POTASSIUM CITRATE- potassium citrate tablet
Upsher-Smith Laboratories, Inc.
POTASSIUM CITRATE- potassium citrate tablet
Upsher-Smith Laboratories, Inc.
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)].
2 DOSAGE AND ADMINISTRATION
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 hemocrit or hemoglobin.
3 DOSAGE FORMS AND STRENGTHS
5 mEq tablets are uncoated, modified ball-shaped, and tan to yellowish in color. Each 5 mEq tablet is debossed with "USL" on one side and "070? on the other side.
10 mEq tablets are uncoated, elliptical-shaped, and tan to yellowish in color. Each 10 mEq tablet is debossed with "USL" on one side and "071? on the other side.
CONTRAINDICATIONS
Potassium Citrate Extended-release Tablets are 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 Extended-release Tablets 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 Tablets 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.
5 WARNINGS AND PRECAUTIONS
5.1 Hyperkalemia
In patients with impaired mechanisms for excreting potassium, Potassium Citrate Extended-release Tablets administration can produce hyperkalemia and cardiac arrest. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Potassium Citrate Extended-release Tablets 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
Because of reports of upper gastrointestinal mucosal lesions following administration of potassium chloride (wax-matrix), an endoscopic examination of the upper gastrointestinal mucosa was performed in 30 normal volunteers after they had taken glycopyrrolate 2 mg p.o. t.i.d., Potassium Citrate Extended-release Tablets 95 mEq/day, wax-matrix potassium chloride 96 mEq/day or wax-matrix placebo, in thrice daily schedule in the fasting state for one week. Potassium Citrate Extended-release Tablets and the wax-matrix formulation of potassium chloride were indistinguishable but both were significantly more irritating than the wax-matrix placebo. In a subsequent, similar study, lesions were less severe when glycopyrrolate was omitted.
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 Extended-release Tablets is limited, but a similar frequency of gastrointestinal lesions should be anticipated.
If there is severe vomiting, abdominal pain or gastrointestinal bleeding, Potassium Citrate Extended-release Tablets should be discontinued immediately and the possibility of bowel perforation or obstruction investigated.
DESCRIPTION
Potassium citrate is a citrate salt of potassium. Its empirical formula is K3 C6 H5 O7 � H2 O,
Potassium Citrate Extended-release Tablets are yellowish to tan, oral wax-matrix tablets, containing either 5 mEq (540 mg) potassium citrate or 10 mEq (1080 mg) potassium citrate each. Inactive ingredients include carnauba wax and magnesium stearate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
When Potassium Citrate Extended-release Tablets are 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 Extended-release Tablets 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 Extended-release Tablets increase urinary potassium by approximately the amount contained in the medication. In some patients, Potassium Citrate Extended-release Tablets cause a transient reduction in urinary calcium.
The changes induced by Potassium Citrate Extended-release Tablets 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 Extended-release Tablets 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 Extended-release Tablets dosage. Following long-term treatment, Potassium Citrate Extended-release Tablets 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 Extended-release Tablets may be relatively ineffective in raising urinary citrate. A higher dose of Potassium Citrate Extended-release Tablets 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 Extended-release Tablets produce a relatively small rise in urinary pH.
Uric acid lithiasis with or without calcium stones
A long-term non-randomized, non-placebo controlled clinical trial with eighteen adult patients with uric acid lithiasis participated in the study. Six patients formed only uric acid stones, and the remaining 12 patients formed mixed stones containing both uric acid and calcium salts or formed both uric acid stones (without calcium salts) and calcium stones (without uric acid) on separate occasions. Eleven of the 18 patients received potassium citrate alone. Six of the 7 other patients also received allopurinol for hyperuricemia with gouty arthritis, symptomatic hyperuricemia, or hyperuricosuria. One patient also received hydrochlorothiazide because of unclassified hypercalciuria. The main inclusion criterion was a history of stone passage or surgical removal of stones during the 3 years prior to initiation of potassium citrate therapy. All patients received potassium citrate at a dosage of 30-80 mEq/day in three-to-four divided doses and were followed every four months for up to 5 years.
While on potassium citrate treatment, urinary pH rose significantly from a low value of 5.3 � 0.3 to within normal limits (6.2 to 6.5). Urinary citrate which was low before treatment rose to the high normal range and only one stone was formed in the entire group of 18 patients.
