Contents

Lithium carbonate USP

Each tablet for oral administration contains lithium carbonate USP, 300 mg and the following inactive ingredients: calcium stearate, microcrystalline cellulose, povidone, purified water, sodium lauryl sulfate, and sodium starch glycolate.

Each capsule for oral administration contains lithium carbonate USP, 150 mg, 300 mg or 600 mg and the following inactive ingredient: talc. The capsule shells contain black monogramming ink, FD&C Red No. 40 (300 mg and 600 mg only), gelatin and titanium dioxide. The black monogramming ink contains ammonium hydroxide, ethanol, iron oxide black, isopropyl alcohol, N-butyl alcohol, propylene glycol and shellac glaze.

Each 5 mL of solution for oral administration contains lithium ion (Li+), 8 mEq (equivalent to amount of lithium in 300 mg of lithium carbonate), alcohol 0.3% v/v and the following other inactive ingredients: citric acid, purified water, raspberry blend, sodium benzoate and sorbitol solution.

Lithium Oral Solution is a palatable oral dosage form of lithium ion. It is prepared in solution from lithium hydroxide and citric acid in a ratio approximately di-lithium citrate.

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.

The empirical formula for Lithium Citrate is C₆H₅Li₃O₇; molecular weight 209.93. Lithium acts as an antimanic.

Lithium Carbonate USP is a granular, white powder with molecular formula Li₂CO₃ and molecular weight 73.89.

INDICATIONS AND USAGE

Lithium is a mood-stabilizing agent indicated as monotherapy for the treatment of bipolar I disorder:

Treatment of acute manic and mixed episodes in patients 7 years and older
Maintenance treatment in patients 7 years and older

Mechanism of Action

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

DOSAGE AND ADMINISTRATION

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.

Recommended Dosage

See Table 1 for dosage recommendations for acute and maintenance treatment of bipolar I disorder in adult and pediatric patients (7 to 17 years).

Obtain serum lithium concentration assay after 3 days, drawn 12 hours after the last oral dose and regularly until patient is stabilized. Fine hand tremor, polyuria, and thirst may occur during initial therapy for the acute manic phase and may persist throughout treatment. 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, or temporary reduction or cessation of dosage.

Each 5 mL of Lithium Oral Solution contains 8 mEq of lithium ion (Li+) which is equivalent to the amount of lithium in 300 mg of lithium carbonate. See Table 2 for lithium carbonate and lithium oral solution dose conversion.

Lithium Carbonate and Lithium Oral Solution Dose Conversion

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.

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.

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 delivery, 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.

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. 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).

CONTRAINDICATIONS

Lithium is contraindicated in patients with known hypersensitivity to any inactive ingredient in the lithium carbonate tablet or capsule or lithium citrate products.

WARNINGS AND PRECAUTIONS

Lithium Toxicity: The toxic concentrations for lithium (≥1.5 mEq/L) are close to the therapeutic range (0.8 to 1.2mEq/L). Some patientsabnormally sensitive to lithium may exhibit toxic signs at serum concentrations that are considered within the therapeuticrange. Lithium may take up to 24 hours to distribute into braintissue, 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.

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.
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.

Lithium-Induced Polyuria: Chronic lithium treatment may be associated with diminution of renal concentrating ability, occasionally presenting asnephrogenic diabetes insipidus, with polyuria and polydipsia. The concentrating defect and natriuretic effect characteristicof this condition may develop within weeks of lithium initiation. Lithium can also cause renal tubular acidosis, resultingin hyperchloremic metabolic acidosis. Such patients should be carefully managed to avoid dehydration with resultinglithium retention and toxicity. This condition is usually reversible when lithium is discontinued, although for patientstreated with long-term lithium, nephrogenic diabetes insipidus may be only partly reversible upon discontinuation oflithium. 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 adequatefluid intake (2500 to 3000 mL) at least during the initial stabilization period. Decreased tolerance to lithium has also beenreported to ensue from protracted sweating or diarrhea and, if such occur, supplemental fluid and salt should beadministered 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 ofmedication.

