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Pronunciation

(LITH ee um)

Index Terms

  • Eskalith
  • Lithium Carbonate
  • Lithium Citrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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Capsule, Oral, as carbonate:

Generic: 150 mg, 300 mg, 600 mg

Solution, Oral, as citrate:

Generic: 8 mEq/5 mL (5 mL, 500 mL)

Tablet, Oral, as carbonate:

Generic: 300 mg

Tablet Extended Release, Oral, as carbonate:

Lithobid: 300 mg [contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Generic: 300 mg, 450 mg

Brand Names: U.S.

  • Lithobid

Pharmacologic Category

  • Antimanic Agent

Pharmacology

The precise mechanism of action in mood disorders is unknown. Traditionally thought to alter cation transport across cell membranes in nerve and muscle cells, influence the reuptake of serotonin and/or norepinephrine, and inhibit second messenger systems involving the phosphatidylinositol cycle (Ward, 1994). May also provide neuroprotective effects by increasing glutamate clearance, inhibiting apoptoctic glycogen synthase kinase activity, increasing the levels of antiapoptotic protein Bcl-2 and, enhancing the expression of neurotropic factors, including brain-derived neurotrophic factor (Sanacora, 2008).

Absorption

Rapid and complete

Distribution

Vd: Initial: 0.307 L/kg; Vdss: 0.7 to 1 L/kg (Ward, 1994)

Metabolism

Not metabolized (Ward, 1994)

Excretion

Urine (primarily; unchanged drug); sweat, saliva and feces (negligible amounts)

Clearance: 80% of filtered lithium is reabsorbed in the proximal convoluted tubules (Ward, 1994)

Time to Peak

Serum: Nonsustained release: ~0.5 to 3 hours; Extended release: 2 to 6 hours; Solution: 15 to 60 minutes (Ward, 1994)

Half-Life Elimination

18 to 36 hours (Ward, 1994)

Protein Binding

Not protein bound (Ward, 1994)

Special Populations: Elderly

Lithium clearance is decreased in the elderly secondary to age-related decreases in renal function. Elderly patients receiving lithium may have a decreased glomerular filtration rate, prolonged half-live (~28.5 hours), decreased volume of distribution (0.52 L/kg) and decrease in renal plasma clearance (13.7 mL/minute) (Ward, 1994).

Use: Labeled Indications

Bipolar disorder: Acute treatment of manic episodes and maintenance therapy for patients with a diagnosis of bipolar disorder.

Use: Unlabeled

Bipolar depression; depression, augmentation of antidepressant

Contraindications

Hypersensitivity to lithium or any component of the formulation; avoid use in patients with severe cardiovascular or renal disease, or with severe debilitation, dehydration, or sodium depletion

Dosage

Note: Monitor serum concentrations and clinical response (efficacy and toxicity) to determine proper dose. Each 5 mL of lithium citrate oral solution contains 8 mEq of lithium ion, equivalent to the amount of lithium in 300 mg of lithium carbonate immediate release capsules/tablets.

Bipolar disorder (acute mania, acute depression [off-label use], and maintenance):

Children 6 to 12 years (off-label use): Oral: 15 to 60 mg/kg/day in 3 to 4 divided doses; dose not to exceed usual adult dosage. Monitor serum concentrations and clinical response (efficacy and toxicity) to determine proper dose (Nelson, 1996)

Children > 12 years, Adolescents, and Adults: Oral:

Immediate release: Initial: Initiate at low dose (eg, 300 mg 3 times daily or less); increase gradually based on response and tolerability (APA, 2002); usual dosage: 900 to 1,800 mg daily in 3 to 4 divided doses

Extended release: Initiate at low dose (eg, 450 mg 2 times daily or less); increase gradually based on response and tolerability (APA, 2002); usual dosage: 900 to 1,800 mg daily in 2 divided doses

Elderly: Initiate therapy with lower doses; refer to adult dosing.

