Clenpiq

1 INDICATIONS AND USAGE CLENPIQ is indicated for cleansing of the colon as a preparation for colonoscopy in adults and pediatric patients 9 years of age and older. CLENPIQ ® 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 and pediatric patients ages 9 years and older.

Administration: CLENPIQ is ready to drink. It does not need to be diluted prior to administration. One bottle of CLENPIQ is equivalent to one dose. Two doses of CLENPIQ are required for a complete preparation for colonoscopy as a Split-Dose regimen. Consume five or more 8-ounce cups of clear liquids after the first dose and four or more 8-ounce cups of clear liquids after the second dose. Consume a variety of clear liquids after each dose of CLENPIQ. Ensure inclusion of balanced electrolyte solution along with other clear liquids. ( 2.1 , 5.1 , 5.5 ) Administer oral medications at least 1 hour before starting CLENPIQ. ( 2.1 , 7.2 ) If taking tetracycline or fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, or penicillamine, take these medications at least 2 hours before and not less than 6 hours after administration of CLENPIQ. ( 2.1 , 7.3 ) For complete information on preparation before colonoscopy and administration of the dosage regimen, see full prescribing information. ( 2.1 , 2.2 ) Split-Dose Dosage Regimen First dose: administer during evening before the colonoscopy Second dose: administer the next day, during the morning prior to the colonoscopy.

2.1Important Administration Instructions Correct

fluid and electrolyte abnormalities before administration of CLENPIQ . CLENPIQ is ready to drink. It is a clear solution with possible presence of visible particles and it does not need to be diluted prior to administration. One bottle of CLENPIQ is equivalent to one dose. Two doses of CLENPIQ are required for a complete preparation for colonoscopy as a Split-Dose regimen.

The Split-Dose method 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 . Consume five or more 8-ounce cups of clear liquids after the first dose and four or more 8-ounce cups of clear liquids after the second dose . Consume a variety of clear liquids. Clear liquids should include balanced electrolyte solution . Additional clear liquids, other than water, include black coffee or tea, plain jello, clear broth or bouillon, clear juices without pulp, ginger ale and other sodas, and frozen juice bars. Do not drink anything colored red or purple.

Consume only clear liquids (no solid food) on the day before colonoscopy and until after the colonoscopy. Do not eat solid food or dairy and do not drink anything colored red or purple. Do not drink alcohol. Stop consumption of all liquids at least 2 hours before the colonoscopy.

Do not take other laxatives while taking CLENPIQ. Administer oral medications at least one hour before starting each dose of CLENPIQ. If taking tetracycline or fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, or penicillamine, take these medications at least 2 hours before and not less than 6 hours after administration of CLENPIQ.

2.2Split-Dose Dosage Regimen The

recommended dosage in adults and pediatric patients 9 years of age and older is shown below. Instruct patients to take two separate doses in conjunction with liquids, as follows: Dose 1 – On the day before colonoscopy: Instruct patients to consume only clear liquids (no solid food or dairy) on the day before the colonoscopy up until 2 hours before the time of the colonoscopy. Take the first dose (1 bottle) of CLENPIQ during the evening before the colonoscopy (e.g., 5:00 PM to 9:00 PM).

Consume at least five 8-ounce cups (cup provided) of clear liquids after the CLENPIQ dose over the next 5 hours. If severe bloating, distention, or abdominal pain occurs, following the first dose, delay the second dose until the symptoms resolve. Dose 2 – Next morning on the day of colonoscopy (start approximately 5 hours prior to colonoscopy): Continue to consume only clear liquids (no solid food or dairy).

Take the second dose (the second bottle) of CLENPIQ. Consume four or more 8-ounce cups (cup provided) of clear liquids after the CLENPIQ dose and up to 2 hours before the colonoscopy.

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 , 7.1 ) Use in patients with renal impairment or taking concomitant medications that affect renal function : Use caution, ensure adequate hydration, and consider testing. ( 4 , 5.3 , 7.1 ) Syncope : Resulted in serious outcomes including falls, head injuries, and fractures; encourage adequate hydration. Mucosal ulcerations : Consider potential for mucosal ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. Suspected GI obstruction or perforation : Rule out diagnosis before administration. ( 4 , 5.7 ) Patients at risk for aspiration : Observe during administration.

