Prescription Drug Information: Lithium Carbonate (Page 3 of 5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy


Risk Summary
Lithium may cause harm when administered to a pregnant woman. Early voluntary reports to international birth registries suggested an increase in cardiovascular malformations, especially for Ebstein’s anomaly, with first trimester use of lithium. Subsequent case-control and cohort studies indicate that the increased risk for cardiac malformations is likely to be small; however, the data are insufficient to establish a drug-associated risk. There are concerns for maternal and/or neonatal lithium toxicity during late pregnancy and the postpartum period [see Clinical Considerations]. Published animal developmental and toxicity studies in mice and rats report an increased incidence of fetal mortality, decreased fetal weight, increased fetal skeletal abnormalities, and cleft palate (mouse fetuses only) with oral doses of lithium that produced serum concentrations similar to the human therapeutic range. Other published animal studies report adverse effects on embryonic implantation in rats after lithium administration. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Dose adjustments during pregnancy and the postpartum period
If the decision is made to continue lithium treatment during pregnancy, serum lithium concentrations should be monitored and the dosage adjusted during pregnancy. Two to three days prior to delivery, lithium dosage should be decreased or discontinued to reduce the risk of maternal and/or neonatal toxicity. Lithium may be restarted in the post-partum period at preconception doses in medically stable patients as long as serum lithium levels are closely monitored [see Dosage and Administration ( 2.7), Warnings and Precautions ( 5.1)].

Fetal/Neonatal adverse reactions
Lithium toxicity may occur in neonates who were exposed to lithium in late pregnancy. A floppy baby syndrome including neurological, cardiac, and hepatic abnormalities that are similar to those seen with lithium toxicity in adults have been observed. Symptoms include hypotonia, respiratory distress syndrome, cyanosis, lethargy, feeding difficulties, depressed neonatal reflexes, neonatal depression, apnea, and bradycardia. Monitor neonates and provide supportive care until lithium is excreted and toxic signs disappear, which may take up to 14 days. Consider fetal echocardiography between 16 and 20 weeks gestation in a woman with first trimester lithium exposure because of the potential increased risk of cardiac malformations.

8.2 Lactation

Risk Summary
Limited published data reports the presence of lithium carbonate in human milk with breast milk levels measured at 0.12 to 0.7 mEq or 40 to 45% of maternal plasma levels. Infants exposed to lithium during breastfeeding may have plasma levels that are 30 to 40% of maternal plasma levels. Signs and symptoms of lithium toxicity such as hypertonia, hypothermia, cyanosis, and ECG changes have been reported in some breastfed neonates and infants. Increased prolactin levels have been measured in lactating women, but the effects on milk production are not known. Breastfeeding is not recommended with maternal lithium use; however, if a woman chooses to breastfeed, the infant should be closely monitored for signs of lithium toxicity. Discontinue breastfeeding if a breastfed infant develops lithium toxicity.
Clinical Considerations
Consider regular monitoring of lithium levels and thyroid function in a breastfed infant.

8.4 Pediatric Use

Dosage recommendations for lithium in patients 12 years and older are similar to that of adults [see Dosage and Administration ( 2.5)]. Safety and effectiveness of lithium in pediatric patients below the age of 12 years have not been established.

8.5 Geriatric Use


Clinical studies of lithium carbonate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other treatment.
Lithium is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Impairment

As lithium is eliminated primarily through the kidney, lithium renal clearance is decreased in patients with abnormal renal function, and the risk of lithium intoxication increases considerably in this setting. Lithium should not be used in severe renal insufficiency (creatinine clearance less than 30 mL/min evaluated by Cockcroft-Gault), especially if the condition requires adherence to a low-sodium diet [see Dosage and Administration ( 2.8)]. Start patients with mild to moderately impaired renal function (creatinine clearance 30 to 89 mL/min evaluated by Cockcroft-Gault) with lower doses of lithium and titrate slowly while frequently monitoring serum lithium concentrations and for signs of lithium toxicity [see Dosage and Administration ( 2.8)].

