Lithium Carbonate 300 MG Oral Tablet
Generic Name: LITHIUM CARBONATE
Brand Name: Lithium Carbonate
- Substance Name(s):
- LITHIUM CARBONATE
7 • 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 )].
Examples: hydrochlorothiazide, chlorothiazide, furosemide 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 )] .
Examples: indomethacin, ibuprofen, naproxen 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 )] .
Examples: lisinopril, enalapril, captopril, valsartan 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 )].
Examples: selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOI) 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 )].
Examples: metronidazole 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 )] .
Examples: acetazolamide, theophylline, sodium bicarbonate 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 )] .
Examples: potassium iodide 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.
Examples: diltiazem, nifedipine, verapamil 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.
Examples: risperidone, haloperidol, thioridazine, fluphenazine, chlorpromazine, perphenazine, clozapine Neuromuscular Blocking Agents Clinical Impact: Lithium may prolong the effects of neuromuscular blocking agents.
Intervention: Monitor for prolonged paralysis.
Examples: succinylcholine, pancuronium
10 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.
11 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 C 6 H 5 Li 3 O 7 ; molecular weight 209.93.
Lithium acts as an antimanic.
Lithium Carbonate USP is a granular, white powder with molecular formula Li 2 CO 3 and molecular weight 73.89.
14 The safety and efficacy of lithium as a treatment for acute manic or mixed episodes of bipolar I disorder in pediatric patients (ages 7 to ≤18 years) was demonstrated in an 8-week, randomized, placebo-controlled, parallel group study (NCT01166425).
In this study, 81 patients with a Young Mania Rating Scale (YMRS) score of 20 or more were randomized to receive lithium or placebo in a 2:1 ratio.
Patients weighing more than 30 kg started lithium at 300 mg three times daily (900 mg/day) and could increase their dose by 300 mg every 3 days.
Patients weighing 20 to 30 kg started lithium at 300 mg twice daily (600 mg/day) and could increase their dose by 300 mg weekly.
No patients weighing less than 20 kg were enrolled.
Lithium (mean serum level 0.98 ± 0.47 mEq/L) was statistically significantly superior to placebo in decreasing acute mania or mixed states as measured by the YMRS (see Table 5).
In a 28-week randomized withdrawal analysis, 31 pediatric patients stabilized on lithium were assigned to either continue lithium or switch to placebo.
The group receiving lithium demonstrated superiority to those receiving placebo in all-cause discontinuation (see Table 5).
Table 5: Primary Efficacy Results Analysis Treatment Group Change From Baseline at Week 8 in YMRS Summary Score N Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Difference Difference (drug minus placebo) in least-squares mean change from baseline.
(95% CI) Acute Efficacy Lithium: 53 29.5 (5.6) -12.9 (3.1) -5.5 (-10.5, -0.5) Placebo: 28 30.0 (6.0) -7.3 (3.1) Analysis Treatment Group Patients analyzed by received treatment.
All-cause Discontinuation N Number of Discontinued Subjects Hazard Ratio Lithium to placebo.
(95% CI) Randomized Withdrawal Lithium: 17 7 (41.2%) 0.28 (0.10, 0.78) Placebo: 14 11 (78.6%) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
16 /STORAGE AND HANDLING Lithium Carbonate Capsules USP 300 mg supplied as opaque, light pink-colored capsules imprinted with product identification “54 463” on both caps and bodies and containing a white powder.
Overbagged with 10 capsules per bag, NDC 55154-4920-0 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
[See USP Controlled Room Temperature.] Dispense in a tight, child-resistant container as defined in the USP/NF.
PROTECT FROM MOISTURE.
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.
DOSAGE FORMS AND STRENGTHS
3 Each 5 mL of clear, nearly colorless lithium oral solution USP contains 8 mEq lithium ion (Li + ) (equivalent to the amount of lithium in 300 mg of lithium carbonate).
Each 300 mg tablet for oral administration contains: lithium carbonate USP and is a white to off-white, biconvex tablet, scored on one side with product identification “54 452” debossed on the other side.