Lithium-Induced Chronic Kidney Disease: The predominant form of chronic renal disease associated with long-term lithium treatment is a chronic tubulointerstitialnephropathy (CTIN). The biopsy findings in patients with lithium induced CTIN include tubular atrophy, interstitialfibrosis, sclerotic glomeruli, tubular dilation, and nephron atrophy with cyst formation. The relationship between renalfunction and morphologic changes and their association with lithium treatment has not been established. CTIN patientsmight present with nephrotic proteinuria (>3.0g/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. Thebiopsy findings in patients with nephrotic syndrome include minimal change disease and focal segmentalglomerulosclerosis. The discontinuation of lithium in patients with nephrotic syndrome has resulted in remission ofnephrotic syndrome.

Encephalopathic Syndrome: An encephalopathic syndrome, characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidalsymptoms, leukocytosis, elevated serum enzymes, BUN and fasting blood glucose, has occurred in patients treated withlithium and an antipsychotic. In some instances, the syndrome was followed by irreversible brain damage. Because of apossible 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 withconcomitant 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.

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).

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 allowsfor 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 beenreported 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 ofBrugada Syndrome. Brugada Syndrome is a disorder characterized by abnormal electrocardiographic (ECG) findings anda risk of sudden death. Lithium should be avoided in patients with Brugada Syndrome or those suspected of havingBrugada Syndrome. Consultation with a cardiologist is recommended if: (1) treatment with lithium is under considerationfor 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 theage 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. Ifundetected, this condition may result in enlargement of the blind spot, constriction of visual fields and eventual blindnessdue to optic atrophy. Consider discontinuing lithium if this syndrome occurs.

DRUG INTERACTIONS

Drugs Having Clinically Important Interactions with Lithium

Diuretics: Diuretic-induced sodium loss may reduce lithiumclearance and increase serum lithium concentrations.

More frequent monitoring of serum electrolyte andlithium concentrations. Reduce lithium dosagebased on serum lithium concentration and clinical response.

Non-Steroidal Anti-inflammatory Drugs (NSAID): NSAID decrease renal blood flow, resulting indecreased renal clearance and increased serum lithium concentrations.

More frequent serum lithium concentration monitoring. Reduce lithium dosage based on serum lithium concentration and clinical response

Renin-Angiotensin System Antagonists: Concomitant use increase steady-state serumlithium concentrations.

More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response

Serotonergic Drugs: Concomitant use can precipitate serotoninsyndrome.

Monitor patients for signs and symptoms of serotonin syndrome, particularly during lithium initiation. If serotonin syndrome occurs, consider discontinuation of lithium and/or concomitant serotonergic drugs

Nitroimidazole Antibiotics: Concomitant use may increase serum lithiumconcentrations due to reduced renal clearance.

More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response

Acetazolamide, Urea, Xanthine Preparations, Alkalinizing Agents: Concomitant use can lower serum lithiumconcentrations by increasing urinary lithiumexcretion.

More frequent serum lithium concentration monitoring. Increase lithium dosage based on erum lithium concentration and clinical response

Methyldopa, Phenytoin and Carbamazepine: Concomitant use may increase risk of adversereactions of these drugs.

Monitor patients closely for adverse reactions of methyldopa, phenytoin, and carbamazepine.

Iodide Preparations: Concomitant use may produce hypothyroidism.

Monitor patients for signs or symptoms of hypothyroidism

Calcium Channel Blocking Agents (CCB): Concomitant use may increase the risk ofneurologic adverse reactions in the form of ataxia,tremors, nausea, vomiting, diarrhea and/or tinnitus.

Monitor for neurologic adverse reactions.

Atypical and Typical Antipsychotic Drugs: Reports of neurotoxic reactions in patients treatedwith both lithium and an antipsychotic, rangingfrom extrapyramidal symptoms to neurolepticmalignant syndrome, as well as reports of an encephalopathic syndrome in few patients treatedwith concomitant therapy.

Monitor for neurologic adverse reactions.

Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor: Concomitant use of lithium with an SGLT2inhibitor may decrease serum lithiumconcentrations.

Monitor serum lithium concentration more frequently during SGLT2 inhibitor initiation and dosage changes.

Neuromuscular Blocking Agents: Lithium may prolong the effects of neuromuscular blocking agents.

Monitor for prolonged paralysis.

