Lithium Carbonate 450 mg Tablet, Extended Release, 100-count — NDC 0054-0020-25 (Billing 00054-0020-25)

WARNINGS Lithium Toxicity The toxic concentrations for lithium (≥1.5 mEq/L) are close to the therapeutic range (0.8 to 1.2mEq/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 in… [Excerpted — this section continues on DailyMed.]

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,… [Excerpted — this section continues on DailyMed.]

Drug Interactions Caution should be used when lithium and diuretics are used concomitantly because diuretic-induced sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity. Patients receiving such combined therapy should have serum lithium levels monitored closely and the lithium dosage adjusted if necessary. Lithium levels should be closely monitored when patients initiate or discontinue NSAID use.

In some cases, lithium toxicity has resulted from interactions between an NSAID and lithium. Indomethacin and piroxicam have been reported to increase significantly steady-state plasma lithium concentrations. There is also evidence that other nonsteroidal anti-inflammatory agents, including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect.

In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg b.i.d. with celecoxib 200 mg b.i.d. as compared to subjects receiving lithium alone. Concomitant use of lithium with a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during SGLT2 inhibitor initiation and dosage changes.

Concurrent use of metronidazole with lithium may provoke lithium toxicity due to reduced renal clearance. Patients receiving such combined therapy should be monitored closely. There is evidence that angiotensin-converting enzyme inhibitors, such as enalapril and captopril, and angiotensin II receptor antagonists, such as losartan, may substantially increase steady-state plasma lithium levels, sometimes resulting in lithium toxicity.

When such combinations are used, lithium dosage may need to be decreased, and plasma lithium levels should be measured more often. Concurrent use of calcium channel blocking agents with lithium may increase the risk of neurotoxicity in the form of ataxia, tremors, nausea, vomiting, diarrhea and/or tinnitus. Caution is recommended.

Concomitant administration of lithium with serotonergic drugs can precipitate serotonin syndrome. 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.

Examples of serotonergic drugs include selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), and monoamine oxidase inhibitors (MAOI). The following drugs can lower serum lithium concentrations by increasing urinary lithium excretion: acetazolamide, urea, xanthine preparations, and alkalinizing agents such as sodium bicarbonate. Concomitant administration of methyldopa, phenytoin, or carbamazepine with lithium may increase the risk of toxic effects of these drugs.

Concomitant extended use of iodide preparations, especially potassium iodide, with lithium may produce hypothyroidism.

PRECAUTIONS General The ability to tolerate lithium is greater during the acute manic phase and decreases when manic symptoms subside [see DOSAGE AND ADMINISTRATION ]. The distribution space of lithium approximates that of total body water. Lithium is primarily excreted in urine with insignificant excretion in feces.

Renal excretion of lithium is proportional to its plasma concentration. The half-life of elimination of lithium is approximately 24 hours. Lithium decreases sodium reabsorption by the renal tubules which could lead to sodium depletion.

Therefore, it is essential for the patient 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 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 to sweating and diarrhea, concomitant infection with elevated temperatures may also necessitate a temporary reduction or cessation of medication.

Previously existing underlying thyroid disorders do not necessarily constitute a contraindication to lithium treatment; where hypothyroidism pre-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. Information for Patients Lithium carbonate may impair mental and/or physical abilities. Caution patients about activities requiring alertness (e.g. operating vehicles or machinery).

A condition known as Brugada Syndrome may pre-exist and be unmasked by lithium therapy. Brugada Syndrome is a heart disorder characterized by abnormal electrocardiographic (ECG) findings and risk of sudden death. Patients should be advised to seek immediate emergency assistance if they experience fainting, lightheadedness, abnormal heart beats, or shortness of breath because they may have a potentially life-threatening heart disorder known as Brugada Syndrome.

Drug Interactions Caution should be used when lithium and diuretics are used concomitantly because diuretic-induced sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity. Patients receiving such combined therapy should have serum lithium levels monitored closely and the lithium dosage adjusted if necessary. Lithium levels should be closely monitored when patients initiate or discontinue NSAID use.

In some cases, lithium toxicity has resulted from interactions between an NSAID and lithium. Indomethacin and piroxicam have been reported to increase significantly steady-state plasma lithium concentrations. There is also evidence that other nonsteroidal anti-inflammatory agents, including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect.

In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg b.i.d. with celecoxib 200 mg b.i.d. as compared to subjects receiving lithium alone. Concomitant use of lithium with a Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during SGLT2 inhibitor initiation and dosage changes.

Concurrent use of metronidazole with lithium may provoke lithium toxicity due to reduced renal clearance. Patients receiving such combined therapy should be monitored closely. There is evidence that angiotensin-converting enzyme inhibitors, such as enalapril and captopril, and angiotensin II receptor antagonists, such as losartan, may substantially increase steady-state plasma lithium levels, sometimes resulting in lithium toxicity.

When such combinations are used, lit… [Excerpted — this section continues on DailyMed.]