Each 150 mg capsule for oral administration contains: lithium carbonate USP and is an opaque, white capsule, imprinted with product identification “54 213” on both the cap and the body and containing a white powder.
Each 300 mg capsule for oral administration contains: lithium carbonate USP and is an opaque, light pink-colored capsule, imprinted with product identification “54 463” on both the cap and the body and containing a white powder.
Each 600 mg capsule for oral administration contains: lithium carbonate USP and is an opaque, light pink-colored cap with white body, imprinted with product identification “54 702” on both the cap and the body and containing a white powder.
• Oral Solution: 8 mEq of lithium (Li+) per 5mL ( 3 ) • Tablets: 300 mg of lithium carbonate ( 3 ) • Capsules: 150 mg, 300 mg, 600 mg of lithium carbonate ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism of action of lithium as a mood stabilizing agent is unknown.
INDICATIONS AND USAGE
1 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 [see Clinical Studies ( 14 )] • Maintenance treatment in patients 7 years and older [see Clinical Studies ( 14 )] 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 ( 1 ) • Maintenance treatment in patients 7 years and older ( 1 )
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.
8.1 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.
WARNING: LITHIUM TOXICITY Lithium toxicity is closely related to serum lithium concentrations, and can occur at doses close to therapeutic concentrations.
Facilities for prompt and accurate serum lithium determinations should be available before initiating treatment [see Dosage and Administration ( 2.3 ),Warnings and Precautions ( 5.1 ) ].
WARNING: LITHIUM TOXICITY See full prescribing information for complete boxed warning.
Lithium toxicity is closely related to serum lithium concentrations, and can occur at doses close to therapeutic concentrations.
Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy ( 2.3 , 5.1 ).
WARNING AND CAUTIONS
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 <120mEq/L are more at risk of developing osmotic demyelination syndrome (previously called central pontine myelinolysis).
Occurrence is more common among patients with alcoholism, undernutrition, or other chronic debilitating illness.
Common signs include flaccid paralysis, dysarthria.
In severe cases with extended lesions patients may develop a locked-in syndrome (generalized motor paralysis).
Damage often is permanent.
If neurologic symptoms start to develop during treatment of hyponatremia, serum sodium correction should be suspended to mitigate the development of permanent neurologic damage.
5.4 Lithium-Induced Chronic Kidney Disease The predominant form of chronic renal disease associated with long-term lithium treatment is a chronic tubulointerstitial nephropathy (CTIN).
The biopsy findings in patients with lithium induced CTIN include tubular atrophy, interstitial fibrosis, sclerotic glomeruli, tubular dilation, and nephron atrophy with cyst formation.
The relationship between renal function and morphologic changes and their association with lithium treatment has not been established.
CTIN patients might 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.
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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read FDA-approved patient labeling (Medication Guide).
Dosage and Administration: Advise patients that lithium is a mood stabilizer, and should only be taken as directed.
Emphasize the importance of compliance with the prescribed treatment and to not adjust the dose of lithium without first consulting their healthcare provider.
Inform patients that they will need to have regular blood draws to determine if their dose of lithium is appropriate.
Instruct patients not to double the dose if a dose is missed, due to the complexity of individualized dosing and potential for lithium toxicity [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.1 )].
Lithium Toxicity: Inform patients on adverse reactions related to lithium toxicity that require medical attention.
Advise patients to discontinue lithium treatment and contact their healthcare provider if clinical signs of lithium toxicity such as diarrhea, vomiting, tremor, lack of muscle coordination, drowsiness, abnormal heart rhythm or muscular weakness occur [see Warnings and Precautions ( 5.1 )].
Lithium-Induced Polyuria: Counsel patients on the adverse reactions related to lithium-induced polyuria, when to seek medical attention, and the importance of maintaining normal diet with salt and staying hydrated [see Warnings and Precautions ( 5.2 )].
