PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 71656-072-50

Lithium Oral Solution, USP

8 mEq per 5 mL

Unit-dose delivers 5 mL

Orange Flavor

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

Rx only

5 Trays contain 50 Unit-dose Cups

WARNING: LITHIUM TOXICITY

1 INDICATIONS AND USAGE

Lithium oral solution is a mood-stabilizing agent indicated as monotherapy for the treatment of bipolar I disorder:

• Treatment of acute manic and mixed episodes in patients 7 years and older [see Clinical Studies (14)].
• Maintenance treatment in patients 7 years and older [see Clinical Studies (14)].

4 CONTRAINDICATIONS

Lithium is contraindicated in patients with known hypersensitivity to any inactive ingredient in the lithium citrate products [see Adverse Reactions (6)].

6 ADVERSE REACTIONS

The following adverse reactions are described in greater detail in other sections:

• Acute Lithium Toxicity [see Warnings and Precautions (5.1)]
• Lithium-Induced Polyuria [see Warnings and Precautions (5.2)]
• Hyponatremia [see Warnings and Precautions (5.3)]
• Lithium-Induced Chronic Kidney Disease [see Warnings and Precautions (5.4)]
• Encephalopathic Syndrome [see Warnings and Precautions (5.5)]
• Serotonin Syndrome [see Warnings and Precautions (5.6)]
• Hypothyroidism or Hyperthyroidism [see Warnings and Precautions (5.7)]
• Hypercalcemia and Hyperparathyroidism [see Warnings and Precautions (5.8)]
• Unmasking of Brugada Syndrome [see Warnings and Precautions (5.9)]
• Pseudotumor Cerebri [see Warnings and Precautions (5.10)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Pediatric Patients (7 years to 17 years):

Bipolar I Disorder: The following findings are based on an 8-week, placebo- controlled study for acute manic or mixed episodes of bipolar I disorder in pediatric patients 7 years to 17 years (N = 81). In this study, lithium was administered at daily doses ranging from 300 to 3,600 (mean dose 1,483 mg ± 584) with serum levels ranging from 0 to 2 (mean level 0.98 mEq/L ± 0.47).

Common Adverse Reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea/vomiting, polyuria, thyroid abnormalities, tremor, thirst/polydipsia, dizziness, rash/dermatitis, ataxia/gait disturbance, decreased appetite, and blurry vision.

Adverse Reactions Occurring at an Incidence of 2% or More in Lithium-Treated Pediatric Patients: Adverse reactions associated with the use of lithium (incidence of 2% or greater, rounded to the nearest percent, and lithium incidence greater than placebo) that occurred during acute therapy (up to 8-weeks in pediatric patients with bipolar disorder) are shown in Table 3.

Table 3: Adverse Reactions Reported in 2% or More of Pediatric Patients on Lithium and That Occurred at Greater Incidence Than in the Placebo Group in the 8-Week Acute Bipolar Trial

Adult Patients:

The following adverse reactions have been identified following use of lithium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central Nervous System: tremor, muscle hyperirritability (fasciculations, twitching, clonic movements of whole limbs), hypertonicity, ataxia, choreoathetotic movements, hyperactive deep tendon reflexes, extrapyramidal symptoms including acute dystonia, cogwheel rigidity, blackout spells, epileptiform seizures, slurred speech, dizziness, vertigo, downbeat nystagmus, incontinence of urine or feces, somnolence, psychomotor retardation, restlessness, confusion, stupor, coma, tongue movements, tics, tinnitus, hallucinations, poor memory, slowed intellectual functioning, startled response, worsening of organic brain syndromes, myasthenic syndromes (rarely).

EEG Changes: diffuse slowing, widening of frequency spectrum, potentiation and disorganization of background rhythm.

Cardiovascular: conduction disturbance (mostly sinus node dysfunction with possibly severe sinus bradycardia and sinoatrial block), ventricular tachyarrhythmia, peripheral vasculopathy (resembling Raynaud’s Syndrome).

ECG Changes: reversible flattening, isoelectricity or rarely inversion of T-waves, prolongation of the QTc interval.

Gastrointestinal: anorexia, nausea, vomiting, diarrhea, gastritis, salivary gland swelling, abdominal pain, excessive salivation, flatulence, indigestion.

