BOXED WARNING

1 INDICATIONS & USAGE

Lithium is a mood-stabilizing agent indicated for the treatment of manic episodes and as maintenance treatment for Bipolar I Disorder.

4 CONTRAINDICATIONS

Lithium is contraindicated in patients with known hypersensitivity to any inactive ingredient in the lithium carbonate capsule or lithium citrate products [see Adverse Reactions ( 6), Description ( 11)].

6 ADVERSE REACTIONS

The following adverse reactions are described in greater detail in other sections:
• Lithium Toxicity [see Warnings and Precautions ( 5.1)]
• Lithium-Induced Polyuria [see Warnings and Precautions ( 5.2)]
• Hyponatremia [see Warnings and Precautions ( 5.3)]
• Lithium-Induced Chronic Kidney Disease [see Warnings and Precautions ( 5.4)]
• Encephalopathic Syndrome [see Warnings and Precautions ( 5.5)]
• Serotonin Syndrome [see Warnings and Precautions ( 5.6)]
• Hypothyroidism or Hyperthyroidism [see Warnings and Precautions ( 5.7)]
• Hypercalcemia and Hyperparathyroidism [see Warnings and Precautions ( 5.8)]
• Unmasking of Brugada Syndrome [see Warnings and Precautions ( 5.9)]
• Pseudotumor Cerebri [see Warnings and Precautions ( 5.10)]

The following adverse reactions have been identified following use of lithium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central Nervous System: tremor, muscle hyperirritability (fasciculations, twitching, clonic movements of whole limbs), hypertonicity, ataxia, choreoathetotic movements, hyperactive deep tendon reflexes, extrapyramidal symptoms including acute dystonia, cogwheel rigidity, blackout spells, epileptiform seizures, slurred speech, dizziness, vertigo, downbeat nystagmus, incontinence of urine or faeces, somnolence, psychomotor retardation, restlessness, confusion, stupor, coma, tongue movements, tics, tinnitus, hallucinations, poor memory, slowed intellectual functioning, startled response, worsening of organic brain syndromes, myasthenic syndromes (rarely).

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

Cardiovascular: conduction disturbance (mostly sinus node dysfunction with possibly severe sinus bradycardia and sinoatrial block), ventricular tachyarrhythmia, peripheral vasculopathy (resembling Raynaud’s Syndrome).

ECG Changes: reversible flattening, isoelectricity or rarely inversion of T-waves, prolongation of the QTc interval.

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, anaesthesia of skin, chronic folliculitis, xerosis cutis, psoriasis onset or exacerbation, generalized pruritus with or without rash, cutaneous ulcers, angioedema.

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

Miscellaneous: fatigue, lethargy, transient scotoma, exopthalmos, dehydration, weight loss, leukocytosis, headache, transient hyperglycemia, hypomagnesemia, excessive weight gain, edematous swelling of ankles or wrists, dysgeusia/taste distortion (e.g., metallic or salty taste), thirst, swollen lips, tightness in chest, swollen and/or painful joints, fever, polyarthralgia, and dental caries.

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Lithium

Table 2: Clinically Important Drug Interactions with Lithium

2 DOSAGE & ADMINISTRATION

2.1 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.

2.2 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.

2.3 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.

2.4 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
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.

2.5 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 Use in Specific Populations ( 8.4)] .

2.6 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 Use in Specific Populations ( 8.5)] .

2.7 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 [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.1)] .

2.8 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)] .

3 DOSAGE FORMS & STRENGTHS

Each 150 mg capsule for oral administration contains: lithium carbonate 150 mg and is a white/white size '4' hard gelatin capsules, imprinted with '97' on body and 'H' on cap, containing white to off-white powder.
Each 300 mg capsule for oral administration contains: lithium carbonate 300 mg and is a pink/pink size '1' hard gelatin capsules, imprinted with '98' on body and 'H' on cap, containing white to off-white powder.
Each 600 mg capsule for oral administration contains: lithium carbonate 600 mg and is a pink/white size '0EL' hard gelatin capsules, imprinted with ' 141' on body and 'H' on cap, containing white to off-white powder.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
Lithium may cause harm when administered to a pregnant woman. Early voluntary reports to international birth registries suggested an increase in cardiovascular malformations, especially for Ebstein’s anomaly, with first trimester use of lithium. Subsequent case-control and cohort studies indicate that the increased risk for cardiac malformations is likely to be small; however, the data are insufficient to establish a drug-associated risk. There are concerns for maternal and/or neonatal lithium toxicity during late pregnancy and the postpartum period [see Clinical Considerations]. Published animal developmental and toxicity studies in mice and rats report an increased incidence of fetal mortality, decreased fetal weight, increased fetal skeletal abnormalities, and cleft palate (mouse fetuses only) with oral doses of lithium that produced serum concentrations similar to the human therapeutic range. Other published animal studies report adverse effects on embryonic implantation in rats after lithium administration. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations
Dose adjustments during pregnancy and the postpartum period

