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.

AMITIZA (NDA-021908)

(LUBIPROSTONE)

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

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11/30/2020 (SUPPL-18)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

Safety and effectiveness have not been established in pediatric patients with IBS-C, pediatric functional constipation (PFC), and OIC.

Efficacy was not demonstrated for the treatment of PFC in patients 6 years of age and older in a 12 week, randomized, double-blind, placebo-controlled trial conducted in 606 patients 6 to 17 years with PFC comparing Amitiza to placebo. The primary efficacy endpoint was an overall response based on spontaneous bowel movement frequency over the duration of the trial; the treatment difference from placebo was not statistically significant. In this age group, adverse reactions to Amitiza were similar to those reported in adults. In a 36-week, long-term safety extension trial after approximately 9 months of treatment with Amitiza, a single case of reversible elevation of ALT (17-times upper limit of normal [ULN]), AST (13-times ULN), and GGT (9-times [ULN]) was observed in a child with baseline elevated values (less than or equal to 2.5-times ULN).

04/26/2018 (SUPPL-16)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Following oral administration, concentrations of lubiprostone in plasma arebelow the level of quantitation; however, one of the metabolites, M3, has measurable systemic concentrations. Limited available data with lubiprostone use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Animal reproduction studies did not show an increase in structural malformations. Although a dose dependent increase in fetal loss was observed in pregnant guinea pigs that received lubiprostone (doses equivalent to 0.2 to 6 times the maximum recommended human dose (MRHD) based on body surface area (mg/m2)), these effects were probably secondary to maternal toxicity and occurred after the period of organogenesis .

The 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 dose-dependent increase in fetal loss occurred when guinea pigs received lubiprostone after the period of organogenesis, on days 40 to 53 of gestation, at daily oral doses of 1, 10, and 25 mcg/kg/day (approximately 0.2, 2 and 6 times the MRHD based on body surface area (mg/m2)); however, these effects were probably secondary to maternal toxicity…

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There are no data available on the presence of lubiprostone in human milk or the effect of lubiprostone on milk production. There are limited data available on the effect of lubiprostone on the breastfed infant. Neither lubiprostone nor its active metabolite (M3) were present in the milk of lactating rats. When a drug is not present in animal milk, it is likely that the drug will not be present in human milk. If present, lubiprostone may cause diarrhea in the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Amitiza and any potential adverse effects on the breastfed infant from Amitiza or from the underlying maternal condition.

Clinical Considerations

Infants of nursing mothers being treated with Amitiza should be monitored for diarrhea.

8.4 Geriatric Use

(Additions and/or revisions are underlined)

Chronic Idiopathic Constipation

The efficacy of Amitiza 24 mcg twice daily in the elderly (at least 65 years of age) subpopulation with CIC was consistent with the efficacy in the overall study population. Of the total number of patients treated in the dose-finding, efficacy, and long-term studies of Amitiza, 16% were at least 65 years of age, and 4% were at least 75 years of age. Elderly patients taking Amitiza experienced a lower rate of associated nausea compared to the overall study population taking Amitiza (19% vs. 29%, respectively).

Opioid-Induced Constipation

The safety profile of Amitiza in the elderly (at least 65 years of age) subpopulation with OIC (9% were at least 65 years of age and 2% were at least 75 years of age) was consistent with the safety profile in the overall study population…

Irritable Bowel Syndrome with Constipation

The safety profile of Amitiza in the elderly (at least 65 years of age) subpopulation with IBS-C (8% were at least 65 years of age and 2% were at least 75 years of age) was consistent with the safety profile in the overall study population…

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Safety and effectiveness have not been established in pediatric patients less than 6 years of age.

Effectiveness has not been established in pediatric patients 6 years and older. Efficacy was not demonstrated for the treatment of Pediatric Functional Constipation (PFC) in a 12 week, randomized, double-blind, placebo controlled trial conducted in 606 patients 6 to 17 years with PFC comparing Amitiza to placebo. The primary efficacy endpoint was an overall response based on spontaneous bowel movement frequency over the duration of the trial; the treatment difference from placebo was not statistically significant. In this age group, adverse reactions to Amitiza were similar to those reported in adults. In a 36-week, long-term safety extension trial after approximately 9 months of treatment with Amitiza, a single case of reversible elevation of ALT (17-times upper limit of normal [ULN]), AST (13-times ULN), and GGT (9-times [ULN]) was observed in a child with baseline elevated values (less than or equal to 2.5-times ULN).

Juvenile Animal Toxicity Data

In a 13-week oral toxicity study in juvenile rats, a significant decrease in total bone mineral density was observed in female pups at 0.5 mg/kg/day; in male pups, a significantly lower cortical thickness at the tibial diaphysis was observed at 0.5 mg/kg. The 0.5 mg/kg/day dose is approximately 101 times the maximum recommended adult dose of 48 mcg/day, based on body surface area (mg/m2).

8.6 Hepatic Impairment

(Additions and/or revisions are underlined)

Patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C) experienced markedly higher systemic exposure of lubiprostone active metabolite M3, when compared to subjects with normal hepatic function…

Adjust the dosage of Amitiza in patients with severe hepatic impairment for all indications. Dosage adjustment is also needed for patients with moderate hepatic impairment treated for CIC, and OIC …

10/11/2016 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Syncope and Hypotension (subsection added)

Syncope and hypotension have been reported with Amitiza in the postmarketing setting and a few of these adverse reactions resulted in hospitalization. Most cases occurred in patients taking 24 mcg twice daily and some occurred within an hour after taking the first dose or subsequent doses of Amitiza. Some patients had concomitant diarrhea or vomiting prior to developing the adverse reaction. Syncope and hypotension generally resolved following Amitiza discontinuation or prior to next dose, but recurrence has been reported with subsequent doses. Several cases reported concomitant use of medications known to lower blood pressure, which may increase the risk for the development of syncope or hypotension.

Patients should be aware of the risk of syncope and hypotension during treatment and that other adverse reactions may increase this risk, such as diarrhea or vomiting.

5.4 Dyspnea(addition underlined)

... Instruct patients to contact their healthcare provider if dyspnea occurs.

6 Adverse Reactions

(addition underlined)

• Syncope and Hypotension

6.2 Postmarketing Experience (addition underlined)

… Voluntary reports of adverse reactions occurring with the use of Amitiza include the following: syncope and/or hypotension, ischemic colitis, hypersensitivity/allergic-type reactions (including rash, swelling, and throat tightness), malaise, tachycardia, muscle cramps or muscle spasms, and asthenia.

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

17 PATIENT COUNSELING INFORMATION (additions underlined)

Administration Instructions

• Instruct patients to take Amitiza orally with food and water to reduce the occurrence of nausea.

• Swallow capsules whole and do not break apart or chew

17.1 Diarrhea

Inform patients that they may experience diarrhea during treatment with Amitiza. Instruct patients to discontinue Amitiza and contact their healthcare provider if severe diarrhea occurs.

Syncope and Hypotension

Inform patients that they may experience syncope and hypotension after taking the first dose or subsequent doses of Amitiza. Syncope and hypotension generally resolve prior to the next dose, but may recur with repeat dosing. Instruct patients to discontinue Amitiza and to contact their healthcare provider if these reactions occur. Inform patients that other adverse reactions may increase the risk of syncope and hypotension, such as diarrhea or vomiting.

Dyspnea

Inform patients that they may experience dyspnea within an hour of the first dose. Dyspnea generally resolves within 3 hours, but may recur with repeat dosing. Instruct patients to inform their healthcare provider if dyspena occurs.