Lithium

Yes

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• acetazolamide (Diamox)
• aminophylline
• angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril, lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik)
• angiotensin II receptor antagonists such as candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), olmesartan (Benicar), telmisartan (Micardis), and valsartan (Diovan)
• antacids such as sodium bicarbonate
• caffeine (found in certain medications to treat drowsiness and headaches)
• calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor, Tiazac, others), felodipine (Plendil), isradipine (DynaCirc), nicardipine (Cardene), nifedipine (Adalat, Procardia), nimodipine (Nymalize), nisoldipine (Sular), and verapamil (Calan, Covera, Verelan)
• carbamazepine (Tegretol)
• medications for mental illness such as haloperidol (Haldol)
• methyldopa (Aldomet)
• metronidazole (Flagyl)
• nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib (Celebrex), indomethacin (Indocin), and piroxicam (Feldene)
• potassium iodide
• selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft)
• theophylline (Theolair, Theochron)

This is not a complete list of lithium drug interactions. Ask your doctor or pharmacist for more information.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of lithium, there are no specific foods that you must exclude from your diet when receiving this medication.

However, it is important to follow a proper diet while taking lithium. This includes adequate amounts of salt and liquids in your diet. Ask your doctor about the diet that is right for you. Also talk to your doctor about drinking drinks that contain caffeine while taking lithium.

In the U.S.

• Eskalith
• Eskalith-CR
• Lithobid

Available Dosage Forms:

• Capsule
• Solution
• Syrup
• Tablet, Extended Release
• Tablet

Therapeutic Class: Nutriceutical

Take lithium exactly as directed by your doctor. Do not take more or less of it, do not take it more or less often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

You might have to take lithium for several weeks before you begin to feel better. Talk to your doctor if you have any questions.

Make sure that your doctor knows if you are on a low-sodium or low-salt diet. Too little salt in your diet could lead to serious side effects.

Talk to your doctor about the correct amount of fluid to take with lithium. Some people need to drink extra fluid every day with the lithium.

Swallow the extended-release tablet whole. Do not break, crush, or chew it.

Measure the oral solution with a marked measuring spoon, oral syringe, or medicine cup. A regular teaspoon may not measure the correct amount of medicine.

There are several different forms of lithium. The dose for each is different and they are used at different times of the day. Do not change the type of medicine you take without talking to your doctor first.

In order for lithium to work properly, it must be taken every day in regularly spaced doses as ordered by your doctor. This is necessary to keep a constant amount of lithium in your blood. To help keep the amount constant, do not miss any doses and do not stop taking the medicine even if you feel better.

Use only the brand of lithium that your doctor prescribed. Different brands may not work the same way.

Dosing

The dose of lithium will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of lithium. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (capsules, solution, and tablets):
  • For acute mania:
    • Adults—600 milligrams (mg) or 10 milliliters (mL) three times a day. Your doctor may adjust your dose if needed.
    • Children—Use and dose must be determined by your doctor.
  • For long-term treatment of mania:
    • Adults—300 milligrams (mg) or 5 milliliters (mL) three or four times a day. Your doctor may adjust your dose if needed.
    • Children—Use and dose must be determined by your doctor.

• For oral dosage form (extended-release tablets):
  • For acute mania:
    • Adults—900 milligrams (mg) two times a day, or 600 mg three times a day.
    • Teenagers and children 12 years of age—Use and dose must be determined by your doctor.
    • Children younger than 12 years of age—Use is not recommended.
  • For long-term treatment of mania:
    • Adults—600 milligrams (mg) two times a day, or three times a day up to 1200 mg per day.
    • Teenagers and children 12 years of age—Use and dose must be determined by your doctor.
    • Children younger than 12 years of age—Use is not recommended.

