Li-Liquid 1018mg/5ml Oral Syrup
1. NAME OF THE MEDICINAL PRODUCT
Li-Liquid 1018mg/5ml Oral Syrup
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Lithium Citrate Tetrahydrate 1018mg/5ml
equivalent to lithium ion 10.8mmol
equivalent to Lithium Carbonate 400mg
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Solution for oral administration
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
• Treatment of mania and hypomania
• Treatment of recurrent bipolar depression, where the use of alternative antidepressants has been ineffective
• Prophylactic treatment of recurrent affective disorders
• Control of aggressive or self mutilating behaviour
Treatment should be directed to stabilise manic depressive illness rather than to establish early control of acute episodes.
4.2 Posology and method of administration
For oral administration only.
A simple treatment schedule has been evolved which except for some minor variations should be followed whether using Li-Liquid therapeutically or prophylactically. The minor variations to this schedule depend on the elements of the illness being treated and these are described later.
Adults:
1. In patients of average weight (70Kg) an initial total daily dose of 1018 -3054mg Lithium citrate (equivalent to 400 - 1200mg Lithium carbonate which is 5-15ml of liquid) should be given in divided doses, in the morning and in the evening.
When changing between lithium preparations, serum lithium levels should first be checked, then Li-liquid therapy commenced at a daily dose as close as possible to that of the other form of lithium. As bioavailability varies from product to product (particularly with regard to 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 Li-liquid dose so as to maintain the serum lithium level permanently within the diurnal range of 0.5 - 1.5mmol/L. Blood samples for measurement of serum lithium concentration should be taken before a dose is due and not less than 12 hours after the previous dose. ‘Target’ serum lithium concentration at 12 hours should be 0.5 - 0.8 mmol/L. Serum lithium levels should be monitored weekly until stabilisation is achieved. Levels of more than 1.5mmol/L must be avoided.
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 changes 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 after the commencement of therapy with Li-Liquid, it 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 therapy with Li-Liquid, treatment is likely to be long term. Careful clinical appraisal of the patient should be exercised throughout medication (see precautions).
Prophylactic treatment of recurrent affective disorders: It is recommended that the described treatment schedule is followed.
Treatment of acute mania, hypomania and recurrent bipolar depression: It is likely that a higher than normal intake of Li-Liquid may be necessary during an acute phase. As soon as control of mania or depression is achieved, the serum lithium level should be determined and it may be necessary, dependent on the results, to lower the dose of Li-Liquid and to re-stabilise serum lithium levels.
Elderly: In elderly patients or those below 50 Kg in weight, it is recommended that a starting dose of 509mg lithium citrate (equivalent to 200mg lithium carbonate which is 2.5ml of liquid) is taken in divided doses, in the morning and in the evening. Elderly patients may be more sensitive to undesirable effects of lithium and may also require lower doses in order to maintain normal serum lithium levels. It follows therefore that long term patients often require a reduction in dosage over a period of years.
Children and adolescents: Not recommended.
4.3. Contraindications
Do not use in patients with a history of hypersensitivity to lithium or to any of the excipients listed in section 6.1, 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 or those with Addison’s disease.
Do not use in patients who are breastfeeding.
Hypersensitivity to any of the excipients.
4.4. Special warnings and precautions for use
When considering therapy with Li-Liquid, it is necessary to ascertain whether patients are receiving lithium in any other form. If so, check serum levels before proceeding.
Lithium therapy may lower the seizure threshold and increase the risks of neurological adverse effects following electroconvulsive therapy (ECT). If ECT is administered to patients on lithium therapy, lithium levels should checked beforehand to ensure that they are moderate (around 0.4-1 mmol/l) and a low electrical dose at the first treatment should be considered.
It is important to ensure that renal function is normal; if necessary a creatinine clearance test or other renal function test should be performed.
Cardiac and thyroid function should be assessed before commencing lithium treatment. Histological changes (including tubulointerstitial nephropathy) have been reported after long-term treatment with lithium. (see section 4.8)
Patients should be euthyroid before the initiation of lithium therapy.
Renal function, cardiac function and thyroid function should be re-assessed periodically.
