Lithium

5 WARNINGS AND PRECAUTIONS Lithium-Induced Polyuria: May develop during initiation of treatment. Increases risk of lithium toxicity. Educate patient to avoid dehydration. Monitor for lithium toxicity and metabolic acidosis. Discontinue lithium or treat with amiloride as a therapeutic agent ( 5.2 ). Hyponatremia: Symptoms are more severe with faster-onset hyponatremia. Dehydration from protracted sweating, diarrhea, or elevated temperatures from infection increases risk of hyponatremia and lithium toxicity. Educate patients on maintaining a normal diet with salt and staying hydrated. Monitor for and treat hyponatremia and lithium toxicity, which may necessitate a temporary reduction or cessation of lithium and infusion of serum sodium ( 5.3 ). Lithium-Induced Chronic Kidney Disease: Associated with structural changes in patients on chronic lithium therapy. Monitor kidney function during treatment with lithium ( 5.4 ). Encephalopathic Syndrome: Increased risk in patients treated with lithium and an antipsychotic. Monitor routinely for changes to cognitive function ( 5.5 ). Hypothyroidism and Hyperthyroidism: Monitor thyroid function regularly ( 5.7 ). Hypercalcemia and Hyperparathyroidism: Associated with long-term lithium use. Monitor serum calcium ( 5.8 ). 5.1 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 ( 2.3 )]. 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 ( 10 )]. 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 Drug Interactions ( 7 ) ]. 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. 5.2 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. 5.3 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 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. 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 re-evaluation of treatment. 5.5 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). 5.6 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. 5.7 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. 5.8 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. 5.9 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. 5.10 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.

