2.1 Dosage Regimen

The recommended dosage of ColPrep Kit is one bottle administered in the evening before colonoscopy and the second bottle administered the morning of colonoscopy as follows:
Dose 1: Early in the evening prior to colonoscopy, 10 to 12 hours before the second dose.
Dose 2: The morning of colonoscopy, at least 3 ½ hours before colonoscopy.

2.2 Important Dosing Instructions

• ColPrep Kit must be reconstituted and diluted in water prior to ingestion. Direct ingestion of the undiluted reconstituted solution may increase the risk of nausea, vomiting, and dehydration [See Warnings and Precautions (5.8)] .
• The ColPrep Kit is comprised of two bottles of ColPrep administered as a two-day regimen. Both doses of ColPrep Kit are required for a complete preparation for colonoscopy.
• Additional fluids must be consumed after each dose of ColPrep [See Dosage and Administration (2.4)] .
• Do not take other laxatives while taking ColPrep Kit.

2.3 Instructions for Use

Dose 1 - On the day before colonoscopy (start 10 to 12 hours prior to Dose 2):

• A light breakfast may be consumed in the morning.
• Only clear liquids may be consumed for the rest of the day after a light breakfast. Do not drink milk.
• Do not eat solid foods for the rest of the day after breakfast until the next day after colonoscopy.
• Do not eat or drink anything colored red or purple.
• Do not drink alcohol.
• Do not take oral medications within one hour of starting the first dose of ColPrep Kit.

Dose 2 - Next morning on the day of colonoscopy (start at least 3 ½ hours prior to colonoscopy):

• Continue to abstain from all solid food and anything to drink other than clear liquids.
• Do not take oral medications within one hour of starting the second dose of ColPrep Kit.
• Complete all ColPrep Kit and required water at least 2 hours prior to colonoscopy or as directed by physician.
• Stop drinking clear liquids at least 2 hours before colonoscopy.

2.4 Preparation and Administration

Two doses of ColPrep Kit are required for a complete preparation for colonoscopy as a split-dose (two-day regimen). The total volume of liquid required is approximately 2.8 L taken orally prior to the colonoscopy, as described below.
Dose 1: Early in the evening prior to colonoscopy, 10 to 12 hours before Dose 2:

1. Open ONE (1) bottle from the ColPrep Kit.
2. Fill the bottle with water up to the neck of the bottle. Shake well and mix thoroughly.
3. Pour the reconstituted solution from the bottle into the mixing container provided.
4. Fill the mixing container with water to the 16 ounce fill line.
5. Drink the entire amount.
6. Important: Drink two additional mixing containers filled to the 16 ounce fill line with water over the next hour (32 ounces of additional water).

Dose 2: The morning of colonoscopy, at least 3 ½ hours before colonoscopy:

1. Repeat Steps 1 through 6 from Dose 1 of the Split-Dose (2-Day Regimen).
2. Complete all ColPrep Kit solution and required water at least two hours prior to colonoscopy.

5.1 Serious Fluid and Serum Chemistry Abnormalities

Advise all patients to hydrate adequately before, during, and after the use of ColPrep Kit. If a patient develops significant vomiting or signs of dehydration after taking ColPrep Kit, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN). Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias, seizures and renal impairment.

Patients with electrolyte abnormalities should have them corrected before treatment with ColPrep Kit. In addition, use caution when prescribing ColPrep Kit for patients with conditions, or who are using medications, that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and renal impairment. [See Drug Interactions (7.1)]

ColPrep Kit can cause temporary elevations in uric acid. [See Adverse Reactions (6.1)] . Uric acid fluctuations in patients with gout may precipitate an acute flare. The potential for uric acid elevation should be considered before administering ColPrep Kit to patients with gout or other disorders of uric acid metabolism.

5.2 Cardiac Arrhythmias

There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing ColPrep Kit for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy ECGs should be considered in patients at increased risk of serious cardiac arrhythmias.

5.3 Seizures

There have been reports of generalized tonic-clonic seizures and/or loss of consciousness associated with use of bowel preparation 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.

Use caution when prescribing ColPrep Kit for patients with a history of seizures and in patients at increased risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia.

5.4 Renal Impairment

Use caution when prescribing ColPrep Kit for patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inflammatory drugs). Advise these patients of the importance of adequate hydration, and consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

5.5 Colonic Mucosal Ulcerations and Ischemic Colitis

Administration of osmotic laxative products may produce colonic mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of stimulant laxatives and ColPrep Kit may increase these risks. The potential for mucosal ulcerations resulting from the bowel preparation should be considered when interpreting colonoscopy findings in patients with known or suspect inflammatory bowel disease (IBD).

5.6 Use in Patients with Significant Gastrointestinal Disease

If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering ColPrep Kit.
Use with caution in patients with severe active ulcerative colitis.

5.7 Aspiration

Use with caution in patients with impaired gag reflex and patients prone to regurgitation or aspiration. Such patients should be observed during administration of ColPrep Kit.

5.8 Not for Direct Ingestion

Each bottle must be reconstituted followed by dilution with water to a final volume of 16 ounces and ingestion of 32 ounces of additional water as recommended is important to patient tolerance. Direct ingestion of the undiluted solution may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances.

