Lithium (Systemic)


VA CLASSIFICATION
Primary: CN750
Secondary: CN900; BL400

Commonly used brand name(s): Carbolith; Cibalith-S; Duralith; Eskalith; Eskalith CR; Lithane; Lithizine; Lithobid; Lithonate; Lithotabs.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antimanic—

antidepressant therapy adjunct—

granulopoietic—

vascular headache prophylactic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Bipolar disorder (treatment)—Lithium is indicated as the primary agent in the treatment of acute manic and hypomanic episodes in bipolar disorder, and for maintenance therapy to help diminish the intensity and frequency of subsequent manic episodes in patients with a history of mania {57} {58}{77}.
—Lithium is used in some patients as the agent of choice in the prevention of bipolar depression {31}. Clinicians have observed a diminished intensity and frequency of severe depressive episodes.

[Depression, mental (treatment)]1 {17}—Lithium is used alone for maintenance therapy in unipolar depression, and for acute and maintenance therapy in schizoaffective disorder. It is also used to {43} augment the antidepressant effect of tricyclic or monoamine oxidase (MAO) inhibitor antidepressants in the treatment of major unipolar depression in patients not responsive to antidepressants alone.

[Headache, vascular (prophylaxis) ]1—Lithium is used to reduce the frequency of {41} the occurrence of episodic and chronic cluster headaches {01} {73} {74}.

[Neutropenia (treatment)]1—Lithium is used to reduce the incidence of infection in patients with chemotherapy-induced neutropenia and in patients with chronic or acquired neutropenia {02}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Lithium carbonate: 73.89
    Lithium citrate: 282.00


Other characteristics
    A monovalent cation easily assayed in biological fluids; salts share some chemical characteristics with salts of sodium and potassium

Mechanism of action/Effect:

Antimanic—Has not been established {57} {58}. The mood-stabilizing effect has been postulated to relate to a reduction of catecholamine neurotransmitter concentration, possibly mediated by lithium ion (Li +) effect on Na +K + adenosine triphosphatase (Na +K +ATPase) to produce improved transneuronal membrane transport of sodium ion. An alternate postulate is that lithium may decrease cyclic adenosine monophosphate (cyclic AMP) concentrations {58}, which would result in decreased sensitivity of hormonal-sensitive adenylcyclase receptors. Another hypothesis is the “second messenger” theory of lithium's interference with lipid inositol metabolism. This theory postulates that a group of improperly regulated {41} neurons may be the underlying cause of manic symptoms. A phospholipase C-type enzyme hydrolyzes the plasma membrane–located lipid, phosphatidylinositol biphosphate, to diacyglycerol and inositol triphosphate, postsynaptic second messengers that contribute to chronic cell stimulation by altering electrical activity in the neuron. Inositol formed during this process is {41} recycled by the inositol phospholipid–synthesizing enzymes in the CNS. There is evidence that cells in the CNS do not have access to plasma sources of inositol but, instead, depend on the synthesis of inositol for the transduction of neuronal signals. Lithium, in therapeutic concentrations, blocks the activity of the enzyme, inositol-1-phosphatase, resulting in a depletion of neuronal inositol and ultimately a decrease in the levels of phosphatidylinositol biphosphate. The lipid will no longer be able to stimulate the formation of adequate quantities of the second messengers or alter electrical activity. Subsequent cells in the CNS become relatively {41} insensitive to the agonist stimulation, and clinical improvement results. {28} {29} {37} {38}

Granulopoietic—The exact mechanism of action has not been established; however, studies have shown that lithium stimulates granulopoiesis, enhances marrow proliferation, elevates neutrophil production, and increases the granulocyte pool {02}.

Vascular headache prophylactic—Specific mechanism has not been established. It has been postulated that the action of lithium in cluster headaches may be directly related to changes in platelet serotonin and histamine concentrations.

Antidepressant—Has not been established. However, the mechanism may involve enhancement of serotonergic activity and downregulation of beta-receptors {27}.

Absorption:

Rapid {58}; complete within 6 to 8 hours. Absorption rate of slow-release capsules is slower and the total amount of lithium absorbed is lower than with other dosage forms. {05} {06} {30}

Protein binding:

Not bound to plasma proteins.

Biotransformation:

None.

Half-life (average)


Elimination:

Adults: 24 hours {57}.

