2.1 Important 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 [see Dosage and Administration (2.2)].
• Additional liquids must be consumed after every dose of CLENPIQ: 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 [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].
• Consume only clear liquids (no solid food) from the start of CLENPIQ treatment until after the colonoscopy.
• Do not eat solid food or dairy and do not drink anything colored red or purple.
• Do not drink alcohol.
• Do not take other laxatives while taking CLENPIQ.
• Do not take oral medications within one hour of 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.
• Stop consumption of all liquids at least 2 hours before the colonoscopy.

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:

5.1 Serious 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) [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 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 [see Drug Interactions (7.1)].

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 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 [see Adverse Reactions (6.2)].

5.3 Use in Patients with Renal Impairment

As with other magnesium containing bowel preparations, use caution when prescribing CLENPIQ 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) [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 CLENPIQ. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. CLENPIQ is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), as accumulation of magnesium in plasma may occur [see Contraindications (4)].

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 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.

5.5 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 CLENPIQ may increase this risk. Consider the potential for mucosal ulcerations 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 CLENPIQ [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 CLENPIQ. Observe these patients during the administration of CLENPIQ.

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.

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 [see Warnings and Precautions (5.5)]

Neurologic: generalized tonic-clonic seizures with and without hyponatremia in epileptic patients [see Warnings and Precautions (5.2)].

7.1 Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities

Use caution when prescribing CLENPIQ for patients with conditions or who are taking other drugs, that increase the risk for fluid and electrolyte disturbances or may increase the risk of renal impairment, seizures, arrhythmias or QT prolongation in the setting of fluid and electrolyte abnormalities [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)].

7.2 Potential for Reduced Drug Absorption

CLENPIQ can reduce the absorption of other co-administered drugs [see Dosage and Administration (2.1)]:

• Administer oral medications at least one hour before of the start of administration of CLENPIQ.
• Administer tetracycline and fluoroquinolone antibiotics [see Drug Interactions (7.3)], iron, digoxin, chlorpromazine, and penicillamine at least 2 hours before and not less than 6 hours after administration of CLENPIQ to avoid chelation with magnesium.

7.3 Antibiotics

Prior or concomitant use of antibiotics with CLENPIQ may reduce efficacy of CLENPIQ as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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 age group is supported by evidence from adequate and well-controlled trials in adults and a single, dose-ranging, controlled trial in 78 pediatric patients 9 to 16 years of age all of which evaluated another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid [see Clinical Studies (14)]. The safety profile in this pediatric population was similar to that seen in adults [see Adverse Reactions (6.1)]. Monitor for possible hypoglycemia in pediatric patients, as CLENPIQ has no caloric substrate.

The safety and effectiveness of CLENPIQ in pediatric patients less than 9 years of age have not been established.

8.5 Geriatric Use

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 [see Warnings and Precautions (5.1)].

8.6 Renal Impairment

CLENPIQ is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), as accumulation of magnesium in plasma may occur [see Contraindications (4)]. Patients with less severe renal impairment or patients taking concomitant medications that may affect renal function may be at increased risk for renal injury [see Warnings and Precautions (5.3)]. Advise these patients of the importance of adequate hydration before, during, and after the use of CLENPIQ [see Dosage and Administration (2.1)]. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

Sodium Picosulfate

• Chemical name: 4,4´-(2-pyridylmethylene) diphenyl bis(hydrogen sulfate) disodium salt, monohydrate
• Chemical formula: C18H13NNa2O8S2∙H2O
• Molecular weight: 499.4
• Structural formula:

  ∙ H2O

  
  Sodium picosulfate

Magnesium citrate, which is formed in solution by the combination of magnesium oxide and anhydrous citric acid, is an osmotic laxative.

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: C6H8O7
• Molecular weight: 192.1
• Structural formula:

  
  Anhydrous citric acid

12.1 Mechanism of Action

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 fluids, produces watery diarrhea.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with CLENPIQ.

