Lithium Carbonate

ESKALITH (lithium carbonate) Capsules 300 mg are gray and yellow capsules imprinted with "ESKALITH (lithium carbonate) " and "SB" on one side of each half of the capsule, in bottles of 100 (NDC 0007-4007-20).

ESKALITH (lithium carbonate) CR Tablets 450 mg are round, yellow, biconvex, controlled-release tablets, debossed with "SKF" and "J10" on one side and scored on the other side, in bottles of 100 (NDC 0007-4010-20).

STORAGE CONDITIONS: Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Manufactured by: Cardinal Health., Winchester, KY 40391 for GlaxoSmithKline., Research Triangle Park, NC 27709. September 2003
FDA rev date: 03/11/2004

Lithium Carbonate Extended-Release Tablets USP contain lithium carbonate, a white odorless alkaline powder with molecular formula Li2 CO3 and molecular weight 73.89. Lithium is an element of the alkali-metal group with atomic number 3, atomic weight 6.94, and an emission line at 671 nm on the flame photometer.

Each peach-colored, film-coated, extended-release tablet contains 300 mg of lithium carbonate. This slowly dissolving film-coated tablet is designed to give lower serum lithium peak concentrations than obtained with conventional oral lithium dosage forms. Inactive ingredients consist of calcium stearate, carnauba wax, cellulose compounds, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, povidone, propylene glycol, sodium chloride, sodium lauryl sulfate, sodium starch glycolate, sorbitol, and titanium dioxide. Product meets USP Drug Release Test 1.

Lithium affects the flow of sodium through nerve and muscle cells in the body. Sodium affects excitation or mania.

Lithium is used to treat the manic episodes of manic depression. Manic symptoms include hyperactivity, rushed speech, poor judgment, reduced need for sleep, aggression, and anger. Lithium also helps to prevent or lessen the intensity of manic episodes.

Lithium may also be used for other purposes not listed in this medication guide.

Do not use this medication without telling your doctor if you are pregnant. It could cause harm to the unborn baby. Use an effective form of birth control, and tell your doctor if you become pregnant during treatment.

Call your doctor at once if you have any early signs of lithium toxicity, such as nausea, vomiting, diarrhea, drowsiness, muscle weakness, tremor, lack of coordination, blurred vision, or ringing in your ears.

Do not crush, chew, or break an extended-release tablet. Swallow the pill whole.

Drink extra fluids to keep from getting dehydrated while you are taking lithium. Tell your doctor if you have been sweating excessively, or if you are sick with fever, vomiting, or diarrhea.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Lithium can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Lithium can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Do not change the amount of salt that you consume in your diet. Changing your intake of salt could alter the amount of lithium in your blood.

Pre-treatment Screening

Before initiating treatment with lithium, renal function, vital signs, serum electrolytes, and thyroid function should be evaluated. Concurrent medications should be assessed, and if the patient is a woman of childbearing potential, pregnancy status and potential should be considered.

Starting Dosage

Consider medical conditions and drug interactions that would affect lithium dosage and administration [see Warnings and Precautions (5.1), Drug Interactions (7.1)]. In the absence of medical conditions and concomitant medications that would suggest starting at a lower dose, the recommended starting dose in adults is:

·         Capsules: 300 mg three times daily

Obtain serum lithium concentration assay after 4 days, drawn 12 hours after the last oral dose. Adjust daily dosage based on serum lithium concentration and clinical response. 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 adverse reactions may subside with continued treatment, concomitant administration with food, temporary reduction or cessation of dosage.

Dosage for Acute Treatment of Manic Episodes in Bipolar I Disorder

Titrate to serum lithium concentrations between 0.8 and 1.2 mEq/L, which may be achieved in adults with:

·              Capsules: 600 mg, two to three times daily

Obtain serum lithium concentrations regularly until the serum concentration and clinical condition of the patient has stabilized [see Dosage and Administration (2.6)]. Adjust daily dosage based on serum lithium concentration and clinical response.