Depression, augmentation of antidepressant (off-label use): Adults: Oral: Initial: Initiate at a low dose (eg, 300 mg once daily or 300 mg twice daily); increase gradually based on response and tolerability; usual dosage: 600 to 1200 mg daily in divided doses (Bauer, 2003a; Bauer 2003b; Nelson, 2014)

Dosage adjustment in renal impairment:

CrCl 10 to 50 mL/minute: Administer 50% to 75% of normal dose

CrCl <10 mL/minute: Administer 25% to 50% of normal dose

End stage renal disease (ESRD) with hemodialysis: Dose after dialysis (Aronoff, 2007).

Dosage adjustment in hepatic impairment: There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

Administer with meals to decrease GI upset. Extended release tablets must be swallowed whole; do not crush or chew.

Dietary Considerations

May be taken with meals to avoid GI upset; maintain adequate fluid intake.

Storage

Store between 15°C and 30°C (59°F to 86°F). Protect tablets and capsules from moisture.

Drug Interactions

ACE Inhibitors: May increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an ACE inhibitor. Monitor patient response to lithium closely following addition or discontinuation of concurrent ACE inhibitor treatment. Consider therapy modification

Amphetamines: Lithium may diminish the stimulatory effect of Amphetamines. Monitor therapy

Angiotensin II Receptor Blockers: May increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Consider therapy modification

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Lithium may enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Monitor therapy

Caffeine and Caffeine Containing Products: May decrease the serum concentration of Lithium. Monitor therapy

Calcitonin: May decrease the serum concentration of Lithium. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the neurotoxic effect of Lithium. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Lithium. Decreased or unaltered lithium concentrations have also been reported with this combination. Exceptions: Bepridil. Monitor therapy

Calcium Polystyrene Sulfonate: May decrease the serum concentration of Lithium. Management: Consider separating administration of lithium from administration of oral calcium polystyrene sulfonate by at least 6 hours. Consider therapy modification

CarBAMazepine: May enhance the adverse/toxic effect of Lithium. Monitor therapy

Carbonic Anhydrase Inhibitors: May decrease the serum concentration of Lithium. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Desmopressin: Lithium may diminish the therapeutic effect of Desmopressin. Desmopressin may increase the serum concentration of Lithium. Monitor therapy

Eplerenone: May increase the serum concentration of Lithium. Monitor therapy

Fosphenytoin: May enhance the adverse/toxic effect of Lithium. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Loop Diuretics: May decrease the serum concentration of Lithium. Loop Diuretics may increase the serum concentration of Lithium. Monitor therapy

MAO Inhibitors: May enhance the adverse/toxic effect of Lithium. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Exceptions: Moclobemide. Consider therapy modification

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methyldopa: May enhance the adverse/toxic effect of Lithium. This may occur without notable changes in serum lithium concentrations. Monitor therapy

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

Mifepristone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Neuromuscular-Blocking Agents: Lithium may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Lithium. Exceptions: Sulindac. Consider therapy modification

Phenytoin: May enhance the adverse/toxic effect of Lithium. Monitor therapy

Potassium Iodide: May enhance the hypothyroid effect of Lithium. Monitor therapy

Selective Serotonin Reuptake Inhibitors: Lithium may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could increase the risk of serotonin toxicity/serotonin syndrome. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Tedizolid. Consider therapy modification

Sodium Bicarbonate: May increase the excretion of Lithium. Monitor therapy

Sodium Chloride: May increase the excretion of Lithium. Monitor therapy

Sodium Polystyrene Sulfonate: May decrease the serum concentration of Lithium. Management: Consider separating administration of lithium from administration of oral sodium polystyrene sulfonate by at least 6 hours. Consider therapy modification

Theophylline Derivatives: May decrease the serum concentration of Lithium. Monitor therapy

Thiazide Diuretics: May decrease the excretion of Lithium. Consider therapy modification

Topiramate: May increase the serum concentration of Lithium. Monitor therapy

Tricyclic Antidepressants: Lithium may enhance the neurotoxic effect of Tricyclic Antidepressants. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Adverse Reactions

Frequency not always defined.

Cardiovascular: Abnormal T waves on ECG, bradycardia, cardiac arrhythmia, chest tightness, circulatory shock, cold extremities, edema, hypotension, myxedema, sinus node dysfunction, startled response, syncope

Central nervous system: Ataxia, blackout spells, cogwheel rigidity, coma, confusion, dizziness, drowsiness, dystonia, EEG pattern changes, extrapyramidal reaction, fatigue, hallucination, headache, hyperactive deep tendon reflex, hypertonia, involuntary choreoathetoid movements, lethargy, local anesthesia, memory impairment, loss of consciousness, metallic taste, myasthenia gravis (rare), pseudotumor cerebri, psychomotor retardation, reduced intellectual ability, restlessness, salty taste, sedation, seizure, slowed intellectual functioning, slurred speech, stupor, tics, vertigo, worsening of organic brain syndromes

Dermatologic: Acne vulgaris, alopecia, blue-gray skin pigmentation, dermal ulcer, dry or thinning of hair, exacerbation of psoriasis, folliculitis, pruritus, psoriasis, skin rash, xerosis

Endocrine & metabolic: Hypothyroidism (females 14%; males 5% [Johnston 1999]), albuminuria, dehydration, diabetes insipidus, euthyroid goiter, glycosuria, hypercalcemia (secondary to hyperparathyroidism [McKnight 2012]), hyperglycemia, hyperparathyroidism, hyperthyroidism, increased radioactive iodine uptake, increased thirst, polydipsia, weight gain, weight loss

Gastrointestinal: Abdominal pain, anorexia, dental caries, diarrhea, dysgeusia, dyspepsia, excessive salivation, flatulence, gastritis, nausea, vomiting, sialadenitis, sialorrhea, swelling of lips, xerostomia

Genitourinary: Impotence, incontinence, oliguria

Hematologic & oncologic: Leukocytosis

Hypersensitivity: Angioedema

Neuromuscular & skeletal: Joint swelling, muscle hyperirritability, neuromuscular excitability, polyarthralgia, tremor

Ophthalmic: Blurred vision, exophthalmos, nystagmus, transient scotoma

Otic: Tinnitus

Renal: Decreased creatinine clearance, polyuria

Miscellaneous: Fever

ALERT: U.S. Boxed Warning

Monitoring:

Lithium toxicity is closely related to serum lithium levels, and can occur at doses close to therapeutic levels. Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Hypercalcemia: Hypercalcemia with or without hyperparathyroidism has been reported. Risks are greater in women and possibly in older patients; symptom onset does not appear to be related to therapy duration (Lehman, 2013). Serum calcium levels typically range from slightly above normal to over 15 mg/dL and PTH levels may range from high normal to several times the upper limit of normal (Lehman, 2013); magnesium levels are often elevated; serum phosphate levels may be either normal or low (Grandjean, 2009). Monitor calcium and PTH levels as clinically indicated. Consider discontinuation if clinical manifestations of hypercalcemia are present (fatigue, weakness, abdominal pain, constipation, nephrolithiasis, bone pain) or if calcium levels are >11.4 mg/dL. Following discontinuation, check serum calcium levels weekly for one month for return to baseline. Changes are usually reversible if lithium is discontinued; however, sustained hypercalcemia and parathyroid gland enlargement has been reported (Lehman, 2013).

• Renal effects: Chronic therapy results in diminished renal concentrating ability (nephrogenic diabetes insipidus); this is usually reversible when lithium is discontinued. Changes in renal function should be monitored, and re-evaluation of treatment may be necessary. Morphologic changes with glomerular and interstitial fibrosis and nephron atrophy have been reported in patients on chronic lithium therapy; morphologic changes have also been reported in manic-depressive patients never exposed to lithium. The relationship between morphologic changes and renal function, and the association with lithium therapy, have not been established.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with mild-moderate cardiovascular disease due to an increased risk of lithium toxicity; monitor serum lithium levels closely. Lithium may unmask Brugada syndrome; avoid use in patients with or suspected of having Brugada syndrome. Consult with a cardiologist if a patient is suspected of having Brugada syndrome or has risk factors for Brugada syndrome (eg, unexplained syncope, a family history of Brugada syndrome, a family history of sudden death before the age of 45 years), or if unexplained syncope or palpitations develop after starting therapy.

• Dehydration: Use with caution in patients with significant fluid loss (protracted sweating, diarrhea, or prolonged fever) due to an increased risk of lithium toxicity; monitor serum lithium levels closely. Temporary reduction or cessation of therapy may be warranted.

• Depression/suicidal ideation: Use with caution in patients at risk of suicide (suicidal thoughts or behavior) by drug overdose; lithium has a narrow therapeutic index (APA, 2002).

• Renal impairment: Use with caution in patients with mild-moderate renal impairment due to an increased risk of lithium toxicity; monitor serum lithium levels closely.

• Thyroid disease: Use with caution in patients with thyroid disease; hypothyroidism may occur with treatment (APA, 2002).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Debilitated: Use with caution in debilitated patients due to an increased risk of lithium toxicity; monitor serum lithium levels closely.

• Elderly: Use with caution in the elderly patients due to an increased risk of lithium toxicity.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Other warnings/precautions:

• Acute manic phase: Higher serum concentrations may be required and tolerated during an acute manic phase; however, the tolerance decreases when symptoms subside.

• Lithium toxicity: [US Boxed Warning]: Lithium toxicity is closely related to serum concentrations and can occur at therapeutic doses; serum lithium determinations are required to monitor therapy. Normal fluid and salt intake must be maintained during therapy.

Monitoring Parameters

Renal function including BUN and SrCr (baseline, every 2 to 3 months during the first 6 months of treatment, then once a year in stable patients or as clinically indicated); serum electrolytes (baseline, then periodically), serum calcium (baseline, 2 to 6 weeks after initiation, then every 6 to 12 months; repeat as clinically indicated) (Broome, 2011); thyroid (baseline, 1 to 2 times with in the first 6 months of treatment, then once a year in stable patients or as clinically indicated); beta-hCG pregnancy test for all females not known to be sterile (baseline); ECG with rhythm strip (baseline for all patients over 40 years, repeat as clinical indicated), CBC with differential (baseline, repeat as clinically indicated); serum lithium levels (twice weekly until both patient's clinical status and levels are stable, then repeat levels every 1 to 3 months or as clinically indicated); weight (baseline, then periodically) (APA, 2002).

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Lithium crosses the placenta in concentrations similar to those in the maternal plasma (Newport, 2005). Cardiac malformations in the infant, including Ebstein's anomaly, are associated with use of lithium during the first trimester of pregnancy. Other adverse events including polyhydramnios, fetal/neonatal cardiac arrhythmias, hypoglycemia, diabetes insipidus, changes in thyroid function, premature delivery, floppy infant syndrome, or neonatal lithium toxicity are associated with lithium exposure when used later in pregnancy (ACOG, 2008). The incidence of adverse events may be associated with higher maternal doses (Newport, 2005).

Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of lithium to achieve euthymia and avoid toxicity (ACOG, 2008; Grandjean, 2009; Yonkers, 2011).

For planned pregnancies, use of lithium during the first trimester should be avoided if possible (Grandjean, 2009). If lithium is needed during pregnancy, the minimum effective dose should be used, maternal serum concentrations should be monitored, and consideration should be given to start therapy after the period of organogenesis; lithium should be suspended 24 to 48 hours prior to delivery or at the onset of labor when delivery is spontaneous, then restarted when the patient is medically stable after delivery (ACOG, 2008; Grandjean, 2009; Newport, 2005). Fetal echocardiography should be considered if first trimester exposure occurs (ACOG, 2008).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience hand tremors, asthenia, dyspepsia, polydipsia, headache, polyuria, or alopecia. Have patient report immediately to prescriber dyspnea, bradycardia, arrhythmia, severe dizziness, syncope, illogical thinking, significant nausea, diarrhea, hyperhidrosis, dehydration, considerable asthenia, akathisia, abnormal gait, myoclonus, edema of hands or feet, weight gain or loss, dysarthria, vision changes, tinnitus, urinary retention, oliguria, urinary or fecal incontinence, or fatigue (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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