Lithium Citrate (lithium citrate)

Dosage of lithium carbonate is expressed in terms of the salt, while dosage of lithium citrate is expressed in terms of lithium.

Lithium is administered orally in divided doses (e.g., 2 or 3 times daily). Lithium carbonate is commercially available as conventional tablets, extended-release tablets, and capsules. Lithium citrate is commercially available only as an oral solution. Extended-release preparations of lithium should be swallowed intact and should not be chewed, crushed, or split in half. Lithium citrate oral solution may be used in patients unable to swallow capsules or tablets; 5 mL of a commercially available solution contains about 8 mEq of lithium and is approximately equivalent to 300 mg of lithium carbonate as conventional tablets or capsules.

Individualize the dosage according to serum lithium concentrations, patient tolerance, and clinical response. The manufacturers state that serum lithium concentrations should be determined 3 days (drawn 12 hours after the previous oral dose and just prior to the next dose) after therapy initiation during the acute phase of therapy with the conventional tablets, capsules or liquid and then regularly until the serum concentration and clinical condition of the patient have been stabilized. When extended-release preparations are used, serum lithium concentrations generally should be monitored twice weekly (drawn immediately prior to the next dose (i.e., 8-12 hours after previous dose)) during initiation of the acute phase of therapy and until the serum concentration and clinical condition of the patient have been stabilized. Thereafter, serum concentrations should be monitored at least every 2 months in most patients. Additional monitoring of serum lithium concentrations is recommended after any change in dosage, change in concomitant medications (e.g., diuretics, nonsteroidal anti-inflammatory agents (NSAIAs), renin-angiotensin system antagonists, metronidazole), marked increase or decrease in routine physical activity, or in the event of a concomitant disease.

Total reliance must not be placed on serum lithium concentrations alone; accurate patient evaluation requires both careful clinical and laboratory evaluation.

Adverse effects such as nausea and general discomfort may develop during the first few days of initial therapy. Fine hand tremor, polyuria, or thirst may also occur during the acute phase, and can persist throughout treatment. Continuation of lithium, administering doses with food, or temporary reduction or cessation in dosage may help to mitigate these adverse effects.

When transitioning a patient from the immediate-release capsules to the extended-release tablets, the same total daily dose should be given and divided into twice daily dosages. When the prior dosage is not available in the exact dosage equivalent of the extended-release product, initiate the extended-release regimen at the closest dosage equivalent below the original daily dosage. If the daily dosage is split into unequal divided doses, administer the larger dose in the evening. Once patients have transitioned to the extended-release tablets, monitor serum levels at 1-2 week intervals and adjust dosage as necessary until serum concentrations and clinical condition are stable.

Lithium carbonate conventional tablets and capsules should be stored in tight, child-resistant containers protected from moisture at 20-25degreesC (with excursions permitted to 15-30degreesC). Lithium carbonate extended-release tablets should be stored between 15-30degreesC.

Lithium citrate oral solution should be stored in tight, child-resistant containers at 20-25degreesC (with excursions permitted to 15-30degreesC).

Lithium is not metabolized.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Lithium/Selected Retinoids (Systemic)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic retinoids(1-7) and lithium(8-9) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(1-7) with lithium(8-9) may increase the risk of intracranial hypertension (pseudotumor cerebri). Early signs of intracranial hypertension include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(10)

PREDISPOSING FACTORS: Women of childbearing age who are overweight or have a previous history of intracranial hypertension are at a greater risk of developing intracranial hypertension.(10)

PATIENT MANAGEMENT: The US manufacturer of tretinoin advises avoiding concomitant use of other products that can cause intracranial hypertension.(1) Patients who present with symptoms of intracranial hypertension should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(1-7)

DISCUSSION: Vitamin A derivatives and lithium have both been strongly associated with intracranial hypertension. In a systematic review of 580 reported cases of medication-induced intracranial hypertension between January 1900 and June 2019 found in MEDLINE, EMBASE, and Cochrane Review Databases, there were 259 verifiable cases of intracranial hypertension. Vitamin A derivatives were implicated in 84 cases, though 25 cases occurred with excessive vitamin A supplementation. Lithium was implicated in 17 cases with lithium levels in therapeutic range.(10)

Lithium/Sibutramine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent administration may result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use of sibutramine and lithium may result in serotonin syndrome, a serious and potentially fatal reaction. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The UK manufacturer of sibutramine formerly stated that sibutramine should not be administered with other drugs that raise serotonin levels in the brain, such as lithium.(1) The US manufacturer of sibutramine stated that in general, sibutramine should not be administered with other serotonergic agents such as lithium. However, if concurrent administration is clinically indicated, the patient should be appropriately observed.(1) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Patients in whom serotonin syndrome is suspected should receive immediate medical attention.

