INDICATIONS AND USAGE Lithium Carbonate Extended-Release Tablets are indicated in the treatment of manic episodes of manic-depressive illness.

Maintenance therapy prevents or diminishes the intensity of subsequent episodes in those manic-depressive patients with a history of mania.

Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, elation, poor judgment, aggressiveness and possibly hostility.

When given to a patient experiencing a manic episode, Lithium Carbonate Extended-Release Tablets may produce a normalization of symptomatology within 1 to 3 weeks.

WARNINGS Lithium Toxicity The toxic concentrations for lithium (≥1.5 mEq/L) are close to the therapeutic range (0.8 to 1.2 mEq/L).

Some patients abnormally sensitive to lithium may exhibit toxic signs at serum concentrations that are considered within the therapeutic range [see BOXED WARNING , DOSAGE AND ADMINISTRATION ].

Lithium may take up to 24 hours to distribute into brain tissue, so occurrence of acute toxicity symptoms may be delayed.

Neurological signs of lithium toxicity range from mild neurological adverse reactions such as fine tremor, lightheadedness, lack of coordination, and weakness; to moderate manifestations like giddiness, apathy, drowsiness, hyperreflexia, muscle twitching, ataxia, blurred vision, tinnitus, and slurred speech; and severe manifestations such as clonus, confusion, seizure, coma, and death.

In rare cases, neurological sequelae may persist despite discontinuing lithium treatment and may be associated with cerebellar atrophy.

Cardiac manifestations involve electrocardiographic changes, such as prolonged QT interval, ST and T-wave changes and myocarditis.

Renal manifestations include urine concentrating defect, nephrogenic diabetes insipidus, and renal failure.

Respiratory manifestations include dyspnea, aspiration pneumonia, and respiratory failure.

Gastrointestinal manifestations include nausea, vomiting, diarrhea, and bloating.

No specific antidote for lithium poisoning is known [see OVERDOSAGE ].

The risk of lithium toxicity is increased by: Recent onset of concurrent febrile illness Concomitant administration of drugs which increase lithium serum concentrations by pharmacokinetic interactions or drugs affecting kidney function [see PRECAUTIONS-DRUG INTERACTIONS ] Acute ingestion Impaired renal function Volume depletion or dehydration Significant cardiovascular disease Changes in electrolyte concentrations (especially sodium and potassium) Monitor for signs and symptoms of lithium toxicity.

If symptoms occur, decrease dosage or discontinue lithium treatment.

Unmasking of Brugada Syndrome There have been postmarketing reports of a possible association between treatment with lithium and the unmasking of Brugada Syndrome.

Brugada Syndrome is a disorder characterized by abnormal electrocardiographic (ECG) findings and a risk of sudden death.

Lithium should generally be avoided in patients with Brugada Syndrome or those suspected of having Brugada Syndrome.

Consultation with a cardiologist is recommended if: (1) treatment with lithium is under consideration for patients suspected of having Brugada Syndrome or patients who have risk factors for Brugada Syndrome, e.g., unexplained syncope, a family history of Brugada Syndrome, or a family history of sudden unexplained death before the age of 45 years, (2) patients who develop unexplained syncope or palpitations after starting lithium therapy.

Pseudotumor Cerebri Cases of pseudotumor cerebri (increased intracranial pressure and papilledema) have been reported with lithium use.

If undetected, this condition may result in enlargement of the blind spot, constriction of visual fields, and eventual blindness due to optic atrophy.

Lithium should be discontinued, if clinically possible, if this syndrome occurs.

Renal Effects Chronic lithium therapy may be associated with diminution of renal concentrating ability, occasionally presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia.

Such patients should be carefully managed to avoid dehydration with resulting lithium retention and toxicity.

This condition is usually reversible when lithium is discontinued.

Post marketing cases consistent with nephrotic syndrome have been reported with the use of lithium.

Biopsy findings in patients with nephrotic syndrome include minimal change disease and focal segmental glomerulosclerosis.

Discontinuation of lithium in patients with nephrotic syndrome has resulted in remission of nephrotic syndrome.

Morphologic changes with glomerular and interstitial fibrosis and nephron atrophy have been reported in patients on chronic lithium therapy.

Morphologic changes have also been seen in manic-depressive patients never exposed to lithium.

The relationship between renal functional and morphologic changes and their association with lithium therapy have not been established.

Kidney function should be assessed prior to and during lithium therapy.

Routine urinalysis and other tests may be used to evaluate tubular function (e.g., urine specific gravity or osmolality following a period of water deprivation, or 24-hour urine volume) and glomerular function (e.g., serum creatinine, creatinine clearance or proteinuria).

During lithium therapy, progressive or sudden changes in renal function, even within the normal range, indicate the need for reevaluation of treatment.

Encephalopathic Syndrome An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN and FBS) has occurred in a few patients treated with lithium plus a neuroleptic.

In some instances, the syndrome was followed by irreversible brain damage.

Because of a possible causal relationship between these events and the concomitant administration of lithium and neuroleptics, patients receiving such combined therapy should be monitored closely for early evidence of neurologic toxicity and treatment discontinued promptly if such signs appear.

This encephalopathic syndrome may be similar to or the same as neuroleptic malignant syndrome (NMS).

Serotonin Syndrome Lithium can precipitate serotonin syndrome, a potentially life-threatening condition.

The risk is increased with concomitant use of other serotonergic drugs (including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, and St.

John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see PRECAUTIONS ].

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Monitor all patients taking lithium for the emergence of serotonin syndrome.

Discontinue treatment with lithium and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

If concomitant use of lithium with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

Concomitant Use with Neuromuscular Blocking Agents Lithium may prolong the effects of neuromuscular blocking agents.