Patients should be warned to report if polyuria or polydipsia develops. Nausea, vomiting, diarrhoea, intercurrent infection, fluid deprivation (e.g. excessive sweating, severe dieting) and drugs likely to upset electrolyte balance, such as diuretics, may all reduce lithium excretion and thereby precipitate intoxication; lithium dosage should be closely monitored and a reduction of dosage may be required. Treatment should be discontinued during any intercurrent infection and should only be reinstituted after the patient’s physical health has returned to normal.
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.
Use with care in elderly patients as lithium excretion may also be reduced. They may exhibit adverse reactions at serum levels ordinarily tolerated by younger patients.
Patients should be warned of the symptoms of impending toxication (see Section 4.8), 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 Section 4.8). Acute renal failure has been reported rarely with lithium toxicity.
Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviours or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.
Renal tumours: 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).
Excipients in the formulation
Lithium 1018mg/5ml Oral Syrup contains methyl and propyl hydroxybenzoates (preservatives) which may cause allergic reactions (possibly delayed).
This product also contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
The medicine contains 1.7g of glucose in each 5ml. When taken according to dosage recommendations, the maximum dose supplies up to 5.1g of glucose. Patients with rare glucose-galactose malabsorption should not take this medicine.
It also contains sunset yellow colouring E110 which can cause allergic reactions including asthma. Allergy is more common in those who are allergic to aspirin.
The flavour contains a small amount of ethanol (alcohol), less than 100mg per dose.
4.5. Interaction with other Medicinal Products and other forms of Interaction
If one of the following drugs is initiated, lithium dosage should either be adjusted or concomitant treatment stopped, as appropriate.
Interactions which increase lithium concentrations
• Metronidazole
• Non-steroidal anti-inflammatory drugs including selective cyclo-oxygenase (COX) II inhibitors (monitor serum lithium concentrations more frequently if NSAID therapy is initiated or discontinued)
• ACE inhibitors
• Angiotensin II receptor antagonists.
• Diuretics should be prescribed with extreme caution and careful monitoring. Similar precautions should be exercised on diuretic withdrawal. Note that thiazides show a paradoxical antidiuretic 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.
• Other drugs affecting electrolyte balance, e.g. steroids, may alter lithium excretion and therefore should be avoided.
• Tetracyclines
Interactions which decrease serum lithium concentrations
• urea
• xanthines
• sodium bicarbonate containing products
• Diuretics (carbonic anhydrase inhibitors)
Interactions causing neurotoxicity
• Neuroleptics (particularly haloperidol at higher dosages), flupentixol, risperidone, diazepam, thioridazine, fluphenazin, chlorpromazine and clozapine may lead in rare cases to neurotoxicity in the form of confusion,
disorientation, lethargy, tremor, extrapyramidal symptoms and myoclonus. Co-administration of lithium with neuroleptics increases the risk of Neuroleptic Malignant Syndrome (NMS).
• Methyldopa
• Selective Serotonin Re-uptake Inhibitors (e.g. fluvoxamine and fluoxetine) as this combination may precipitate a serotonergic syndrome.
• 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.
• Tri-cyclic antidepressants
• 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.
Drugs which prolong QT interval
• Use with drugs that prolong QT interval is not recommended Other
• Raised plasma levels of ADH may occur during treatment. Symptoms of nephrogenic diabetes insipidus are particularly prevalent in patients receiving concurrent treatment with tricyclic or tetracyclic antidepressants
4.6. Fertility, Pregnancy and Lactation
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 prenatal 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 advisable that women treated with lithium should adopt adequate contraceptive methods. 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.
Babies may show signs of lithium toxicity necessitating fluid therapy in the neonatal period. Babies born with low serum concentrations may have a flaccid appearance which returns to normal without any treatment. Lithium is secreted in breast milk, therefore bottle feeding is recommended. (See section 4.3 Contraindications).
4.7 Effects on ability to drive and use machines
Lithium may impair alertness. Patients should be warned of these risks, and advised not to drive or operate machinery until their susceptibilities are known.
4.8. Undesirable Effects
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 and nausea may occur.
Body as a whole:
Peripheral oedema, muscle weakness, arthralgia, myalgia Cardiovascular:
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, cardiomyopathy.
CNS:
Ataxia, peripheral sensorimotor neuropathy, hyperactive deep tendon reflexes, extrapyramidal symptoms, seizures, slurred speech, dizziness, nystagmus, stupor, coma, pseudotumor cerebri, myasthenia gravis, vertigo, giddiness, dazed feeling, memory impairment.