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. There is no published documentation to support this interaction. Because sibutramine inhibits serotonin reuptake and serotonin syndrome has been reported during concomitant use of selective serotonin reuptake inhibitors and lithium, the UK manufacturer of sibutramine states that sibutramine should not be administered with lithium.(2)

Serotonergic Agents/Dapoxetine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent administration of dapoxetine with other serotonergic agents may result in additive effects on serotonin, resulting in serotonin syndrome.(1,2)

CLINICAL EFFECTS: Concurrent use of dapoxetine with other serotonergic agents may result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: Use of multiple drugs which increase serotonin levels is associated with an increased risk for this toxidrome.

PATIENT MANAGEMENT: Dapoxetine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort.(1,2) Dapoxetine should not be initiated within 14 days of receiving other serotonergic agents. Other serotonergics should not be initiated within 7 days of receiving dapoxetine.(2)

DISCUSSION: This interaction is based on class labeling for these agents. Although there is no clinical documentation for an interaction between dapoxetine and either the elective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents, including sumatriptan and dihydroergotamine.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Iodide/Radioactive Iodide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(2) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(3)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1)

Agents That Affect Iodide/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds can affect iodide protein binding and alter iodide pharmacokinetics and pharmacodynamics.(1,2)

CLINICAL EFFECTS: Compounds that affect iodide pharmacokinetics and pharmacodynamics may impact the effectiveness of radioactive iodide.(1,2)

PREDISPOSING FACTORS: Compounds that affect iodide pharmacokinetics and pharmacodynamics are expected to have the most impact during therapy using radioactive iodide. Diagnostic procedures would be expected to be impacted less.

PATIENT MANAGEMENT: Discuss the use of agents that affect iodide pharmacokinetics and pharmacodynamics with the patient's oncologist.(1,2) Because indocyanine green contains sodium iodide, the iodine-binding capacity of thyroid tissue may be reduced for at least one week following administration. Do not perform radioactive iodine uptake studies for at least one week following administration of indocyanine green.(3) The manufacturer of iopamidol states administration may interfere with thyroid uptake of radioactive iodine and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post administration of iopamidol.(4)

DISCUSSION: Many agents interact with radioactive iodine. The average duration of effect is: anticoagulants - 1 week antihistamines - 1 week anti-thyroid drugs, e.g: carbimazole, methimazole, propylthiouracil - 3-5 days corticosteroids - 1 week iodide-containing medications, e.g: amiodarone - 1-6 months expectorants - 2 weeks Lugol solution - 3 weeks saturated solution of potassium iodine - 3 weeks vitamins - 10-14 days iodide-containing X-ray contrast agents - up to 1 year lithium - 4 weeks phenylbutazone - 1-2 weeks sulfonamides - 1 week thyroid hormones (natural or synthetic), e.g.: thyroxine - 4 weeks tri-iodothyronine - 2 weeks tolbutamide - 1 week topical iodide - 1-9 months (1,2)

Lithium/Ace Inhibitors; Arbs

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Angiotensin converting enzyme inhibitors (ACEI) or angiotensin II receptor blocker (ARB)-induced sodium loss or volume depletion may result in decreased renal clearance of lithium.(1)

CLINICAL EFFECTS: Concurrent use of ACEI or ARBs may result in elevated lithium levels and lithium toxicity. Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, bradycardia, tinnitus, or nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.(1)

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: acute renal impairment, chronic renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(1) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: If concurrent therapy cannot be avoided, monitor closely. Evaluate renal function and most recent lithium levels. If renal function is not stable, whenever possible delay initiation of concurrent therapy until renal function is stable. The onset of lithium toxicity due to concomitant therapy with an ACEI or ARB may be delayed for 3-5 weeks.(2) Patients receiving this combination should be observed for signs of lithium toxicity when the ACEI or ARB dose is increased or if additional risk factors for lithium toxicity emerge. If an ACEI or ARB is required in a patient stabilized on lithium therapy, check baseline lithium concentration, consider empirically lowering the lithium dose, then recheck lithium levels 5 to 7 days after ACEI or ARB initiation. Adjust lithium, ACEI or ARB dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on an ACEI or ARB, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged.(1) Monitor lithium concentrations frequently until stabilized on the combination. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(1) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: Elevated lithium levels and lithium toxicity have been reported during concomitant administration of lithium and an ACEI(3-17) or an ARB(18-20). Other factors, such as dehydration, acute or worsening of chronic renal impairment, or acute changes in sodium intake may increase the occurrence of a clinically important interaction.

Lithium/Loop Diuretics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lithium is eliminated unchanged by the kidney; diuretic induced sodium elimination may lead to decreased renal clearance of lithium.

CLINICAL EFFECTS: Lithium has a narrow therapeutic range; even modest, unintended increases in lithium concentration may result in lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: Monitor closely to decrease the risk for lithium toxicity. Evaluate renal function and most recent lithium levels. If renal function is not stable, it would be prudent to withhold combination therapy until renal function is stable. If a loop diuretic is started, or if the dose is increased in a patient stabilized on lithium therapy, consider empirically lowering the lithium dose, and recheck lithium levels 5 to 7 days after diuretic initiation. Adjust lithium or diuretic dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on a loop diuretic, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged. Monitor lithium concentrations until stabilized on the combination. Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: The documentation for this interaction is conflicting. A large epidemiologic study in elderly bipolar patients and case reports describe interactions between lithium and furosemide or bumetanide which resulted in increased levels of lithium and lithium toxicity. Several studies in healthy subjects have found that furosemide had no effect on lithium clearance or lithium serum concentrations. Other studies performed to assess the accuracy of lithium clearance in assessing proximal tubular reabsorption found that furosemide and bumetanide increased lithium clearance.

