Kloref-S

Betaine Hydrochloride:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Kloref-S (Betaine Hydrochloride) reviews

1 INDICATIONS AND USAGE

Cystadane® (betaine anhydrous for oral solution) is indicated for the treatment of homocystinuria to decrease elevated homocysteine blood levels. Included within the category of homocystinuria are:

• Cystathionine beta-synthase (CBS) deficiency
• 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency
• Cobalamin cofactor metabolism (cbl) defect
  

• Usual dose in adult and pediatric patients is 6 grams per day, administered orally in divided doses of 3 grams two times a day.(2)
• In children less than 3 years of age, may initiate dosing at 100 mg/kg/day, divided in twice daily doses, and then increased weekly by 50 mg/kg increments.(2)
• Dose can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts.(2)
• Monitor patient response by plasma homocysteine levels.(2)
• Prescribed amount of Cystadane should be measured with the measuring scoop provided and then dissolved in 4 to 6 ounces of water, juice, milk, or formula, or mixed with food for immediate ingestion.(2)
  

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

The usual dosage in adult and pediatric patients is 6 grams per day administered orally in divided doses of 3 grams twice daily. In pediatric patients less than 3 years of age, dosage may be started at 100 mg/kg/day divided in twice daily doses, and then increased weekly by 50 mg/kg increments.

Therapy with Cystadane should be directed by physicians knowledgeable in the management of patients with homocystinuria. Patient response to Cystadane can be monitored by homocysteine plasma levels. Dosage in all patients can be gradually increased until plasma total homocysteine is undetectable or present only in small amounts. Response usually occurs within several days and steady state within a month. Plasma methionine concentrations should be monitored in patients with CBS deficiency .

Dosages of up to 20 grams per day have been necessary to control homocysteine levels in some patients. However, one pharmacokinetic and pharmacodynamic in vitro simulation study indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg/kg/day dosage for Cystadane.

2.2 Administration

The prescribed amount of Cystadane should be measured with the measuring scoop provided (one level 1.7 mL scoop is equal to 1 gram of Kloref-S (Betaine Hydrochloride) anhydrous powder) and then dissolved in 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula, or mixed with food for immediate ingestion.

• Powder for oral solution available in bottles containing 180 grams of Kloref-S (Betaine Hydrochloride) anhydrous.(3)
  

3 DOSAGE FORMS AND STRENGTHS

Cystadane is a white, granular, hygroscopic powder for oral solution available in bottles containing 180 grams of Kloref-S (Betaine Hydrochloride) anhydrous.

• None (4)

4 CONTRAINDICATIONS

None.

• Hypermethioninemia: Cystadane may worsen elevated plasma methionine concentrations in patients with CBS deficiency. Cerebral edema has been reported in patients receiving Cystadane.( 5.1)
• Monitoring: Monitor plasma methionine concentrations in patients with CBS deficiency. Keep plasma methionine concentrations below 1,000 µmol/L through dietary medication and, if necessary, a reduction of Cystadane dose. ( 5.1)

5 WARNINGS AND PRECAUTIONS

5.1 Hypermethioninemia

Risk of Hypermethioninemia in Patients with CBS Deficiency

Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may also have elevated plasma methionine concentrations. Treatment with Cystadane may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Cerebral edema has been reported in patients with hypermethioninemia, including patients treated with Cystadane. Plasma methionine concentrations should be monitored in patients with CBS deficiency. Plasma methionine concentrations should be kept below 1,000 µmol/L through dietary modification and, if necessary, a reduction of Cystadane dose.

• Most common adverse reactions (incidence > 2%) were nausea and gastrointestinal distress, based on physician survey.
  

  To report SUSPECTED ADVERSE REACTIONS, contact 877-828-8874, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

6.1 Adverse Reactions in Clinical Studies

The most serious adverse reaction reported with Cystadane treatment is the development of hypermethioninemia and cerebral edema in patients with CBS Deficiency .

The assessment of clinical adverse reactions is based on a survey study of 41 physicians, who treated a total of 111 homocystinuria patients with Cystadane. Adverse reactions were retrospectively recalled and were not collected systematically in this open-label, uncontrolled, physician survey. Thus, this list may not encompass all types of potential adverse reactions, reliably estimate their frequency, or establish a causal relationship to drug exposure. The following adverse reactions were reported (Table 1):

Table 1: Number of Patients with Adverse Reactions to Cystadane by Physician Survey

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Cystadane. 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.