10 OVERDOSAGE

The toxic concentrations for lithium (≥ 1.5 mEq/L) are close to the therapeutic concentrations [see Warnings and Precautions ( 5.1)]. At lithium concentrations greater than 3 mEq/L, patients may progress to seizures, coma, and irreversible brain damage.
Treatment
For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1800-222-1222 or www.poison.org.
No specific antidote for lithium poisoning is known. Early symptoms of lithium toxicity can usually be treated by reduction or cessation of dosage of the drug and resumption of the treatment at a lower dose after 24 to 48 hours.
In severe cases of lithium poisoning, the first and foremost goal of treatment consists of elimination of this ion from the patient. Administration of gastric lavage should be performed, but use of activated charcoal is not recommended as it does not significantly absorb lithium ions. Hemodialysis is the treatment of choice as it is an effective and rapid means of removing lithium in patients with severe toxicity. As an alternative option, urea, mannitol and aminophylline can induce a significant increase in lithium excretion. Appropriate supportive care for the patient should be undertaken. In particular, patients with impaired consciousness should have their oral airway protected and it is critical to correct any volume depletion or electrolyte imbalance. Specifically, patients should be monitored to prevent hypernatremia while receiving normal saline and careful regulation of kidney function is of utmost importance. Serum lithium concentrations should be closely monitored as there may be a rebound in serum lithium concentrations as a result of delayed diffusion from the body tissues. Likewise, during the late recovery phase, lithium should be re-administered with caution taking into account the possible release of significant lithium stores in body tissues.

11 DESCRIPTION

Lithium is an element of the alkali-metal group with atomic weight of 6.94.
Lithium Carbonate is a white, light, alkaline powder with molecular formula Li 2 CO 3 and molecular weight 73.89
Each capsule contains 150 mg, 300 mg, or 600 mg lithium carbonate, USP and the following inactive ingredients: gelatin, sodium lauryl sulfate, talc, titanium dioxide and the imprinting ink contains black iron oxide E172 dye, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of lithium as a mood stabilizing agent is unknown.

12.3 Pharmacokinetics


After oral administration, lithium is reported to be completely absorbed in the upper gastrointestinal tract. Peak serum concentrations (T max ) occur 0.25 to 3 hours after oral administration of immediate release preparations and 2 to 6 hours after sustained-release preparations.
The distribution space of lithium approximates that of total body water, and the plasma protein binding is negligible. After equilibrium, the apparent volume of distribution is 0.7 to 1 L/kg. Lithium is not metabolized.
Lithium is primarily excreted in urine, proportionally to its serum concentration. Lithium is filtered by the glomerulus, and 80% is reabsorbed by passive diffusion in the proximal tubule. The elimination half-life of lithium is approximately 18 to 36 hours. Lithium excretion in feces is insignificant.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Carcinogenesis
There have been no long-term studies performed in animals to evaluate the carcinogenic potential of lithium.
Mutagenesis
There have been no adequate studies conducted to evaluate the mutagenic and genotoxic potential of lithium.
Impairment of Fertility
There have been no adequate studies performed in animals at current standards to evaluate the effect of lithium treatment on fertility. However, published studies in male mice and rats administered repeated daily dosing of lithium carbonate report adverse effects on male reproductive organs, decreased spermatogenesis and decreased testosterone levels. The clinical significance of these findings is not clear.

16 HOW SUPPLIED/STORAGE AND HANDLING

Lithium Carbonate Capsules, USP
Lithium Carbonate Capsules USP, 150 mg are white/white size ‘4’ hard gelatin capsules, imprinted with ’97’ on body and ‘H’ on cap, containing white to off-white powder. They are supplied in

Bottles of 30 Capsules (NDC 31722-544-30)
Bottles of 100 Capsules (NDC 31722-544-01)
Bottles of 500 Capsules (NDC 31722-544-05)
Bottles of 1000 Capsules (NDC 31722-544-10)
Lithium Carbonate Capsules USP, 300 mg are pink/pink size ‘1’ hard gelatin capsules, imprinted with ’98’ on body and ‘H’ on cap, containing white to off-white powder. They are supplied in
Bottles of 30 Capsules (NDC 31722-545-30)
Bottles of 100 Capsules (NDC 31722-545-01)
Bottles of 500 Capsules (NDC 31722-545-05)
Bottles of 1000 Capsules (NDC 31722-545-10)
Bottles of 5000 Capsules (NDC 31752- 545-50)
Blister Pack of 3×10′ s (NDC 31722-545-03)

Lithium Carbonate Capsules USP, 600 mg are pink/white size ‘0EL’ hard gelatin capsules, imprinted with ‘141’ on body and ‘H’ on cap, containing white to off-white powder. They are supplied in
Bottles of 30 Capsules (NDC 31722-546-30)
Bottles of 100 Capsules (NDC 31722-546-01)
Bottles of 500 Capsules (NDC 31722-546-05)
Bottles of 1000 Capsules (NDC 31722-546-10)
Storage:
Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature.] Protect from moisture. Dispense in a tight container as defined in the USP/NF.

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