Dosage for Maintenance Treatment of Bipolar I Disorder

Titrate to serum lithium concentrations between 0.8 and 1 mEq/L, which may be achieved in adults with:

·              Capsules: 300 mg to 600 mg, two to three times daily or

Monitor the patient’s clinical state and serum lithium concentrations regularly [see Dosage and Administration (2.6)]. Adjust daily dosage based on serum lithium concentration and clinical response.

Dosage Recommendations in Pediatric Patients 12 to 17 Years of Age

Dosage recommendations for lithium in patients 12 years and older are similar to that of adults [see Specific Populations (8.4)].

Serum Lithium Monitoring

Blood samples for serum lithium determination should be drawn immediately prior to the next dose when lithium concentrations are relatively stable (i.e., 12 hours after the previous dose). Total reliance must not be placed on serum concentrations alone. Accurate patient evaluation requires both clinical and laboratory analysis.

In addition to regular monitoring of serum lithium concentrations for patients on maintenance treatment, serum lithium concentrations should be monitored after any change in dosage, concurrent medication (e.g., diuretics, non-steroidal anti-inflammatory drugs, renin-angiotensin system antagonists, or metronidazole), marked increase or decrease in routinely performed strenuous physical activity (such as an exercise program) and in the event of a concomitant disease [See Boxed Warning, Warnings and Precautions (5.1), Drug Interactions (7.1)].

Patients abnormally sensitive to lithium may exhibit toxic signs at serum concentrations that are within what is considered the therapeutic range. Geriatric patients often respond to reduced dosage, and may exhibit signs of toxicity at serum concentrations ordinarily tolerated by other patients [see Specific Populations (8.5)].

Dosage Adjustments during Pregnancy and the Postpartum Period

If the decision is made to continue lithium treatment during pregnancy, monitor serum lithium concentrations and adjust the dosage as needed in a pregnant woman because renal lithium clearance increases during pregnancy. Avoid sodium restriction or diuretic administration. To decrease the risk of postpartum lithium intoxication, decrease or discontinue lithium therapy two to three days before the expected delivery date to reduce neonatal concentrations and reduce the risk of maternal lithium intoxication due to the change in vascular volume which occurs during delivery. At deliver y, vascular volume rapidly decreases and the renal clearance of lithium may decrease to pre-pregnancy concentrations. Restart treatment at the preconception dose when the patient is medically stable after delivery with careful monitoring of serum lithium concentrations [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Dosage Adjustments for Patients with Renal Impairment

Start patients with mild to moderately impaired renal function (creatinine clearance 30 to 89 mL/min evaluated by Cockcroft-Gault) with dosages less than those for patients with normal renal function [see Dosage and Administration (2.2)]. Titrate slowly while frequently monitoring serum lithium concentrations and monitoring for signs of lithium toxicity. Lithium is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min evaluated by Cockcroft-Gault) [see Use in Specific Populations (8.6)].

Acute 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 (2.6)]. Lithium may take up to 24 hours to distribute into brain tissue, so occurrence of acute toxicity symptoms may be delayed.

Diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination ma y be early signs of lithium toxicity, and can occur at lithium concentrations below 2 mEq/L. At higher concentrations, giddiness, ataxia, blurred vision, tinnitus and a large output of dilute urine may be seen. Serum lithium concentrations above 3 mEq/L may produce a complex clinical picture involving multiple organs and organ systems, coma, and eventually death. Serum lithium concentrations should not be permitted to exceed 2 mEq/L.

Neurological signs of lithium toxicity range from mild neurological adverse reactions such as fine tremor, lightheadedness, and weakness; to moderate manifestations like apathy, drowsiness, hyperreflexia, muscle twitching, and slurred speech; and severe manifestations such as clonus, confusion, seizure, coma and death. 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, and bloating. No specific antidote for lithium poisoning is known. Early symptoms of lithium toxicity can usually be treated by reduction or cessation of lithium, before restarting treatment at a lower dose 24 to 48 hours later [see Overdosage (10)].

