Summary of medicine characteristics - PRIADEL 400 MG PROLONGED-RELEASE TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Priadel 400mg prolonged release tablets.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 400 mg lithium carbonate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged-release tablet.
White, circular, bi-convex tablets engraved PRIADEL on one side, scored on the other side, in a prolonged-release formulation.
The tablet can be divided into equal doses.
4 CLINICAL PARTICULARS
4 CLINICAL PARTICULARS4.1 Therapeutic indications
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.
4.2 Posology and method of administration
Dosage must be individualised depending on serum lithium levels and clinical response. The dosage necessary to maintain serum lithium levels within the therapeutic range varies from patient to patient. The minimum effective dose should be sought and maintained.
As a general rule, the following dosing schedule is recommended. Please refer also to the specific recommendations for the different indications as listed below:
1. In patients of average weight (70 kg) an initial dose of 400–1,200 mg 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. hen changing between lithium preparations serum lithium levels should first be checked, then Priadel therapy started 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 a maximum of seven days after starting treatment, serum lithium levels should be measured. Optimal maintenance serum levels may vary from patient to patient.
3. Blood samples should be taken 12 or 24 hours after the previous dose of lithium, just before the next dose is due, to measure the serum lithium level at its trough. The serum level should not exceed 1.5 mmol/l.
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)
At 12 hours At 24 hours
Once daily
dosage 0.7 – 1.0 0.5 – 0.8
Twice daily
dosage 0.5 – 0.8
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 measurements can be increased gradually, but should not normally exceed two to 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 (see section 4.9).
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.
It is recommended that the described treatment schedule is followed. The dosage needed may vary from patient to patient. As a general rule, serum lithium levels should be maintained within the range of 0.5 to 1.0 mmol/L, and should not exceed 1.5 mmol/L. Optimal maintenance serum lithium levels may vary from patient to patient.
It is likely that a higher than normal Priadel intake may be necessary during an acute phase and divided doses would be required here. As a general rule the monitoring should maintain serum levels at 0.8–1.2 mmol/l until acute symptoms have been controlled. In all other details the described treatment schedule is recommended. The dosage needed may vary from patient to patient. Serum lithium levels should be monitored (see above) and should not exceed 1.5 mmol/L. Once clinical control is achieved, dosage should be reduced to the prophylactic dose.
Elderly patients or those below 50 kg in weight, often require lower lithium dosage to achieve therapeutic serum lithium levels. Starting doses of 200 mg to 400 mg are recommended. Dosage increments of 200 to 400 mg every 3 to 5 days are usual. Total daily doses of 800 to 1800 mg 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.
Paediatric population:
Not recommended.
Women of child-bearing potential should use effective contraceptive methods during treatment with lithium.
Breast-feeding
Lithium is secreted in breast milk and there have been case reports of neonates showing signs of lithium toxicity. Therefore lithium should not be used during breastfeeding (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.
Fertility
Published studies in rats exposed to lithium have reported spermatogenesis abnormalities that may lead to impairment of fertility. This risk may also potentially apply to humans.
4.7 Effects on ability to drive and use machines
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.
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. 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. Fine hand tremors, polyuria and mild thirst may persist.