Lithium/Thiazide Diuretics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lithium is eliminated unchanged by the kidney; thiazide induced sodium elimination may lead to decreased renal clearance of lithium.

CLINICAL EFFECTS: Lithium has a narrow therapeutic range; even modest, unintended increases in lithium concentration may result in lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: If concurrent therapy cannot be avoided, monitor closely to decrease the risk for lithium toxicity. Evaluate renal function and most recent lithium levels. If renal function is not stable, it would be prudent to withhold combination therapy until renal function is stable. If a thiazide diuretic is started, or if the dose is increased in a patient stabilized on lithium therapy, consider empirically lowering the lithium dose, and recheck lithium levels 5 to 7 days after diuretic initiation. Adjust lithium or thiazide dose as required and continue frequent (e.g. weekly) monitoring of lithium until levels have stabilized. If lithium is to be started in a patient stabilized on a thiazide diuretic, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged. Monitor lithium concentrations until stabilized on the combination. Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: This interaction is well documented.(1-15)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Lithium/Aldosterone Receptor Antagonists; Baxdrostat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aldosterone receptor antagonists, including eplerenone, finerenone and spironolactone, bind to mineralocorticoid receptors, blocking the action of aldosterone. Baxdrostat inhibits aldosterone synthesis. The subsequent increase in sodium and water excretion may lead to reduced renal clearance of lithium.(1-4)

CLINICAL EFFECTS: Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.(5)

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics).(5) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: Evaluate renal function and most recent lithium levels. If renal function is not stable or if the lithium level is in the high therapeutic range, then consider lowering the lithium dose when an aldosterone antagonist is started, or consider withholding the aldosterone antagonist until renal function is stable. If renal function is stable and baseline lithium concentrations are in the therapeutic range, recheck lithium levels 5 to 7 days after initiation of baxdrostat, eplerenone, finerenone, or spironolactone. Adjust the lithium dose as necessary based on lithium serum levels and patient response. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(5) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: Although the magnitude and frequency of this specific diuretic interaction is not clear, manufacturer product information for spironolactone and lithium state that lithium patients should generally not receive diuretics.(2,3) The manufacturer of eplerenone recommends frequent monitoring of lithium levels in patients who receive concomitant therapy.(1)

Lithium/Carbamazepine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism of the interaction is unknown. Neurotoxicity symptoms (confusion, delirium, seizures, encephalopathy, and EKG changes) may be due to potentiation or an additive effect of the antipsychotic agent and the lithium.

CLINICAL EFFECTS: Neurotoxicity with therapeutic serum lithium levels has been reported.

PREDISPOSING FACTORS: Large doses of lithium, central nervous system disease and a history of lithium neurotoxicity may predispose this interaction.

PATIENT MANAGEMENT: Monitor patients for lithium toxicity during concomitant administration of carbamazepine. Adjust therapy accordingly.

DISCUSSION: Although lithium and carbamazepine have been given concurrently to successfully treat manic episodes and rapid-cycling bipolar affective disorder, other investigators have reported central nervous system toxicity, including ataxia, hyperreflexia, lethargy, muscular weakness and tremor.

Lithium/Carbonic Anhydrase Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbonic anhydrase inhibitors may increase the renal excretion of lithium, either by alkalinization of the urine or by impairing the proximal tubular reabsorption of lithium.

CLINICAL EFFECTS: Concurrent use of a carbonic anhydrase inhibitor may result in decreased levels and clinical effectiveness of lithium.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels should be monitored in patients receiving concurrent therapy or if the carbonic anhydrase inhibitor is withdrawn from concurrent therapy. The dose of lithium may need to be adjusted.

DISCUSSION: One study involving six subjects showed that the concurrent use of a single dose of both lithium carbonate and acetazolamide caused a 27% to 31% increase in the urinary excretion of lithium.(1) Acetazolamide has been used in combination with other agents to treat lithium toxicity.(2)

Lithium/Glp-1 Receptor Agonists

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown but may be related to nausea, vomiting, and/or diarrhea caused by volume depletion resulting in the decreased renal clearance of lithium. Weight loss may also cause stable doses of lithium to be too high for weight-based dosing.(1-6)