Dermatological:
Alopecia, acne, folliculitis, pruritus, exacerbation or occurrence of psoriasis, allergic rashes, acneiform eruptions, papular skin disorder, cutaneous ulcers.
Endocrine:
Euthyroid goitre, hypothyroidism, hyperthyroidism, hyperparathyroidism, thyrotoxicosis. Lithium induced hypothyroidism may be managed successfully with concomitant thyroxine.
Gastro-intestinal:
Anorexia, nausea, vomiting, diarrhoea, gastritis, excessive salivation, dry mouth, abdominal discomfort, gastritis.
Haematological:
Leukocytosis
Metabolic and Nutritional:
Hyperglycaemia, hypercalcaemia, hypermagnesaemia, weight gain 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. Frequency unknown: Microcysts, oncocytoma and collecting duct renal carcinoma (in long-term therapy) (see Section 4.4).
Reproductive:
Sexual dysfunction
Senses:
Scotomata, dysgeusia, blurred vision.
Rare cases of nephrotic syndrome, speech disorder, confusion, impaired consciousness, myoclony 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.
Reporting of suspected adverse reactions
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.
4.9 Overdose
Any overdose in a patient who has been taking chronic lithium therapy should be regarded as potentially serious. 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.
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).
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.
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 dysrhythmias including sino-atrial 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. Particular attention should be paid to maintenance of fluid and electrolyte balance and adequate renal function. Where convulsions are present, diazepam may be used. 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 one 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. Whole bowel irrigation may be helpful in patients ingesting large quantities of a slow-release preparation.
Note: Activated charcoal does not adsorb lithium.
Peritoneal or haemodialysis is the treatment of choice for severe poisoning and should be considered in all patients with 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. Note: Clinical improvement generally takes longer than reduction of serum lithium concentrations regardless of the method used.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: N05A N01
Although lithium is a simple ion it can exert a profound effect on both human behaviour and early embryonic development. Manic depressive psychosis, characterised by dramatic savings in mood can be effectively controlled.
Little is known about the way the lithium ion can modify neurotransmission within the CNS. Many of the proposed mechanisms have suggested an inhibitory effect on components of various neurotransmitter signalling pathways, such as cyclic AMP formation, cyclic GMP formation, G-proteins or inositol phosphate metabolism.
5.2 Pharmacokinetic properties
Lithium is rapidly and completely absorbed from the gastrointestinal tract when taken in solution as one of its salts.
Peak plasma concentrations are obtained about 0.75 hours after ingestion of Li-Liquid. Lithium is reported to have a plasma half life of about 7 to 20 hours during the daytime. Lithium is excreted by the kidneys. There is a narrow margin between the therapeutic and the toxic plasma concentration. Therefore, not only is individual titration of lithium dosage essential to ensure constant plasma concentrations for the patient involved, but the conditions under which the blood samples are taken for monitoring must be carefully controlled. In practice a blood sample drawn 12 hours after the last dose of lithium in a patient who has been taking his daily lithium requirement at the scheduled hours during the past 48 hours is measured. Under such conditions the usual therapeutic plasma concentrations of lithium are 0.6 - 1.25 mmol/L, with a reported effective range of 0.5 - 1.5mmol/L
5.3 Preclinical safety data
There is epidemiological evidence that lithium may be harmful to the foetus in human pregnancy. Therefore it is recommended that lithium be discontinued or if the lithium is necessary, the levels in the patient should be monitored closely. Lithium is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Citric acid monohydrate, saccharin sodium, sorbitol solution, syrup liquid glucose, propylene glycol, methyl and propyl hydroxybenzoate, colouring E110, cherry flavour (containing ethanol and propylene glycol) and purified water
6.2 Incompatibilities
None known
6.3 Shelf life
24 months 6 months opened
6.4 Special precautions for storage
Store above 4°C and protect from light.
6.5. Nature and Contents of Container
Bottles: Amber (Type III) glass bottles with capacity of 150ml.
Closures: HDPE EPE wadded, tamper evident, child resistant.
6.6. Special Precautions for Disposal and Other Handling
Keep out of the sight and reach of children.
7 MARKETING AUTHORISATION HOLDER
Rosemont Pharmaceuticals Ltd Rosemont House Yorkdale Industrial Park
Braithwaite Street Leeds LS11 9XE UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 00427/0075
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27 January 1992
10 DATE OF REVISION OF THE TEXT
21/07/2015