In postmarketing experience with Cystadane, severe cerebral edema and hypermethioninemia have been reported within 2 weeks to 6 months of starting Kloref-S (Betaine Hydrochloride) therapy, with complete recovery after discontinuation of Cystadane. All patients who developed cerebral edema had homocystinuria due to CBS deficiency and had severe elevation in plasma methionine levels (range 1,000 to 3,000 µM). As cerebral edema has also been reported in patients with hypermethioninemia, secondary hypermethioninemia due to Kloref-S (Betaine Hydrochloride) therapy has been postulated as a possible mechanism of action.

The following adverse reactions have been reported in patients during postmarketing use of Cystadane: anorexia, agitation, depression, irritability, personality disorder, sleep disturbed, dental disorders, diarrhea, glossitis, nausea, stomach discomfort, vomiting, hair loss, hives, skin odor abnormalities, and urinary incontinence.

• Pregnancy: Animal reproduction studies have not been conducted with Cystadane. Use only if clearly needed.(8.1)
• Nursing women: It is not known whether Cystadane is excreted in human milk. Use only if clearly needed.(8.3)
• Pediatrics: Pediatric patients ranging in age from 24 days to 17 years have been treated with Cystadane. Children younger than 3 years of age may benefit from dose titration.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with Cystadane. It is also not known whether Cystadane can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cystadane should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether Cystadane is excreted in human milk. Use only if clearly needed.

8.4 Pediatric Use

The majority of case studies of homocystinuria patients treated with Cystadane have been pediatric patients, including patients ranging in age from 24 days to 17 years . Children younger than 3 years of age may benefit from dose titration .

10 OVERDOSAGE

In an acute toxicology study in rats, death occurred frequently at doses equal to or greater than 10 g/kg.

11 DESCRIPTION

Cystadane (betaine anhydrous for oral solution) is an agent for the treatment of homocystinuria. It contains no ingredients other than anhydrous Kloref-S (Betaine Hydrochloride). Cystadane is a white, granular, hygroscopic powder, which is diluted in water and administered orally. The chemical name of Kloref-S (Betaine Hydrochloride) anhydrous powder is trimethylglycine. It has a molecular weight of 117.15. The structural formula is:

Chemical Structure for Kloref-S (Betaine Hydrochloride)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cystadane acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. Cystadane occurs naturally in the body. It is a metabolite of choline and is present in small amounts in foods such as beets, spinach, cereals, and seafood.

12.2 Pharmacodynamics

Cystadane was observed to lower plasma homocysteine levels in three types of homocystinuria, including CBS deficiency; MTHFR deficiency; and cbl defect. Patients have taken Cystadane for many years without evidence of tolerance. There has been no demonstrated correlation between Cystadane levels and homocysteine levels.

In CBS-deficient patients, large increases in methionine levels over baseline have been observed. Cystadane has also been demonstrated to increase low plasma methionine and S-adenosylmethionine levels in patients with MTHFR deficiency and cbl defect.

12.3 Pharmacokinetics

Pharmacokinetic studies of Cystadane are not available. Plasma levels of Cystadane have not been measured in patients and have not been correlated to homocysteine levels.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity and fertility studies have not been conducted with Cystadane. No evidence of genotoxicity was demonstrated in the following tests: metaphase analysis of human lymphocytes; bacterial reverse mutation assay; and mouse micronucleus test.

14 CLINICAL STUDIES

Cystadane was studied in a double-blind, placebo-controlled, crossover study in 6 patients with CBS deficiency, ages 7 to 32 years at enrollment. Cystadane was administered at a dosage of 3 grams twice daily, for 12 months. Plasma homocystine levels were significantly reduced (p<0.01) compared to placebo. Plasma methionine levels were variable and not significantly different compared to placebo. No adverse events were reported in any patient.

