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MONOBASIC SODIUM PHOSPHATE AND DIBASIC SODIUM PHOSPHATE — sodium phosphate, monobasic, monohydrate and sodium phosphate, dibasic anhydrous tablet
Novel Laboratories, Inc.

Rx Only

DESCRIPTION

Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablet is a purgative used to clean the colon prior to colonoscopy. Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are manufactured with a highly soluble tablet binder and does not contain microcrystalline cellulose (MCC). Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are white to off-white modified oval shaped, biconvex, bisect on one side and plain on the other debossed “N” on the left side of bisect and “03” on the right side of the bisect. Each Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablet contains 1.102 grams of monobasic sodium phosphate, USP and 0.398 grams of dibasic sodium phosphate, USP for a total of 1.5 grams of sodium phosphate per tablet. Inert ingredients include polyethylene glycol 8000; and magnesium stearate. Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablet is gluten-free.

The structural and molecular formulae and molecular weights of the active ingredients are shown below:

Monobasic sodium phosphate, USP

Molecular Formula: NaH₂ PO₄ • H₂ O

Molecular Weight: 137.99

Dibasic sodium phosphate, USP

Molecular Formula: Na₂ HPO₄

Molecular Weight: 141.96

Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are for oral administration only.

CLINICAL PHARMACOLOGY

Monobasic sodium phosphate and dibasic sodium phosphate tablets, a dosing regimen containing 48 grams of sodium phosphate (32 tablets), induces diarrhea, which effectively cleanses the entire colon. Each administration has a purgative effect for approximately 1 to 3 hours. The primary mode of action is thought to be through the osmotic effect of sodium, causing large amounts of water to be drawn into the colon, promoting evacuation.

Pharmacokinetics

Pharmacokinetic studies with monobasic sodium phosphate and dibasic sodium phosphate tablets have not been conducted. However, the following pharmacokinetic study was conducted with Visicol tablets which contain the same active ingredients (sodium phosphate) as Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets. In addition, Visicol is administered at a dose that is 25% greater than the monobasic sodium phosphate and dibasic sodium phosphate tablets dose.

An open-label pharmacokinetic study of Visicol in healthy volunteers was performed to determine the concentration-time profile of serum inorganic phosphorus levels after Visicol administration. All subjects received the approved Visicol dosing regimen (60 grams of sodium phosphate with a total liquid volume of 3.6 quarts) for colon cleansing. A 30 gram dose (20 tablets given as 3 tablets every 15 minutes with 8 ounces of clear liquids) was given beginning at 6 PM in the evening. The 30 gram dose (20 tablets given as 3 tablets every 15 minutes with 8 ounces of clear liquids) was repeated the following morning beginning at 6 AM.

Twenty-three healthy subjects (mean age 57 years old; 57% male and 43% female; and 65% Hispanic, 30% Caucasian, and 4% African-American) participated in this pharmacokinetic study. The serum phosphorus level rose from a mean (± standard deviation) baseline of 4.0 (± 0.7) mg/dL to 7.7 (± 1.6 mg/dL), at a median of 3 hours after the administration of the first 30 gram dose of sodium phosphate tablets (see Figure 1). The serum phosphorus level rose to a mean of 8.4 (± 1.9) mg/dL, at a median of 4 hours after the administration of the second 30 gram dose of sodium phosphate tablets. The serum phosphorus level remained above baseline for a median of 24 hours after the administration of the initial dose of sodium phosphate tablets (range 16 to 48 hours).

Figure 1. Mean (± standard deviation) serum phosphorus concentrations

(click image for full-size original)

The upper (4.5 mg/dL) and lower (2.6 mg/dL) reference limits for serum phosphate are represented by solid bars.

Special Populations

Renal Insufficiency: The effect of renal dysfunction on the pharmacokinetics of monobasic sodium phosphate and dibasic sodium phosphate tablets has not been studied. Since the inorganic form of phosphate in the circulating plasma is excreted almost entirely by the kidneys, patients with renal disease may have difficulty excreting a large phosphate load. Thus, monobasic sodium phosphate and dibasic sodium phosphate tablets should be used with caution in patients with impaired renal function (see WARNINGS).

Hepatic Insufficiency:

Monobasic sodium phosphate and dibasic sodium phosphate tablets have not been investigated in patients with hepatic failure.

Geriatric:

In a single pharmacokinetic study of sodium phosphate tablets, which included 6 elderly volunteers, plasma half-life increased two-fold in subjects >70 years of age compared to subjects <50 years of age (3 subjects and 5 subjects, respectively).

Gender:

No difference in serum phosphate AUC values were observed in the single pharmacokinetic study conducted with sodium phosphate tablets in 13 male and 10 female healthy volunteers.

CLINICAL STUDIES

The colon-cleansing efficacy and safety of monobasic sodium phosphate and dibasic sodium phosphate tablets was evaluated in 2 randomized, investigator-blinded, actively-controlled, multi center, U.S. trials in patients scheduled to have an elective colonoscopy. The trials consisted of a dose ranging and a confirmatory phase 3 study.

In the phase 3 trial, patients were randomized into one of the following three sodium phosphate treatment groups: 1) Visicol containing 60 grams of sodium phosphate given in split doses (30 grams in the evening before the colonoscopy and 30 grams on the next day) with at least 3.6 quarts of clear liquids; 2) monobasic sodium phosphate and dibasic sodium phosphate tablets containing 60 grams of sodium phosphate given in split doses (30 grams in the evening before the colonoscopy and 30 grams on the next day) with 2.5 quarts of clear liquids; and 3) Monobasic sodium phosphate and dibasic sodium phosphate tablets containing 48 grams of sodium phosphate (30 grams in the evening before the colonoscopy and 18 grams on the next day) with 2 quarts of clear liquids. Patients were instructed to eat a light breakfast before noon on the day prior to the colonoscopy and then were told to drink only clear liquids after noon on the day prior to the colonoscopy.

The primary efficacy endpoint was the overall colon cleansing response rate in the 4-point Colonic Contents Scale. Response was defined as a rating of “excellent” or “good” on the 4-point scale as determined by the blinded colonoscopist. This phase 3 study was planned to assess the non-inferiority of the two monobasic sodium phosphate and dibasic sodium phosphate tablets groups compared to the Visicol group.

The efficacy analysis included 704 adult patients who had an elective colonoscopy. Patients ranged in age from 21 to 89 years old (mean age 56 years old) with 55% female and 45% male patients. Race was distributed as follows: 87% Caucasian, 10% African American, and 3% other race. The monobasic sodium phosphate and dibasic sodium phosphate tablets 60 gram and 48 gram treatment groups demonstrated non-inferiority compared to Visicol. See Table 1 for the results.

¹ Colon-cleansing efficacy was based on response rate to treatment. A patient was considered to be a responder if overall colon cleansing was rated as “excellent” or “good” on a 4-point scale based on the amount of retained “colonic contents”. Excellent was defined as >90% of mucosa seen, mostly liquid stool, minimal suctioning need for adequate visualization. Good was defined as >90% of mucosa seen, mostly liquid stool, significant suctioning needed for adequate visualization. Fair was defined as >90% of mucosa seen, mixture of liquid and semisolid stool, could be suctioned and/or washed. Inadequate was defined as <90% of mucosa seen, mixture of semisolid and/or solid stool which could not be suctioned or washed.

² On the day of the colonoscopy, study medication was taken 3 to 5 hours before the start of the colonoscopy.

Electrolyte Changes

In the monobasic sodium phosphate and dibasic sodium phosphate tablets clinical studies, expected serum electrolyte changes (including phosphate, calcium, potassium, and sodium levels) have been observed in patients taking monobasic sodium phosphate and dibasic sodium phosphate tablets. In the overwhelming majority of patients, electrolyte abnormalities were not associated with any adverse events.

In the monobasic sodium phosphate and dibasic sodium phosphate tablets phase 3 study, 96%, 96%, and 93% of patients who took 60 grams of Visicol, 60 grams of monobasic sodium phosphate and dibasic sodium phosphate tablets, and 48 grams of monobasic sodium phosphate and dibasic sodium phosphate tablets, respectively, developed hyperphosphatemia (defined as phosphate level > 5.1 mg/dL) on the day of the colonoscopy. In this study, patients who took 60 grams of Visicol, 60 grams of monobasic sodium phosphate and dibasic sodium phosphate tablets, and 48 grams of monobasic sodium phosphate and dibasic sodium phosphate tablets had baseline mean phosphate levels of 3.5, 3.5, and 3.6 mg/dL and subsequently developed mean phosphate levels of 7.6, 7.9, and 7.1 mg/dL, respectively, on the day of the colonoscopy.

In the monobasic sodium phosphate and dibasic sodium phosphate tablets phase 3 study, 20%, 22%, and 18% of patients who took 60 grams of Visicol, 60 grams of monobasic sodium phosphate and dibasic sodium phosphate tablets, and 48 grams of monobasic sodium phosphate and dibasic sodium phosphate tablets, respectively, developed hypokalemia (defined as a potassium level <3.4 mEq/L) on the day of the colonoscopy. In this study, patients who took 60 grams of Visicol, 60 grams of monobasic sodium phosphate and dibasic sodium phosphate tablets, and 48 grams of monobasic sodium phosphate and dibasic sodium phosphate tablets all had baseline potassium levels of about 4.3 mEq/L and then developed a mean potassium level of 3.7 mEq/L on the day of the colonoscopy.

In the monobasic sodium phosphate and dibasic sodium phosphate tablets phase 3 trial, several patients on all three sodium phosphate regimens developed hypocalcemia and hypernatremia that did not require treatment.

INDICATIONS AND USAGE

Monobasic Sodium Phosphate and Dibasic Sodium Phosphate Tablets are indicated for cleansing of the colon as a preparation for colonoscopy in adults 18 years of age or older.

CONTRAINDICATIONS

Monobasic sodium phosphate and dibasic sodium phosphate tablets are contraindicated in patients with biopsy-proven acute phosphate nephropathy.

Monobasic sodium phosphate and dibasic sodium phosphate tablets are contraindicated in patients with a known allergy or hypersensitivity to sodium phosphate salts or any of its ingredients.

WARNINGS

Administration of sodium phosphate products prior to colonoscopy for colon cleansing has resulted in fatalities due to significant fluid shifts, severe electrolyte abnormalities, and cardiac arrhythmias. These fatalities have been observed in patients with renal insufficiency, in patients with bowel perforation, and in patients who misused or overdosed sodium phosphate products. It is recommended that patients receiving monobasic sodium phosphate and dibasic sodium phosphate tablets be advised to adequately hydrate before, during, and after the use of monobasic sodium phosphate and dibasic sodium phosphate tablets.

Considerable caution should be advised before monobasic sodium phosphate and dibasic sodium phosphate tablets are used in patients with the following illnesses: severe renal insufficiency (creatinine clearance less than 30 mL/minute), congestive heart failure, ascites, unstable angina, gastric retention, ileus, acute bowel obstruction, pseudo-obstruction of the bowel, severe chronic constipation, bowel perforation, acute colitis, toxic megacolon, gastric bypass or stapling surgery, or hypomotility syndrome.

Consider performing baseline and post-colonoscopy labs (phosphate, calcium, potassium, sodium, creatinine, and BUN) in patients who may be at increased risk for serious adverse events, including those with history of renal insufficiency, history of-or at greater risk of-acute phosphate nephropathy, known or suspected electrolyte disorders, seizures, arrhythmias, cardiomyopathy, prolonged QT, recent history of a MI and those with known or suspected hyperphosphatemia, hypocalcemia, hypokalemia, and hypernatremia. Also if patients develop vomiting and/or signs of dehydration then measure post-colonoscopy labs (phosphate, calcium, potassium, sodium, creatinine, and BUN).

Renal Disease, Acute Phosphate Nephropathy, and Electrolyte Disorders

There have been rare, but serious, reports of renal failure, acute phosphate nephropathy, and nephrocalcinosis in patients who received oral sodium phosphate products (including oral sodium phosphate solutions and tablets) for colon cleansing prior to colonoscopy. These cases often resulted in permanent impairment of renal function and several patients required long-term dialysis. The time to onset is typically within days; however, in some cases, the diagnosis of these events has been delayed up to several months after the ingestion of these products. Patients at increased risk of acute phosphate nephropathy may include patients with the following: hypovolemia, baseline kidney disease, increased age, and patients using medicines that affect renal perfusion or function [such as diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and possibly nonsteroidal anti-inflammatory drugs (NSAIDs).

Use monobasic sodium phosphate and dibasic sodium phosphate tablets with caution in patients with impaired renal function, patients with a history of acute phosphate nephropathy, known or suspected electrolyte disturbances (such as dehydration), or people taking concomitant medications that may affect electrolyte levels (such as diuretics). Patients with electrolyte abnormalities such as hypernatremia, hyperphosphatemia, hypokalemia, or hypocalcemia should have their electrolytes corrected before treatment with monobasic sodium phosphate and dibasic sodium phosphate tablets.

Seizures

There have been rare reports of generalized tonic-clonic seizures and/or loss of consciousness associated with use of sodium phosphate products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of fluid and electrolyte abnormalities. Monobasic sodium phosphate and dibasic sodium phosphate tablets should be used with caution in patients with a history of seizures and in patients at higher risk of seizure [patients using concomitant medications that lower the seizure threshold (such as tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia].

Cardiac Arrhythmias

There have been rare, but serious, reports of arrhythmias associated with the use of sodium phosphate products. Monobasic sodium phosphate and dibasic sodium phosphate tablets should be used with caution in patients with higher risk of arrhythmias (patients with a history of cardiomyopathy, patients with prolonged QT, patients with a history of uncontrolled arrhythmias, and patients with a recent history of a myocardial infarction). Pre-dose and post-colonoscopy ECGs should be considered in patients with high risk of serious, cardiac arrhythmias.