1 INDICATIONS AND USAGE Prepopik® (sodium picosulfate, magnesium oxide and anhydrous citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Prepopik® is a combination of sodium picosulfate, a stimulant laxative, and magnesium oxide and anhydrous citric acid which form magnesium citrate, an osmotic laxative, indicated for cleansing of the colon as a preparation for colonoscopy in adults (1)
3 DOSAGE FORMS AND STRENGTHS For oral solution: Each of the two packets contains 10 mg of sodium picosulfate, 3.5 grams of magnesium oxide, and 12.0 grams of anhydrous citric acid in 16.1grams of powder for orange flavor or 16.2 grams of powder for cranberry flavor. For oral solution: Each of 2 packets contains 16.1 g of powder for orange flavor or 16.2 grams of powder for cranberry flavor: 10 mg sodium picosulfate, 3.5 g magnesium oxide, and 12 g anhydrous citric acid (3)
4 CONTRAINDICATIONS Prepopik® is contraindicated in the following conditions: Patients with severely reduced renal function (creatinine clearance less than 30 mL/minute ) which may result in accumulation of magnesium [see Warnings and Precautions (5.3)] Gastrointestinal obstruction or ileus [see Warnings and Precautions (5.6)] Bowel perforation Toxic colitis or toxic megacolon Gastric retention An allergy to any of the ingredients in Prepopik® Patients with severely reduced renal function (creatinine clearance less than 30 mL/minute) (4) Gastrointestinal (GI) obstruction or ileus (4) Bowel perforation (4) Toxic colitis or toxic megacolon (4) Gastric retention (4)
5 WARNINGS AND PRECAUTIONS Risk of fluid and electrolyte abnormalities, arrhythmia, seizures, and renal impairment: Encourage adequate hydration, assess concurrent medications, and consider laboratory assessments prior to and after use (5.1, 5.2, 5.3, 5.4) Risks in patients with renal insufficiency or patients taking concomitant medications that affect renal function: Use caution, ensure adequate hydration and consider testing (5.3) Mucosal ulcerations: Consider potential for mucosal ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease (5.5) Suspected GI obstruction or perforation: Rule out diagnosis before administration (4, 5.6) Patients at risk for aspiration: Observe during administration (5.7) Not for direct ingestion: Dissolve and take with additional water (5.8) 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 ADVERSE REACTIONS Most common adverse reactions (>1%) are nausea, headache and vomiting (abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected) (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ferring at 1-888-FERRING (1-888-337-7464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 1: Treatment-Emergent Adverse Reactions observed in at Least (>1%) of Patients using the Split-Dose Regimen and Day-Before Regimen abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected Adverse Reaction Study 1: Split-Dose Regimen Study 2: Day-Before Regimen PREPOPIK® (N=305) n (% = n/N) 2L PEG+E2L PEG + E = two liters polyethylene glycol plus electrolytes solution. with 2 × 5-mg bisacodyl tablets (N=298) n (% = n/N) PREPOPIK® (N=296) n (% = n/N) 2L PEG+E with 2 × 5-mg bisacodyl tablets (N=302) n (% = n/N) Nausea 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) Electrolyte Abnormalities In general, Prepopik® was associated with numerically higher rates of abnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing 2L of PEG + E plus two × 5-mg bisacodyl tablets (Table 2). These shifts were transient in nature and numerically similar between treatment arms at the Day 30 visit. Table 2: Shifts from Normal Baseline to Outside the Normal Range at Day 7 and Day 30 Laboratory Parameter (direction of change) Visit Study 1: Split-Dose Regimen Study 2: Day-Before Regimen PREPOPIK® 2L PEG+E with 2× 5 mg bisacodyl tablets PREPOPIK® 2L PEG+E with 2× 5 mg bisacodyl tablets n/N (%) n/N (%) Potassium (low) Day of Colonoscopy 19/260 (7.3) 11/268 ( 4.1 ) 13/274 (4.7) 13/271 (4.8) 24-48 hours 3/302 (1.0) 2/294 (0.7) 3/287 (1.0) 5/292 (1.7) Day 7 11/285 (3.9) 8/279 (2.9) 6/276 (2.2) 14/278 (5.0) Day 30 11/284 (3.9) 8/278 (2.9) 7/275 (2.5) 8/284 (2.8) Sodium (low) Day of Colonoscopy 11/298 (3.7) 3/295 (1.0) 3/286 (1.0) 3/295 (1.0) 24-48 hours 1/303 (0.3) 1/295 (0.3) 1/288 (0.3) 1/293 (0.3) Day 7 2/300 (0.7) 1/292 (0.3) 1/285 (0.4) 1/291 (0.3) Day 30 2/299( 0.7) 3/291 (1.0) 1/284( 0.4) 1/296 (0.3) Chloride (low) Day of Colonoscopy 11/301 (3.7) 1/298 (0.3) 3/287 (1.0) 0/297 (0.0) 24-48 hours 1/303 (0.3) 0/295 (0.0) 2/288 (0.7) 0/293 (0.0) Day 7 1/303 (0.3) 3/295 (1.0) 0/285 (0.0) 0/293 (0.0) Day 30 2/302 (0.7) 3/294 (1.0) 0/285 (0.0) 0/298 (0.0) Magnesium (high) Day of Colonoscopy 34/294 (11.6) 0/294 (0.0) 25/288 (8.7) 1/289 (0.3) 24-48 hours 0/303 (0.0) 0/295 (0.0) 0/288 (0.0) 