The risk of acute toxicity is increased with a recent onset of concurrent illness or with the concomitant administration of drugs which increase lithium serum concentrations by pharmacokinetic interactions [see Drug Interactions (7)]. Additional risk factors for acute lithium toxicity include acute ingestion, age-related decline in renal function, volume depletion and/or changes in electrolyte concentrations, especially sodium and potassium. Dose requirements during the acute manic phase are higher to maintain therapeutic serum concentrations and decrease when manic symptoms subside. The risk of lithium toxicity is very high in patients with significant renal or cardiovascular disease, severe debilitation or dehydration, or sodium depletion, and for patients receiving prescribed medications that may affect kidney function, such as angiotensin converting enzyme inhibitors (ACE inhibitors), diuretics (loops and thiazides) and NSAIDs. For these patients, consider starting with lower doses and titrating slowly while frequently monitoring serum lithium concentrations and signs of lithium toxicity.

To reduce the risk of acute lithium toxicity during treatment initiation, facilities for prompt and accurate serum lithium determinations should be available before initiating treatment [see Boxed Warning, Dosage and Administration (2.6)]. Advise patients and caregivers to watch for signs of early toxicity and to discontinue lithium and immediately inform their health care provider if they occur.

Lithium-Induced Polyuria

Chronic lithium treatment may be associated with diminution of renal concentrating ability, occasionally presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia. The concentrating defect and natriuretic effect characteristic of this condition may develop within weeks of lithium initiation. Lithium can also cause renal tubular acidosis, resulting in hyperchloremic metabolic acidosis. Such patients should be carefully managed to avoid dehydration with resulting lithium retention and toxicity. This condition is usually reversible when lithium is discontinued, although for patients treated with long-term lithium, nephrogenic diabetes insipidus may be only partly reversible upon discontinuation of lithium. Amiloride may be considered as a therapeutic agent for lithium-induced nephrogenic diabetes insipidus.

Hyponatremia

Lithium can cause hyponatremia by decreasing sodium reabsorption by the renal tubules, leading to sodium depletion. Therefore, it is essential for patients receiving lithium treatment to maintain a normal diet, including salt, and an adequate fluid intake (2500 to 3000 mL) at least during the initial stabilization period. Decreased tolerance to lithium has also been reported to ensue from protracted sweating or diarrhea and, if such occur, supplemental fluid and salt should be administered under careful medical supervision and lithium intake reduced or suspended until the condition is resolved. In addition, concomitant infection with elevated temperatures may also necessitate a temporary reduction or cessation of medication.

Symptoms are also more severe with faster-onset hyponatremia. Mild hyponatremia (i.e., serum Na > 120 mEq/L) can be asymptomatic. Below this threshold, clinical signs are usually present, consisting mainly of changes in mental status, such as altered personality, lethargy, and confusion. For more severe hyponatremia (serum Na < 115 mEq/L), stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma, and death can result. During treatment of hyponatremia, serum sodium should not be elevated by more than 10 to 12 meq/L in 24 hours, or 18 meq/L in 48 hours. In the case of severe hyponatremia where severe neurologic symptoms are present, a faster infusion rate to correct serum sodium concentration may be needed. Patients rapidly treated or with serum sodium <120 mEq/L are more at risk of developing osmotic demyelination syndrome (previously called central pontine myelinolysis). Occurrence is more common among patients with alcoholism, undernutrition, or other chronic debilitating illness. Common signs include flaccid paralysis, dysarthria. In severe cases with extended lesions patients may develop a locked-in syndrome (generalized motor paralysis). Damage often is permanent. If neurologic symptoms start to develop during treatment of hyponatremia, serum sodium correction should be suspended to mitigate the development of permanent neurologic damage.