5.1Serious Fluid and Electrolyte Abnormalities Advise

patients to hydrate adequately before, during, and after the use of CLENPIQ. 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 CLENPIQ, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN) and treat accordingly. Approximately 20% of patients in both arms (sodium picosulfate, magnesium oxide, and anhydrous citric acid, or 2 L of PEG + E plus two × 5-mg bisacodyl tablets) of clinical trials of another oral sodium picosulfate, magnesium oxide, and anhydrous citric acid product had orthostatic changes in blood pressure and/or heart rate on the day of colonoscopy and up to seven days post colonoscopy.

In a single study of patients 9 to 16 years of age, approximately 20% of patients who received another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid had orthostatic changes (changes in blood pressure and/or heart rate) compared with approximately 7% of those who received the comparator (PEG) . These changes occurred up to five days post colonoscopy. Fluid and electrolyte disturbances can lead to serious adverse reactions including cardiac arrhythmias, seizures, renal impairment, and syncope . Correct fluid and electrolyte abnormalities before treatment with CLENPIQ. Advise patients to consume a variety of clear liquids (e.g., balanced electrolyte solution), and not only water after each dose of CLENPIQ. In addition, use caution when prescribing CLENPIQ 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 seizure, arrhythmia, and renal impairment .

5.2Seizures There

have been reports of generalized tonic-clonic seizures and/or loss of consciousness 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 CLENPIQ 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 .

5.3Use in Patients with Renal Impairment

CLENPIQ is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), accumulation of magnesium in plasma may occur. Use caution when prescribing CLENPIQ 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) . 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 CLENPIQ. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

5.4Cardiac 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 CLENPIQ 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.

5.5Syncope Syncope

has been reported with CLENPIQ in the postmarketing setting. Some cases were serious events that included falls with associated head injuries or fractures requiring hospitalization. In some cases, electrolyte abnormalities were also present (e.g., hyponatremia and hypokalemia). Cases have been reported after one or two CLENPIQ doses and many of these cases occurred within 12 hours of dosing.

Patients should be aware of the risk of syncope during treatment and adequately hydrate before, during, and after the use of CLENPIQ. Advise patients to consume a variety of clear liquids (e.g., balanced electrolyte solution), not only water after each dose of CLENPIQ and to get up gradually from a lying or sitting position .

5.6Colonic 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 CLENPIQ may increase this risk. Consider the potential for mucosal ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease .

5.7Use in Patients with Significant Gastrointestinal Disease

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

5.8Aspiration Patients with

impaired gag reflex are at risk for regurgitation or aspiration during the administration of CLENPIQ. Observe these patients during the administration of CLENPIQ.

4 CONTRAINDICATIONS CLENPIQ is contraindicated in the following conditions: Patients with severe renal impairment (creatinine clearance less than 30 mL/minute), which may result in accumulation of magnesium . Gastrointestinal obstruction or ileus . Bowel perforation . Toxic colitis or toxic megacolon. Gastric retention. Hypersensitivity to any of the ingredients in CLENPIQ . Severe renal impairment (creatinine clearance less than 30 mL/minute) ( 4 , 5.3 , 8.6 ) Gastrointestinal (GI) obstruction or ileus Bowel perforation Toxic colitis or toxic megacolon Gastric retention Hypersensitivity to any of the ingredients in CLENPIQ

8.1Pregnancy Risk Summary There

are no data with CLENPIQ use in pregnant women to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats when sodium picosulfate, magnesium oxide, and anhydrous citric acid were administered orally at doses 1.2 times the recommended human dose based on body surface area during organogenesis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Reproduction studies with sodium picosulfate, magnesium oxide, and anhydrous citric acid have been performed in pregnant rats following oral administration of up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on body surface area) during the period of organogenesis.

There was no evidence of harm to the fetus due to sodium picosulfate, magnesium oxide, and anhydrous citric acid. The reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. A pre and postnatal development study with sodium picosulfate, magnesium oxide, and anhydrous citric acid 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 body surface area).

Published reproduction studies with sodium picosulfate in pregnant rats and rabbits during the period of organogenesis did not show evidence of harm to the fetus at doses up to 100 mg/kg (approximately 49 and 98 times, respectively, the recommended human dose of 10 mg sodium picosulfate based on body surface area).

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.

6.1Clinical 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.

6.2Postmarketing 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 .