CLINICAL EFFECTS: Lithium has a narrow therapeutic range; even modest, unintended increases in lithium concentration may result in lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, tinnitus and nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: The manufacturer of semaglutide states consider increased clinical or laboratory monitoring for medications that have a narrow therapeutic index or that require clinical monitoring.(1) An expert review article on the interaction between GLP-1 agonists and lithium states that clinicians may need to monitor lithium more closely when a GLP-1 agonist is initiated, whether clinically or through therapeutic drug monitoring. A cautious approach might be to consider monitoring at the following time points when there is a plan to introduce a GLP-1 agonist with lithium: 1. Before GLP-1 agonist initiation, 2. Near 1 week after starting a GLP-1 agonist, 3. Near 1 weak after each dose increases (i.e., several monthly intervals for weekly subcutaneous semaglutide and tirzepatide), and 4. Longitudinally, at more frequent intervals than guidelines recommend during the first year after GLP-1 agonist initiation, when weight loss begins to plateau. Increased monitoring may also be considered when switching between GLP-1 agonists.(7) Monitor closely to decrease the risk for lithium toxicity. Evaluate renal function and most recent lithium levels. If renal function is not stable, it would be prudent to withhold combination therapy until renal function is stable. Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: The impact of GLP-1 agonists on the pharmacokinetics of lithium has not been investigated in clinical studies. Literature is limited to a small number of case reports. In a case report, a 23-year-old male established on semaglutide was started on lithium and titrated to 1800 mg daily, corresponding to a lithium level of 0.9mEq/L. The patient was then switched from semaglutide to tirzepatide 5 mg weekly. Four days after his first dose of tirzepatide, he reported early symptoms of potential lithium toxicity, which progressed significantly after his second dose. Symptoms corresponded to a 15-hour post-dose level of 1.7 mEq/L, despite no changes in renal function, hydration status, or other concurrent medications. Management with intravenous fluids was sufficient, and close monitoring of lithium levels and tapering of the lithium dose prevented future toxicity. The patient remained on tirzepatide and a maintenance dose of lithium extended-release 1200 mg daily, with a lithium level measured 15-hour post-dose of 0.6mEq/L. The patient's weight remained the same from the start of tirzepatide therapy.(8) In a case report, a 62-year-old male stable on lithium for 6 years (lithium ER 600 mg daily) started semaglutide 0.25 mg twice weekly 2 to 3 weeks prior to visiting the emergency department. Patient had multiple comorbidities and medications were unchanged except for semaglutide. 6 weeks prior to visiting the ED, the patient was instructed to decrease his fluid intake due to urinary proteinuria symptoms. Lithium level was 1.8mmol/L in ED. Both lithium and semaglutide were discontinued. Lithium was restarted at 300 mg, increased to lithium ER 450 mg 10 days later and lithium levels increased to 0.8 and 0.9mmol/L. Further dose adjustment back to 300 mg resulted in a steady lithium serum level of 0.6mmol/L. No significant changes to kidney function were observed. Semaglutide was not reintroduced.(9) In another case report, a 23-year-old female was admitted to hospital for lithium toxicity. Medication list included lithium carbonate ER 900 mg and she was reported as restarting semaglutide recently. Further questioning revealed inconsistent semaglutide use over the previous 2 years, with unclear timing of a recent restart. Her lithium level on admission was found to be 2.1mmol/L. Both lithium and semaglutide were discontinued. Lithium ER had been a long-standing medication at 900 mg dose since she was 9 years old with no previous incidents of clinical lithium toxicity. She was recorded as having significant side effects to semaglutide, including nausea and vomiting. At the time of discharge, 4 days after admission, the lithium level was 0.5mmol/L and it was recommended to avoid combining lithium and semaglutide in the future. No significant changes to kidney function were observed.(9) In a case report, a 22-year-old-male stable on 2100 mg lithium carbonate ER daily was initiated on semaglutide for weight management. Patient had regular monitoring of his lithium level prior to and during dose escalation with semaglutide. During the semaglutide increase and tapering of his lithium dose, there were no report of nausea, vomiting, diarrhea, decreased oral/fluid intake, and no medication changes were made. There were no changes in mental status, symptoms concerning psychiatric decompensation, or symptoms of lithium toxicity.(9) In a 40-week study of patients with stable bipolar disorder, liraglutide resulted in a significantly greater weight loss as compared with placebo. 7 of the 60 participants were on lithium, no instances of lithium toxicity was reported and liraglutide was well tolerated.(10)

Lithium/Iodide Salts

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Concurrent administration of lithium and iodide salts may produce hypothyroidism.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If both drugs are given, monitor patient for signs and symptoms of hypothyroidism. If hypothyroidism develops, thyroid hormone may be used to treat symptoms.

DISCUSSION: Hypothyroidism is a side effect that may occur with long-term lithium treatment. Thyroid gland enlargement and increased thyroid stimulating hormone may also be present. Iodide administration to patients receiving lithium may increase the risk of patients developing hypothyroidism.

