Potassium Citrate

1 INDICATIONS AND USAGE Potassium Citrate Extended-Release Tablets are a citrate salt of potassium indicated for the management of: • Renal tubular acidosis (RTA) with calcium stones ( 1.1 ) • Hypocitraturic calcium oxalate nephrolithiasis of any etiology ( 1.2 ) • Uric acid lithiasis with or without calcium stones ( 1.3 ) 1.1 Renal Tubular Acidosis (RTA) with Calcium Stones Potassium citrate is indicated for the management of renal tubular acidosis [see Clinical Studies ( 14.1 )] . 1.2 Hypocitraturic Calcium Oxalate Nephrolithiasis of any Etiology Potassium citrate is indicated for the management of hypocitraturic calcium oxalate nephrolithiasis [see Clinical Studies ( 14.2 )] . 1.3 Uric Acid Lithiasis with or without Calcium Stones Potassium citrate is indicated for the management of uric acid lithiasis with or without calcium stones [see Clinical Studies ( 14.3 )] .

2 DOSAGE AND ADMINISTRATION Objective: To restore normal urinary citrate (greater than 320 mg/day and as close to the normal mean of 640 mg/day as possible), and to increase urinary pH to a level of 6.0 to 7.0. Severe hypocitraturia (urinary citrate 150 mg/day): therapy should be initiated at 30 mEq per day; a dose of 15 mEq two times per day or 10 mEq three times per day with meals or within 30 minutes after meals or bedtime snack ( 2.3 ) 2.1 Dosing Instructions Treatment with extended release potassium citrate should be added to a regimen that limits salt intake (avoidance of foods with high salt content and of added salt at the table) and encourages high fluid intake (urine volume should be at least two liters per day). The objective of treatment with Potassium Citrate extended-release tablets is to provide Potassium Citrate extended-release tablets in sufficient dosage to restore normal urinary citrate (greater than 320 mg/day and as close to the normal mean of 640 mg/day as possible), and to increase urinary pH to a level of 6.0 or 7.0. Monitor serum electrolytes (sodium, potassium, chloride and carbon dioxide), serum creatinine and complete blood counts every four months and more frequently in patients with cardiac disease, renal disease or acidosis. Perform electrocardiograms periodically. Treatment should be discontinued if there is hyperkalemia, a significant rise in serum creatinine or a significant fall in blood hematocrit or hemoglobin. 2.2 Severe Hypocitraturia In patients with severe hypocitraturia (urinary citrate 150 mg/day) therapy should be initiated at 30 mEq/day (15 mEq two times/day or 10 mEq three times/day with meals or within 30 minutes after meals or bedtime snack). Twenty-four hour urinary citrate and/or urinary pH measurements should be used to determine the adequacy of the initial dosage and to evaluate the effectiveness of any dosage change. Doses of Potassium Citrate extended-release tablets greater than 100 mEq/day have not been studied and should be avoided.

3 DOSAGE FORMS AND STRENGTHS 5 mEq tablets are tan to yellowish, speckled, uncoated, round shaped tablets, debossed with “A67” on one side and plain on the other side. 10 mEq tablets are tan to yellowish, speckled, uncoated, modified capsule shaped tablets, debossed with “A94” on one side and plain on the other side. 15 mEq tablets are tan to yellowish, speckled, uncoated, modified oval shaped tablets, debossed with “A96” on one side and plain on the other side. Tablets: 5 mEq, 10 mEq and 15 mEq ( 3 )

4 CONTRAINDICATIONS Patients with hyperkalemia (or who have conditions predisposing them to hyperkalemia). Such conditions include chronic renal failure, uncontrolled diabetes mellitus, acute dehydration, strenuous physical exercise in unconditioned individuals, adrenal insufficiency, extensive tissue breakdown (4) Patients for whom there is cause for arrest or delay in tablet passage through the gastrointestinal tract such as those suffering from delayed gastric emptying, esophageal compression, intestinal obstruction or stricture (4) Patients with peptic ulcer disease (4) Patients with active urinary tract infection (4) Patients with renal insufficiency (glomerular filtration rate of less than 0.7 ml/kg/min) (4) Potassium citrate extended-release tablets are contraindicated: In patients with hyperkalemia (or who have conditions predisposing them to hyperkalemia), as a further rise in serum potassium concentration may produce cardiac arrest. Such conditions include: chronic renal failure, uncontrolled diabetes mellitus, acute dehydration, strenuous physical exercise in unconditioned individuals, adrenal insufficiency, extensive tissue breakdown or the administration of a potassium-sparing agent (such as triamterene, spironolactone or amiloride). In patients in whom there is cause for arrest or delay in tablet passage through the gastrointestinal tract, such as those suffering from delayed gastric emptying, esophageal compression, intestinal obstruction or stricture, or those taking anticholinergic medication. In patients with peptic ulcer disease because of its ulcerogenic potential. In patients with active urinary tract infection (with either urea-splitting or other organisms, in association with either calcium or struvite stones). The ability of potassium citrate extended-release tablet to increase urinary citrate may be attenuated by bacterial enzymatic degradation of citrate. Moreover, the rise in urinary pH resulting from potassium citrate extended-release tablet therapy might promote further bacterial growth. In patients with renal insufficiency (glomerular filtration rate of less than 0.7 ml/kg/min), because of the danger of soft tissue calcification and increased risk for the development of hyperkalemia.