Tabulated list of adverse reactions
| System Organ Class | Adverse reactions |
| Blood and lymphatic system disorders | Leucocytosis. |
| Endocrine disorders | Long-term adverse effects may include thyroid function disturbances such as euthyroid goitre and/or hypothyroidism and thyrotoxicosis. Lithium-induced hypothyroidism may be managed successfully with concurrent thyroxine. Hypercalcaemia, hypermagnesaemia, hyperparathyroidism have been reported. |
| Metabolism and nutrition disorders | Weight increase, hyperglycaemia. |
| Psychiatric disorders | Confusion, delirium |
| Nervous system disorders | Ataxia, hyperactive deep tendon reflexes, slurred speech, dizziness, stupor, coma, 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), extrapyramidal disorders, encephalopathy, cerebellar syndrome (usually reversible), nystagmus. The above symptoms may result in fall. Peripheral neuropathy may occur on longterm treatment and is usually reversible at cessation of lithium. Dysgeusia. Serotonin syndrome Neuroleptic malignant syndrome |
| Eye disorders | Blurred vision, scotoma. |
| Cardiac disorders | Cardiac arrhythmia, mainly bradycardia, sinus node dysfunction, peripheral circulatory collapse, hypotension, 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 | Abdominal discomfort, taste disorder, nausea, vomiting, diarrhoea, gastritis, salivary hypersecretion, dry mouth, anorexia. |
| Skin and subcutaneous tissue disorder | Folliculitis, pruritus, papular skin disorders, acne or acneform eruptions, aggravation or occurrence of psoriasis, allergic rashes, alopecia, cutaneous ulcers |
| Frequency unknown: lichenoid drug reaction. | |
| Musculoskeletal and connective tissue disorders | Muscle weakness, rhabdomyolysis |
| Renal and urinary disorders | Polydipsia and/or polyuria and 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. 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 and breast disorders | Sexual dysfunction. |
| General disorders and administration site conditions | Peripheral oedema. Urticaria and angioedema, attributed to some excipients such as acacia powder (or Arabic gum). |
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
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 5 g.
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.
Symptoms of lithium intoxication include:
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.
Gastrointestinal disorders: increasing anorexia and vomiting.
Nervous system disorders: Encephalopathy, cerebellar syndrome with symptoms such as muscle weakness, lack of coordination, drowsiness or lethargy, giddiness, ataxia, nystagmus, coarse tremor. Tinnitus, dysarthria, twitching, myoclonus, extrapyramidal disorders.
ECG changes (flat or inverted T waves, QT prolongation), AV block, dehydration and electrolyte disturbances.
At blood levels above 2–3 mmol/l, there may be a large output of dilute urine and renal insufficiency, with increasing confusion, convulsions, coma and death.
Management
There is no specific antidote to lithium. In the event of lithium overdose, lithium should be discontinued and lithium serum levels monitored closely.
Supportive treatment should be initiated, which includes correction of fluid and electrolyte balance, if necessary.
Diuretics should not be used (see section 4.5). 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.
Haemodialysis is the treatment of choice for severe lithium intoxication (especially in patients manifesting with severe nervous system disorders), or in cases of overdose accompanied by renal impairment.
Haemodialysis should be continued until there is no lithium in the serum or dialysis fluid. Serum lithium levels should be monitored for at least another 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics; Lithium, ATC code: N05AN01
Mood-stabilising agent
Lithium is an alkali metal available for medical use as lithium carbonate or lithium citrate. The exact mechanism of action of lithium in the treatment of bipolar disorders is not known.
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.
5.2 Pharmacokinetic properties
Time to peak serum level for prolonged release Priadel tablets is about 2 hours and approximately 90% bioavailability would be expected.
Absorption
Lithium is rapidly absorbed from the gastrointestinal tract.
Steady-state lithium levels may not be obtained until 4–6 days.
Distribution
Lithium has a low volume of distribution (0.7 to 0.9 L/kg).
It is not bound to plasma proteins.
Lithium crosses the placenta and is excreted in breast milk.
Biotransformation
Lithium is not metabolised in the liver.
Elimination
Lithium is primarily excreted by the kidneys (>95% of the dose).
Elimination half-life ranges from 18 to 36 hours.
Lithium can be eliminated by haemodialysis.
Special populations
Elimination half-life may be increased in elderly patients due to age related decrease in renal function and also in patients with renal impairment (see sections 4.2 and 4.4).
5.3 Preclinical safety data
Nothing of therapeutic relevance.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Glycerol distearate
Mannitol (E421)
Acacia spray dried
Sodium laurilsulfate (E487)
Magnesium stearate
Maize starch
Sodium starch glycolate (Type A)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store below 25°C. Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Securitainers: 1000, 100 or 50 tablets
Blister packs: 100 tablets
Hospital packs: 100 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Essential Pharma Ltd, Vision Exchange Building Triq it-Territorjals, Zone 1, Central Business District, Birkirkara, CBD 1070, Malta
8 MARKETING AUTHORISATION NUMBER(S)
PL 50301/0002
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
Date of first authorisation: 15 August 1985