Lithium/Meperidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The combination of lithium with meperidine may have additive effects on serotonin levels.(1,2)

CLINICAL EFFECTS: Some patients may develop an increase in serotonergic activity in the CNS, which could result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: Renal dysfunction and chronic use of meperidine would be expected to increase the risk for serotonin toxicity. The use of multiple drugs that increase serotonin levels is associated with an increased risk for this toxidrome.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be observed for signs of serotonergic side effects. When clinically appropriate, consider monitoring serum concentrations for toxicity. Counsel patients to report new or worsening muscle twitching, tremors, shivering or stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, decreased coordination, or severe diarrhea. Discontinue one or both medications if symptoms occur. Although toxicity has been reported, based upon cases and interaction studies the likelihood of a drug-drug interaction appears to be uncommon, perhaps rare.(4)

DISCUSSION: Serotonin syndrome has been reported from the combination of lithium with serotonergic drugs, including SSRIs, SNRIs, and tramadol. Although there are no reports of serotonin syndrome specifically with the combination of lithium and meperidine, a pharmacological basis for an interaction exists, and caution is still warranted. While toxicity has been reported, based upon cases and interaction studies the likelihood of a drug-drug interaction appears to be uncommon, perhaps rare.(4) Some of the reported cases may represent drug-disease interactions (e.g. mania with lithium and antidepressant).

Lithium/Metronidazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of action is not fully known. Possible renal damage may occur with concurrent use leading to decreased renal clearance of lithium.(1,2)

CLINICAL EFFECTS: Concurrent use of metronidazole may result in elevated lithium levels and lithium toxicity. Lithium has a narrow therapeutic range. Unintended increases in lithium concentrations may lead to lithium toxicity. Early symptoms of lithium toxicity may include: lethargy, muscle weakness or stiffness, new onset or coarsening of hand tremor, vomiting, diarrhea, confusion, ataxia, blurred vision, bradycardia, tinnitus, or nystagmus. Severe toxicity may produce multiple organ dysfunction (e.g. seizures, coma, renal failure, cardiac arrhythmias, cardiovascular collapse) and may be fatal.(3)

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: acute renal impairment, chronic renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ACEI, ARBs, NSAIDs, diuretics).(3) Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: The US prescribing information for metronidazole states patients should be monitored closely with concurrent lithium therapy by obtaining serum lithium and creatinine levels several days after initiation of metronidazole.(2) If possible, lithium treatment should be tapered or withdrawn before administering metronidazole.(1) If concurrent therapy cannot be avoided, monitor closely. Evaluate renal function and most recent lithium levels. If renal function is not stable, whenever possible delay initiation of concurrent therapy until renal function is stable. If an interacting drug is discontinued, the lithium level may fall. Monitor lithium concentration and adjust dose if needed.(3) Counsel patient to assure they know signs and symptoms of lithium toxicity and understand the importance of follow-up laboratory testing.

DISCUSSION: Lithium has a narrow therapeutic index with potential fatal consequences.(2) Other factors, such as dehydration, acute or worsening of chronic renal impairment, or acute changes in sodium intake may increase the occurrence of a clinically important interaction.

Lithium/Nsaids; Salicylates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Decreased renal excretion of lithium, possibly resulting from NSAID-induced prostaglandin inhibition.

CLINICAL EFFECTS: May observe increased lithium toxicity.

PREDISPOSING FACTORS: Risk factors for lithium toxicity include: renal impairment or worsening of existing renal disease, dehydration, low sodium diet, and concomitant use of multiple medications which may impair renal elimination of lithium (e.g. ARBs, ACE Inhibitors, NSAIDs, diuretics). Patients who require higher therapeutic lithium levels to maintain symptom control are particularly susceptible to these factors.

PATIENT MANAGEMENT: The magnitude of this interaction is highly variable. Patients with predisposing factors, e.g. dehydration, renal impairment, or concurrent use of other agents which may impair lithium elimination, are expected to have a higher risk for lithium toxicity. If both drugs are administered, monitor plasma lithium levels and observe the patient for signs and symptoms of lithium toxicity or changes in renal function. Full effects of the addition or an increase in NSAID dose may not be seen for one to two weeks. Adjust the dose of lithium accordingly. If lithium is to be started in a patient stabilized on chronic NSAID therapy, consider starting with a lower lithium dose and titrate slowly as half-life may be prolonged. Monitor lithium concentrations until stabilized on the combination. Counsel the patient to contact their prescriber before starting an OTC NSAID. Assure that patients are familiar with signs and symptoms of lithium toxicity (e.g. new or worsening tremor, nausea/vomiting, diarrhea, ataxia, or altered mental status) and to report signs and symptoms of toxicity.

DISCUSSION: Numerous studies and case reports have been documented that administration of a NSAID to a patient stabilized on lithium therapy may result in increased serum lithium levels and possible toxicity. Full effects may take 1 to 2 weeks to develop and may persist for a week after the NSAID is discontinued.

Lithium/Polystyrene Sulfonate

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Polystyrene sulfonate may bind and delay or prevent the absorption of lithium from the gastrointestinal tract.(1)

CLINICAL EFFECTS: Simultaneous administration of polystyrene sulfonate may result in decreased levels of and effectiveness from lithium.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium polystyrene sulfonate states that oral medications should be administered at least 3 hours apart from polystyrene sulfonate. Patients with gastroparesis may require a 6 hour separation. If concurrent therapy is warranted, consider monitoring lithium levels and clinical response.(1)

DISCUSSION: Because polystyrene sulfonate may bind and delay or prevent the absorption of lithium from the gastrointestinal tract, the US manufacturer of sodium polystyrene sulfonate states that lithium should be administered at least 3 hours apart from polystyrene sulfonate.(1)

Lithium/Selected Antipsychotics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism of the interaction is unknown. Neurotoxicity symptoms (confusion, delirium, seizures, encephalopathy, and EEG changes) may be due to potentiation or an additive effect of the antipsychotic agent and lithium.