6 ADVERSE REACTIONS Some patients may develop minor gastrointestinal complaints such as abdominal discomfort, vomiting, diarrhea, loose bowel movements or nausea. These may be alleviated by taking the dose with meals or snacks or by reducing the dosage (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Postmarketing Experience Some patients may develop minor gastrointestinal complaints during potassium citrate therapy, such as abdominal discomfort, vomiting, diarrhea, loose bowel movements or nausea. These symptoms are due to the irritation of the gastrointestinal tract, and may be alleviated by taking the dose with meals or snacks, or by reducing the dosage. Patients may find intact matrices in their feces.

7 DRUG INTERACTIONS The following drug interactions may occur with potassium citrate: • Potassium-sparing diuretics: concomitant administration should be avoided since the simultaneous administration of these agents can produce severe hyperkalemia ( 7.1 ) • Drugs that slow gastrointestinal transit time: These agents (such as anticholinergics) can be expected to increase the gastrointestinal irritation produced by potassium salts ( 7.2 ) • Renin-angiotensin-aldosterone inhibitors: Monitor for hyperkalemia ( 7.3 ) • Nonsteroidal anti-inflammatory drugs (NSAIDs): Monitor for hyperkalemia ( 7.4 ) 7.1 Potential Effects of Potassium Citrate on Other Drugs Potassium-sparing Diuretics: Concomitant administration of potassium citrate extended-release tablets and a potassium-sparing diuretic (such as triamterene, spironolactone or amiloride) should be avoided since the simultaneous administration of these agents can produce severe hyperkalemia. 7.2 Potential Effects of Other Drugs on Potassium Citrate Drugs that slow gastrointestinal transit time: These agents (such as anticholinergics) can be expected to increase the gastrointestinal irritation produced by potassium salts. 7.3 Renin-Angiotensin-Aldosterone System Inhibitors Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), spironolactone, eplerenone, or aliskiren produce potassium retention by inhibiting aldosterone production. Closely monitor potassium in patients receiving concomitant RAAS therapy. 7.4 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) NSAIDs may produce potassium retention by reducing renal synthesis of prostagladin E and impairing the renin-angiotensin system. Closely monitor potassium in patients on concomitant NSAIDs.

8 USE IN SPECIFIC POPULATIONS • Pregnant women: Animal reproduction studies have not been conducted. It is not known whether potassium citrate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium citrate extended-release tablets should be given to a pregnant woman only if clearly needed ( 8.1 ) • Nursing mothers: The normal potassium ion content of human milk is about 13 mEq/L. It is not known if potassium citrate has an effect on this content. Potassium citrate extended-release tablets should be given to a woman who is breastfeeding only if clearly needed ( 8.3 ) • Pediatric Use: Safety and effectiveness in children have not been established ( 8.4 ) 8.1 Pregnancy Animal reproduction studies have not been conducted. It is also not known whether potassium citrate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Potassium citrate extended-release tablets should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers The normal potassium ion content of human milk is about 13 mEq/L. It is not known if potassium citrate has an effect on this content. Potassium citrate extended-release tablets should be given to a woman who is breastfeeding only if clearly needed. 8.4 Pediatric Use Safety and effectiveness in children have not been established.

12.1 Mechanism of Action When potassium citrate is given orally, the metabolism of absorbed citrate produces an alkaline load. The induced alkaline load in turn increases urinary pH and raises urinary citrate by augmenting citrate clearance without measurably altering ultrafilterable serum citrate. Thus, potassium citrate therapy appears to increase urinary citrate principally by modifying the renal handling of citrate, rather than by increasing the filtered load of citrate. The increased filtered load of citrate may play some role, however, as in small comparisons of oral citrate and oral bicarbonate, citrate had a greater effect on urinary citrate. In addition to raising urinary pH and citrate, potassium citrate increases urinary potassium by approximately the amount contained in the medication. In some patients, potassium citrate causes a transient reduction in urinary calcium. The changes induced by potassium citrate produce urine that is less conducive to the crystallization of stone-forming salts (calcium oxalate, calcium phosphate and uric acid). Increased citrate in the urine, by complexing with calcium, decreases calcium ion activity and thus the saturation of calcium oxalate. Citrate also inhibits the spontaneous nucleation of calcium oxalate and calcium phosphate (brushite). The increase in urinary pH also decreases calcium ion activity by increasing calcium complexation to dissociated anions. The rise in urinary pH also increases the ionization of uric acid to the more soluble urate ion. Potassium citrate therapy does not alter the urinary saturation of calcium phosphate, since the effect of increased citrate complexation of calcium is opposed by the rise in pH-dependent dissociation of phosphate. Calcium phosphate stones are more stable in alkaline urine. In the setting of normal renal function, the rise in urinary citrate following a single dose begins by the first hour and lasts for 12 hours. With multiple doses the rise in citrate excretion reaches its peak by the third day and averts the normally wide circadian fluctuation in urinary citrate, thus maintaining urinary citrate at a higher, more constant level throughout the day. When the treatment is withdrawn, urinary citrate begins to decline toward the pre-treatment level on the first day. The rise in citrate excretion is directly dependent on the potassium citrate dosage. Following long-term treatment, potassium citrate at a dosage of 60 mEq/day raises urinary citrate by approximately 400 mg/day and increases urinary pH by approximately 0.7 units. In patients with severe renal tubular acidosis or chronic diarrheal syndrome where urinary citrate may be very low (<100 mg/day), potassium citrate may be relatively ineffective in raising urinary citrate. A higher dose of potassium citrate may therefore be required to produce a satisfactory citraturic response. In patients with renal tubular acidosis in whom urinary pH may be high, potassium citrate produces a relatively small rise in urinary pH.

