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.

PREPOPIK (NDA-202535)

(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-6)

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 Prepopik. 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 Prepopik, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN) and treat accordingly. Approximately 20% of adult patients in both arms (Prepopik, 2L of PEG + E plus two x 5-mg bisacodyl tablets) of clinical trials of Prepopik had orthostatic changes (changes in blood pressure and/or heart rate) on the day of colonoscopy. In adult clinical trials orthostatic changes were documented up to seven days post colonoscopy. In a single study of patients 9 to 16 years of age, approximately 20% of patients in Prepopik arms 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 Prepopik [see Dosage and Administration (2.1)]. Advise patients to consume a variety of clear liquids (e.g., balanced electrolyte solution), not only water after each dose of Prepopik. In addition, use caution when prescribing Prepopik 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 adverse events 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 Prepopik 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, or patients with known or suspected hyponatremia [see Adverse Reactions (6.2)].

5.5 Syncope

(Newly added subsection)

Syncope has been reported with Prepopik 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 Prepopik doses and many 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 Prepopik. Advise patients to consume a variety of clear liquids (e.g., balanced electrolyte solution), not only water after each dose of Prepopik 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 (5.6)]
Use in Patients with Significant Gastrointestinal Disease [see Warnings and Precautions (5.7)]
Aspiration [see Warnings and Precautions (5.8)]
Risk of Vomiting and Other Gastrointestinal Complications with Ingestion of Undissolved Powder [see Warnings and Precautions (5.9)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of other oral formulations of sodium picosulfate, magnesium oxide and anhydrous citric acid similar to Prepopik. 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, purpura, and anaphylaxis [see Contraindications (4)]

Gastrointestinal: abdominal pain, diarrhea, fecal incontinence, aphthoid ileal ulcers, 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 Prepopik for patients with conditions and/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:

Each packet must be dissolved in 5 ounces of cold water and administered according to the dosing regimen. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances [see Warnings and Precautions (5.9).
Two doses (one packet per dose) of Prepopik are required for a complete preparation for colonoscopy either as a Split-Dose (preferred) or Day-Before dosing regimen.
Follow the directions in the Instructions for Use, for either the Split-Dose or the Day-Before regimen, as prescribed.
Consume five or more 8-ounce cups of clear liquids after the first dose and three or more 8-ounce cups of clear liquids after the second dose [see Dosage and Administration (2.3, 2.4)].
Consume a variety of clear liquids after each dose of Prepopik. 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 take other laxatives while taking Prepopik.
Do not drink alcohol.
Administer oral medications at least one hour before starting each dose of Prepopik.
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 Prepopik.
Delay the second dose of Prepopik, 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 Prepopik or if they experience confusion, delirium, dizziness, lightheadedness, fainting, loss of consciousness, or seizures [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5)].

08/15/2018 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Serious Fluid and Electrolyte Abnormalities

(additions underlined)

…In adult clinical trials orthostatic changes were documented up to seven days post colonoscopy. In a single study of patients 9 to 16 years of age, approximately 20% of patients in Prepopik 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.

…

5.4 Use in Patients with Renal Impairment

(additions underlined)

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

6 Adverse Reactions

(additions underlined)

The following serious or otherwise important adverse reactions for bowel preparations are described elsewhere in the labeling:

Serious Fluid and Electrolyte Abnormalities
Cardiac Arrhythmias
Seizures
Use in Patients with Renal Impairment
Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis
Use in Patients with Significant Gastrointestinal Disease
Aspiration
Risk of Vomiting and Other Gastrointestinal

6.1 Clinical Trials Experience

(additions underlined)

…

Pediatrics

In the pediatric patients aged 9 to 16 years who received Prepopik, 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 Prepopik and one received the comparator (PEG). The abnormal values occurred at the colonoscopy visit for one patient (Prepopik) and at the 5-day follow up visit for the other two patients (Prepopik and PEG). All three patients were asymptomatic.

6.2 Postmarketing Experience

(additions underlined)

Hypersensitivity: rash, urticaria, purpura, and anaphylaxis.

…

7 Drug Interactions

7.1 Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities

(additions underlined)

Use caution when prescribing Prepopik for patients with conditions and/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.

7.2 Potential for Reduced Drug Absorption

(additions underlined)

Prepopik can reduce the absorption of other co-administered drugs.

Administer oral medications at least one hour before of the start of administration of Prepopik
Administer tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, and penicillamine at least 2 hours before and not less than 6 hours after administration of Prepopik

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are no data with Prepopik use in pregnant women to determine a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In an animal reproduction study, 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

A reproduction study with sodium picosulfate, magnesium oxide, and anhydrous citric acid has 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. A 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).

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of magnesium oxide or anhydrous citric acid in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Published data on lactating women indicate that the active metabolite of sodium picosulfate, bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM) remained below the limit of detection (1 ng/mL) in breast milk after both single and multiple doses of 10 mg/day. There are no data on the effects of sodium picosulfate on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Prepopik and any potential adverse effects on the breastfed infant from Prepopik or the underlying maternal condition.

8.4 Pediatric Use

(subsection revised, additions underlined)

The safety and effectiveness of Prepopik have been established for cleansing of the colon as a preparation for colonoscopy in pediatric patients 9 years of age and older. Use of Prepopik in this age group is supported by evidence from adequate and well-controlled trials of Prepopik in adults and a single, dose-ranging, controlled trial in 78 pediatric patients 9 to 16 years of age.The safety profile of Prepopik in this pediatric population was similar to that seen in adults.Monitor for possible hypoglycemia in pediatric patients, as Prepopik has no caloric substrate.

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

8.5 Geriatric Use

(additions underlined)

Of the 1201 patients in clinical trials who received Prepopik, 215 (18%) patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients. However, 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.

8.6 Renal Impairment

(additions underlined)

Prepopik is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), as accumulation of magnesium in plasma may occur. Patients with mild to moderate renal impairment or patients taking concomitant medications that may affect renal function may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before, during and after the use of Prepopik. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

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

MEDICATION GUIDE

(additions, please refer to label)

PATIENT COUNSELING INFORMATION

(additions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Each packet must be dissolved in 5 ounces of cold water and administered according to the dosing regimen. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances
Two doses (one packet per dose) of Prepopik are required for a complete preparation for colonoscopy either as a Split-Dose (preferred) or Day-Before dosing regimen.
Not to take other laxatives while they are taking Prepopik.
Do not eat solid food or dairy and do not drink anything colored red or purple.
Do not drink alcohol.
Do not take oral medications within one hour of starting Prepopik.
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 Prepopik.
To follow the directions in the Instructions for Use, for either the Split-Dose or the Day-Before regimen, as prescribed.
To consume additional fluids after each dose of Prepopik.
To delay the second dose of Prepopik, if severe bloating, distention, or abdominal pain occurs following the first dose until the symptoms resolve.
To contact their healthcare provider if they develop significant vomiting or signs of dehydration after taking Prepopik or if they experience altered consciousness (e.g. confusion, delirium, loss of consciousness) or seizures.