Cystadane has also been evaluated in observational studies without concurrent controls in patients with homocystinuria due to CBS deficiency, MTHFR deficiency, or cbl defect. A review of 16 case studies and the randomized controlled trial previously described was also conducted, and the data available for each study were summarized; however, no formal statistical analyses were performed. The studies included a total of 78 male and female patients with homocystinuria who were treated with Cystadane. This included 48 patients with CBS deficiency, 13 with MTHFR deficiency, and 11 with cbl defect, ranging in age from 24 days to 53 years. The majority of patients (n=48) received 6 gm/day, 3 patients received less than 6 gm/day, 12 patients received doses from 6 to 15 gm/day, and 5 patients received doses over 15 gm/day. Most patients were treated for more than 3 months (n=57) and 30 patients were treated for 1 year or longer (range 1 month to 11 years). Homocystine is formed nonenzymatically from two molecules of homocysteine, and both have be used to evaluate the effect of Cystadane in patients with homocystinuria. Plasma homocystine or homocysteine levels were reported numerically for 62 patients, and 61 of these patients showed decreases with Cystadane treatment. Homocystine decreased by 83-88% regardless of pre-treatment level, and homocysteine decreased by 71-83%, regardless of the pre-treatment level. Clinical improvement, such as improvement in seizures, or behavioral and cognitive functioning, was reported by the treating physicians in about three-fourths of patients. Many of these patients were also taking other therapies such as vitamin B6 (pyridoxine), vitamin B12 (cobalamin), and folate with variable biochemical responses. In most cases, adding Cystadane resulted in a further reduction of either homocystine or homocysteine.

16 HOW SUPPLIED/STORAGE AND HANDLING

Cystadane is available in plastic bottles containing 180 grams of Kloref-S anhydrous. Each bottle is equipped with a plastic child-resistant cap and is supplied with a polystyrene measuring scoop. One level scoop (1.7 mL) is equal to 1 gram of Kloref-S (Betaine Hydrochloride) anhydrous powder.

NDC 66621-4000-1 180 g/bottle

Cystadane can be ordered by calling AnovoRx Group, LLC, Customer service at 1-888-487-4703

16.1 Storage

Store at room temperature, 15 – 30 ˚C (59 – 86 ˚F). Protect from moisture.

17 PATIENT COUNSELING INFORMATION

Patients should be advised of the following information before beginning treatment with Cystadane:

17.1 Dosing and Administration

• Instruct patients and caregivers that Cystadane should only be taken as directed by their healthcare professional.
• Instruct patients and caregivers to administer Cystadane as follows:
• Shake bottle lightly before removing cap.

- Measure with the scoop provided.

- Measure the number of scoops as prescribed by their healthcare professional. One level scoop (1.7 mL) is equivalent to 1 gram of Kloref-S (Betaine Hydrochloride) anhydrous powder.

- Mix powder with 4 to 6 ounces (120 to 180 mL) of water, juice, milk, or formula until completely dissolved, or mix with food, then ingest mixture immediately.

- Always replace the cap tightly after using, and protect powder from moisture.

Manufactured For:

Rare Disease Therapeutics, Inc.

Franklin, TN 37067

Under License From:

Orphan Europe, s.a.r.l. Puteaux France

Distributed By:

AnovoRx Distribution, LLC

Memphis, TN 38134

Part No.: RDT C PI007

Part No.: Orphan Europe OEP 829

Cystadane (betaine anhydrous) for oral solution

Potassium Bicarbonate:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Kloref-S (Potassium Bicarbonate) reviews

Kloref-S (Potassium Bicarbonate) CHLORIDE EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Kloref-S (Potassium Bicarbonate) chloride containing 1500 mg of microencapsulated Kloref-S (Potassium Bicarbonate) chloride, USP equivalent to 20 mEq of Kloref-S (Potassium Bicarbonate) in a tablet.

These formulations are intended to slow the release of Kloref-S (Potassium Bicarbonate) so that the likelihood of a high localized concentration of Kloref-S (Potassium Bicarbonate) chloride within the gastrointestinal tract is reduced.

Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Kloref-S (Potassium Bicarbonate) chloride, and the structural formula is KCl. Kloref-S (Potassium Bicarbonate) chloride, USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Kloref-S (Potassium Bicarbonate) chloride crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Kloref-S (Potassium Bicarbonate) chloride.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The Kloref-S (Potassium Bicarbonate) ion is the principal intracellular cation of most body tissues. Kloref-S (Potassium Bicarbonate) ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of Kloref-S (Potassium Bicarbonate) is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Kloref-S (Potassium Bicarbonate) is a normal dietary constituent and under steady-state conditions the amount of Kloref-S (Potassium Bicarbonate) absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of Kloref-S (Potassium Bicarbonate) is 50 to 100 mEq per day.

