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warnings and cautions
5 WARNINGS AND PRECAUTIONS Risk of fluid and electrolyte abnormalities: Encourage adequate hydration, assess concurrent medications, and consider laboratory assessments prior to and after use. ( 5.1 , 5.2 , 7.1 ) Cardiac arrhythmias: Consider pre-dose and post-colonoscopy ECGs in patients at increased risk. ( 5.2 ) Seizures: Use caution in patients with a history of seizures and patients at increased risk of seizure, including medications that lower the seizure threshold. ( 5.3 , 7.1 ) Patients with mild to moderate renal impairment or taking concomitant medications that affect renal function: Use caution, ensure adequate hydration and consider testing. ( 4 , 5.4 , 7.1 ) 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 ) Risk of vomiting and other GI complications with ingestion of undissolved powder: Dissolve each packet in 5 ounces of cold water and administered at separate times according to the dosing regimen. ( 2.3 , 2.4 , 5.8 ) 5.1 Serious Fluid and Electrolyte 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 adult 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 adult clinical trials orthostatic changes were documented up to seven days post colonoscopy. In a single study of patients 9 to 16 years of age, approximately 20% of patients in Prepopik arms had orthostatic changes (changes in blood pressure and/or heart rate) compared with approximately 7% of those who received the comparator (PEG) [see Clinical Studies (14) ] . These changes occurred up to five days post colonoscopy . Fluid and electrolyte disturbances can lead to serious adverse reactions including cardiac arrhythmias or seizures and renal impairment. Correct fluid and electrolyte abnormalities 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 . Fluid and electrolyte disturbances can lead to serious adverse reactions including cardiac arrhythmias or seizures and renal impairment. Correct fluid and electrolyte abnormalities before treatment with Prepopik [see Dosage and Administration (2.1) ] . 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 [see Drug Interactions (7.1) ] . 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 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). Consider pre-dose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. 5.3 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, or patients with known or suspected hyponatremia [see Adverse Reactions (6.2) ]. 5.4 Use in Patients with Renal Impairment Prepopik is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), accumulation of magnesium in plasma may occur [see Contraindications (4) ] . As with other magnesium containing bowel preparations, use caution when prescribing Prepopik for patients with mild to moderate renal impairment 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) [see Drug Interactions (7.1) ] . 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. 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 [see Contraindications (4) ] . Use with caution in patients with severe active ulcerative colitis. 5.7 Aspiration Patients with impaired gag reflex are at risk for regurgitation or aspiration during the administration of Prepopik. Observe these patients during the administration of Prepopik. Use with caution in these patients. 5.8 Risk of Vomiting and Other Gastrointestinal Complications with Ingestion of Undissolved Powder Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen [see Dosage and Administration (2.3 , 2.4) ] . 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 The following serious or otherwise important adverse reactions for bowel preparations are described elsewhere in the labeling: Serious Fluid and Electrolyte Abnormalities [see Warnings and Precautions (5.1) ] Cardiac Arrhythmias [see Warnings and Precautions (5.2) ] Seizures [see Warnings and Precautions (5.3) ] Use in Patients with Renal Impairment [see Warnings and Precautions (5.4) ] Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis [see Warnings and Precautions (5.5) ] Use in Patients with Significant Gastrointestinal Disease [see Warnings and Precautions (5.6) ] Aspiration [see Warnings and Precautions (5.7) ] Risk of Vomiting and Other Gastrointestinal Complications with Ingestion of Undissolved Powder [see Warnings and Precautions (5.8) ] Most common adverse reactions are: Adults (>1%): nausea, headache and vomiting. ( 6.1 ) Pediatrics 9 to 16 years (>5%): nausea, vomiting, and abdominal pain. ( 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+E 2L 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) Pediatrics In the pediatric patients aged 9 to 16 years who received Prepopik, the most common adverse reactions (> 5%) were nausea, vomiting, and abdominal pain [see Clinical Trials (14) ] . Electrolytes abnormalities were observed in pediatric patients similar to those seen in adults. Three patients had abnormally low glucose levels (40 to 47 mg/dL). Two patients received Prepopik and one received the comparator (PEG). The abnormal values occurred at the colonoscopy visit for one patient (Prepopik) and at the 5-day follow up visit for the other two patients (Prepopik and PEG). All three patients were asymptomatic. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of other oral formulations of sodium picosulfate, magnesium oxide and anhydrous citric acid similar to Prepopik. 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. Hypersensitivity: rash, urticaria, purpura, and anaphylaxis [see Contraindications (4) ] Gastrointestinal: abdominal pain, diarrhea, fecal incontinence, aphthoid ileal ulcers, ischemic colitis [see Warnings and Precautions (5.5) ] Neurologic: generalized tonic-clonic seizures with and without hyponatremia in epileptic patients [see Warnings and Precautions (5.3) ].