Missed Dose

If you miss a dose of lithium, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Confusion, poor memory, or lack of awareness
• fainting
• fast or slow heartbeat
• frequent urination
• increased thirst
• irregular pulse
• stiffness of the arms or legs
• troubled breathing (especially during hard work or exercise)
• unusual tiredness or weakness
• weight gain

• Blue color and pain in the fingers and toes
• coldness of the arms and legs
• dizziness
• eye pain
• headache
• noise in the ears
• vision problems

• Dry, rough skin
• fast, irregular, pounding, or racing heartbeat or pulse
• hair loss
• hoarseness
• lightheadedness
• mental depression
• sensitivity to cold
• shortness of breath
• swelling of the feet or lower legs
• swelling of the neck
• unusual excitement

Get emergency help immediately if any of the following symptoms of overdose occur:

• Blurred vision
• clumsiness or unsteadiness
• convulsions (seizures)
• diarrhea
• drowsiness
• increase in the amount of urine
• lack of coordination
• loss of appetite
• muscle weakness
• nausea or vomiting
• ringing in the ears
• slurred speech
• trembling (severe)

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acne or skin rash
• bloated feeling or pressure in the stomach
• muscle twitching (slight)

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Acute Lithium Toxicity

The toxic concentrations for Lithium (≥1.5 mEq/L) are close to the therapeutic range (0.8 to 1.2mEq/L). Some patients abnormally sensitive to Lithium may exhibit toxic signs at serum concentrations that are considered within the therapeutic range [see Boxed Warning, Dosage and Administration (2.6)]. Lithium may take up to 24 hours to distribute into brain tissue, so occurrence of acute toxicity symptoms may be delayed.

Diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination may be early signs of Lithium toxicity, and can occur at Lithium concentrations below 2.0 mEq/L. At higher concentrations, giddiness, ataxia, blurred vision, tinnitus and a large output of dilute urine may be seen. Serum Lithium concentrations above 3.0 mEq/L may produce a complex clinical picture involving multiple organs and organ systems, coma, and eventually death. Serum Lithium concentrations should not be permitted to exceed 2.0 mEq/L.

Neurological signs of Lithium toxicity range from mild neurological adverse reactions such as fine tremor, lightheadedness, and weakness; to moderate manifestations like apathy, drowsiness, hyperreflexia, muscle twitching, and slurred speech; and severe manifestations such as clonus, confusion, seizure, coma and death. Cardiac manifestations involve electrocardiographic changes, such as prolonged QT interval, ST and T-wave changes and myocarditis. Renal manifestations include urine concentrating defect, nephrogenic diabetes insipidus, and renal failure. Respiratory manifestations include dyspnea, aspiration pneumonia, and respiratory failure. Gastrointestinal manifestations include nausea, vomiting, and bloating. No specific antidote for Lithium poisoning is known. Early symptoms of Lithium toxicity can usually be treated by reduction or cessation of Lithium, before restarting treatment at a lower dose 24 to 48 hours later [see Overdosage (10)].

The risk of acute toxicity is increased with a recent onset of concurrent illness or with the concomitant administration of drugs which increase Lithium serum concentrations by pharmacokinetic interactions [see Drug Interactions (7)]. Additional risk factors for acute Lithium toxicity include acute ingestion, age-related decline in renal function, volume depletion and/or changes in electrolyte concentrations, especially sodium and potassium. Dose requirements during the acute manic phase are higher to maintain therapeutic serum concentrations and decrease when manic symptoms subside. The risk of Lithium toxicity is very high in patients with significant renal or cardiovascular disease, severe debilitation or dehydration, or sodium depletion, and for patients receiving prescribed medications that may affect kidney function, such as angiotensin converting enzyme inhibitors (ACE inhibitors), diuretics (loops and thiazides) and NSAIDs. For these patients, consider starting with lower doses and titrating slowly while frequently monitoring serum Lithium concentrations and signs of Lithium toxicity.

To reduce the risk of acute Lithium toxicity during treatment initiation, facilities for prompt and accurate serum Lithium determinations should be available before initiating treatment [seeBoxed Warning, Dosage and Administration (2.6)]. Advise patients and caregivers to watch for signs of early toxicity and to discontinue Lithium and immediately inform their health care provider if they occur.