CLINICAL EFFECTS: Concurrent use of lithium and selected antipsychotic agents may produce neurotoxic symptoms, including extrapyramidal symptoms, neuroleptic malignant syndrome, and encephalopathic syndrome.

PREDISPOSING FACTORS: Large doses of either drug, pre-existing brain damage or other conditions (e.g. infection, dehydration) may increase the risk for neurotoxicity.

PATIENT MANAGEMENT: Lithium and antipsychotic agents are commonly co-prescribed for the acute management of manic or mixed manic episodes associated with bipolar disorder. Concurrent use should be approached with caution. Consider additional clinical monitoring for signs and symptoms of neurotoxicity, including confusion, fever, lethargy, tremors, stupor, weakness, leukocytosis, and increased blood urea nitrogen. If signs of neurotoxicity appear, discontinuation of the antipsychotic agent may be required. The US manufacturer of lithium carbonate states concurrent use with antipsychotic agents, including chlorpromazine, clozapine, fluphenazine, haloperidol, perphenazine, risperidone, and thioridazine, should be monitored closely. Although uncommon to rare, cases of severe neurotoxicity have been reported with this combination. Monitoring plasma levels is not always beneficial in preventing neurotoxic symptoms. Patients may experience neurotoxic symptoms with plasma concentrations in the therapeutic ranges. Close monitoring for signs of neurotoxicity, EEG monitoring, adequate hydration, and electrolyte status are recommended to minimize toxic potential.

DISCUSSION: Lithium and antipsychotic agents are commonly co-prescribed for the acute management of manic or mixed manic episodes associated with bipolar disorder. Several case reports have been published describing acute and irreversible neurotoxicity with the combination of lithium and antipsychotic agents, though these episodes often resemble rare serious events that can be attributed to the administration of either agent alone (e.g., delirium, dysphoria, encephalopathy, dyskinesias, neuroleptic malignant syndrome, etc.). Signs and symptoms of neurotoxicity associated with concomitant use have included confusion, fever, lethargy, tremors, stupor, weakness, leukocytosis, and increased blood urea nitrogen. Extrapyramidal effects, which in some cases were irreversible, and permanent brain damage have also been reported. Selected antipsychotics linked to this monograph include: benperidol, clozapine, haloperidol, and risperidone.

Lithium/Selected Phenothiazines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism of the interaction is unknown. Neurotoxicity symptoms (confusion, delirium, seizures, encephalopathy, and EEG changes) may be due to potentiation or an additive effect of the antipsychotic agent and the lithium.(1) Cardiotoxic effects may be the result of additive effects from thioridazine, and lithium. Lithium may lower intracellular potassium levels, which may increase the potential for thioridazine toxcity.(2)

CLINICAL EFFECTS: Phenothiazines and lithium may produce electrocardiogram changes and neurotoxic symptoms.(1,3-5) Ventricular arrhythmia, sinus bradycardia, and first degree AV block have been seen with concurrent use of thioridazine and lithium.(2)

PREDISPOSING FACTORS: Large doses of either drug, pre-existing brain damage or other conditions (e.g. infection, dehydration) may increase the risk for neurotoxicity.

PATIENT MANAGEMENT: Lithium and phenothiazines or other antipsychotics are commonly co-prescribed in the treatment of bipolar disorder. Although uncommon to rare, cases of severe neurotoxicity have been reported with this combination. During initiation of concurrent treatment with lithium and haloperidol, observe the patient closely for signs of neurotoxic or extrapyramidal effects. Monitoring plasma levels is not always beneficial in preventing neurotoxic symptoms. Patients may experience neurotoxic symptoms with plasma concentrations in the therapeutic ranges. EEG monitoring may be of benefit in the prevention of neurotoxicity. Consider avoiding concurrent therapy.

DISCUSSION: Neurotoxicity symptoms, ventricular arrhythmia, sinus bradycardia, first degree AV block, and sleepwalking have been observed with concurrent use of lithium carbonate and thioridazine.(1,3-5) Neurotoxicity symptoms and sleepwalking have also been seen when lithium was given with thiothixene(4,5), fluphenazine(3,5-7), perphenazine(5,8), and chlorpromazine.(5) It is unknown if the toxicities seen with thioridazine and lithium are due to concomitant use of the drugs or from just one agent. Ventricular arrhythmia, sinus bradycardia, and first degree AV block resolved when one of the agents was removed or the dose decreased.(2) It is best if these agents are not used concomitantly. If necessary, close monitoring of EEG status and neurotoxic symptoms should be practiced.