Kloref-S (Potassium Bicarbonate) depletion will occur whenever the rate of Kloref-S (Potassium Bicarbonate) loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of Kloref-S (Potassium Bicarbonate) intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of Kloref-S (Potassium Bicarbonate) in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Kloref-S (Potassium Bicarbonate) depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Kloref-S (Potassium Bicarbonate) depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If Kloref-S (Potassium Bicarbonate) depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental Kloref-S (Potassium Bicarbonate) in the form of high Kloref-S (Potassium Bicarbonate) food or Kloref-S (Potassium Bicarbonate) chloride may be able to restore normal Kloref-S (Potassium Bicarbonate) levels.

In rare circumstances (eg, patients with renal tubular acidosis) Kloref-S (Potassium Bicarbonate) depletion may be associated with metabolic acidosis and hyperchloremia. In such patients Kloref-S (Potassium Bicarbonate) replacement should be accomplished with Kloref-S (Potassium Bicarbonate) salts other than the chloride, such as Kloref-S (Potassium Bicarbonate) bicarbonate, Kloref-S (Potassium Bicarbonate) citrate, Kloref-S (Potassium Bicarbonate) acetate, or Kloref-S (Potassium Bicarbonate) gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Kloref-S (Potassium Bicarbonate) CHLORIDE PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT Kloref-S (Potassium Bicarbonate) PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of Kloref-S (Potassium Bicarbonate) salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum Kloref-S (Potassium Bicarbonate) should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with Kloref-S (Potassium Bicarbonate) salts may be indicated.

CONTRAINDICATIONS

Kloref-S (Potassium Bicarbonate) supplements are contraindicated in patients with hyperkalemia since a further increase in serum Kloref-S (Potassium Bicarbonate) concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of Kloref-S (Potassium Bicarbonate) chloride have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Kloref-S (Potassium Bicarbonate) supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Kloref-S (Potassium Bicarbonate) Chloride (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Kloref-S (Potassium Bicarbonate) chloride are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting Kloref-S (Potassium Bicarbonate), the administration of Kloref-S (Potassium Bicarbonate) salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given Kloref-S (Potassium Bicarbonate) by the intravenous route but may also occur in patients given Kloref-S (Potassium Bicarbonate) orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of Kloref-S (Potassium Bicarbonate) salts in patients with chronic renal disease, or any other condition which impairs Kloref-S (Potassium Bicarbonate) excretion, requires particularly careful monitoring of the serum Kloref-S (Potassium Bicarbonate) concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of Kloref-S (Potassium Bicarbonate) salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some Kloref-S (Potassium Bicarbonate) retention by inhibiting aldosterone production. Kloref-S (Potassium Bicarbonate) supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Kloref-S (Potassium Bicarbonate) chloride can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Kloref-S (Potassium Bicarbonate) chloride are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Kloref-S (Potassium Bicarbonate) chloride and thus to minimize the possibility of a high local concentration of Kloref-S (Potassium Bicarbonate) near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Kloref-S (Potassium Bicarbonate) chloride therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Kloref-S (Potassium Bicarbonate) chloride administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Kloref-S (Potassium Bicarbonate) chloride products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing Kloref-S (Potassium Bicarbonate) salt such as Kloref-S (Potassium Bicarbonate) bicarbonate, Kloref-S (Potassium Bicarbonate) citrate, Kloref-S (Potassium Bicarbonate) acetate, or Kloref-S (Potassium Bicarbonate) gluconate.

PRECAUTIONS

General

The diagnosis of Kloref-S depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for Kloref-S (Potassium Bicarbonate) depletion. In interpreting the serum Kloref-S (Potassium Bicarbonate) level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body Kloref-S (Potassium Bicarbonate) while acute acidosis per se can increase the serum Kloref-S (Potassium Bicarbonate) concentration into the normal range even in the presence of a reduced total body Kloref-S (Potassium Bicarbonate). The treatment of Kloref-S (Potassium Bicarbonate) depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Kloref-S (Potassium Bicarbonate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma Kloref-S it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (see WARNINGS ).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Kloref-S is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq. It is unlikely that Kloref-S (Potassium Bicarbonate) supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal Kloref-S ion content of human milk is about 13 mEq per liter. Since oral Kloref-S (Potassium Bicarbonate) becomes part of the body Kloref-S (Potassium Bicarbonate) pool, so long as body Kloref-S (Potassium Bicarbonate) is not excessive, the contribution of Kloref-S (Potassium Bicarbonate) chloride supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Kloref-S (Potassium Bicarbonate) Chloride 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 responses 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 drug therapy.