Lithium-Induced Polyuria

Chronic Lithium treatment may be associated with diminution of renal concentrating ability, occasionally presenting as nephrogenic diabetes insipidus, with polyuria and polydipsia. The concentrating defect and natriuretic effect characteristic of this condition may develop within weeks of Lithium initiation. Lithium can also cause renal tubular acidosis, resulting in hyperchloremic metabolic acidosis. Such patients should be carefully managed to avoid dehydration with resulting Lithium retention and toxicity. This condition is usually reversible when Lithium is discontinued, although for patients treated with long-term Lithium, nephrogenic diabetes insipidus may be only partly reversible upon discontinuation of Lithium. Amiloride may be considered as a therapeutic agent for Lithium-induced nephrogenic diabetes insipidus.

Hyponatremia

Lithium can cause hyponatremia by decreasing sodium reabsorption by the renal tubules, leading to sodium depletion. Therefore, it is essential for patients receiving Lithium treatment to maintain a normal diet, including salt, and an adequate fluid intake (2500 to 3000 mL) at least during the initial stabilization period. Decreased tolerance to Lithium has also been reported to ensue from protracted 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 medication.

Symptoms are also more severe with faster-onset hyponatremia. Mild hyponatremia (i.e., serum Na > 120 mEq/L) can be asymptomatic. Below this threshold, clinical signs are usually present, consisting mainly of changes in mental status, such as altered personality, lethargy, and confusion. For more severe hyponatremia (serum Na < 115 mEq/L), stupor, neuromuscular hyperexcitability, hyperreflexia, seizures, coma, and death can result. During treatment of hyponatremia, serum sodium should not be elevated by more than 10 to 12 meq/L in 24 hours, or 18 meq/L in 48 hours. In the case of severe hyponatremia where severe neurologic symptoms are present, a faster infusion rate to correct serum sodium concentration may be needed. Patients rapidly treated or with serum sodium <120mEq/L are more at risk of developing osmotic demyelination syndrome (previously called central pontine myelinolysis). Occurrence is more common among patients with alcoholism, undernutrition, or other chronic debilitating illness. Common signs include flaccid paralysis, dysarthria. In severe cases with extended lesions patients may develop a locked-in syndrome (generalized motor paralysis). Damage often is permanent. If neurologic symptoms start to develop during treatment of hyponatremia, serum sodium correction should be suspended to mitigate the development of permanent neurologic damage.

Lithium-Induced Chronic Kidney Disease

The predominant form of chronic renal disease associated with long-term Lithium treatment is a chronic tubulointerstitial nephropathy (CTIN). The biopsy findings in patients with Lithium induced CTIN include tubular atrophy, interstitial fibrosis, sclerotic glomeruli, tubular dilation, and nephron atrophy with cyst formation. The relationship between renal function and morphologic changes and their association with Lithium treatment has not been established. CTIN patients might present with nephrotic proteinuria (>3.0g/dL), worsening renal insufficiency and/or nephrogenic diabetes insipidus. Postmarketing cases consistent with nephrotic syndrome in patients with or without CTIN have also been reported. The biopsy findings in patients with nephrotic syndrome include minimal change disease and focal segmental glomerulosclerosis. The discontinuation of Lithium in patients with nephrotic syndrome has resulted in remission of nephrotic syndrome.

Kidney function should be assessed prior to and during Lithium treatment. Routine urinalysis and other tests may be used to evaluate tubular function (e.g., urine specific gravity or osmolality following a period of water deprivation, or 24-hour urine volume) and glomerular function (e.g., serum creatinine, creatinine clearance, or proteinuria). During Lithium treatment, progressive or sudden changes in renal function, even within the normal range, indicate the need for re-evaluation of treatment.

Encephalopathic Syndrome

An encephalopathic syndrome, characterized by weakness, lethargy, fever, tremulousness and confusion,extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN and fasting blood glucose, has occurred in patients treated with Lithium and an antipsychotic. In some instances, the syndrome was followed by irreversible brain damage. Because of a possible causal relationship between these events and the concomitant administration of Lithium and antipsychotics, patients receiving such combined treatment should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear. This encephalopathic syndrome may be similar to or the same as neuroleptic malignant syndrome (NMS).

Serotonin Syndrome

Lithium can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, triptans, tricyclic antidepressants, fentanyl, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Drug Interactions (7.1)].