Hyponatremia: Counsel patients on the adverse reactions of hyponatremia, when to seek medical attention, the importance of maintaining a normal diet including adequate salt intake and staying hydrated [see Warnings and Precautions ( 5.3 )].
Salt supplements and additional fluids may be required if excessive losses occur.
SerotoninSyndrome: Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of lithium with other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, St.
John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions ( 5.6 ) and Drug Interactions ( 7 )].
Drug Interactions: Advise patients that many drugs can interact with lithium and to inform their doctor and pharmacist if they are taking any over the counter medication, including herbal medication, or are started on a new prescription [see Drug Interactions ( 7 )].
Somnolence: Tell patients that lithium may cause somnolence particularly when initiating treatment and to be cautious about operating vehicles or hazardous machinery, until they are reasonably certain that lithium treatment does not affect them adversely [see Adverse Reactions ( 6 )].
Pregnancy: Advise pregnant women of the potential risk to a fetus and/or neonate [see Use in Specific Populations ( 8.1 )].
Lactation: Advise women that breastfeeding is not recommended during treatment with lithium [see Use in Specific Populations ( 8.2 )].
by: West-Ward Pharmaceuticals Corp.
Eatontown, NJ 07724 Distributed by: Cardinal Health Dublin, OH 43017 L29954881118 Revised February 2020 10008909/08
DOSAGE AND ADMINISTRATION
2 • Recommended starting dosage for adults and pediatric patients over 30 kg ( 2.2 ): • Tablets or Capsules: 300 mg, three times daily, or • Oral Solution: 8mEq lithium (5 mL) three times daily • Recommended starting dosage for pediatric patients 20 to 30 kg ( 2.2 ): • Tablets or Capsules: 300 mg twice daily, or • Oral Solution: 8mEq (5mL), twice daily • Obtain serum lithium concentration assay after 3 days, drawn 12 hours after the last oral dose and regularly until patient is stabilized.
• Acute Manic or Mixed Episodes (patients 7 years and older): Titrate to serum lithium concentrations 0.8 to 1.2 mEq/L ( 2.2 ).
• Maintenance Treatment for Bipolar I Disorder (patients 7 years and older): Titrate to serum lithium concentrations 0.8 to 1 mEq/L ( 2.2 ).
• Pre-treatment Screening: Evaluate renal function, vital signs, electrolytes, thyroid function, concurrent medications, and pregnancy status ( 2.1 ).
• Mild to Moderate Renal Impairment (CLer 30 to 89 mL/min): Start with dosages less than those for patients with normal renal function, titrate slowly with frequent monitoring ( 2.5 ).
• Severe Renal Impairment (CLer<30mL/min): Avoid use of lithium ( 2.5 ).
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 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.
Lithium Dosing for Bipolar I Disorder Patient Group Formulation Starting Dose Dose Titration Acute Goal Maintenance Goal Serum Level Usual Dose Serum Level Usual Dose Adult and Pediatric Patients over 30 kg Tablets or capsules 300 mg three times daily 300 mg every 3 days 0.8 to 1.2 mEq/L 600 mg two to three times daily 0.8 to 1.0 mEq/L 300 to 600 mg two to three times daily Liquid 8 mEq (5 mL) three times daily 8 mEq (5 mL) every 3 days 16 mEq (10mL) two to three times daily 8 to 16 mEq (5 to 10 mL) two to three times daily Pediatric Patients 20 to 30 kg Tablets or capsules 300 mg twice daily 300 mg weekly 600 to 1500 mg in divided doses daily 600 to 1200 mg in divided doses daily Liquid 8 mEq (5 mL) twice daily 8 mEq (5 mL) weekly 16 to 40 mEq (10 to 25 mL) in divided doses daily 16 to 32 mEq (10 to 20 mL) in divided doses daily 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 Lithium Carbonate Tablets or Capsules Lithium Oral Solution 150 mg 4 mEq (2.5 mL) 300 mg 8 mEq (5 mL) 600 mg 16 mEq (10 mL) 2.3 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 Specific Populations ( 8.5 )].
2.4 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 )].
2.5 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 )].