This drug is known to be substantially excreted by the kidney, 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.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral Kloref-S (Potassium Bicarbonate) salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral Kloref-S (Potassium Bicarbonate) salts to persons with normal excretory mechanisms for Kloref-S (Potassium Bicarbonate) rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if Kloref-S (Potassium Bicarbonate) is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum Kloref-S (Potassium Bicarbonate) concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing Kloref-S (Potassium Bicarbonate) and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum Kloref-S (Potassium Bicarbonate) concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of Kloref-S (Potassium Bicarbonate) by the average adult is 50 to 100 mEq per day. Kloref-S (Potassium Bicarbonate) depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of Kloref-S (Potassium Bicarbonate) from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of Kloref-S (Potassium Bicarbonate) depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablet USP, 20 mEq provides 20 mEq of Kloref-S (Potassium Bicarbonate) chloride.

Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Kloref-S (Potassium Bicarbonate) Chloride that is not taken immediately should be discarded. The use of other liquids for suspending Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Kloref-S (Potassium Bicarbonate) Chloride Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Kloref-S (Potassium Bicarbonate) chloride 20 Meq

Potassium Chloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Kloref-S (Potassium Chloride) reviews

Kloref-S (Potassium Chloride) EXTENDED RELEASE TABLETS USP 20 mEq K

Rx Only

DESCRIPTION

The Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq product is an immediately dispersing extended release oral dosage form of Kloref-S (Potassium Chloride) containing 1500 mg of microencapsulated Kloref-S (Potassium Chloride), USP equivalent to 20 mEq of potassium in a tablet.

These formulations are intended to slow the release of potassium so that the likelihood of a high localized concentration of Kloref-S (Potassium Chloride) within the gastrointestinal tract is reduced.

Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq is an electrolyte replenisher. The chemical name of the active ingredient is Kloref-S (Potassium Chloride), and the structural formula is KCl. Kloref-S (Potassium Chloride), USP occurs as a white, granular powder or as colorless crystals. It is odorless and has a saline taste. Its solutions are neutral to litmus. It is freely soluble in water and insoluble in alcohol.

Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulation (not enteric coated or wax matrix) containing individually microencapsulated Kloref-S (Potassium Chloride) crystals which disperse upon tablet disintegration. In simulated gastric fluid at 37°C and in the absence of outside agitation, Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq begin disintegrating into microencapsulated crystals within seconds and completely disintegrates within 1 minute. The microencapsulated crystals are formulated to provide an extended release of Kloref-S (Potassium Chloride).

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, diethyl phthalate, ethyl-cellulose, microcrystalline cellulose.

CLINICAL PHARMACOLOGY

The potassium ion is the principal intracellular cation of most body tissues. Potassium ions participate in a number of essential physiological processes including the maintenance of intracellular tonicity; the transmission of nerve impulses; the contraction of cardiac, skeletal, and smooth muscle; and the maintenance of normal renal function.

The intracellular concentration of potassium is approximately 150 to 160 mEq per liter. The normal adult plasma concentration is 3.5 to 5 mEq per liter. An active ion transport system maintains this gradient across the plasma membrane.

Potassium is a normal dietary constituent and under steady-state conditions the amount of potassium absorbed from the gastrointestinal tract is equal to the amount excreted in the urine. The usual dietary intake of potassium is 50 to 100 mEq per day.

Potassium depletion will occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually develops as a consequence of therapy with diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, or inadequate replacement of potassium in patients on prolonged parenteral nutrition. Depletion can develop rapidly with severe diarrhea, especially if associated with vomiting. Potassium depletion due to these causes is usually accompanied by a concomitant loss of chloride and is manifested by hypokalemia and metabolic alkalosis. Potassium depletion may produce weakness, fatigue, disturbances or cardiac rhythm (primarily ectopic beats), prominent U-waves in the electrocardiogram, and in advanced cases, flaccid paralysis and/or impaired ability to concentrate urine.

If potassium depletion associated with metabolic alkalosis cannot be managed by correcting the fundamental cause of the deficiency, eg, where the patient requires long-term diuretic therapy, supplemental potassium in the form of high potassium food or Kloref-S (Potassium Chloride) may be able to restore normal potassium levels.