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Monitor all patients taking Lithium for the emergence of serotonin syndrome. Discontinue treatment with Lithium and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Lithium with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

Hypothyroidism or Hyperthyroidism

Lithium is concentrated within the thyroid and can inhibit thyroid synthesis and release which can lead to hypothyroidism. Where hypothyroidism exists, careful monitoring of thyroid function during Lithium stabilization and maintenance allows for correction of changing thyroid parameters, if any. Where hypothyroidism occurs during Lithium stabilization and maintenance, supplemental thyroid treatment may be used. Paradoxically, some cases of hyperthyroidism have been reported including Grave’s disease, toxic multinodular goiter and silent thyroiditis.

Monitor thyroid function before the initiation of treatment, at three months and every six to twelve months while treatment is ongoing. If serum thyroid tests warrant concern, monitoring should occur more frequently.

Hypercalcemia and Hyperparathyroidism

Long-term Lithium treatment is associated with persistent hyperparathyroidism and hypercalcemia. When clinical manifestations of hypercalcemia are present, Lithium withdrawal and change to another mood stabilizer may be necessary. Hypercalcemia may not resolve upon discontinuation of Lithium, and may require surgical intervention. Lithium-induced cases of hyperparathyroidism are more often multiglandular compared to standard cases. False hypercalcemia due to plasma volume depletion resulting from nephrogenic diabetes insipidus should be excluded in individuals with mildly increased serum calcium. Monitor serum calcium concentrations regularly.

Unmasking of Brugada Syndrome

There have been postmarketing reports of a possible association between treatment with Lithium and the unmasking of Brugada Syndrome. Brugada Syndrome is a disorder characterized by abnormal electrocardiographic (ECG) findings and a risk of sudden death. Lithium should be avoided in patients with Brugada Syndrome or those suspected of having Brugada Syndrome. Consultation with a cardiologist is recommended if: (1) treatment with Lithium is under consideration for patients suspected of having Brugada Syndrome or patients who have risk factors for Brugada Syndrome, e.g., unexplained syncope, a family history of Brugada Syndrome, or a family history of sudden unexplained death before the age of 45 years, (2) patients who develop unexplained syncope or palpitations after starting Lithium treatment.

Pseudotumor Cerebri

Cases of pseudotumor cerebri (increased intracranial pressure and papilledema) have been reported with Lithium use. If undetected, this condition may result in enlargement of the blind spot, constriction of visual fields and eventual blindness due to optic atrophy. Consider discontinuing Lithium if this syndrome occurs.

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

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, generalizedpruritus with or without rash, cutaneous ulcers, angioedema.

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.

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).

Absorption

Rapid and complete

Distribution

Vd: Initial: 0.307 L/kg; Vdss: 0.7 to 1 L/kg; decreased in elderly patients (Ward 1994)

Metabolism

Not metabolized (Ward 1994)

Excretion

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

Clearance: 80% of filtered lithium is reabsorbed in the proximal convoluted tubules; decreased in elderly patients secondary to age-related decreases in renal function (Ward 1994)

Time to Peak

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

Half-Life Elimination

Pediatric patients 7 to 17 years: t1/2 (beta): 27 hours (Findling 2010)

Adults: 18 to 36 hours; prolonged in elderly patients (28.5 hours) (Ward 1994)

Protein Binding

Not protein bound (Ward 1994)

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.

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).

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Taking lithium can make it easier for you to become dehydrated, especially if you have any vomiting or diarrhea, if you are outdoors in the sun, or if you exercise vigorously or sweat more than usual. Dehydration can increase some of the side effects of lithium.

Call your doctor if you have are sick with a fever and vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking lithium, which may affect your dose needs. Do not change your dose or medication schedule without your doctor's advice.

Drink extra fluids each day to prevent dehydration.

It may take up to 3 weeks before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not begin to improve after 1 week of treatment.

If you need surgery, tell the surgeon ahead of time that you are using lithium.

While using lithium, you may need frequent blood tests.

Store at room temperature away from moisture and heat. Keep the bottle tightly closed when not in use.