Lithium Carbonate

INDICATIONS AND USAGE Lithium carbonate extended-release tablets, USP is indicated in the treatment of manic episodes of Bipolar Disorder. Bipolar Disorder, Manic (DSM-IV) is equivalent to Manic Depressive illness, Manic, in the older DSM-II terminology. Lithium carbonate extended-release tablets, USP is also indicated as a maintenance treatment for individuals with a diagnosis of Bipolar Disorder. Maintenance therapy reduces the frequency of manic episodes and diminishes the intensity of those episodes which may occur. 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 may produce a normalization of symptomatology within 1 to 3 weeks.

DOSAGE AND ADMINISTRATION Doses of controlled-release tablets are usually given b.i.d. (approximately 12-hour intervals). When initiating therapy with controlled-release lithium, dosage must be individualized according to serum levels and clinical response. When switching a patient from immediate-release capsules to Lithium Carbonate Extended-Release Tablets, give the same total daily dose when possible. Most patients on maintenance therapy are stabilized on 900 mg daily, e.g., Lithium Carbonate Extended-Release Tablets 450 mg b.i.d. When the previous dosage of immediate-release lithium is not a multiple of 450 mg, e.g., 1,500 mg, initiate Lithium Carbonate Extended-Release Tablets at the multiple of 450 mg nearest to, but below , the original daily dose, i.e., 1,350 mg. When the 2 doses are unequal, give the larger dose in the evening. In the above example, with a total daily dose of 1,350 mg, generally 450 mg of Lithium Carbonate Extended-Release Tablets should be given in the morning and 900 mg of Lithium Carbonate Extended-Release Tablets in the evening. If desired, the total daily dose of 1,350 mg can be given in 3 equal 450-mg doses of Lithium Carbonate Extended-Release Tablets. These patients should be monitored at 1- to 2-week intervals, and dosage adjusted if necessary, until stable and satisfactory serum levels and clinical state are achieved. When patients require closer titration than that available with doses of Lithium Carbonate Extended-Release Tablets in increments of 450 mg, immediate-release capsules should be used. Acute Mania: Optimal patient response to Lithium Carbonate Extended-Release Tablets can usually be established and maintained with 1,800 mg per day in divided doses. Such doses will normally produce the desired serum lithium level ranging between 1.0 and 1.5 mEq/L. Dosage must be individualized according to serum levels and clinical response. Regular monitoring of the patient’s clinical state and serum lithium levels is necessary. Serum levels should be determined twice per week during the acute phase, and until the serum level and clinical condition of the patient have been stabilized. Long-Term Control: The desirable serum lithium levels are 0.6 to 1.2 mEq/L. Dosage will vary from one individual to another, but usually 900 mg to 1,200 mg per day in divided doses will maintain this level. Serum lithium levels in uncomplicated cases receiving maintenance therapy during remission should be monitored at least every two months. Patients unusually sensitive to lithium may exhibit toxic signs at serum levels below 1.0 mEq/L. Important Considerations • Blood samples for serum lithium determinations should be drawn immediately prior to the next dose when lithium concentrations are relatively stable (i.e., 8 to 12 hours after the previous dose). Total reliance must not be placed on serum levels alone. Accurate patient evaluation requires both clinical and laboratory analysis. • Elderly patients often respond to reduced dosage, and may exhibit signs of toxicity at serum levels ordinarily tolerated by younger patients. • Lithium Carbonate Extended-Release Tablets must be swallowed whole and never chewed or crushed.

WARNINGS 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 and 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. Psuedotumor 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 nephr …

ADVERSE REACTIONS The occurrence and severity of adverse reactions are generally directly related to serum lithium concentrations and to individual patient sensitivity to lithium. They generally occur more frequently and with greater severity at higher concentrations. Adverse reactions may be encountered at serum lithium concentrations below 1.5 mEq/L. Mild to moderate adverse reactions may occur at concentrations from 1.5 to 2.5 mEq/L, and moderate to severe reactions may be seen at concentrations from 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 with a temporary reduction or cessation of dosage. If persistent, a 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 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. Serum lithium concentrations 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 concentrations, including concentrations within the therapeutic range: Central Nervous System: tremor, muscle hyperirritability (fasciculations, twitching, clonic movements of whole limbs), hypertonicity, ataxia, choreoathetotic 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. 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. 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 PATIENT COUNSELING INFORMATION ). 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, acne, chronic folliculitis, xerosis cutis, psoriasis or its exacerbation, generalized pruritus with or without rash, cutaneous ulcers, angioedema. Autonomic Nervous System: blurred vision, dry mouth, impotence/sexual dysfunction. Thyroid Abnormalities: euthyroid goiter and/or hypothyroidism (including myxedema) accompanied by lower T3 and T4. 131 Iodine uptake may be elevated (see PRECAUTIONS ). Paradoxically, rare cases of hyperthyroidism have been reported. EEG Changes: diffuse slowing, widening of frequency spectrum, potentiation and disorganization of background rhythm. EKG Changes: reversible flattening, isoelectricity or inversion of T-waves. Miscellaneous: fatigue, lethargy, transient scotomata, exophthalmos …