Adolescents: 18 hours.

Elderly patients: Up to 36 hours.

Note: When therapy is initiated {33}, the serum concentration decreases rapidly during the initial 5 or 6 hours, followed by a more gradual decline over the next 24 hours.



Time to peak serum concentration

Syrup—0.5 hours.

Capsules or tablets—1 to 3 hours {25}.

Extended-release tablets—4 hours.

Slow-release capsules—3 hours {05}.

Steady-state serum concentrations—4 days.

Therapeutic serum concentration


Bipolar disorder:

Acute: 0.8 to 1.2 mEq per liter, occasionally up to 1.5 mEq per liter {28} {57}.

Maintenance: 0.5 to 1.0 {28} mEq per liter {58}. Occasionally may require same concentration range as acute illness {28}.


Onset of therapeutic action

Clinical improvement—1 to 3 weeks {57}.

Elimination:


Renal—
        95% unchanged; rapid initially, slower with extended therapy; 80% may be actively reabsorbed in the proximal tubule {58}; rate of excretion decreases with age. {57} {58}



Fecal—
        <1%. {57} {58}



Sweat—
        4 to 5%.



Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
First trimester: Use of lithium is not recommended during pregnancy, especially in the first trimester, because of possible teratogenicity. Lithium crosses the placenta and is present in almost equal concentrations in the fetal and maternal serum. Data from lithium birth registers suggest an increased incidence of neonatal goiter and congenital cardiovascular malformations, especially Ebstein"s anomaly {28} {36} {57} {58}{77}.

FDA Pregnancy Category D.

Delivery—

Lithium toxicity may be manifested as hypotonia, lethargy, and cyanosis in newborn infants of mothers taking lithium at term. Risk-benefit must be considered.

Breast-feeding

Lithium is excreted in breast milk {57} {58} at a concentration about one-half {58} that in maternal serum. Signs and symptoms of lithium toxicity such as hypotonia, hypothermia, cyanosis, and electrocardiogram (ECG) changes have been reported in some infants. With rare exceptions, infants should not be breast-fed while the mother is receiving lithium therapy.{77}

Pediatrics

Appropriate studies on the relationship of age to the effects of lithium have not been performed in the pediatric population. However, lithium may decrease bone formation or density in children by altering parathyroid hormone concentrations. Also, lithium is deposited in bone, replacing calcium in hydroxyapatite, an effect more pronounced in immature bone. {38} {40}


Geriatrics


Geriatric patients and patients with organic mental disease {41} usually require lower lithium dosage, lower serum concentration {41}{77}, and more frequent monitoring than younger adults because renal clearance rate and distribution volume are reduced. Lithium is more {41} toxic to the central nervous system (CNS) in the elderly, even when serum lithium concentrations are within the therapeutic range for younger adults. Also, the elderly possibly may be more prone to develop lithium-induced goiter and clinical hypothyroidism. Excessive thirst and larger volume of urine as early side effects of lithium therapy may be more frequent in the elderly. {21}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Amphetamines {59}    (concurrent use with lithium may antagonize the CNS stimulating effects of amphetamines)


Angiotensin-converting enzyme (ACE) inhibitors {62} {63} {64} {65} {66} {67} {68} {69}{77}    (reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use with ACE inhibitors; frequent monitoring of serum lithium concentrations is recommended during concurrent use)


Antidepressants, tricyclic    (since tricyclics may cause a swing into mania and a rapid recycling between mania and depression, lithium plasma concentrations at or greater than 0.8 mEq per liter may be needed to prevent the tricyclic switch process {28} {41})


» Acetazolamide {77}    (may lower lithium concentrations by increasing urinary lithium excretion )


» Anti-inflammatory drugs, nonsteroidal (NSAIDs) {04} {57} {58} {76}{77}    (concurrent use may increase the toxic effects of lithium by decreasing its renal excretion, thereby increasing the steady-state plasma lithium concentration by 39 to 50%; patient should be observed for symptoms of lithium toxicity, and increased monitoring of lithium plasma concentrations is recommended during concurrent use)


Atracurium or
Pancuronium {59} {76} or
Succinylcholine {59} {76}    (neuromuscular blocking effects may be potentiated or prolonged when these medications are used concurrently with chronic lithium therapy {57})