Sodium picosulfate was not mutagenic in the Ames test, the mouse lymphoma assay, and the mouse bone marrow micronucleus test.

In an oral fertility study in rats, sodium picosulfate, magnesium oxide, and anhydrous citric acid did not cause any significant adverse effect on male or female fertility parameters up to a maximum dose of 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on body surface area).

Adults

Pediatric Patients 9 Years of Age and Older

The safety and efficacy of CLENPIQ in pediatric patients 9 years of age and older has been established based on another oral product of sodium picosulfate, magnesium oxide and anhydrous citric acid provided in powder packets for reconstitution (NCT01928862).

Sodium picosulfate, magnesium oxide, and anhydrous citric acid was evaluated for colon cleansing in a randomized, assessor-blind, multicenter, dose-ranging, active-controlled study in 78 pediatric patients 9 years to 16 years of age. The majority of patients were female (68%), white (91%), and of non-Hispanic or non-Latino ethnicity (95%). The mean age was 12 years of age. All 78 patients were included in the primary efficacy analysis.

Patients aged 9 years to 12 years were randomized into 3 arms (1:1:1):

• Sodium picosulfate, magnesium oxide, and anhydrous citric acid one-half packet per dose administered as two doses
• Sodium picosulfate, magnesium oxide, and anhydrous citric acid one packet per dose administered as two doses
• Comparator (oral PEG-based solution per local standard of care).

Patients aged 13 years to 16 years were randomized into 2 arms (1:1):

• Sodium picosulfate, magnesium oxide, and anhydrous citric acid one packet per dose administered as two doses
• Comparator (oral PEG-based solution per local standard of care)

Patients randomized to sodium picosulfate, magnesium oxide, and anhydrous citric acid had two options for dosing, as determined by the investigator. The "Split-Dose" regimen was the preferred method and the "Day-Before" regimen was the alternative method if the "Split-Dose" was not appropriate.

"Split-Dose" Regimen: (evening before and day of) dosing, where the first dose was taken the evening before the colonoscopy (between 5:00 and 9:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second dose was taken the morning of the colonoscopy (at least 5 hours prior to but no more than 9 hours prior to colonoscopy), followed by three (3) 8-ounce glasses of clear liquid.

"Day-Before" Regimen: (afternoon/evening before only) dosing, where both doses were taken separately on the day before the colonoscopy, with the first dose taken in the afternoon (between 4:00 and 6:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second dose taken in the late evening (approximately 6 hours later, between 10:00 PM and 12:00 AM), followed by three (3) 8-ounce glasses of clear liquid.

All patients randomized to sodium picosulfate, magnesium oxide, and anhydrous citric acid was limited to a clear liquid diet on the day before the procedure. Those who received the comparator were given dietary instructions per the trial site's standard of care.

The primary efficacy endpoint was the proportion of patients with successful colon cleansing as defined as a rating of either "Excellent" (> 90% of mucosa seen, mostly liquid stool, minimal suctioning needed for adequate visualization) or "Good" (> 90% of mucosa seen, mostly liquid stool, significant suctioning needed for adequate visualization) using the Aronchick scale, as assessed by blinded colonoscopists.

The sodium picosulfate, magnesium oxide, and anhydrous citric acid regimen of one-half packet per dose administered as two doses did not demonstrate comparable efficacy to the comparator, PEG, in patients 9 to 12 years of age and is not a CLENPIQ recommended dosage regimen [see Dosage and Administration (2)].

The sodium picosulfate, magnesium oxide, and anhydrous citric acid regimen of one packet per dose administered as two doses demonstrated successful colon cleansing in both the 9 to 12 year age group and the 13 to 16 year age group. The efficacy rates were similar to those observed in the PEG groups, as shown in Table 6.

How Supplied

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 fluids for hydration is also supplied.

CLENPIQ Cranberry flavor: NDC# 55566-6800-1.

Storage

Store CLENPIQ at 25°C (77°F). Excursions permitted at 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Do not refrigerate or freeze.