Lithium-Induced Chronic Kidney Disease

The predominant form of chronic renal disease associated with long-term lithium treatment is a chronic tubulointerstitial nephropathy (CTIN). The biopsy findings in patients with lithium induced CTIN include tubular atrophy, interstitial fibrosis, sclerotic glomeruli, tubular dilation, and nephron atrophy with cyst formation. The relationship between renal function and morphologic changes and their association with lithium treatment has not been established. CTIN patients might present with nephrotic proteinuria (>3 g/dL), worsening renal insufficiency and/or nephrogenic diabetes insipidus. Postmarketing cases consistent with nephrotic syndrome in patients with or without CTIN have also been reported. The biopsy findings in patients with nephrotic syndrome include minimal change disease and focal segmental glomerulosclerosis. The discontinuation of lithium in patients with nephrotic syndrome has resulted in remission of nephrotic syndrome.

Kidney function should be assessed prior to and during lithium treatment. 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 treatment, 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 fasting blood glucose, has occurred in patients treated with lithium and an antipsychotic. 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 antipsychotics, patients receiving such combined treatment should be monitored closely for early evidence of neurological 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 Drug Interactions (7.1)].

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.

Hypothyroidism or Hyperthyroidism

Lithium is concentrated within the thyroid and can inhibit thyroid synthesis and release which can lead to hypothyroidism. Where hypothyroidism exists, careful monitoring of thyroid function during lithium stabilization and maintenance allows for correction of changing thyroid parameters, if any. Where hypothyroidism occurs during lithium stabilization and maintenance, supplemental thyroid treatment may be used. Paradoxically, some cases of hyperthyroidism have been reported including Grave’s disease, toxic multinodular goiter and silent thyroiditis. 

Monitor thyroid function before the initiation of treatment, at three months and every six to twelve months while treatment is ongoing. If serum thyroid tests warrant concern, monitoring should occur more frequently.

Hypercalcemia and Hyperparathyroidism

Long-term lithium treatment is associated with persistent hyperparathyroidism and hypercalcemia. When clinical manifestations of hypercalcemia are present, lithium withdrawal and change to another mood stabilizer may be necessary. Hypercalcemia may not resolve upon discontinuation of lithium, and may require surgical intervention. Lithium-induced cases of hyperparathyroidism are more often multiglandular compared to standard cases. False hypercalcemia due to plasma volume depletion resulting from nephrogenic diabetes insipidus should be excluded in individuals with mildly increased serum calcium. Monitor serum calcium concentrations regularly.

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 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 treatment.

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. Consider discontinuing lithium if this syndrome occurs.

Lithium is an element of the alkali-metal group with atomic weight of 6.94.

Lithium Carbonate is a white, light, alkaline powder with molecular formula Li2CO3 and molecular weight 73.89.

Each capsule contains 150 mg, 300 mg, or 600 mg Lithium Carbonate, USP and the following inactive ingredients: talc, gelatin, FD&C Red No. 40, titanium dioxide, D&C Yellow No. 10, FD&C Yellow No. 6, and the imprinting ink contains black iron oxide, & Pharmaceutical glaze.

Mechanism of Action

The mechanism of action of lithium as a mood stabilizing agent is unknown.

Pharmacokinetics

After oral administration, lithium is reported to be completely absorbed in the upper gastrointestinal tract. Peak serum concentrations (Tmax) occur 0.25 to 3 hours after oral administration of immediate release preparations and 2 to 6 hours after sustained-release preparations.

The distribution space of lithium approximates that of total body water, and the plasma protein binding is negligible. After equilibrium, the apparent volume of distribution is 0.7 to 1 L/kg. Lithium is not metabolized.

Lithium is primarily excreted in urine, proportionally to its serum concentration. Lithium is filtered by the glomerulus, and 80% is reabsorbed by passive diffusion in the proximal tubule. The elimination half-life of lithium is approximately 18 to 36 hours. Lithium excretion in feces is insignificant.

Lithium Carbonate Capsules USP 600 mg (30 Capsules in 1 Bottle)
Each hard gelatin capsule contains: Lithium Carbonate USP 600 mg
62332-015-30