11 DESCRIPTION Potassium citrate is a citrate salt of potassium. Its molecular formula is K 3 C 6 H 5 O 7 • H 2 O, and it has the following chemical structure: Potassium citrate, USP is a transparent crystals or white, granular powder. It is freely soluble in water and slightly soluble in alcohol. Potassium citrate extended-release tablets, USP intended for oral administration, each contains 5 mEq (540 mg), 10 mEq (1,080 mg) or 15 mEq (1,620 mg) of potassium citrate, USP as monohydrate. In addition, each tablet contains the following inactive ingredients: carnauba wax and magnesium stearate. Meets USP Dissolution Test 2 Potassium citrate

10 OVERDOSAGE Treatment of Overdosage : The administration of potassium salts to persons without predisposing conditions for hyperkalemia rarely causes serious hyperkalemia at recommended dosages. It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration and characteristic electrocardiographic changes (peaking of T-wave, loss of P-wave, depression of S-T segment and prolongation of the QT interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest. Treatment measures for hyperkalemia include the following: 1. Patients should be closely monitored for arrhythmias and electrolyte changes. 2. Elimination of medications containing potassium and of agents with potassium-sparing properties such as potassium-sparing diuretics, ARBs, ACE inhibitors, NSAIDs, certain nutritional supplements and many others. 3. Elimination of foods containing high levels of potassium such as almonds, apricots, bananas, beans (lima, pinto, white), cantaloupe, carrot juice (canned), figs, grapefruit juice, halibut, milk, oat bran, potato (with skin), salmon, spinach, tuna and many others. 4. Intravenous calcium gluconate if the patient is at no risk or low risk of developing digitalis toxicity. 5. Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10 to 20 units of crystalline insulin per 1,000 mL. 6. Correction of acidosis, if present, with intravenous sodium bicarbonate. 7. Hemodialysis or peritoneal dialysis. 8. Exchange resins may be used. However, this measure alone is not sufficient for the acute treatment of hyperkalemia. Lowering potassium levels too rapidly in patients taking digitalis can produce digitalis toxicity.

16 HOW SUPPLIED/STORAGE AND HANDLING Potassium Citrate Extended-release Tablets USP, 5 mEq are tan to yellowish color, round shaped, biconvex uncoated tablets debossed with "536" on one side and plain on the other side and are supplied as follows: NDC 65841-536-06 in bottle of 30 tablets with child-resistant closure NDC 65841-536-16 in bottle of 90 tablets with child-resistant closure NDC 65841-536-01 in bottle of 100 tablets with child-resistant closure NDC 65841-536-05 in bottle of 500 tablets NDC 65841-536-10 in bottle of 1,000 tablets NDC 65841-536-30 in unit-dose blister cartons of 100 (10×10) unit dose tablets Potassium Citrate Extended-release Tablets USP, 10 mEq are tan to yellowish color, oval shaped, biconvex uncoated tablets debossed with "537" on one side and plain on the other side and are supplied as follows: NDC 65841-537-06 in bottle of 30 tablets with child-resistant closure NDC 65841-537-16 in bottle of 90 tablets with child-resistant closure NDC 65841-537-01 in bottle of 100 tablets with child-resistant closure NDC 65841-537-05 in bottle of 500 tablets NDC 65841-537-10 in bottle of 1,000 tablets NDC 65841-537-30 in unit-dose blister cartons of 100 (10×10) unit dose tablets Potassium Citrate Extended-release Tablets USP, 15 mEq are tan to yellowish color, oblong shaped, biconvex uncoated tablets debossed with "538" on one side and plain on the other side and are supplied as follows: NDC 65841-538-06 in bottle of 30 tablets with child-resistant closure NDC 65841-538-16 in bottle of 90 tablets with child-resistant closure NDC 65841-538-01 in bottle of 100 tablets with child-resistant closure NDC 65841-538-05 in bottle of 500 tablets NDC 65841-538-10 in bottle of 1,000 tablets NDC 65841-538-30 in unit-dose blister cartons of 100 (10×10) unit dose tablets Storage: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP.