PONCTUEL

(sodium picosulfate, magnesium oxide, and anhydrous citric acid) oral solution is a stimulant and osmotic laxative that is provided as a cranberry-flavored, colorless to slightly yellow, clear solution with possible presence of visible particles.

CLENPIQ is supplied as two bottles in each carton.

Each bottle of

CLENPIQ contains 10 mg sodium picosulfate, USP; 3.5 g magnesium oxide, USP; and 12 g anhydrous citric acid, USP.

The product also contains the following inactive ingredients: acesulfame potassium, cranberry flavor, disodium edetate, malic acid, sodium benzoate, sodium hydroxide, sodium metabisulfite, sucralose, and water.

The cranberry flavor contains glyceryl triacetate (triacetin), maltodextrin, and sodium octenyl succinated starch.

The following is a description of the three active ingredients contained in CLENPIQ: Sodium picosulfate is a stimulant laxative.

Chemical name: 4,4´-(2-pyridylmethylene) diphenyl bis(hydrogen sulfate) disodium salt, monohydrate Chemical formula: C 18 H 13 NNa 2 O 8 S 2 ∙H 2 O Molecular weight: 499.4 Structural formula: Sodium picosulfate Magnesium citrate, which is formed in solution by the combination of magnesium oxide and anhydrous citric acid, is an osmotic laxative.

Chemical Structure Magnesium Oxide Chemical name

Magnesium oxide Chemical formula: Mg O Molecular weight: 40.3 Structural formula: Mg O Anhydrous Citric Acid Chemical name: 2-hydroxypropane-1,2,3-tricarboxylic acid Chemical formula: C 6 H 8 O 7 Molecular weight: 192.1 Structural formula: Anhydrous citric acid Chemical Structure.

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.

Sodium picosulfate is hydrolyzed by colonic bacteria to form an active metabolite: bis-(p-hydroxy-phenyl)-pyridyl-2-methane, BHPM, which acts directly on the colonic mucosa to stimulate colonic peristalsis.

Magnesium oxide and citric acid react to create magnesium citrate in solution, which is an osmotic agent that causes water to be retained within the gastrointestinal tract. 12.2 Pharmacodynamics The stimulant laxative activity of sodium picosulfate together with the osmotic laxative activity of magnesium citrate produces a purgative effect which, when ingested with additional liquids, produces watery diarrhea. 12.3 Pharmacokinetics Absorption After administration of the first dose of another oral sodium picosulfate, magnesium oxide, and anhydrous citric acid product in 16 healthy subjects, the mean ± SD maximum plasma concentration (C max ) for picosulfate of 2.3 ± 1.4 ng/mL was reached at 2 hours.

After administration of two doses separated by 6 hours, the mean ± SD plasma C max for picosulfate of 3.2 ± 2.6 ng/mL was reached at approximately 7 hours after the first dose administration.

In the same study, the uncorrected plasma magnesium concentration reached a C max of approximately 1.9 mEq/L at 10 hours after the first dose administration, which represents an approximately 20% increase from baseline.

In patients scheduled to have an elective colonoscopy who received the Split-Dose dosage regimen of CLENPIQ, the mean ± SD plasma concentration for picosulfate was 1.05 ± 0.83 ng/mL at 15 minutes pre-second dose, 2.98 ± 1.27 ng/mL at 1-2 hours post-second dose, and 1.81 ± 0.86 ng/mL at 3-6 hours post-second dose.

Metabolism and Elimination Metabolism and Excretion

Plasma concentrations of the free BHPM were below the lower limit of quantification (0.1 ng/mL) in 13 out of 16 subjects studied.

The fraction of the sodium picosulfate dose excreted unchanged in urine was 0.1%.

In urine, the majority of excreted BHPM was in the glucuronide-conjugated form.

The terminal half-life of sodium picosulfate was 7.4 hours.

Pharmacokinetics of picosulfate was studied in pediatric patients aged from to 16 years old.

The half-life of picosulfate was 7 hours.

The picosulfate reached the mean ± SD C max of 3.5 ± 2.1 ng/mL at approximately to 7 hours.

The baseline uncorrected mean serum magnesium concentration was 2.02 mEq/L at 10 hours after the first dose of sodium picosulfate, magnesium oxide, and anhydrous citric acid and ranged from 1.7 to 2.46 mEq/L. Drug Interaction Studies In an in vitro study using human liver microsomes, sodium picosulfate did not inhibit the major CYP enzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5) evaluated.

Based on an in vitro study using freshly isolated hepatocyte culture, sodium picosulfate is not an inducer of CYP1A2, CYP2B6, or CYP3A4/5.

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 to 16 years (>5%): nausea, vomiting, and abdominal pain.

To report SUSPECTED ADVERSE

REACTIONS, contact Ferring Pharmaceuticals Inc.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

• 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 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 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 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.

Overdosage of more than the recommended dose of CLENPIQ may lead to severe electrolyte disturbances, as well as dehydration and hypovolemia, with signs and symptoms of these disturbances.

Monitor for fluid and electrolyte disturbances and treat symptomatically.

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) Gastrointestinal (GI) obstruction or ileus Bowel perforation Toxic colitis or toxic megacolon Gastric retention Hypersensitivity to any of the ingredients in CLENPIQ.

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.

Administer oral medications at least 1 hour before starting 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.

For complete information on preparation before colonoscopy and administration of the dosage regimen, see full prescribing information.

First dose: administer during evening before the colonoscopy Second dose: administer the next day, during the morning prior to the colonoscopy. 2.1 Important Administration Instructions Correct fluid and electrolyte abnormalities before administration of CLENPIQ.

It is a clear solution with possible presence of visible particles and it does not need to be diluted prior to administration.

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 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. 2.2 Split-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.

CLENPIQ is supplied in a carton containing two bottles, each holding 175 mL of cranberry-flavored, colorless to slightly yellow, clear oral solution with possible presence of visible particles.

Each bottle contains 10 mg sodium picosulfate, 3.5 g magnesium oxide, and 12 g anhydrous citric acid.

An eight-ounce cup for measuring liquids for hydration is also supplied.

CLENPIQ Cranberry flavor

NDC# 55566-6800-1.

CLENPIQ at 25°C (77°F).

Excursions permitted at 15°C to 30°C (59°F to 86°F). .

Do not refrigerate or freeze.

CLENPIQ at 25°C (77°F).

Excursions permitted at 15°C to 30°C (59°F to 86°F). .

Do not refrigerate or freeze.

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 to 4% and to 20%, respectively.

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 and 98 times, respectively, the recommended human dose of 10 mg sodium picosulfate based on body surface area).

The safety and effectiveness of

CLENPIQ have been established for cleansing of the colon as a preparation for colonoscopy in pediatric patients 9 years of age and older.

Use of

CLENPIQ in this is supported by evidence from adequate and well-controlled trials in adults and a single, dose-ranging, controlled trial in 78 pediatric patients to 16 years of age all of which evaluated another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid.

The safety profile in this pediatric population was similar to that seen in adults.

Monitor for possible hypoglycemia in pediatric patients, as CLENPIQ has no caloric substrate.

CLENPIQ in pediatric patients less than 9 years of age have not been established.

Of the 448 adult patients in Study 1 who received CLENPIQ, 124 (28%) patients were 65 years of age or older.

No overall differences in safety or effectiveness were observed between geriatric patients and younger patients, and other reported clinical experience has not identified differences in responses between elderly and younger patients.

Elderly patients are more likely to have decreased hepatic, renal, or cardiac function and may be more susceptible to adverse reactions resulting from fluid and electrolyte abnormalities.