Calcium channel blocking agents {59}{77}    (concurrent use with lithium may increase the risk of neurotoxicity in the form of ataxia, tremors, nausea, vomiting, diarrhea, and/or tinnitus; caution is recommended {47})


» Calcium iodide or
» Iodinated glycerol or
» Potassium iodide {59}    (concurrent use with lithium may potentiate the hypothyroid and goitrogenic effects of either these medications or lithium)


Carbamazepine {58} {59}{77} or
Desmopressin or
Lypressin or
Posterior pituitary or
Vasopressin    (lithium may decrease the antidiuretic effect of these medications when used concurrently)

    (lithium may prevent or decrease carbamazepine-induced leukopenia with a possible increase in therapeutic effect when carbamazepine is used to treat psychotic disorders or bipolar {28} conditions {13})


» Chlorpromazine and possibly other phenothiazines {04} {58} {59} {76}    (concurrent use with lithium may reduce gastrointestinal absorption of the phenothiazine, thereby decreasing its serum concentrations by as much as 40%; phenothiazines, especially chlorpromazine, increase intracellular lithium concentration {28}; concurrent use may increase rate of renal excretion of lithium; extrapyramidal symptoms, delirium, and cerebellar function impairment {11} may be increased, especially in elderly patients {11}; also, nausea and vomiting, early indications of lithium toxicity, may be masked by the antiemetic effect of some phenothiazines; admixture of lithium citrate syrup with any liquid forms of phenothiazines may form a precipitate of the free phenothiazine {28})


» Diuretics {04} {57} {58} {59} {76}{77}    (concurrent use with lithium may provoke severe lithium toxicity by delaying renal excretion of lithium and consequently increasing serum and red blood cell lithium concentrations; close monitoring of lithium plasma concentrations is essential since sodium and lithium reabsorption in the proximal tubule is increased, due to the body sodium deficit {28}; a reduction in lithium dosage may be necessary)


Fludrocortisone {60} {61}    (in one published case report, lithium antagonized the mineralocorticoid effects of fludrocortisone; increased fludrocortisone dose and dietary sodium supplementation were required during concurrent use {60} {61})


» Haloperidol {04} {58} {59} {76}    (lithium is frequently used concurrently with haloperidol during the first 1 or 2 weeks of treatment for acute manic episodes, but lithium alone may be adequate thereafter. However, concurrent use with lithium has been reported, in a few cases, to be associated with irreversible neurological toxicity and brain damage, especially in patients with organic mental syndrome or other CNS impairment, although this interaction is controversial; extrapyramidal symptoms may be increased by enhancement of dopamine blockade by haloperidol; patients should be monitored closely during concurrent use; dosage adjustments may be necessary)

    (admixture of the liquid forms of lithium and haloperidol may precipitate free haloperidol)


Methyldopa {58} {59} {76}{77}    (concurrent use may increase the risk of lithium toxicity even though serum lithium concentrations remain within the recommended therapeutic range {26})


Metronidazole {57} {59}{77}    (concurrent use may promote renal retention of lithium, leading to lithium toxicity; reducing the dose or discontinuing the use of lithium may be necessary during metronidazole therapy; if not feasible to discontinue, frequent monitoring of serum creatinine, electrolyte and lithium concentrations, and urine osmolality to detect possible nephrogenic diabetes insipidus are recommended {09})


» Molindone {04} {59} {75}    (concurrent use with lithium may produce neurotoxic symptoms such as confusion, delirium, seizures, somnambulism, or abnormal electroencephalogram [EEG] changes )


Norepinephrine {59}    (concurrent use with lithium may decrease the pressor response to norepinephrine; a higher dose of norepinephrine may be required to achieve the desired effect )


Selective serotonin reuptake inhibitors{77}, such as:
Fluoxetine{50} {51} {52} {53} {54} {55} {59} or
Fluvoxamine or
Paroxetine or
Sertraline     (concurrent use with lithium has been reported to result in symptoms such as agitation, confusion, diarrhea, dizziness, and tremor;{50} {51} {52} {53} {54} {55} {59}lithium concentrations may be altered, leading to toxicity; close monitoring of lithium concentrations is recommended {50} {51} {52} {53} {54} {55} {59})


Sodium-containing medications or foods, especially sodium bicarbonate {57} {58} {59}{77} or sodium chloride {59}    (high sodium intake enhances lithium excretion, possibly resulting in decreased efficacy)


