Citricside effects

The following serious or otherwise important adverse reactions for bowel preparations are described elsewhere in the labeling: Serious Fluid and Electrolyte Abnormalities Seizures Use in Patients with Renal Impairment Cardiac Arrhythmias Syncope Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis Use in Patients with Significant Gastrointestinal Disease Aspiration Most common adverse reactions are: Adults (≥2%): nausea, headache, hypermagnesemia, abdominal pain and dehydration or dizziness. Pediatrics 9 to 16 years (>5%): nausea, vomiting, and abdominal pain. To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. 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. Adults Clinical Study of CLENPIQ - Study 1 Table 1 displays the most common adverse reactions in a randomized, multicenter, assessor-blinded, non-inferiority trial of CLENPIQ for colon cleansing in adults (Study 1). CLENPIQ was compared to another oral sodium picosulfate, magnesium oxide, and anhydrous citric acid product, both administered according to the Split-Dose dosage regimen.

Table 1: Common Adverse Reactions Observed in at Least 2% of Patients Undergoing Colon Cleansing in Study 1 Adverse Reaction Split-Dose Regimen CLENPIQ (N=448) % Sodium picosulfate, magnesium oxide, and anhydrous citric acid Powder for reconstitution (N=453) % Nausea 3 3 Headache 3 3 Hypermagnesemia Magnesium levels returned to normal within one week after colonoscopy in all patients in the CLENPIQ group. 2 5 Abdominal pain Abdominal pain included reports of abdominal pain, abdominal pain upper, and abdominal pain lower. 2 2 Dehydration or dizziness 2 2 Clinical Study of Another Sodium Picosulfate, Magnesium Oxide and Anhydrous Citric Acid Product - Study 2 In a randomized, multicenter, investigator-blinded, active-controlled clinical trial for colon cleansing in adults, another oral sodium picosulfate, magnesium oxide, and anhydrous citric acid product was compared with a regimen of two liters (2 L) of polyethylene glycol plus electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets (Study 2). In this study the protocol specified that abdominal bloating, distention, pain/cramping, and watery diarrhea, which are known to occur in response to bowel preparation, were documented as adverse events only if they required medical intervention (such as a change in study drug or led to discontinuation, therapeutic or diagnostic procedures, met the criteria for 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. The most common adverse reactions in Study 2 are shown in Table 2.

Table 2: Common Adverse Reactions abdominal bloating, distention, pain/cramping, and watery diarrhea not requiring an intervention were not collected Observed in at Least 1% of Patients Undergoing Colon Cleansing in Study 2 Adverse Reaction Split-Dose Regimen Sodium picosulfate, magnesium oxide, and anhydrous citric acid (N=305) % 2 L PEG + E 2 L PEG + E = two liters polyethylene glycol plus electrolytes solution with 2 × 5-mg bisacodyl tablets (N=298) % Nausea 3 4 Headache 2 2 Vomiting 1 3 Electrolyte Abnormalities In Study 1, rates of abnormal electrolyte shifts were generally similar between CLENPIQ and another sodium picosulfate, magnesium oxide, and anhydrous citric acid product (Table 3). In general, these shifts were transient and not clinically significant. In Study 2, sodium picosulfate, magnesium oxide, and anhydrous citric acid was in general associated with numerically higher rates of abnormal electrolyte shifts on the day of colonoscopy compared to the control regimen (Table 3). These shifts were transient in nature and numerically similar between treatment arms at the Day 28 visit.

Table 3: Shifts from Normal Baseline to Outside the Normal Range Post-Baseline Laboratory Parameter (direction of change) Visit Split-Dose Regimen Study 1 Split-Dose Regimen Study 2 CLENPIQ Sodium picosulfate, magnesium oxide, and anhydrous citric acid Powder for reconstitution Sodium picosulfate, magnesium oxide, and anhydrous citric acid 2 L PEG+E with 2 × 5 mg bisacodyl tablets n/N (%) n/N (%) N/A: not applicable. Potassium (low) Day of Colonoscopy 34/422 10/423 19/260 11/268 24-48 hours 13/417 3/423 3/302 2/294 Day 7 7/420 6/425 11/285 8/279 Day 28 3/421 7/423 11/284 8/278 Sodium (low) Day of Colonoscopy 4/426 23/443 11/298 3/295 24-48 hours 6/423 9/441 1/303 1/295 Day 7 6/423 9/440 2/300 1/292 Day 28 8/427 9/439 2/299 3/291 Chloride (low) Day of Colonoscopy 23/437 16/444 11/301 1/298 24-48 hours 3/434 3/442 1/303 0/295 Day 7 3/434 2/441 1/303 3/295 Day 28 4/438 1/440 2/302 3/294 Magnesium (high) Day of Colonoscopy 112/431 143/440 34/294 0/294 24-48 hours 23/427 21/440 0/303 0/295 Day 7 11/428 9/440 0/297 1/291 Day 28 10/432 12/438 1/296 2/290 Calcium (low) Day of Colonoscopy 8/436 1/446 2/292 1/286 24-48 hours 1/434 0/444 0/303 0/295 Day 7 0/434 0/444 0/293 1/283 Day 28 0/439 2/442 0/292 1/282 Bicarbonate (low) Day of Colonoscopy 6/431 35/438 N/A Bicarbonate was not analyzed in Study 2. N/A 24-48 hours 40/430 43/434 N/A N/A Day 7 37/430 40/438 N/A N/A Day 28 33/433 43/436 N/A N/A Creatinine (high) Day of Colonoscopy 6/427 1/432 5/260 13/268 24-48 hours 6/425 5/431 1/303 0/295 Day 7 5/426 4/431 10/264 13/267 Day 28 4/429 6/429 11/264 14/265 Pediatrics In the pediatric patients aged 9 to 16 years who received another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid, the most common adverse reactions (> 5%) were nausea, vomiting, and abdominal pain. 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 sodium picosulfate, magnesium oxide, and anhydrous citric acid and one received the comparator (PEG). The abnormal values occurred at the colonoscopy visit for one patient (sodium picosulfate, magnesium oxide, and anhydrous citric acid) and at the 5-day follow up visit for the other two patients (sodium picosulfate, magnesium oxide, and anhydrous citric acid and PEG). All three patients were asymptomatic.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post approval use of oral sodium picosulfate, magnesium oxide, and anhydrous citric acid products. 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, and purpura Gastrointestinal: abdominal pain, diarrhea, fecal incontinence, proctalgia, vomiting, reversible aphthoid ileal ulcers, and ischemic colitis Neurologic: generalized tonic-clonic seizures with and without hyponatremia in epileptic patients, and syncope.