Potassium Citrate

1 INDICATIONS AND USAGE

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)]. Potassium Citrate is 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)

• 10 mEq tablets are uncoated, tan to yellowish in color, elliptical shaped, with M10 debossed on one side and blank on the other
• 15 mEq tablets are uncoated, tan to yellowish in color, modified rectangle shaped, with M15 debossed on one side and blank on the other blets: 10 mEq and 15 mEq (3)

Potassium Citrate is contraindicated: In patients with hyperkalemia (or who have conditions pre-disposing 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 to increase urinary citrate may be attenuated by bacterial enzymatic degradation of citrate. Moreover, the rise in urinary pH resulting from Potassium Citrate 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. 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)

5 WARNINGS AND PRECAUTIONS

5.1 Hyperkalemia In patients with impaired mechanisms for excreting potassium, Potassium Citrate administration can produce hyperkalemia and cardiac arrest. Potentially fatal hyperkale- mia can develop rapidly and be asymptomatic. The use of Potassium Citrate in patients with chronic renal failure, or any other condition which impairs potassium excretion such as severe myocardial damage or heart failure, should be avoided. Closely monitor for signs of hyperkalemia with periodic blood tests and ECGs.

5.2 Gastrointestinal Lesions Solid dosage forms of potassium chlorides have produced stenotic and/or ulcerative lesions of the small bowel and deaths. These lesions are caused by a high local concentration of potassium ions in the region of the dissolving tablets, which injured the bowel. In addition, perhaps because wax-matrix preparations are not enteric-coated and release some of their potassium content in the stomach, there have been reports of upper gastrointestinal bleeding associated with these products. The frequency of gastrointestinal lesions with wax-matrix potassium chloride products is estimated at one per 100,000 patient-years. Experience with Potassium Citrate is limited, but a similar frequency of gastrointestinal lesions should be anticipated. If there is severe vomiting, abdominal pain or gastrointestinal bleeding, Potassium Citrate should be discontinued immediately and the possibility of bowel perforation or obstruction investigated. Hyperkalemia: In patients with impaired mechanisms for excreting potassium, Potassium Citrate administration can produce hyperkalemia and cardiac arrest. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Potassium Citrate in patients with chronic renal failure, or any other condition which impairs potassium excretion such as severe myocardial damage or heart failure, should be avoided (5.1) Gastrointestinal lesions: if there is severe vomiting, abdominal pain or gastrointestinal bleeding, Potassium Citrate should be discontinued immediately and the possibility of bowel perforation or obstruction investigated (5.2)

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. 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 contact BioComp Pharma at 1-866-762-2365 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS

7.1 Potential Effects of Potassium Citrate on Other Drugs Potassium-sparing Diuretics: Concomitant administration of Potassium Citrate 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. 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)

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 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 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) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2021

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 should be given to a pregnant woman only if clearly needed. Pregnancy Category C 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 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 should be given to a woman who is breast feeding only if clearly needed.

8.4 Pediatric Use Safety and effectiveness in children have not been established.

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.