Urea    (may increase the renal excretion of lithium, thereby decreasing its effects {48} {57} {59}{77})


Xanthines {04} {57}{77} such as:
Aminophylline {04} {59} {76}
Caffeine {04} {59}
Dyphylline
Oxtriphylline
Theophylline {12} {59} {76}    (concurrent use of these medications with lithium increases urinary excretion of lithium, thereby possibly reducing its therapeutic effect)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Glucose, blood    (may be increased during treatment with lithium; concentrations return to normal when lithium administration is discontinued {15})


Parathyroid hormone, immunoreactive and
Calcium    (serum concentrations may rise above normal after long-term therapy {19})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Leukemia, history of    (leukemia may be reactivated by lithium {28})


Risk-benefit should be considered when the following medical problems exist
» Cardiovascular disease {57} {58}{77}    (may be exacerbated; possible interference with lithium excretion)


» CNS disorders, such as epilepsy and parkinsonism    (may be exacerbated; lithium-induced neurotoxicity may be masked)


» Dehydration, severe {57} {58}{77}    (risk of toxicity is increased; the loss of large volumes of body fluid as in prolonged vomiting, diarrhea, or profuse perspiration due to fever, exercise, saunas, or hot baths may result in increased serum lithium concentration; such loss of body fluid may necessitate dosage adjustment of lithium and/or the supplemental intake of sodium and fluids until hydration status and electrolytes are stable {28})


Diabetes mellitus    (serum insulin concentration may be increased)


Goiter or
Hypothyroidism {57}    (latent hypothyroidism may be induced in predisposed or elderly patients )


Hyperparathyroidism    (calcium metabolism may be altered after long-term use)


» Infections, severe    (fever with prolonged sweating, diarrhea, or vomiting may necessitate a decrease in lithium dosage {28} to prevent lithium toxicity )


Organic mental disease or
Schizophrenia    (patients may be hypersensitive to lithium and exhibit increased confusion, seizures, or electroencephalogram [EEG] changes at normal serum lithium concentrations )


Psoriasis    (may be aggravated by lithium; dosage adjustments of lithium and/or other medications may be necessary {32})


» Renal insufficiency {57} {58}{77} or
» Urinary retention    (lithium excretion may be delayed, leading to toxicity)


Sensitivity to lithium
Caution should be used also in severely debilitated patients or in patients on a sodium-restricted diet because these conditions may increase the risk of toxicity {57} {58}{77} by delaying renal excretion of lithium.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Calcium concentrations, serum and
Phosphate concentrations, serum    (determinations recommended in children under 12 years of age prior to initiation of therapy and periodically during treatment since lithium increases parathyroid hormone concentrations and risk of hypercalcemia and hypophosphatemia {28} {40})


» Electrocardiogram (ECG) {58}    (recommended at least once prior to therapy in all patients, and especially in patients over 40 years of age and those with a history suggestive of cardiovascular disease; should be repeated if symptoms such as palpitations, irregular pulse, weight gain with edema, {41} or diminished consciousness occur; also, lithium may cause the benign effect of flattening of T-waves and prominent U-waves {24})


Electrolyte concentrations, serum    (determinations recommended prior to therapy to detect preexisting hyponatremia, which will decrease lithium excretion {28})


Height and {28}
Weight evaluation    (baseline weight measurement prior to therapy and every 3 months are recommended; weight gain, possibly due to a high intake of calorie-containing liquids as a result of lithium-induced polydipsia or to fluid retention to balance the increase in cations {41}, may lead to a patient"s noncompliance with lithium therapy; in children, height and weight charts should be maintained, and lithium therapy re-evaluated or discontinued if there is any decrease in growth rate {40})


» Lithium concentrations, serum    (determinations recommended once or {41} twice weekly during treatment of acute manic episode until serum concentrations and patient"s clinical condition have stabilized; recommended at least every 2 to 3 months during remission when patient is stabilized; blood samples should be drawn in the morning immediately prior to the next dose, 10 to 14 {28} {38} hours following the previous dose, when there is maximal stability in serum concentration. Some side effects may occur at serum lithium concentrations below 1.5 mEq per liter, and mild to moderate toxic reactions are likely to occur at concentrations from 1.5 to 2.5 mEq per liter. {57} {58} Serum lithium concentrations should not be permitted to exceed 1.5 mEq per liter during the acute treatment phase; concentrations above 2.0 mEq per liter in chronic consumption of lithium can produce complex and serious clinical problems {57}. Severe toxicity can occur at 2.5 mEq per liter {41}. Close monitoring is recommended if lithium is used during the last trimester {31} of pregnancy, used concurrently with any other medication, and used in the elderly when renal clearance rate and distribution volume are reduced)


