(LITH ee um)
Bipolar disorder: Acute treatment of manic episodes and maintenance therapy for patients with a diagnosis of bipolar disorder.
Hypersensitivity to lithium or any component of the formulation
Immediate-release capsule, solution and tablet: Severe cardiovascular or renal disease, severe debilitation, dehydration, sodium depletion, concurrent use with diuretics
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.
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): 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/day 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/day in 2 divided doses
Depression, augmentation of antidepressant (off-label use): 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 to1200 mg daily in divided doses (Bauer 2003a; Bauer 2003b; Nelson 2014)
Bipolar disorder (acute mania, acute depression [off-label use], and maintenance): Initiate therapy with lower doses; refer to adult dosing.
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:
Children 6 to 12 years (off-label use): Oral: Immediate-release: 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 and Adolescents: Refer to adult dosing.
CrCl 10 to 50 mL/minute: Administer 50% to 75% of normal dose (Aronoff 2007).
CrCl <10 mL/minute: Administer 25% to 50% of normal dose (Aronoff 2007).
End-stage renal disease (ESRD) with hemodialysis: Dose after dialysis (Aronoff 2007).
Continuous renal replacement therapy (CRRT): Administer 50% to 75% of normal dose (Aronoff 2007).
There are no dosage adjustments provided in manufacturer 's labeling.
Administer with meals to decrease GI upset. Extended release tablets must be swallowed whole; do not crush or chew.
May be taken with meals to avoid GI upset; maintain adequate salt and fluid intake.
Store between 15 � �C and 30 � �C (59 � �F to 86 � �F). Protect tablets and capsules from moisture.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
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
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
Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. 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
Linezolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Management: Due to a risk of serotonin syndrome/serotonin toxicity, discontinue serotonin modulators 2 weeks prior to the administration of linezolid. If urgent initiation of linezolid is needed, discontinue serotonin modulators immediately and monitor closely. 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
Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination
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: Nicergoline; Tedizolid. Monitor therapy
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 and Thiazide-Like Diuretics: May decrease the excretion of Lithium. Consider therapy modification
Topiramate: May increase the serum concentration of Lithium. Monitor therapy
TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. 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
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 patients clinical status and levels are stable, then repeat levels every 1 to 3 months or as clinically indicated); weight (baseline, then periodically) (APA 2002).
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
Elderly patients receiving lithium may have a decreased glomerular filtration rate and decrease in renal plasma clearance (13.7 mL/minute) (Ward, 1994).
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 (Lehmann 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 (Lehmann 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 (Lehmann 2013).
- Renal effects: Chronic therapy results in diminished renal concentrating ability (nephrogenic diabetes insipidus); this is usually reversible when lithium is discontinued. Monitor for changes in renal function and avoid dehydration; 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 patients with bipolar disorder 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: Generally avoid use in patients with significant cardiovascular disease due to an increased risk of lithium toxicity; if use is unavoidable, use with extreme caution and 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: Generally avoid use in patients with significant fluid loss or sodium depletion due to an increased risk of lithium toxicity. If use is unavoidable, use extreme caution and monitor serum lithium levels closely. Decreased tolerance to lithium has been reported with 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 therapy.
- 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: Generally avoid use in patients with significant renal disease due to an increased risk of lithium toxicity. If use is unavoidable, use extreme caution and 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: Generally avoid use in severely debilitated patients due to an increased risk of lithium toxicity; if use is unavoidable, use extreme caution and 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.
- Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997, Zar 2007). 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 doses close to therapeutic levels. Facilities for prompt and accurate serum lithium determinations should be available before initiating therapy. Normal fluid and salt intake must be maintained during therapy. Lithium should generally not be given to patients with significant renal or cardiovascular disease, severe debilitation or dehydration, or sodium depletion due to risk of lithium toxicity; if use is unavoidable, lithium may be undertaken with extreme caution, including frequent serum lithium determinations and possibly hospitalization. Discontinue therapy if such clinical signs of lithium toxicity occur (eg, diarrhea, vomiting, tremor, mild ataxia, drowsiness, or muscular weakness).
D
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 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).
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 apoptotic 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).
Rapid and complete
Vd: Initial: 0.307 L/kg; Vdss: 0.7 to 1 L/kg; decreased in elderly patients (Ward 1994)
Not metabolized (Ward 1994)
Urine (primarily; unchanged drug); sweat, saliva and feces (negligible amounts)
Clearance: 80% of filtered lithium is reabsorbed in the proximal convoluted tubules; decreased in elderly patients secondary to age-related decreases in renal function (Ward 1994)
Serum: Nonsustained release: ~0.5 to 3 hours; Extended release: 2 to 6 hours; Solution: 15 to 60 minutes (Ward 1994)
18 to 36 hours; prolonged in elderly patients (28.5 hours) (Ward 1994)
Not protein bound (Ward 1994)
- 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, increased thirst, headache, dry hair, thin hair, or hair loss. Have patient report immediately to prescriber signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), shortness of breath, abnormal heartbeat, confusion, fatigue, severe nausea, diarrhea, severe vomiting, blurred vision, tinnitus, muscle weakness, tremors, twitching, seizures, involuntary eye movements, change in balance, bradycardia, severe dizziness, hallucinations, memory impairment, passing out, sweating a lot, dehydration, severe loss of strength and energy, agitation, abnormal gait, abnormal muscle action, swelling of hands or feet, weight gain or loss, slurred speech, vision changes, tinnitus, or urinary or fecal incontinence (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 health care 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.