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: Acute 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 )] Common Adverse Reactions: Adult Patients: fine hand tremor, polyuria, mild thirst, nausea, general discomfort during initial treatment ( 6 ) Pediatric Patients (7-17 years): nausea/vomiting, polyuria, thyroid abnormalities, tremor, thirst/polydipsia, dizziness, rash/dermatitis, ataxia/gait disturbance, decreased appetite, and blurry vision ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact PAI Pharma at 1-800-845-8210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pediatric Patients (7 to 17 years): Bipolar I Disorder: The following findings are based on an 8-week, placebo-controlled study for acute manic or mixed episodes of bipolar I disorder in pediatric patients 7 to 17 years (N= 81). In this study, lithium was administered at daily doses ranging from 300 to 3600 (mean dose 1483 mg ± 584) with serum levels ranging from 0 to 2.0 (mean level 0.98 mEq/L ± 0.47). Common Adverse Reactions (incidence ≥ 5% and at least twice the rate of placebo ): nausea/vomiting, polyuria, thyroid abnormalities, tremor, thirst/polydipsia, dizziness, rash/dermatitis, ataxia/gait disturbance, decreased appetite, and blurry vision. Adverse Reactions Occurring at an Incidence of 2% or More in Lithium-Treated Pediatric Patients : Adverse reactions associated with the use of lithium (incidence of 2% or greater, rounded to the nearest percent, and lithium incidence greater than placebo) that occurred during acute therapy (up to 8-weeks in pediatric patients with bipolar disorder) are shown in Table 3. Table 3: Adverse Reactions Reported in 2% or More of Pediatric Patients on Lithium and That Occurred at Greater Incidence Than in the Placebo Group in the 8-Week Acute Bipolar Trial System Organ Class/ Preferred Term Placebo N=28 % Lithium N=53 % Gastrointestinal Disorders Nausea/vomiting 29 57 General Disorders Fatigue 4 26 Genitourinary Disorders Polyuria (Including Enuresis) 14 38 Investigations Increased TSH 0 25 Metabolism and nutrition disorders Thirst/polydipsia 11 28 Decreased appetite 4 9 Nervous system disorders Ataxia/gait disturbance 0 13 Blurry vision 0 9 Disorientation 0 6 Dizziness 7 23 Tremor 7 32 Skin and subcutaneous tissue disorders Rash/dermatitis 0 13 Adult Patients: 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 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, 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, 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. Miscellaneous: fatigue, lethargy, transient scotoma, exopthalmos, dehydration, weight loss, leukocytosis, headache, transient hyperglycemia, hypermagnesemia, 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 Diuretics, NSAID, renin-angiotensin system antagonists, or metronidazole may increase lithium serum concentrations. Recommend frequent monitoring of serum lithium concentration and adjust dosage when necessary. ( 2.3 , 7.1 ) Serotonergic Agents: Increased risk of serotonin syndrome when co- administered with lithium. ( 5.6 , 7.1 ) Antipsychotics: There have been reports of neurologic adverse reactions in patients treated with lithium and an antipsychotic, ranging from extrapyramidal symptoms to neuroleptic malignant syndrome. ( 5.5 , 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Lithium Table 4: Clinically Important Drug Interactions with Lithium Diuretics Clinical Impact: Diuretic-induced sodium loss may reduce lithium clearance and increase serum lithium concentrations . Intervention: More frequent monitoring of serum electrolyte and lithium concentrations. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration ( 2.3 ), Warning and Precautions ( 5.3 )]. Non-Steroidal Anti-inflammatory Drugs (NSAID) Clinical Impact: NSAID decrease renal blood flow, resulting in decreased renal clearance and increased serum lithium concentrations. Intervention: More frequent serum lithium concentration monitoring. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration ( 2.3 )] . Renin-Angiotensin System Antagonists Clinical Impact: Concomitant use increase steady-state serum lithium concentrations. Intervention: More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration ( 2.3 )] . Serotonergic Drugs Clinical Impact: Concomitant use can precipitate serotonin syndrome. Intervention: 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 [see Warnings and Precautions ( 5.6 )]. Nitroimidazole Antibiotics Clinical Impact: Concomitant use may increase serum lithium concentrations due to reduced renal clearance. Intervention: More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration ( 2.3 )]. Acetazolamide, Urea, Xanthine Preparations, Alkalinizing Agents Clinical Impact: Concomitant use can lower serum lithium concentrations by increasing urinary lithium excretion. Intervention: More frequent serum lithium concentration monitoring. Increase lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration ( 2.3 )] . Methyldopa, Phenytoin and Carbamazepine Clinical Impact: Concomitant use may increase risk of adverse reactions of these drugs. Intervention: Monitor patients closely for adverse reactions of methyldopa, phenytoin, and carbamazepine. Iodide Preparations Clinical Impact: Concomitant use may produce hypothyroidism. Intervention: Monitor patients for signs or symptoms of hypothyroidism [see Warnings and Precautions ( 5.7 )] . Calcium Channel Blocking Agents (CCB) Clinical Impact: Concomitant use may increase the risk of neurologic adverse reactions in the form of ataxia, tremors, nausea, vomiting, diarrhea and/or tinnitus. Intervention: Monitor for neurologic adverse reactions. Atypical and Typical Antipsychotic Drugs Clinical Impact: Reports of neurotoxic reactions in patients treated with both lithium and an antipsychotic, ranging from extrapyramidal symptoms to neuroleptic malignant syndrome, as well as reports of an encephalopathic syndrome in few patients treated with concomitant therapy [see Warnings and Precautions ( 5.5 )]. Intervention: Monitor for neurologic adverse reactions. Sodium-Glucose Cotransporter 2 (SGLT2) inhibitor Intervention: Monitor serum lithium concentration more frequently during SGLT2 inhibitor initiation and dosage changes. Clinical Impact: Concomitant use of lithium with an SGLT2 inhibitor may decrease serum lithium concentrations. Neuromuscular Blocking Agents Clinical Impact: Lithium may prolong the effects of neuromuscular blocking agents. Intervention: Monitor for prolonged paralysis.

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal and/or neonatal harm ( 8.1 ) Renal Impairment: Use caution during dose selection, starting with dosages less than those for patients with normal renal function while carefully monitoring for side effects ( 2.5 , 6 ) 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 ( 2.4 ), 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 The safety and effectiveness of lithium for monotherapy treatment of acute manic or mixed episodes of bipolar I disorder and maintenance monotherapy of bipolar I disorder in pediatric patients ages 7 to 17 years of age have been established in an acute-phase clinical trial of 8 weeks in duration followed by a 28-week randomized withdrawal phase [see Dosage and Administration ( 2.1 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )] . The safety and effectiveness of lithium has not been established in pediatric patients less than 7 years of age with bipolar I disorder. 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 ( 2.5 )]. 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 ( 2.5 )].

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 ( 2.4 ), 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.

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 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 re-administered with caution taking into account the possible release of significant lithium stores in body tissues.