In rare circumstances (eg, patients with renal tubular acidosis) potassium depletion may be associated with metabolic acidosis and hyperchloremia. In such patients potassium replacement should be accomplished with potassium salts other than the chloride, such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

INDICATIONS AND USAGE

BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEDING WITH CONTROLLED-RELEASE Kloref-S (Potassium Chloride) PREPARATIONS, THESE DRUGS SHOULD BE RESERVED FOR THOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TO TAKE LIQUID OR EFFERVESCENT POTASSIUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WITH THESE PREPARATIONS.

1. For the treatment of patients with hypokalemia with or without metabolic alkalosis, in digitalis intoxication, and in patients with hypokalemic familial periodic paralysis. If hypokalemia is the result of diuretic therapy, consideration should be given to the use of a lower dose of diuretic, which may be sufficient without leading to hypokalemia.

2. For the prevention of hypokalemia in patients who would be at particular risk if hypokalemia were to develop, eg, digitalized patients or patients with significant cardiac arrhythmias.

The use of potassium salts in patients receiving diuretics for uncomplicated essential hypertension is often unnecessary when such patients have a normal dietary pattern and when low doses of the diuretic are used. Serum potassium should be checked periodically, however, and if hypokalemia occurs, dietary supplementation with potassium-containing foods may be adequate to control milder cases. In more severe cases, and if dose adjustment of the diuretic is ineffective or unwarranted, supplementation with potassium salts may be indicated.

CONTRAINDICATIONS

Potassium supplements are contraindicated in patients with hyperkalemia since a further increase in serum potassium concentration in such patients can produce cardiac arrest. Hyperkalemia may complicate any of the following conditions: chronic renal failure, systemic acidosis, such as diabetic acidosis, acute dehydration, extensive tissue breakdown as in severe burns, adrenal insufficiency, or the administration of a potassium-sparing diuretic (eg, spironolactone, triamterene, amiloride) (see OVERDOSAGE ).

Controlled-release formulations of Kloref-S (Potassium Chloride) have produced esophageal ulceration in certain cardiac patients with esophageal compression due to enlarged left atrium. Potassium supplementation, when indicated in such patients, should be given as a liquid preparation or as an aqueous (water) suspension of Kloref-S (Potassium Chloride) (see PRECAUTIONS: Information for Patients , and DOSAGE AND ADMINISTRATION sections).

All solid oral dosage forms of Kloref-S (Potassium Chloride) are contraindicated in any patient in whom there is structural, pathological (eg, diabetic gastroparesis), or pharmacologic (use of anticholinergic agents or other agents with anticholinergic properties at sufficient doses to exert anticholinergic effects) cause for arrest or delay in tablet passage through the gastrointestinal tract.

WARNINGS

Hyperkalemia (see OVERDOSAGE )

In patients with impaired mechanisms for excreting potassium, the administration of potassium salts can produce hyperkalemia and cardiac arrest. This occurs most commonly in patients given potassium by the intravenous route but may also occur in patients given potassium orally. Potentially fatal hyperkalemia can develop rapidly and be asymptomatic. The use of potassium salts in patients with chronic renal disease, or any other condition which impairs potassium excretion, requires particularly careful monitoring of the serum potassium concentration and appropriate dosage adjustment.

Interaction with Potassium-Sparing Diuretics

Hypokalemia should not be treated by the concomitant administration of potassium salts and a potassium-sparing diuretic (eg, spironolactone, triamterene, or amiloride) since the simultaneous administration of these agents can produce severe hyperkalemia.

Interaction with Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors (eg, captopril, enalapril) will produce some potassium retention by inhibiting aldosterone production. Potassium supplements should be given to patients receiving ACE inhibitors only with close monitoring.

Gastrointestinal Lesions

Solid oral dosage forms of Kloref-S (Potassium Chloride) can produce ulcerative and/or stenotic lesions of the gastrointestinal tract. Based on spontaneous adverse reaction reports, enteric-coated preparations of Kloref-S (Potassium Chloride) are associated with an increased frequency of small bowel lesions (40-50 per 100,000 patient years) compared to sustained release wax matrix formulations (less than one per 100,000 patient years). Because of the lack of extensive marketing experience with microencapsulated products, a comparison between such products and wax matrix or enteric-coated products is not available. Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq is a tablet formulated to provide a controlled rate of release of microencapsulated Kloref-S (Potassium Chloride) and thus to minimize the possibility of a high local concentration of potassium near the gastrointestinal wall.

Prospective trials have been conducted in normal human volunteers in which the upper gastrointestinal tract was evaluated by endoscopic inspection before and after 1 week of solid oral Kloref-S (Potassium Chloride) therapy. The ability of this model to predict events occurring in usual clinical practice is unknown. Trials which approximated usual clinical practice did not reveal any clear differences between the wax matrix and microencapsulated dosage forms. In contrast, there was a higher incidence of gastric and duodenal lesions in subjects receiving a high dose of a wax matrix controlled-release formulation under conditions which did not resemble usual or recommended clinical practice (ie, 96 mEq per day in divided doses of Kloref-S (Potassium Chloride) administered to fasted patients, in the presence of an anticholinergic drug to delay gastric emptying). The upper gastrointestinal lesions observed by endoscopy were asymptomatic and were not accompanied by evidence of bleeding (Hemoccult testing). The relevance of these findings to the usual conditions (ie, non-fasting, no anticholinergic agent, smaller doses) under which controlled-release Kloref-S (Potassium Chloride) products are used is uncertain; epidemiologic studies have not identified an elevated risk, compared to microencapsulated products, for upper gastrointestinal lesions in patients receiving wax matrix formulations. Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq should be discontinued immediately and the possibility of ulceration, obstruction, or perforation should be considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleeding occurs.

Metabolic Acidosis

Hypokalemia in patients with metabolic acidosis should be treated with an alkalinizing potassium salt such as potassium bicarbonate, potassium citrate, potassium acetate, or potassium gluconate.

PRECAUTIONS

General

The diagnosis of potassium depletion is ordinarily made by demonstrating hypokalemia in a patient with a clinical history suggesting some cause for potassium depletion. In interpreting the serum potassium level, the physician should bear in mind that acute alkalosis per se can produce hypokalemia in the absence of a deficit in total body potassium while acute acidosis per se can increase the serum potassium concentration into the normal range even in the presence of a reduced total body potassium. The treatment of potassium depletion, particularly in the presence of cardiac disease, renal disease, or acidosis requires careful attention to acid-base balance and appropriate monitoring of serum electrolytes, the electrocardiogram, and the clinical status of the patient.

Information for Patients

Physicians should consider reminding the patient of the following: To take each dose with meals and with a full glass of water or other liquid. To take each dose without crushing, chewing, or sucking the tablets. If those patients are having difficulty swallowing whole tablets, they may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous suspension as follows:
  

  1. Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  

  2. Allow approximately 2 minutes for the tablet(s) to disintegrate.
  

  3. Stir for about half a minute after the tablet(s) has disintegrated.
  

  4. Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  

  5. Add another 1 fluid ounce of water, swirl, and consume immediately.
  

  6. Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Kloref-S (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

To take this medicine following the frequency and amount prescribed by the physician. This is especially important if the patient is also taking diuretics and/or digitalis preparations.

To check with the physician at once if tarry stools or other evidence of gastrointestinal bleeding is noticed.

Laboratory Tests

When blood is drawn for analysis of plasma potassium it is important to recognize that artifactual elevations can occur after improper venipuncture technique or as a result of in vitro hemolysis of the sample.

Drug Interactions

Potassium-sparing diuretics, angiotensin-converting enzyme inhibitors.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, mutagenicity, and fertility studies in animals have not been performed. Potassium is a normal dietary constituent.

Pregnancy Category C

Animal reproduction studies have not been conducted with Kloref-S Extended Release Tablets USP, 20 mEq. It is unlikely that potassium supplementation that does not lead to hyperkalemia would have an adverse effect on the fetus or would affect reproductive capacity.

Nursing Mothers

The normal potassium ion content of human milk is about 13 mEq per liter. Since oral potassium becomes part of the body potassium pool, so long as body potassium is not excessive, the contribution of Kloref-S (Potassium Chloride) supplementation should have little or no effect on the level in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Kloref-S (Potassium Chloride) 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 responses 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 drug therapy.

This drug is known to be substantially excreted by the kidney, 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.

ADVERSE REACTIONS

One of the most severe adverse effects is hyperkalemia (see CONTRAINDICATIONS , WARNINGS , and OVERDOSAGE ). There have also been reports of upper and lower gastrointestinal conditions including obstruction, bleeding, ulceration, and perforation (see CONTRAINDICATIONS and WARNINGS ). The most common adverse reactions to oral potassium salts are nausea, vomiting, flatulence, abdominal pain/discomfort, and diarrhea. These symptoms are due to irritation of the gastrointestinal tract and are best managed by diluting the preparation further, taking the dose with meals or reducing the amount taken at one time.