Pregnancy test, beta-HCG    (recommended prior to initiation of therapy in all women of child-bearing potential {28})


» Renal function determinations {58}{77}    (close assessment recommended prior to initiation of lithium therapy and periodically thereafter, even in asymptomatic patients with stable serum lithium concentrations; blood urea nitrogen [BUN]; serum creatinine; {41} and urinalysis should be performed prior to initiating therapy to determine hydration status, renal flow, and presence of pre-existing renal concentrating defect {28} {43} {44})


Thyroid function determinations {58}    (serum thyroxine and thyroxine-stimulating hormone [TSH] {28} should be evaluated at baseline before lithium therapy is initiated and at 6-month intervals during therapy; patient should be monitored for symptoms of hypothyroidism; maintenance of adequate thyroid function is important in children to maintain a satisfactory growth rate {40})


» White blood cell count, total and differential    (recommended prior to therapy and repeated if signs of unusual tiredness or weakness develop because of possible rare leukemia that may develop during lithium therapy; however, the association of lithium with leukemia is controversial; benign leukocytosis may be reversible on discontinuation of therapy {20})




Side/Adverse Effects

Note: The occurrence and severity of lithium–associated side/adverse effects are generally related directly to the serum lithium concentrations as well as to individual patient sensitivity to lithium. Lithium–related effects tend to occur with increasing frequency and severity at higher concentrations.{77}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Cardiovascular problems {57} {58} (fainting; fast or slow {43} heartbeat ; irregular pulse; troubled breathing [dyspnea] on exertion)
    
extrapyramidal symptoms {77} (muscle dysfunction or rigidity)
    
leukocytosis {57} {58} (unusual tiredness or weakness)
    
genitourinary effects {77} (glucose or protein in the urine)
    
nephrogenic diabetes insipidus {77} (frequent urination; increased thirst)—may persist after discontinuation of lithium
    
neurologic effects {77} (blackout spells ; confusion, poor memory or stupor; dizziness ; slurred speech)
    
weight gain {04} {57} {58}

Note: Sinus node function impairment, sinoatrial block, or ventricular irritability may occur at therapeutic serum lithium concentrations; possibly reversible when lithium is discontinued.
Leukocytosis is usually reversible upon discontinuation of lithium, but a rare leukemia may develop during lithium therapy {28}.


Incidence rare
    
Blue color and pain in fingers and toes {57}
    
coldness of arms and legs {57}
    
pseudotumor cerebri {57} ( dizziness; eye pain; headache; nausea or vomiting; noises in ears; vision problems)

Note: If undetected, pseudotumor cerebri may result in enlargement of blind spot, constriction of visual fields, and eventual blindness, due to optic atrophy {03} {57}.


Symptoms of hypothyroidism
    
Dry, rough skin {57} {58}
    
hair loss {57} {58}
    
hoarseness
    
mania (unusual excitement)
    
mental depression {28}
    
sensitivity to cold
    
swelling of feet or lower legs {57}
    
swelling of neck



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea {28} {57} {58}
    
increased thirst {57} {58}
    
nausea, mild {57} {58}
    
stress incontinence or urinary urgency {22} (increased frequency of urination; loss of bladder control)
    
trembling of hands, slight {57} {58}

Note: Stress incontinence or urinary urgency is dose-related; more common in women; usually begins 2 to 7 years after start of treatment with lithium {21} {22}.


Incidence less frequent
    
Acne or skin rash {57} {58}
    
bloated feeling or pressure in the stomach {57} {58}
    
muscle twitching, slight {57} {58}





Overdose
For specific information on the agents used in the management of lithium overdose, see:
   • Acetazolamide in Carbonic Anhydrase Inhibitors (Systemic) monograph; and/or
   • Mannitol (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Early symptoms of toxicity
    
Diarrhea {57} {58}{77}
    
drowsiness {57} {58}{77}
    
lack of coordination {77}
    
loss of appetite
    
muscle weakness {57} {58}{77}
    
nausea or vomiting {57} {58}{77}
    
slurred speech
    
trembling {57} {58}

Late symptoms of toxicity
    
Ataxia (clumsiness or unsteadiness )
    
blurred vision {57} {58}{77}
    
confusion {57} {58}
    
convulsions {57} {58}
    
dizziness {57} {58}
    
increase in amount of urine {57} {58}{77}
    
tinnitus{77} (ringing in the ears)
    
trembling, severe {57} {58}


Treatment of overdose
No specific antidote is available. Early toxic symptoms can usually be treated by reducing or stopping administration of lithium and resuming treatment at a lower dosage after 24 to 48 hours {57}{77}.

Treatment of more severe toxicity or acute overdose may include the following:


To decrease absorption:
Inducing vomiting or using small volume (100 mL) {38} gastric lavage (in acute overdose) {57} {58}{77}.



To enhance elimination:
Utilizing intermittent hemodialysis if plasma lithium does not drop more than 10% every 3 hours or half-life is greater than 36 hours {38}. Since plasma lithium determinations immediately after dialysis do not take into account the rebound increase that occurs as lithium redistributes from tissue to blood, determinations must be obtained 6 hours later {45}.

Possibly increasing lithium excretion with single dose of intravenous acetazolamide or using mannitol as an osmotic diuretic {42} {58}.



Monitoring:
Measuring plasma lithium concentrations every 3 hours until lithium is less than 1.0 mEq per liter {38}.

Monitoring patient closely.



Supportive care:
Maintaining electrolyte balance and body fluids {57} {58}{77}.

Regulating kidney function {57}{77}.

Maintaining adequate respiration {57}{77}.

Preventing infection {57}{77}.

Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Lithium (Systemic)

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to lithium

Pregnancy—Lithium crosses placenta; contraindicated in first trimester because of possible neonatal goiter and cardiovascular malformations; at delivery, hypotonia, lethargy, and cyanosis in newborns of mothers taking lithium at term





Breast-feeding—Excreted in breast milk; may cause hypotonia, hypothermia, cyanosis, and ECG changes in some babies





Use in children—May decrease bone formation or density






Use in the elderly—Elderly more prone to develop CNS toxicity, hypothyroidism and goiter; lower doses and more frequent monitoring required
Other medications, especially acetazolamide, iodine-containing preparations, nonsteroidal anti-inflammatory drugs, chlorpromazine (and possibly other phenothiazines), diuretics, haloperidol, or molindone
Other medical problems, especially history of leukemia, cardiovascular disease, epilepsy, parkinsonism, severe dehydration, renal insufficiency, urinary retention, or severe infections with prolonged sweating, vomiting, or diarrhea

Proper use of this medication
Taking after a meal or snack {41} to prevent laxative action and to decrease the severity of stomach upset, tremors, or weakness by slowing absorption rate {10} {28} {31}

» Importance of adequate fluid (2.5 to 3 liters each day) and sodium intake

» Importance of not taking more medication than the amount prescribed

» Compliance with therapy; improvement in condition may require 1 to 3 weeks; importance of maintaining adequate blood levels even though symptoms improved

» Proper dosing
Taking as soon as possible, unless within 4 {28} hours (6 hours for extended-release tablets or slow-release capsules) of next scheduled dose; not doubling doses

» Proper storage

For extended-release or slow-release {05} dosage form
Swallowing tablet or capsule whole

Not breaking, crushing, or chewing

For syrup dosage form
Diluting dose with fruit juice or other flavored beverage before taking

Precautions while using this medication
» Regular visits to physician to check progress during therapy; importance of serum lithium monitoring

Caution in drinking large amounts of coffee, tea, or colas because of diuretic effect

» Possible drowsiness or dizziness; caution if driving or doing jobs requiring alertness {57}

» Caution during exercise, saunas, and hot weather

» Caution during illnesses that cause high fevers with profuse sweating, vomiting, or diarrhea {57}

» Caution on self-imposed dieting

» Importance of patient and family knowing early symptoms of overdose or toxicity

For slow-release dosage form
» Not using interchangeably with any other dosage form


Side/adverse effects
» Early symptoms of lithium overdose or toxicity:

Diarrhea

Drowsiness

Lack of coordination

Loss of appetite

Muscle weakness

Nausea or vomiting

Slurred speech

Trembling

Side effects are more likely to occur in the elderly

Signs of potential side effects, especially cardiovascular problems, extrapyramidal symptoms, genitourinary problems, leukocytosis, nephrogenic diabetes insipidus, neurologic effects, weight gain, blue color and pain in fingers and toes, coldness of arms and legs, pseudotumor cerebri, symptoms of hypothyroidism


General Dosing Information
Warning—Lithium toxicity can occur with doses at or near therapeutic serum concentrations {57} {58}{77}. Facilities for prompt and accurate serum lithium determinations must {28} be available during therapy {57}. Accurate patient evaluation requires both clinical and laboratory analysis {57}.

During the acute manic phase, the patient may have a greater ability to tolerate lithium. This tolerance decreases as the manic symptoms subside and often necessitates a corresponding dosage adjustment. {57} {58}

During the acute manic phase, lithium administration of 300 (8 mEq) {28} to 600 mg three times a day should usually produce effective serum concentrations ranging from 0.8 to 1.2 {28} mEq per liter {57}, with weekly adjustments based on plasma lithium concentrations. An increase of 8 mEq a day will increase plasma concentrations by 0.3±0.1 mEq per liter {28} {40}. The maintenance dose of 300 mg three or four times a day usually produces effective serum concentrations ranging from 0.5 to 1.0 {28} mEq per liter.

If a satisfactory therapeutic response to lithium at the highest tolerated serum concentrations within the therapeutic range {41} is not achieved within 3 {34} {35} weeks, lithium therapy should be discontinued.

Slow-release lithium carbonate capsules {06} {56} and tablets {49} are not bioequivalent to other lithium dosage forms and should not be used interchangeably with them.

Diet/Nutrition
Since lithium decreases sodium reabsorption by the renal tubules, a normal diet with an average consumption of salt and adequate fluid intake, 2.5 to 3 liters of fluid per day, is essential to prevent sodium depletion leading to lithium toxicity {57} {58}.

This medication may be taken with food, juice, or milk, if necessary, to lessen laxative action, stomach irritation, tremors, or weakness, by slowing absorption of lithium. The syrup must {41} be diluted in juice or other flavored beverage before administration. {28}

For treatment of adverse effects
Early side effects—If slight hand tremor, mild nausea or diarrhea, unusual drowsiness, or acne do not subside with continued treatment, a reduction in lithium dosage may be necessary {57}. If hand tremor is especially bothersome, shifting a majority of the dose to bedtime, decreasing caffeine intake, or adding a beta-blocker such as propranolol may be helpful.

Suppression of thyroid activity—May necessitate thyroid hormone replacement therapy {57}.

Urinary incontinence—Lowering dose of lithium whenever possible, adding an anticholinergic agent or an antidepressant with anticholinergic properties, or switching to another medication for treatment of bipolar disorder {22}.

Polyuria—Lowering dose of lithium alone, whenever possible. If the lower plasma lithium concentration is inadequate to maintain a response, adding a thiazide diuretic and reducing the lithium dose by 50%, then readjusting it to reproduce the original plasma lithium concentration, may be effective. Alternatively, extended-release or slow-release lithium products can improve the patient"s renal concentrating ability. {41}

Weight gain—May be safely and effectively treated by limiting calorie intake with emphasis on adequate fluid and sodium intake.


Oral Dosage Forms

LITHIUM CARBONATE CAPSULES USP

Usual adult and adolescent dose
Antimanic
Acute mania: Oral, initially 300 to 600 mg (8 to 16 mEq) three times a day, the dosage being adjusted as needed and tolerated at weekly intervals {58}.

Maintenance: Oral, 300 mg three or four times a day, the dosage being adjusted as needed and tolerated {58}{77}.


Note: Geriatric or debilitated patients usually require a lower dosage.


Usual adult prescribing limits
Up to 2.4 grams a day.

Usual pediatric dose
Antimanic
Children up to 12 years of age: Oral, initially 15 to 20 mg (0.4 to 0.5 mEq) per kg of body weight a day in two or three divided doses, the dosage being adjusted at weekly intervals, based on plasma lithium concentrations {28} {41}.

Children 12 to 18 years of age: See Usual adult and adolescent dose .


Strength(s) usually available
U.S.—


150 mg (Rx)[Generic]


300 mg (Rx) [Eskalith] [Lithonate][Generic]


600 mg (Rx)[Generic]

Canada—


150 mg (Rx) [Carbolith]


300 mg (Rx) [Carbolith] [Lithane]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • May cause drowsiness.
   • Take after a meal or snack.


LITHIUM CARBONATE SLOW-RELEASE CAPSULES

Usual adult and adolescent dose
Antimanic
Acute mania: Oral, initially 600 to 900 mg a day on the first day, the dosage being increased, thereafter, to 1200 to 1800 mg a day in three divided doses, as needed and tolerated {56}.

Maintenance: Oral, 900 to 1200 mg a day in three divided doses, the dosage being adjusted as needed and tolerated {56}.


Usual adult prescribing limits
Up to 2.4 grams a day.

Usual pediatric dose
Antimanic
Children up to 12 years of age: Dosage has not been established {56}.

Children 12 to 18 years of age: See Usual adult and adolescent dose .


Usual geriatric dose
Antimanic
Oral, 600 to 1200 mg a day in three divided doses {56}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


150 mg (Rx) [Lithizine]


300 mg (Rx) [Lithizine]

Note: Not bioequivalent to other lithium dosage forms and should not be used interchangeably with them {56}.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • Swallow whole {05}.
   • May cause drowsiness.


LITHIUM CARBONATE TABLETS USP

Usual adult and adolescent dose
See Lithium Carbonate Capsules USP.

Usual adult prescribing limits
See Lithium Carbonate Capsules USP.

Usual pediatric dose
See Lithium Carbonate Capsules USP.

Strength(s) usually available
U.S.—


300 mg (Rx) [Lithotabs][Generic]

Canada—


300 mg (Rx) [Lithane]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.

Auxiliary labeling:
   • May cause drowsiness.
   • Take after a meal or snack.


LITHIUM CARBONATE EXTENDED-RELEASE TABLETS

Usual adult and adolescent dose
Antimanic
Acute mania: Oral, 450 to {28} 900 mg two times a day {57} or 300 to 600 mg three times a day, the dosage being adjusted as needed and tolerated.

Maintenance: Oral, 450 mg two times a day {57} or 300 mg three times a day, the dosage being adjusted as needed and tolerated.


Note: Geriatric or debilitated patients usually require a lower dosage.


Usual adult prescribing limits
Up to 2.4 grams a day.

Usual pediatric dose
Antimanic
Children up to 12 years of age: Dosage has not been established {57}.

Children 12 to 18 years of age: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


300 mg (Rx) [Lithobid]


450 mg (Rx) [Eskalith CR (scored)]

Canada—


300 mg (Rx) [Duralith (scored)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Swallow whole.
   • May cause drowsiness.
   • Take after a meal or snack.


LITHIUM CITRATE SYRUP USP

Usual adult and adolescent dose
Antimanic
Acute mania: Oral, the equivalent of 300 to 600 mg (8 to 16 mEq) of lithium carbonate three times a day, the dosage being adjusted as needed and tolerated.

Maintenance: Oral, the equivalent of 300 mg of lithium carbonate three or four times a day, the dosage being adjusted as needed and tolerated.


Note: Geriatric or debilitated patients usually require a lower dosage.


Usual adult prescribing limits
Up to the equivalent of 2.4 grams of lithium carbonate a day.

Usual pediatric dose
Antimanic
Children up to 12 years of age: Oral, initially the equivalent of 15 to 20 mg (0.4 to 0.5 mEq) of lithium carbonate {41} per kg of body weight a day in two or three divided doses, the dosage being adjusted at weekly intervals, based on plasma lithium concentrations {28} {41}.

Children 12 to 18 years of age: See Usual adult and adolescent dose.


Strength(s) usually available
U.S.—


8 mEq of lithium ion (equivalent to approximately 300 mg of lithium carbonate) per 5 mL (Rx) [Cibalith-S][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing.

Incompatibilities:
Lithium citrate syrup should not be mixed with or administered at the same time as other medication, solid or liquid, that contains a basic form, such as chlorpromazine concentrate, haloperidol, thioridazine, or trifluoperazine, and tricyclic antidepressants {28} {41}.

Auxiliary labeling:
   • May cause drowsiness.
   • Take after a meal or snack.
   • Dilute with juice or other beverage before taking.



Revised: 02/02/2000



References
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