Lithium/Sodium-Glucose Co-Transporter 2 (Sglt2) Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors may increase the renal excretion of lithium by impairing the proximal tubular reabsorption of lithium.(1,2)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors may result in decreased levels and clinical effectiveness of lithium.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels should be monitored more frequently when starting or changing the dose of SGLT2 inhibitors. The dose of lithium may need to be adjusted.(3-6)

DISCUSSION: A 29 year old patient stabilized on lithium with good therapeutic response was started on empagliflozin on day 10 of lithium therapy. Three days later, lithium level was subtherapeutic. Empagliflozin was stopped. After 1 week, lithium levels returned to therapeutic range. Two days later, the patient had another trial of empagliflozin and again developed subtherapeutic lithium levels.(1) A post hoc analysis of 2 dapagliflozin trials (IMPROVE and DapKid) examined the effects of dapagliflozin on volume status in diabetic patients with albuminuric kidney disease. Lithium excretion, which served as a marker of proximal tubular sodium excretion, was found to increase by 19.6% (p < 0.01).(2)

Lithium/Theophylline Derivatives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Theophylline derivatives increase the renal excretion of lithium.

CLINICAL EFFECTS: Decreased levels of lithium which may result in decreased clinical effectiveness.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels and response should be monitored in patients in whom theophylline therapy is initiated or withdrawn. Patients receiving concurrent therapy should be monitored for increased adverse effects.

DISCUSSION: In a study involving ten volunteers, the concurrent administration of lithium and theophylline resulted in a significant decrease in lithium serum levels. Upon discontinuation of theophylline, lithium levels and half-life increased, and the clearance of lithium decreased. Individual variability in these parameters was significant. The overall incidence of adverse effects was significantly greater with concurrent therapy including restlessness, tremor, and anorexia. In another study in ten normal subjects, lithium (1200 mg/day for seven days) was administered and it was reported that theophylline infusion (dosed to achieve a plasma level of 14 mcg/ml) increased lithium clearances by 51%. In a case report, reduced lithium levels as well as worsening of manic symptoms occurred after increasing doses of theophylline were administered. It has been shown that aminophylline increases the lithium/creatinine clearance ratio, which may result in decreased serum lithium below the therapeutic level. Caffeine withdrawal has been reported to increase lithium levels in several case reports. This interaction is most important to consider in patients who have been previously sensitive to relapse with decreased lithium levels and in whom levels are maintained at the therapeutic/prophylactic borderline.

Serotonergic Agents/Centanafadine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor.(1) Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of centanafadine with other serotonergic agents may increase the risk of serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,2)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of centanafadine with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue centanafadine and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin.(1)

Serotonergic Agents/Gepirone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gepirone is a serotonin receptor agonist. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of gepirone with other serotonergic agents may increase the risk of hypertensive crisis and serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of gepirone with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue gepirone and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors. Use with other agents that also increase serotonin in the body must be undertaken with caution and monitored closely due to the risk of serotonin syndrome.(1)

Serotonergic Agents/Ziprasidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1)

DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6)

*Prior hypersensitivity to any inactive ingredient in lithium carbonate or lithium citrate products.

• Lactation

• Brugada syndrome
• Dehydration
• Diabetes insipidus
• Hypokalemia
• Hyponatremia
• Infection
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Myasthenia gravis
• Pregnancy
• Serotonin syndrome

• Coronary artery disease
• Hypercalcemia
• Hypothyroidism

Common adverse effects in adults receiving lithium include fine hand tremor, polyuria, mild thirst, nausea, and general discomfort during lithium initiation.

Common adverse effects in pediatric patients 7-17 years of age receiving lithium therapy include nausea/vomiting, polyuria, thyroid abnormalities, tremor, thirst/polydipsia, dizziness, rash/dermatitis, ataxia/gait disturbances, decreased appetite, and blurry vision.

Less Frequent

• Diabetes insipidus
• Leukocytosis
• Syncope

Rare or Very Rare

• Abnormal ECG
• Accidental fall
• Acquired dystonia
• Angioedema
• Bradycardia
• Brugada pattern
• Chorea
• Coma
• DRESS syndrome
• Encephalopathy
• Goiter
• Hallucinations
• Hypercalcemia
• Hypermagnesemia
• Hyperparathyroidism
• Hyperthyroidism
• Hypertonia
• Hyponatremia
• Hypotension
• Hypothyroidism
• Idiopathic intracranial hypertension
• Intracranial hypertension
• Nephrotic syndrome
• Palpitations
• Seizure disorder
• Serotonin syndrome
• Sinoatrial block
• Sinus bradycardia
• Sinus node dysfunction
• Ventricular premature beats

More Frequent

• Diarrhea
• Dizziness
• Fatigue
• Increased urinary frequency
• Nausea
• Polydipsia
• Tremor
• Urinary incontinence
• Vomiting

Less Frequent

• Acne vulgaris
• Ataxia
• Constipation
• Dysgeusia
• Edema
• Gait abnormality
• Muscle weakness
• Skin inflammation
• Skin rash
• Weight gain