Genitourinary: glycosuria, decreased creatinine clearance, albuminuria, oliguria, and symptoms of nephrogenic diabetes insipidus including polyuria, thirst, and polydipsia.

Dermatologic: drying and thinning of hair, alopecia, anesthesia of skin, chronic folliculitis, xerosis cutis, psoriasis onset or exacerbation, generalized pruritus with or without rash, cutaneous ulcers, angioedema, drug reaction with eosinophilia and systemic symptoms (DRESS).

Autonomic Nervous System: blurred vision, dry mouth, impotence/sexual dysfunction.

Miscellaneous: fatigue, lethargy, transient scotoma, exopthalmos, dehydration, weight loss, leukocytosis, headache, transient hyperglycemia, hypermagnesemia, excessive weight gain, edematous swelling of ankles or wrists, dysgeusia/taste distortion (e.g., metallic or salty taste), thirst, swollen lips, tightness in chest, swollen and/or painful joints, fever, polyarthralgia, and dental caries.

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Lithium

Table 4: Clinically Important Drug Interactions with Lithium

3 DOSAGE FORMS AND STRENGTHS

Each 5 mL of clear, slightly yellow lithium oral solution, USP contains 8 mEq lithium ion (Li+) (equivalent to the amount of lithium in 300 mg of lithium carbonate, USP).

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 (2.4), 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 weeks 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 mEq 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

The safety and effectiveness of lithium for monotherapy treatment of acute manic or mixed episodes of bipolar I disorder and maintenance monotherapy of bipolar I disorder in pediatric patients ages 7 years to 17 years of age have been established in an acute-phase clinical trial of 8 weeks in duration followed by a 28-week randomized withdrawal phase [see Dosage and Administration (2.1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)].

The safety and effectiveness of lithium has not been established in pediatric patients less than 7 years of age with bipolar I disorder.

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 (2.5)].

Start patients with mild to moderately impaired renal function (creatinine clearance 30 mL/min 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 (2.5)].

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 1-800-222-1222 or www.poison.org.

No specific antidote for lithium poisoning is known. Mild symptoms of lithium toxicity can usually be treated by reduction in dose or cessation of the drug.

In severe cases of lithium poisoning, the goal of treatment is 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. Patients with impaired consciousness should have their airway protected and it is critical to correct any volume depletion or electrolyte imbalance. 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

Each 5 mL of solution for oral administration contains lithium ion (Li+), 8 mEq (equivalent to amount of lithium in 300 mg of lithium carbonate, USP), and the following other inactive ingredients: citric acid, glycerin, orange flavor, propylene glycol, purified water, sodium benzoate, sorbitol solution, and sucralose.

Lithium oral solution, USP is a palatable oral dosage form of lithium ion. It is prepared in solution from lithium carbonate, USP and citric acid in a ratio approximately di-lithium citrate.

Lithium is an element of the alkali-metal group with atomic number 3, atomic weight 6.94, and an emission line at 671 nm on the flame photometer.

The empirical formula for lithium citrate is C6H5Li3O7; molecular weight 209.93. Lithium acts as an antimanic.

16 HOW SUPPLIED/STORAGE AND HANDLING

Lithium oral solution, USP, is supplied as a clear, slightly yellow liquid with citrus aroma packed in 16 oz white HDPE modern round bottle with CRC or 7 mL blue unit-dose cup with peelable HDPE lidding.

Bottle of 473 mL (16 oz) NDC 71656-072-16

5 mL (8 mEq) fill, case of 5 trays x 10s NDC 71656-072-50

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Dispense in a tight, child-resistant container as defined in the USP/NF.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Absorption:

After oral administration, lithium is reported to be completely absorbed in the upper gastrointestinal tract. Peak serum concentrations (Tmax) occur 0.25 hour to 3 hours after oral administration of immediate release preparations and 2 hours to 6 hours after sustained-release preparations.

Distribution:

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 L/kg to 1 L/kg.

Metabolism:

Lithium is not metabolized.

Excretion:

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 hours to 36 hours. Lithium excretion in feces is insignificant.

