Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

CLENPIQ (NDA-209589)

(CITRIC ACID; MAGNESIUM OXIDE; SODIUM PICOSULFATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/29/2023 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Fluid and Electrolyte Abnormalities

(Additions and/or revisions underlined)

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 x 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, seizures, renal impairment, and syncope [see Warnings and Precautions (5.5)]. 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 [see Drug Interactions (7.1)].

5.2 Seizures

(Additions and/or revisions underlined)

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 [see Adverse Reactions (6.2)].

5.3 Use in Patients with Renal Impairment

(Additions and/or revisions underlined)

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) [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.

5.5 Syncope

(Newly added subsection)

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 andadequately 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 [see Warnings and Precautions (5.1)].

6 Adverse Reactions

(Additions and/or revisions underlined)

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)]
Seizures [see Warnings and Precautions (5.2)]
Use in Patients with Renal Impairment [see Warnings and Precautions (5.3)]
Cardiac Arrhythmias [see Warnings and Precautions (5.4)]
Syncope [see Warnings and Precautions (5.5)]
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)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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, and syncope [see Warnings and Precautions (5.2, 5.5)].

7 Drug Interactions

7.1 Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities

(Additions and/or revisions underlined)

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, syncope, arrhythmias or QT prolongation in the setting of fluid and electrolyte abnormalities [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Instruct patients:

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. See Instructions for Use.
Follow the directions in the Instructions for Use, for the Split-Dose regimen, as prescribed.
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 [see Dosage and Administration (2.2)].
Consume a variety of clear liquids after each dose of CLENPIQ. Ensure inclusion of balanced electrolyte solution, along with other clear liquids [see Dosage and Administration (2.1), Warnings and Precautions (5.1, 5.5)].
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.
Do not take other laxatives while taking CLENPIQ.

Do not eat solid food or dairy and do not drink anything colored red or purple.
Do not drink alcohol.

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.
Delay the second dose of CLENPIQ, if severe bloating, distention, or abdominal pain occurs following the first dose until the symptoms resolve.
Tell their healthcare provider if they have a history of fainting [see Warnings and Precautions (5.5)].
Contact their healthcare provider if they develop significant vomiting or signs of dehydration during or after taking CLENPIQ or if they experience confusion, delirium, dizziness, lightheadedness, fainting, loss of consciousness, or seizures [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5)].

10/18/2019 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

Extensive changes; please refer to label for complete information.

8 Use in Specific Populations

Geriatric Use

Additions and/or revisions underlined:

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.

Pregnancy

Additions and/or revisions underlined:

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Additions and/or revisions underlined:

How should I take CLENPIQ?

· 1 bottle of CLENPIQ equals 1 dose. Two separate doses of CLENPIQ are required for complete colonoscopy preparation.

· CLENPIQ is taken using the Split-Dose method.

The most common side effects of CLENPIQ in adults include:

• nausea • high magnesium levels in your blood • dehydration or dizziness

• headache • stomach area (abdominal) pain

How should I store CLENPIQ?

• Store CLENPIQ at room temperature, between 68 to 77°F (20° to 25°C).

• Do not put CLENPIQ in the refrigerator or freezer.

Removal of Day-Before dosing regimen

Additions and/or revisions underlined:

Instruct patients:

· To consume additional liquids after each 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.

08/08/2019 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Fluid and Electrolyte Abnormalities

(Additions and/or revisions are underlined)

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, 2 L of PEG + E plus two x 5-mg bisacodyl tablets) of clinical trials of another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid 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 in another oral product of sodium picosulfate, magnesium oxide, and anhydrous citric acid arms 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.

6 Adverse Reactions

(Additions and/or revisions are underlined)

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
Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis
Use in Patients with Significant Gastrointestinal Disease
Aspiration

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

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.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

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. 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.

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling Medication Guide and Instructions for Use). Instruct patients:

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.

Medication Guide

(Extensive changes; please refer to labeling)