Rare or Very Rare

• Acute abdominal pain
• Acute cognitive impairment
• Alopecia
• Anorexia
• Anticholinergic toxicity
• Arthralgia
• Blurred vision
• Dehydration
• Depression
• Drowsy
• Dry hair
• Dry skin
• Erectile dysfunction
• Exophthalmos
• Fecal incontinence
• Finger pain
• Flatulence
• Folliculitis
• Gastritis
• Glycosuria
• Headache disorder
• Hyperglycemia
• Hyperreflexia
• Indifference
• Lethargy
• Muscle fasciculation
• Nervousness
• Nystagmus
• Oliguria
• Polyuria
• Proteinuria
• Pruritus of skin
• Psoriasis
• Raynaud's phenomenon
• Scotomata
• Sensation of cold
• Skin ulcer
• Slurred speech
• Stupor
• Swelling of ankles
• Swelling of wrists
• Vertigo
• Weight loss
• Xerostomia

No enhanced messaging available.

Safety and efficacy of lithium monotherapy (as conventional tablets, capsules, or lithium citrate oral solution) for the treatment of acute manic or mixed episodes and maintenance monotherapy of bipolar I disorder have been established in pediatric patients 7 to 17 years of age. Safety and efficacy were established based on an acute-phase study of 8 weeks' duration followed by a 28-week randomized withdrawal study.

Safety and efficacy of lithium therapy (as conventional tablets, capsules, or lithium citrate oral solution) in children <7 years of age with bipolar I disorder have not been established.

Safety and efficacy of lithium carbonate as extended-release tablets have not been established in pediatric patients <12 years of age.

There is potential for fetal harm when lithium is used during pregnancy. Reports from international birth registries suggest an increased risk of cardiovascular malformation, particularly Ebstein's anomaly, with first trimester exposure to lithium. Additional case-control and cohort studies indicate risk of cardiovascular malformations is likely small; however, current data are insufficient to establish a drug-associated risk. There are additional concerns for maternal and/or neonatal lithium toxicity during late pregnancy and during the postpartum period. Animal developmental and toxicity studies indicate an increased risk of fetal mortality, decreased fetal weight, increased fetal skeletal malformations, and cleft palate with oral doses of lithium that produce lithium concentrations similar to the human therapeutic range. Inform pregnant females of the potential fetal risk with lithium therapy.

Consider fetal echocardiography between 16 to 20 weeks' gestation in females with first trimester lithium exposure because of the fetal risk of cardiac malformations.

The renal excretion of lithium increases during pregnancy; therefore, if the decision is made to continue lithium, the dosage generally needs to be increased, serum concentrations monitored, and the dosage of lithium adjusted as needed. The lithium dosage should be reduced 2 to 3 days prior to delivery to reduce the risk of maternal and/or neonatal toxicity. Lithium may then be resumed during the postpartum period at preconception dosages in medically stable patients as long as lithium levels are closely monitored.

Lithium toxicity has been reported in neonates exposed to lithium during late pregnancy. Floppy baby syndrome, along with neurologic, cardiac, and hepatic abnormalities similar to that observed in adults with lithium toxicity, has been reported. Symptoms of floppy baby syndrome include hypotonia, respiratory distress syndrome, cyanosis, lethargy, feeding difficulties, depressed neonatal reflexes, neonatal depression, apnea, and bradycardia. Neonates should be monitored and supportive care provided until lithium is excreted and symptoms of toxicity disappear, which may take up to 14 days.

Lithium carbonate is excreted into breast milk at levels measured at 0.12 to 0.7 mEq/L or 40-45% of maternal plasma concentrations. Infants exposed to lithium through breast-feeding may have plasma concentrations that are 30-40% of maternal plasma levels. Signs and symptoms of lithium toxicity, which include hypertonia, hypothermia, cyanosis, and ECG changes have been reported in some breast-fed infants and neonates. Increased prolactin levels have also been detected in some breast-feeding females; however, the effect on milk production is not known.

Breast-feeding is not recommended when the mother is receiving lithium therapy; however, if the mother chooses to breast-feed, the infant should be closely monitored for signs of lithium toxicity. Breast-feeding should be discontinued if the infant develops lithium toxicity.

Regular monitoring of lithium levels and thyroid function should be considered in breast-fed infants exposed to lithium.

Although the manufacturer does not provide specific dosage recommendations in geriatric patients, due to the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and other medication therapy in this population, patients in this age group should receive initial dosages of lithium on the lower end of the usual range. Geriatric patients often respond to a reduce dosage, and may exhibit signs of toxicity at serum concentrations tolerated by other patients.

Lithium is substantially excreted by the kidneys and the risk of severe adverse reactions may be increased in patients with impaired renal function. Because geriatric patients may have decreased renal function, renal function should be monitored and dosage adjusted accordingly.

Clinical studies of lithium carbonate as extended-release tablets did not include sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger patients. While clinical experience with lithium generally has not revealed age-related differences in response, care should be taken in dosage selection. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and other medication therapy in geriatric patients, patients should receive initial dosages on the lower end of the usual range. Lithium is substantially excreted by the kidneys and risk of severe adverse reactions may be increased in patients with impaired renal function. Because geriatric patients may have decreased renal function, renal function should be monitored and dosage adjusted accordingly.