If the decision is made to continue lithium treatment during pregnancy, serum lithium concentrations should be monitored and the dosage adjusted during pregnancy. Two to three days prior to delivery, lithium dosage should be decreased or discontinued to reduce the risk of maternal and/or neonatal toxicity. Lithium may be restarted in the post-partum period at preconception doses in medically stable patients as long as serum lithium levels are closely monitored [see Dosage and Administration ( 2.7), Warnings and Precautions ( 5.1)].

Fetal/Neonatal adverse reactions
Lithium toxicity may occur in neonates who were exposed to lithium in late pregnancy. A floppy baby syndrome including neurological, cardiac, and hepatic abnormalities that are similar to those seen with lithium toxicity in adults have been observed. Symptoms include hypotonia, respiratory distress syndrome, cyanosis, lethargy, feeding difficulties, depressed neonatal reflexes, neonatal depression, apnea, and bradycardia. Monitor neonates and provide supportive care until lithium is excreted and toxic signs disappear, which may take up to 14 days.

Consider fetal echocardiography between 16 and 20 weeks gestation in a woman with first trimester lithium exposure because of the potential increased risk of cardiac malformations.

8.2 Lactation

Risk Summary
Limited published data reports the presence of lithium carbonate in human milk with breast milk levels measured at 0.12 to 0.7 mEq or 40 to 45% of maternal plasma levels. Infants exposed to lithium during breastfeeding may have plasma levels 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.

Clinical Considerations
Consider regular monitoring of lithium levels and thyroid function in a breastfed infant.

8.4 Pediatric Use

Dosage recommendations for lithium in patients 12 years and older are similar to that of adults [see Dosage and Administration ( 2.5)]. Safety and effectiveness of lithium in pediatric patients below the age of 12 years have not been established.

8.5 Geriatric Use

Clinical studies of lithium carbonate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in 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 cardiac function, 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.

8.6 Renal Impairment

As lithium is eliminated primarily through the kidney, lithium renal clearance is decreased in patients with abnormal renal function, and the risk of lithium intoxication increases considerably in this setting. Lithium should not be used in severe renal insufficiency (creatinine clearance less than 30 mL/min evaluated by Cockcroft-Gault), especially if the condition requires adherence to a low-sodium diet [see Dosage and Administration ( 2.8)].

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 [see Dosage and Administration ( 2.8)].

10 OVERDOSAGE

The toxic concentrations for lithium (≥ 1.5 mEq/L) are close to the therapeutic concentrations [see Warnings and Precautions ( 5.1)]. At lithium concentrations greater than 3 mEq/L, patients may progress to seizures, coma, and irreversible brain damage.

Treatment
For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1800-222-1222 or www.poison.org.
No specific antidote for lithium poisoning is known. Early symptoms of lithium toxicity can usually be treated by reduction or cessation of dosage of the drug and resumption of the treatment at a lower dose after 24 to 48 hours.

In severe cases of lithium poisoning, the first and foremost goal of treatment consists of 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. In particular, patients with impaired consciousness should have their oral airway protected and it is critical to correct any volume depletion or electrolyte imbalance. Specifically, 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 re-administered with caution taking into account the possible release of significant lithium stores in body tissues.

11 DESCRIPTION

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 Li 2CO 3 and molecular weight 73.89

Each capsule contains 150 mg, 300 mg, or 600 mg lithium carbonate, USP and the following inactive ingredients: gelatin, sodium lauryl sulfate, talc, titanium dioxide and the imprinting ink contains black iron oxide E172 dye, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.