USE IN SPECIFIC POPULATIONS

Pregnancy: Lithium may cause harm when administered to a pregnant woman. Early voluntary reports to international birth registriessuggested an increase in cardiovascular malformations, especially for Ebstein’s anomaly, with first trimester use oflithium. Subsequent case-control and cohort studies indicate that the increased risk for cardiac malformations is likely tobe small; however, the data are insufficient to establish a drug-associated risk. There are concerns for maternal and/orneonatal lithium toxicity during late pregnancy and the postpartum period. Published animaldevelopmental and toxicity studies in mice and rats report an increased incidence of fetal mortality, decreased fetalweight, increased fetal skeletal abnormalities, and cleft palate (mouse fetuses only) with oral doses of lithium thatproduced serum concentrations similar to the human therapeutic range. Other published animal studies report adverseeffects on embryonic implantation in rats after lithium administration. Advise pregnant women of the potential risk to a fetus.

Lactation: Limited published data reports the presence of lithium carbonate in human milk with breast milk levels measured at 0.12to 0.7 mEq or 40 to 45% of maternal plasma levels. Infants exposed to lithium during breastfeeding may have plasmalevels that are 30 to 40% of maternal plasma levels. Signs and symptoms of lithium toxicity such as hypertonia, hypothermia, cyanosis, and ECG changes have been reported in some breastfed neonates and infants. Increased prolactin levels have been measured in lactating women, but the effects on milk production are not known. Breastfeeding is not recommended with maternal lithium use; however, if a woman chooses to breastfeed, the infant should be closely monitored for signs of lithium toxicity. Discontinue breastfeeding if a breastfed infant develops lithium toxicity.

Pediatric Use: The safety and effectiveness of lithium for monotherapy treatment of acute manic or mixed episodes of bipolar I disorderand maintenance monotherapy of bipolar I disorder in pediatric patients ages 7 to 17 years of age have been established inan acute-phase clinical trial of 8 weeks in duration followed by a 28-week randomized withdrawal phase.

The safety and effectiveness of lithium has not been established in pediatric patients less than 7 years of age with bipolar I disorder.

Geriatric Use: Clinical studies of lithium carbonate tablets did not include sufficient numbers of subjects aged 65 and over to determinewhether they respond differently from younger subjects. Other reported clinical experience has not identified differencesin response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious,usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiacfunction, and of concomitant disease or other treatment.

Lithium is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal Impairment: As lithium is eliminated primarily through the kidney, lithium renal clearance is decreased in patients with abnormal renalfunction, and the risk of lithium intoxication increases considerably in this setting. Lithium should not be used in severerenal insufficiency (creatinine clearance less than 30 mL/min evaluated by Cockcroft-Gault), especially if the conditionrequires adherence to a low-sodium diet.

Start patients with mild to moderately impaired renal function (creatinine clearance 30 to 89 mL/min evaluated by Cockcroft-Gault) with lower doses of lithium and titrate slowly while frequently monitoring serum lithium concentrations and for signs of lithium toxicity.

OVERDOSAGE

The toxic concentrations for lithium (≥ 1.5 mEq/L) are close to the therapeutic concentrations. At lithium concentrations greater than 3 mEq/L, patients may progress to seizures, coma, andirreversible brain damage.

Treatment: For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

No specific antidote for lithium poisoning is known. Mild symptoms of lithium toxicity can usually be treated by reduction in dose or cessation of the drug.

In severe cases of lithium poisoning, the goal of treatment is elimination of this ion from the patient. Administration of gastric lavage should be performed, but use of activated charcoal is not recommended as it does not significantly absorb lithium ions. Hemodialysis is the treatment of choice as it is an effective and rapid means of removing lithium in patients with severe toxicity. As an alternative option, urea, mannitol and aminophylline can induce a significant increase in lithium excretion. Appropriate supportive care for the patient should be undertaken. Patients with impaired consciousness should have their airway protected and it is critical to correct any volume depletion or electrolyte imbalance. Patients should be monitored to prevent hypernatremia while receiving normal saline and careful regulation of kidney function is of utmost importance.

Serum lithium concentrations should be closely monitored as there may be a rebound in serum lithium concentrations as a result of delayed diffusion from the body tissues. Likewise, during the late recovery phase, lithium should be readministered with caution taking into account the possible release of significant lithium stores in body tissues.

West-Ward Pharmaceuticals Corp |Lithium carbonate

Lithium carbonate USP