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice.
The safety of ColPrep Kit has been established from adequate and well-controlled trials of another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) [See Clinical Studies (14)] . Below is a display of the adverse reactions of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) in these adequate and well-controlled studies.
In a multicenter, controlled clinical trial comparing another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) with a bowel prep containing polyethylene glycol and electrolytes (PEG + E) that were administered in a split-dose (2-day) regimen, the most common adverse reactions after administration of another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) were overall discomfort, abdominal distention, abdominal pain, nausea, vomiting, and headache; See Table 1, below.
Less common adverse reactions occurring were atrioventricular (AV) block (1 case) and creatine kinase (CK) increase. In this study, patients receiving another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) were limited to a light breakfast followed by clear liquids; patients receiving the PEG + E bowel prep were allowed to have a normal breakfast and a light lunch, followed by clear liquids.

Table 2 shows the percentages of patients who developed new abnormalities of important electrolytes and uric acid after completing the bowel preparation with either another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g)or PEG+E administered as a split-dose (2-day) regimen.

There were also 408 patients who participated in a study in which another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) or PEG+E were administered in an evening-only (1-day) regimen. Higher rates of overall discomfort, abdominal distention, and nausea were observed with the evening-only (1- day) regimen compared to the split-dose (2-day) regimen for both preparations. Patients treated with another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) had increased rates of vomiting with the evening-only (1- day) regimen. An evening-only (1-day) dosing regimen was associated with higher rates of abnormal values for some electrolytes when compared to the split-dose (2-day) regimen for both preparations. For another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g), the evening only (1-day) regimen was associated with higher rates of total bilirubin (high), BUN (high), creatinine (high), osmolality (high), potassium (high) and uric acid (high) than the split dose (2-day) regimen. Administration of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) in an evening-only (1-day) dosing regimen is not recommended.

7.1 Drugs That May Increase Risks Due to Fluid and Electrolyte Abnormalities

Use caution when prescribing ColPrep Kit for patients with conditions, or who are using medications, that increase the risk for fluid and electrolyte disturbances or may increase the risk of adverse events of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. Consider additional patient evaluations as appropriate [See Warnings (5)] in patients taking these concomitant medications.

7.2 Potential for Altered Drug Absorption

Oral medication administered within one hour of the start of each ColPrep Kit dose may be flushed from the gastrointestinal tract, and the medication may not be absorbed properly.

8.1 Pregnancy

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

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ColPrep Kit is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of ColPrep Kit have not been established in pediatric patients.

8.5 Geriatric Use

Of the 375 patients who received another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) in clinical trials, 94 (25%) were 65 years of age or older, and 25 (7%) were 75 years of age or older. No overall differences in safety or effectiveness of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) administered as a split-dose (2-day) regimen were observed between geriatric patients and younger patients. Geriatric patients reported more vomiting when sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) was given as a one- day preparation.

12.1 Mechanism of Action

Sulfate salts provide sulfate anions, which are poorly absorbed. The osmotic effect of unabsorbed sulfate anions and the associated cations causes water to be retained within the gastrointestinal tract.

12.2 Pharmacodynamics

The osmotic effect of the unabsorbed ions, when ingested with a large volume of water, produces a copious watery diarrhea.

12.3 Pharmacokinetics

Absorption
After administration of another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) in six healthy subjects, the time at which serum sulfate reached its highest point (T max) was approximately 17 hours after the first half dose or approximately 5 hours after the second dose.

Elimination
Serum sulfate concentrations declined with a half-life of 8.5 hours. The mean sulfate levels returned to baseline level by Day 6 after dose initiation. Fecal excretion was the primary route of sulfate elimination in healthy subjects.

Specific Populations
Hepatic and Renal Impairment

The disposition of sulfate after administration of another oral formulation of sodium sulfate (17.5 g), potassium sulfate (3.13 g), and magnesium sulfate (1.6 g) was studied in patients (N=6) with mild-moderate hepatic impairment (Child-Pugh grades A and B) and in patients (N=6) with moderate renal impairment (creatinine clearance of 30 to 49 mL/min). The renal impairment group had the highest serum sulfate AUC and C max, followed by the hepatic impairment group, and then by healthy subjects. The mean sulfate levels of all three groups returned to their respective baseline levels by Day 6 after dose initiation.

The systemic exposure of serum sulfate (AUC and C max) was similar between healthy subjects and patients with mild to moderate hepatic impairment. Urinary excretion of sulfate over 30 hours, starting after the first half dose, was similar between hepatically impaired patients and healthy subjects.

In patients with moderate renal impairment, mean AUC and Cmax were 54% and 44% higher than those in healthy subjects, respectively. Urinary excretion of sulfate over 30 hours, starting after the first half dose, was approximately 16% lower in moderate renal impairment patients than in healthy subjects.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of ColPrep Kit. Studies to evaluate the possible impairment of fertility or mutagenic potential of ColPrep Kit have not been performed.

13.2 Animal Toxicology and/or Pharmacology

The sulfate salts of sodium, potassium, and magnesium contained in BC Powder for Oral Solution Kit were administered orally (gavage) to rats and dogs up to 28 days up to a maximum daily dose of 5 g/kg/day (approximately 0.9 and 3 times for rats and dogs, respectively, the recommended human dose of 44 g/day or 0.89 g/kg based on the body surface area). In rats, the sulfate salts caused diarrhea and electrolyte and metabolic changes, including hypochloremia, hypokalemia, hyponatremia, lower serum osmolality, and high serum bicarbonate. Significant renal changes included increased fractional sodium excretion, increased urinary sodium and potassium excretion, and alkaline urine in both males and females. In addition, creatinine clearance was significantly decreased in females at the highest dose. No microscopic renal changes were seen. In dogs, the sulfate salts caused emesis, excessive salivation, excessive drinking of water, and abnormal excreta (soft and/or mucoid feces and/or diarrhea) and increased urine pH and sodium excretion.