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. Usage in Pregnancy Teratogenic Effects: (See WARNINGS ). Usage in Nursing Mothers Because of the potential for serious adverse reactions in nursing infants and neonates from lithium, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see WARNINGS ).

DESCRIPTION Lithium Carbonate Extended-Release Tablets, USP contain lithium carbonate, USP a white, light alkaline powder with molecular formula Li 2 CO 3 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. The tablets meet the requirements of USP Dissolution Test 2 in the USP monograph for Lithium Carbonate Extended-release Tablets, USP. Lithium Carbonate Extended-Release Tablets: Each speckled, off-white to yellow, round biconvex tablet, debossed with “54 346” on one side and scored on the other side, contains lithium carbonate, 450 mg. Inactive ingredients consist of iron oxide (yellow), magnesium stearate, povidone, sodium alginate and sodium starch glycolate. Lithium Carbonate Extended-Release Tablets USP, 450 mg are designed to release a portion of the dose initially and the remainder gradually; the release pattern of the controlled release tablets reduces the variability in lithium blood levels seen with the immediate release dosage forms.

DOSAGE AND ADMINISTRATION Acute Mania Optimal patient response can usually be established with 1800 mg/day in the following dosages: Acute Mania Morning Afternoon Nighttime Lithium carbonate extended-release tablets 1 3 tabs (900 mg) 3 tabs (900 mg) 1 Can also be administered on 600 mg TID recommended dosing interval. Such doses will normally produce an effective serum lithium concentration ranging between 1 and 1.5 mEq/L. Dosage must be individualized according to serum concentrations and clinical response. Regular monitoring of the patient’s clinical state and of serum lithium concentrations is necessary. Serum concentrations should be determined twice per week during the acute phase, and until the serum concentrations and clinical condition of the patient have been stabilized. Long-Term Control Desirable serum lithium concentrations are 0.6 to 1.2 mEq/L which can usually be achieved with 900 to 1200 mg/day. Dosage will vary from one individual to another, but generally the following dosages will maintain this concentration: Long-Term Control Morning Afternoon Nighttime Lithium carbonate extended-release tablets 1 2 tabs (600 mg) 2 tabs (600 mg) 1 Can be administered on TID recommended dosing interval up to 1200 mg/day. Serum lithium concentrations in uncomplicated cases receiving maintenance therapy during remission should be monitored at least every two months. Patients abnormally sensitive to lithium may exhibit toxic signs at serum concentrations of 1 to 1.5 mEq/L. Geriatric patients often respond to reduced dosage, and may exhibit signs of toxicity at serum concentrations ordinarily tolerated by other 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 cardiac function, and of concomitant disease or other drug therapy. Important Considerations Blood samples for serum lithium determinations should be drawn immediately prior to the next dose when lithium concentrations are relatively stable (i.e., 8 to 12 hours after previous dose). Total reliance must not be placed on serum concentrations alone. Accurate patient evaluation requires both clinical and laboratory analysis. Lithium carbonate extended-release tablets must be swallowed whole and never chewed or crushed.

HOW SUPPLIED Lithium carbonate extended-release tablets USP, 300 mg are peach colored, round shaped, film coated tablets debossed with “104” on one side and “L” on the other side. NDC 62332-148-30 Bottle of 30 Tablets NDC 62332-148-31 Bottle of 100 Tablets NDC 62332-148-91 Bottle of 1000 Tablets NDC 62332-148-08 Carton of 80 Tablets (8 x 10 unit-dose) Storage Conditions Store at 20° to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Protect from moisture. Dispense in tight, child-resistant container (USP). Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information, call Alembic Pharmaceuticals Limited at 1-866-210-9797. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Panelav 389350, Gujarat, India Manufactured for: Alembic Pharmaceuticals, Inc. 750 Route 202, Bridgewater, NJ 08807 USA Revised: 02/2020