Therefore, neuromuscular blocking agents should be given with caution to patients receiving lithium.

Usage in Pregnancy Adverse effects on implantation in rats, embryo viability in mice and metabolism in vitro of rat testes and human spermatozoa have been attributed to lithium, as have teratogenicity in submammalian species and cleft palates in mice.

In humans, lithium carbonate may cause fetal harm when administered to a pregnant woman.

Data from lithium birth registries suggest an increase in cardiac and other anomalies, especially Ebstein’s anomaly.

If this drug is used in women of childbearing potential, or during pregnancy, or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Usage in Nursing Mothers Lithium is excreted in human milk.

Nursing should not be undertaken during lithium therapy except in rare and unusual circumstances where, in the view of the physician, the potential benefits to the mother outweigh possible hazards to the infant or neonate.

Signs and symptoms of lithium toxicity such as hypertonia, hypothermia, cyanosis, and ECG changes have been reported in some infants and neonates.

Usage in Pediatric Patients Safety and effectiveness in pediatric patients under 12 years of age have not been determined; its use in these patients is not recommended.

There has been a report of a transient syndrome of acute dystonia and hyperreflexia occurring in a 15 kg child who ingested 300 mg of lithium carbonate.

ADVERSE REACTIONS The occurrence and severity of adverse reactions are generally directly related to serum lithium concentrations as well as to individual patient sensitivity to lithium, and generally occur more frequently and with greater severity at higher concentrations.

Adverse reactions may be encountered at serum lithium levels below 1.5 mEq/L.

Mild to moderate adverse reactions may occur at levels from 1.5 to 2.5 mEq/L, and moderate to severe reactions may be seen at levels of 2 mEq/L and above.

Fine hand tremor, polyuria, and mild thirst may occur during initial therapy for the acute manic phase, and may persist throughout treatment.

Transient and mild nausea and general discomfort may also appear during the first few days of lithium administration.

These side effects usually subside with continued treatment or a temporary reduction or cessation of dosage.

If persistent, cessation of lithium therapy may be required.

Diarrhea, vomiting, drowsiness, muscular weakness, and lack of coordination may be early signs of lithium intoxication, and can occur at lithium levels below 2 mEq/L.

At higher levels, ataxia, giddiness, tinnitus, blurred vision, and a large output of dilute urine may be seen.

Serum lithium levels above 3 mEq/L may produce a complex clinical picture, involving multiple organs and organ systems.

Serum lithium levels should not be permitted to exceed 2 mEq/L during the acute treatment phase.

The following reactions have been reported and appear to be related to serum lithium levels, including levels within the therapeutic range: Neuromuscular/Central Nervous System: Tremor, muscle hyperirritability (fasciculations, twitching, clonic movements of whole limbs), hypertonicity, ataxia, choreo-athetotic movements, hyperactive deep tendon reflex, extrapyramidal symptoms including acute dystonia, cogwheel rigidity, blackout spells, epileptiform seizures, slurred speech, dizziness, vertigo, downbeat nystagmus, incontinence of urine or feces, somnolence, psychomotor retardation, restlessness, confusion, stupor, coma, tongue movements, tics, tinnitus, hallucinations, poor memory, slowed intellectual functioning, startled response, worsening of organic brain syndromes, myasthenia gravis (rarely).

Cardiovascular: Cardiac arrhythmia, hypotension, peripheral circulatory collapse, bradycardia, sinus node dysfunction with severe bradycardia (which may result in syncope), Unmasking of Brugada Syndrome [see WARNINGS and PRECAUTIONS , Information for Patients ].

Gastrointestinal - Anorexia, nausea, vomiting, diarrhea, gastritis, salivary gland swelling, abdominal pain, excessive salivation, flatulence, indigestion.

Genitourinary: Glycosuria, decreased creatinine clearance, albuminuria, oliguria, and symptoms of nephrogenic diabetes insipidus including polyuria, thirst and polydipsia.

Dermatologic: Drying and thinning of hair, alopecia, anesthesia of skin, chronic folliculitis, xerosis cutis, psoriasis onset or exacerbation, generalized pruritus with or without rash, cutaneous ulcers, angioedema, drug reaction with eosinophilia and systemic symptoms (DRESS).

Autonomic Nervous System: Blurred vision, dry mouth, impotence/sexual dysfunction.

Thyroid Abnormalities: Euthyroid goiter and/or hypothyroidism (including myxedema) accompanied by lower T 3 and T 4 .I 131 uptake may be elevated [see PRECAUTIONS ].

Paradoxically, rare cases of hyperthyroidism have been reported.

EEG Changes: Diffuse slowing, widening of the frequency spectrum, potentiation and disorganization of background rhythm.

EKG Changes: Reversible flattening, isoelectricity or inversion of T-waves.

Miscellaneous: Fatigue, lethargy, transient scotomata, exophthalmos, dehydration, weight loss, leukocytosis, headache, transient hyperglycemia, hypercalcemia, hyperparathyroidism, excessive weight gain, edematous swelling of ankles or wrists, metallic taste, dysgeusia/taste distortion, salty taste, thirst, swollen lips, tightness in chest, swollen and/or painful joints, fever, polyarthralgia, dental caries.

Some reports of nephrogenic diabetes insipidus, hyperparathyroidism, and hypothyroidism which persist after lithium discontinuation have been received.

A few reports have been received of the development of painful discoloration of fingers and toes and coldness of the extremities within one day of the starting of treatment with lithium.

The mechanism through which these symptoms (resembling Raynaud's syndrome) developed is not known.

Recovery followed discontinuance.