brugada Syndrome or a family history of Brugada Syndrome (see Section 4.3). Caution is advised in patients with a family history of cardiac arrest or sudden death.
Elderly patients are particularly liable to lithium toxicity and may exhibit adverse reactions at serum levels ordinarily tolerated by younger patients. Caution is also advised since lithium excretion may be reduced in the elderly due to age related disease in renal function (see Sections 4.2 and 5.2).
The use in children is not recommended.
Li-lithium 509mg/5ml Oral Syrup contains methyl and propyl hydroxybenzoates (preservatives) which may cause allergic reactions (possibly delayed).
The medicine contains 1.7g of glucose in each 5ml. When taken according to dosage recommendations, the maximum dose supplies up to 10.2g of glucose.
It also contains 0.4g of sorbitol. When taken according to dosage recommendations, the maximum dose supplies up to 2.2g of sorbitol. It is unsuitable for those with an hereditary fructose intolerance.
The flavour contains a small amount of ethanol (alcohol), less than 100mg per dose.
If one of the following drugs is initiated, lithium dosage should either be adjusted or concomitant treatment stopped, as appropriate.
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:
*Urea
*Xanthines (such as caffeine and theophylline)
*Sodium bicarbonate containing products
*Diuretics (osmotic and carbonic anhydrase inhibitors)
*Calcitonin
Caution is advised if lithium is co-administered with other drugs that prolong the QT interval (see Sections 4.4 and 4.8), 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. The list is not comprehensive.
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. The list is not comprehensive.
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.
Raised plasma levels of ADH may occur during treatment.
Serotonin syndrome is a potentially life-threatening adverse reaction, which is caused by an excess of serotonin (e.g. from overdose or concomitant use of serotonergic drugs), necessitating hospitalisation and even causing death.
Symptoms may include:
Strict adherence to the recommended doses is an essential factor for the prevention of the occurrence of this syndrome.
Lithium therapy should not be used during pregnancy, especially during the first trimester, unless considered essential. There is epidemiological evidence that lithium 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, have been 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.
It is strongly recommended that lithium be discontinued before a planned pregnancy. If it is considered essential to maintain treatment with Li-Liquid during pregnancy, serum lithium levels should be monitored closely since renal function changes gradually during pregnancy and suddenly at parturition, requiring dosage adjustments. It is recommended that administration of Li-Liquid be discontinued shortly before delivery and recommenced a few days post-partum.
Neonates may show signs of lithium toxicity including symptoms such as lethargy, flaccid muscle tone, or hypotonia. Careful clinical observation of the neonate exposed to lithium during pregnancy is recommended and lithium levels may need to be monitored as necessary.
It is advisable that women treated with lithium should adopt adequate contraceptive methods.
Lithium is secreted in breast milk therefore bottle feeding is recommended. (See section 4.3 Contraindications).
There have been case reports of neonates showing signs of lithium toxicity (see Pregnancy). 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.
Lithium may cause disturbances of the CNS. Since lithium may slow reaction time, and considering the adverse reactions profile of lithium (see Section 4.8), 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. The adverse reactions usually subside with a temporary reduction or discontinuation of 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.
Initial therapy: Fine tremor of the hands, polyuria and thirst and nausea may occur.
Blood and lymphatic system disorders: Leucocytosis
Endocrine disorders: Euthyroid goitre, hypothyroidism, hyperthyroidism, hyperparathyroidism, thyrotoxicosis. Lithium induced hypothyroidism may be managed successfully with concomitant thyroxine.
Metabolism and nutrition disorders: Hyperglycaemia, hypercalcaemia, hypermagnesaemia, weight gain.
Psychiatric disorders: Confusion, delirium.
Nervous system disorders: Ataxia, peripheral sensorimotor neuropathy, hyperactive deep tendon reflexes, extrapyramidal symptoms, seizures, slurred speech, dizziness, stupor, coma, pseudotumor cerebri, myasthenia gravis, giddiness, dazed feeling, memory impairment, tremor, especially fine hand tremors, dysarthria, myoclonus, benign intracranial hypertension (see section 4.4), vertigo, impaired consciousness, abnormal reflexes, convulsions (see sections 4.4 and 4.5), encephalopathy, cerebellar syndrome (usually reversible), nystagmus.
The above symptoms may result in fall.
Peripheral neuropathy may occur on long-term treatment and is usually reversible at cessation of lithium.
Eye disorders: Scotomata, blurred vision.
Cardiac disorders: Reported cardiovascular effects are cardiac arrhythmia, bradycardia, sinus node dysfunction, peripheral circulatory collapse, hypotension, oedema, Raynaud’s phenomenon and ECG changes, such as reversible flattening or inversion of T-waves and QT prolongation, (see sections 4.4 and 4.5), AV block, cardiomyopathy.
Gastrointestinal disorders: Anorexia, nausea, vomiting, diarrhoea, gastritis, excessive salivation, dry mouth, abdominal discomfort, taste disorder.
Skin and subcutaneous tissue disorders: Alopecia, acne, folliculitis, pruritus, exacerbation or occurrence of psoriasis, allergic rashes, acneiform eruptions, papular skin disorder, cutaneous ulcers.
Musculoskeletal and connective tissue disorder: Muscle weakness, rhabdomyolysis, arthralgia, myalgia, myoclony and abnormal reflex
Renal and urinary disorders: Polydipsia and/or polyuria, symptoms of nephrogenic diabetes insipidus, histological renal changes with interstitial fibrosis after long term treatment have been reported (see section 4.4). This is usually reversible on lithium withdrawal.
Long-term treatment with lithium may 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 cases of nephrotic syndrome have been reported.
Frequency unknown: microcysts, oncocytoma and collecting duct renal carcinoma (in long-term therapy) (see Section 4.4).
Reproductive system disorders: Sexual dysfunction.
General disorders and administration site conditions: Peripheral oedema and urticaria attributed to some excipients.
If any of the above symptoms appear, treatment should be stopped immediately and arrangements made for serum lithium measurement.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
None known.
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