OVERDOSAGE

The administration of oral potassium salts to persons with normal excretory mechanisms for potassium rarely causes serious hyperkalemia. However, if excretory mechanisms are impaired or if potassium is administered too rapidly intravenously, potentially fatal hyperkalemia can result (see CONTRAINDICATIONS and WARNINGS ). It is important to recognize that hyperkalemia is usually asymptomatic and may be manifested only by an increased serum potassium concentration (6.5-8.0 mEq/L) and characteristic electrocardiographic changes (peaking of T-waves, loss of P-waves, depression of S-T segment, and prolongation of the QT-interval). Late manifestations include muscle paralysis and cardiovascular collapse from cardiac arrest (9-12 mEq/L).

Treatment measures for hyperkalemia include the following:

• Patients should be closely monitored for arrhythmias and electrolyte changes.
• Elimination of foods and medications containing potassium and of any agents with potassium-sparing properties such as potassium-sparing diuretics, ARBS, ACE inhibitors, NSAIDS, certain nutritional supplements and many others.
• Intravenous calcium gluconate if the patient is at no risk of developing digitalis toxicity.
• Intravenous administration of 300 to 500 mL/hr of 10% dextrose solution containing 10-20 units of crystalline insulin per 1,000 mL.
• Correction of acidosis, if present, with intravenous sodium bicarbonate.
• Use of exchange resins, hemodialysis, or peritoneal dialysis.

In treating hyperkalemia, it should be recalled that in patients who have been stabilized on digitalis, too rapid a lowering of the serum potassium concentration can produce digitalis toxicity.

The extended release feature means that absorption and toxic effects may be delayed for hours.

Consider standard measures to remove any unabsorbed drug.

DOSAGE AND ADMINISTRATION

The usual dietary intake of potassium by the average adult is 50 to 100 mEq per day. Potassium depletion sufficient to cause hypokalemia usually requires the loss of 200 or more mEq of potassium from the total body store.

Dosage must be adjusted to the individual needs of each patient. The dose for the prevention of hypokalemia is typically in the range of 20 mEq per day. Doses of 40-100 mEq per day or more are used for the treatment of potassium depletion. Dosage should be divided if more than 20 mEq per day is given such that no more than 20 mEq is given in a single dose.

Each Kloref-S (Potassium Chloride) Extended Release Tablet USP, 20 mEq provides 20 mEq of Kloref-S (Potassium Chloride).

Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq should be taken with meals and with a glass of water or other liquid. This product should not be taken on an empty stomach because of its potential for gastric irritation (see WARNINGS ).

Patients having difficulty swallowing whole tablets may try one of the following alternate methods of administration:

• Break the tablet in half, and take each half separately with a glass of water.
• Prepare an aqueous (water) suspension as follows:
  • Place the whole tablet(s) in approximately 1/2 glass of water (4 fluid ounces).
  • Allow approximately 2 minutes for the tablet(s) to disintegrate.
  • Stir for about half a minute after the tablet(s) has disintegrated.
  • Swirl the suspension and consume the entire contents of the glass immediately by drinking or by the use of a straw.
  • Add another 1 fluid ounce of water, swirl, and consume immediately.
  • Then, add an additional 1 fluid ounce of water, swirl, and consume immediately.

Aqueous suspension of Kloref-S (Potassium Chloride) that is not taken immediately should be discarded. The use of other liquids for suspending Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq is not recommended.

HOW SUPPLIED

Kloref-S (Potassium Chloride) Extended Release Tablets USP, 20 mEq are available in bottles of 100 (NDC 62037-999-01), bottles of 500 (NDC 62037-999-05), and bottles of 1000 (NDC 62037-999-10). Potassium Chloride Extended Release Tablets USP, 20 mEq are capsule shaped, white to off-white tablets, with “ABRS-123” imprinted on one side and scored on the other side for flexibility of dosing.

Storage Conditions

Keep tightly closed. Store at controlled room temperature, 20°-25°C (68°-77°F).

Manufactured by:

Eurand, Inc.

Vandalia, OH 45377 USA

Distributed by:

Watson Pharma, Inc.

Rev. Date (01/09) 173714

Kloref-S (Potassium Chloride) 20 Meq