0/293 (0.0) Day 7 0/297 (0.0) 1/291 (0.3) 1/286 (0.3) 1/285 (0.4) Day 30 1/296 (0.3) 2/290 (0.7) 0/286 (0.0) 0/290 (0.0) Calcium (low) Day of Colonoscopy 2/292 (0.7) 1/286 (0.3) 0/276 (0.0) 2/282 (0.7) 24-48 hours 0/303 (0.0) 0/295 (0.0) 0/288 (0.0) 0/293 (0.0) Day 7 0/293 (0.0) 1/283 (0.4) 0/274 (0.0) 0/278 (0.0) Day 30 0/292 (0.0) 1/282 (0.4) 0/274 (0.0) 1/283 (0.4) Creatinine (high) Day of Colonoscopy 5/260 (1.9) 13/268 (4.9) 12/266 (4.5) 16/270 (5.9) 24-48 hours 1/303 (0.3) 0/295 (0.0) 0/288 (0.0) 0/293 (0.0) Day 7 10/264 (0.4) 13/267 (4.8) 10/264 (3.8) 10/265 (3.8) Day 30 11/264 (4.2) 14/265(5.3) 18/264 (6.8) 10/272 (3.7) eGFR (low) Day of Colonoscopy 22/221 (10.0) 17/214 (7.9) 26/199 (13.1) 25/224 (11.2) 24-48 hours 76/303 (25.1) 72/295 (24.4) 82/288 (28.5) 62/293 (21.2) Day 7 22/223 (10.0) 17/213 (8.0) 11/198 (5.6) 28/219 (12.8) Day 30 24/223(10.8) 21/211 (10.0) 21/199 (10.6) 24/224 (10.7) 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. Allergic reactions Cases of hypersensitivity reactions including rash, urticaria, and purpura have been reported. Electrolyte abnormalities There have been reports of hypokalemia, hyponatremia and hypermagnesemia with the use of Prepopik® for colon preparation prior to colonoscopy. Gastrointestinal: Abdominal pain, diarrhea, fecal incontinence, and proctalgia have been reported with the use of Prepopik® for colon preparation prior to colonoscopy. There have been isolated reports of reversible aphthoid ileal ulcers. Ischemic colitis has been reported with the use of Prepopik® for colon preparation prior to colonoscopy. However, a causal relationship between these ischemic colitis cases and the use of Prepopik® has not been established. Neurologic, There have been reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients.
7 DRUG INTERACTIONS Drugs that increase risks due to fluid and electrolyte change (7.1) Oral medication taken within 1 hour of start of each dosing: Might not be properly absorbed (7.2) Antibiotics: Prior or concomitant use of antibiotics may reduce efficacy of Prepopik®(7.3) 7.1 Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Use caution when prescribing Prepopik® for patients with conditions or who are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk of seizure, arrhythmias, and prolonged QT in the setting of fluid and electrolyte abnormalities. This includes patients receiving drugs which may be associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when Prepopik® is used in patients on nonsteroidal anti-inflammatory drugs (NSAIDS) or drugs known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, antipsychotic drugs and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance. Consider additional patient evaluations as appropriate. [see Adverse Reactions (6.1, 6.2)] 7.2 Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of Prepopik® solution may be flushed from the GI tract and the medication may not be absorbed. Tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of Prepopik® to avoid chelation with magnesium. 7.3 Antibiotics Prior or concomitant use of antibiotics with Prepopik® may reduce efficacy of Prepopik® as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria.
8 USE IN SPECIFIC POPULATIONS Pregnancy: Prepopik® should be used during pregnancy only if clearly needed (8.1) 8.1 Pregnancy Pregnancy Category B Reproduction studies with Prepopik® have been performed in pregnant rats at oral doses up to 2000 mg/kg/day (about 1.2 times the recommended human dose based on the body surface area), and did not reveal any evidence of impaired fertility or harm to the fetus due to Prepopik®. The reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Prepopik® should be used during pregnancy 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 Prepopik® is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of Prepopik® in pediatric patients has not been established. 8.5 Geriatric Use In controlled clinical trials of Prepopik®, 215 of 1201 (18%) patients were 65 years of age or older. The overall incidence of treatment-emergent adverse events was similar among patients ≥65 years of age (73%) and patients <65 years of age (71%). Among all patients ≥65 years of age, the proportion of patients with successful colon cleansing was greater in the Prepopik® group (81.1%) than in the comparator group (70.9%). 8.6 Renal Insufficiency 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) may be at increased risk for further 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. The signs and symptoms of hypermagnesemia may include, but are not limited to, diminished or absent deep tendon reflexes, somnolence, hypocalcemia, hypotension, bradycardia, muscle, respiratory paralysis, complete heart block, and cardiac arrest.