2.1 Dosing Overview

Prepopik®, supplied as a powder, must be reconstituted with cold water right before its use [see Dosage and Administration (2.2)]. There are two dosing regimens, each requires two separate dosing times:

• The preferred method is the "Split-Dose" method and consists of two separate doses: the first dose during the evening before the colonoscopy and the second dose the next day, during the morning prior to the colonoscopy [see Dosage and Administration (2.3)]
• The alternative method is the "DayBefore" method and consists of two separate doses: the first dose during the afternoon or early evening before the colonoscopy and the second dose 6 hours later during the evening before the colonoscopy [see Dosage and Administration (2.4)].

Additional fluids must be consumed after every dose in both dosing regimens [see Dosage and Administration (2.3, 2.4)]. Instruct patients to consume only clear liquids (no solid food or milk) on the day before the colonoscopy up until 2 hours before the time of the colonoscopy. Instruct patients that if they experience severe bloating, distention, or abdominal pain following the first dose, delay the second dose until their symptoms resolve.

2.2 Reconstitution of the Prepopik® Powder

(a)

Reconstitute the Prepopik ® powder right before each administration. Do not prepare the solution in advance.

(b)

Fill the supplied dosing cup with cold water up to the lower (5-ounce) line on the cup and pour in the contents of one packet of Prepopik ® powder.

(c)

Stir for 2 to 3 minutes. The reconstituted Prepopik ® solution may become slightly warm as the powder dissolves.

2.3 Split-Dose Dosing Regimen (Preferred Method)

The Split-Dose regimen is the preferred dosing method. Instruct patients to take two separate doses in conjunction with fluids, as follows:

• Take the first dose during the evening before the colonoscopy (e.g., 5:00 to 9:00 PM) followed by five 8-ounce drinks (upper line on the dosing cup) of clear liquids before bed. Consume clear liquids within 5 hours.
• Take second dose the next day approximately 5 hours before the colonoscopy followed by at least three 8-ounce drinks of clear liquids before the colonoscopy. Consume clear liquids within 5 hours up until 2 hours before the time of the colonoscopy.

2.4 Day-Before Dosing Regimen (Alternative Method)

The Day-Before regimen is the alternative dosing method for patients for whom the Split-Dosing is inappropriate. Instruct patients to take two separate doses in conjunction with fluids, as follows:

• Take the first dose in the afternoon or early evening (e.g., 4:00 to 6:00 PM) before the colonoscopy followed by five 8-ounce drinks (upper line on the dosing cup) of clear liquids before the next dose. Consume clear liquids within 5 hours.
• Take the second dose approximately 6 hours later in the late evening (e.g., 10:00 PM to 12:00 AM), the night before the colonoscopy followed by three 8-ounce drinks of clear liquids before bed. Consume clear liquids within 5 hours.

5.1 Serious Fluid and Serum Chemistry Abnormalities

Advise patients to hydrate adequately before, during, and after the use of Prepopik®. Use caution in patients with congestive heart failure when replacing fluids. If a patient develops significant vomiting or signs of dehydration including signs of orthostatic hypotension after taking Prepopik®, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN) and treat accordingly. Approximately 20% of patients in both arms (Prepopik®, 2L of PEG + E plus two × 5-mg bisacodyl tablets) of clinical trials of Prepopik® had orthostatic changes (changes in blood pressure and/or heart rate) on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seven days post colonoscopy. [see Adverse Reactions (6.1, 6.2)]

Fluid and electrolyte disturbances can lead to serious adverse events including cardiac arrhythmias or seizures and renal impairment. Fluid and electrolyte abnormalities should be corrected before treatment with Prepopik®. In addition, use caution when prescribing Prepopik® for patients who have conditions or who are using medications that increase the risk for fluid and electrolyte disturbances or that may increase the risk of adverse events of seizure, arrhythmia, and renal impairment.

5.2 Seizures

There have been reports of generalized tonic-clonic seizures with the 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 Prepopik® for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with known or suspected hyponatremia. [see Adverse Reactions (6.2)]

5.3 Use in Patients with Renal Impairment

As in other magnesium containing bowel preparations, use caution when prescribing Prepopik® 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). These patients may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before, during and after the use of Prepopik®. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

5.4 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 Prepopik® 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.

5.5 Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis

Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of additional stimulant laxatives with Prepopik® may increase this risk. The potential for mucosal ulcerations should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. [see Adverse Reactions (6.2)]

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 Prepopik®. Use with caution in patients with severe active ulcerative colitis.

5.7 Aspiration

Patients with impaired gag reflex and patients prone to regurgitation or aspiration should be observed during the administration of Prepopik®. Use with caution in these patients.

5.8 Not for Direct Ingestion

Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen. Ingestion of additional water is important to patient tolerance. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common adverse reactions (>1%) following Prepopik® administration. The patients were not blinded to the study drug. Since abdominal bloating, distension, pain/cramping, and watery diarrhea are known to occur in response to colon cleansing preparations, these effects were documented as adverse events in the clinical trials only if they required medical intervention (such as a change in study drug or led to study discontinuation, therapeutic or diagnostic procedures, met the criteria for a serious adverse event), or showed clinically significant worsening during the study that was not in the frame of the usual clinical course, as determined by the investigator.

Prepopik® was compared for colon cleansing effectiveness with a preparation containing two liters (2L) of polyethylene glycol plus electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, all administered the day before the procedure. Table 1 displays the most common adverse reactions in Study 1 and Study 2 for the Prepopik® Split-Dose and Day-Before dosing regimens, respectively, each as compared to the comparator preparation.

6.2 Postmarketing Experience

The following foreign spontaneous reports have been identified during use of formulations similar to Prepopik®. Because these events 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.