Specific Populations:

Pediatric Use: A pharmacokinetic study of lithium was performed in 39 subjects with bipolar I disorder. Both apparent clearance and apparent volume of distribution increase as body weight increases. A lower dose in patients < 30 kg is necessary to achieve lithium exposures in pediatric patients similar to those observed in adults treated at recommended doses of lithium [see Dosage and Administration (2.2)]. The estimated plasma clearance was 0.59 L/h, 0.79 L/h and 1.17 L/h for pediatric patients weighing 20 kg, 30 kg and 50 kg, respectively.

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.

14 CLINICAL STUDIES

The safety and efficacy of lithium as a treatment for acute manic or mixed episodes of bipolar I disorder in pediatric patients (ages 7 years to 18 years) was demonstrated in an 8-week, randomized, placebo-controlled, parallel group study (NCT01166425). In this study, 81 patients with a Young Mania Rating Scale (YMRS) score of 20 or more were randomized to receive lithium or placebo in a 2:1 ratio. Patients weighing more than 30 kg started lithium at 300 mg three times daily (900 mg/day) and could increase their dose by 300 mg every 3 days. Patients weighing 20 kg to 30 kg started lithium at 300 mg twice daily (600 mg/day) and could increase their dose by 300 mg weekly. No patients weighing less than 20 kg were enrolled. Lithium (mean serum level 0.98 ± 0.47 mEq/L) was statistically significantly superior to placebo in decreasing acute mania or mixed states as measured by the YMRS (see Table 5).

In a 28-week randomized withdrawal analysis, 31 pediatric patients stabilized on lithium were assigned to either continue lithium or switch to placebo. The group receiving lithium demonstrated superiority to those receiving placebo in all-cause discontinuation (see Table 5).

1. Difference (drug minus placebo) in least-squares mean change from baseline.
2. Patients analyzed by received treatment.
3. Lithium to placebo.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read FDA-approved patient labeling (Medication Guide).

Dosage and Administration:

Advise patients that lithium is a mood stabilizer, and should only be taken as directed. Emphasize the importance of compliance with the prescribed treatment and to not adjust the dose of lithium without first consulting their healthcare provider. Inform patients that they will need to have regular blood draws to determine if their dose of lithium is appropriate.

Instruct patients not to double the dose if a dose is missed, due to the complexity of individualized dosing and potential for lithium toxicity [see Dosage and Administration (2), Warnings and Precautions (5.1)].

Lithium Toxicity:

Inform patients on adverse reactions related to lithium toxicity that require medical attention. Advise patients to discontinue lithium treatment and contact their healthcare provider if clinical signs of lithium toxicity such as diarrhea, vomiting, tremor, lack of muscle coordination, drowsiness, abnormal heart rhythm or muscular weakness occur [see Warnings and Precautions (5.1)].

Lithium-Induced Polyuria:

Counsel patients on the adverse reactions related to lithium-induced polyuria, when to seek medical attention, and the importance of maintaining normal diet with salt and staying hydrated [see Warnings and Precautions (5.2)].

Hyponatremia:

Counsel patients on the adverse reactions of hyponatremia, when to seek medical attention, the importance of maintaining a normal diet including adequate salt intake and staying hydrated [see Warnings and Precautions (5.3)]. Salt supplements and additional fluids may be required if excessive losses occur.

Serotonin Syndrome:

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of lithium with other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.6) and Drug Interactions (7)].

Drug Interactions:

Advise patients that many drugs can interact with lithium and to inform their doctor and pharmacist if they are taking any over the counter medication, including herbal medication, or are started on a new prescription [see Drug Interactions (7)].

Somnolence:

Tell patients that lithium may cause somnolence particularly when initiating treatment and to be cautious about operating vehicles or hazardous machinery, until they are reasonably certain that lithium treatment does not affect them adversely [see Adverse Reactions (6)].

Pregnancy:

Advise pregnant women of the potential risk to a fetus and/or neonate [see Use in Specific Populations (8.1)].

Lactation:

Advise women that breastfeeding is not recommended during treatment with lithium [see Use in Specific Populations (8.2)].

Distributed by:
Saptalis Pharmaceuticals, LLC
Hauppauge, NY 11788

MADE IN USA

October 2023-R1

PPM-0050