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.

PROMACTA (NDA-207027)

(ELTROMBOPAG OLAMINE)

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

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07/24/2018 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added, directly underneath Table 4

a Includes PTs of Urinary tract infection, Cystitis, Urinary tract infection bacterial, and Bacteruria

Additions and/or revisions underlined:

… Seventy-two percent of patients had preexisting risk factors, including corticosteroid use. The safety of PROMACTA was also assessed in all patients treated in 7 adult chronic ITP clinical trials (N=763 PROMACTA-treated patients and 179 placebo-treated patients). Thromboembolic events were reported in 6% of PROMACTA-treated patients versus 0% of placebo-treated patients and thrombotic microangiopathy with acute renal failure was reported in less than 1% of PROMACTA-treated patients versus 0% of placebo-treated patients …

Newly added, directly underneath Table 7

a Includes PTs of Insomnia, Initial insomnia, and Poor quality sleep

Additions and/or revisions underlined:

… In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with PROMACTA and 5% of patients treated with placebo.

The safety of PROMACTA was also assessed in all patients treated with PROMACTA in the two controlled trials, including patients who initially received PROMACTA in the pre-antiviral treatment phase of the trial and were later randomized to the placebo arm (N=1520 PROMACTA-treated patients). Hepatic failure was reported in 0.8% of PROMACTA-treated patients and 0.4% of placebo-treated patients …

Following Table 8, additions and/or revisions underlined:

Rash and hyperbilirubinemia were reported in 7% of patients; cataract was reported in 2% of patients.

In this trial, concurrent ALT or AST greater than 3 x ULN with total bilirubin greater than 1.5 x ULN were reported in 5% of patients. Total bilirubin greater than 1.5 x ULN occurred in 14% of patients.

In this trial, patients had bone marrow aspirates …

7 Drug Interactions

7.4 Peginterferon alfa-2a/b Therapy

Additions and/or revisions underlined:

No dose adjustments are recommended when PROMACTA is coadministered with peginterferon alfa-2a (PEGASYS®) or -2b (PEGINTRON®)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined below:

Risk Summary

Available data from a small number of published case reports and postmarketing experience with PROMACTA use in pregnant women are insufficient to assess any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, oral administration of eltrombopag to pregnant rats during organogenesis resulted in embryolethality and reduced fetal weights at maternally toxic doses. These effects were observed at doses resulting in exposures that were 6 times the human clinical exposure based on AUC in patients with chronic ITP at 75 mg/day, and 3 times the AUC in patients with chronic hepatitis C at 100 mg/day.

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 of miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an early embryonic development study …

… In an embryo-fetal development study eltrombopag was administered orally to pregnant rats during the period of organogenesis at doses of 10, 20, or 60 mg/kg/day …

… In an embryo-fetal development study eltrombopag was administered orally to pregnant rabbits during the period of organogenesis at doses of 30, 80, or 150 mg/kg/day …

… In a pre- and post-natal developmental toxicity study in pregnant rats (F0), oral eltrombopag was administered from gestation day 6 through lactation day 20. No adverse effects …

8.2 Lactation

Risk Summary

PLLR conversion; additions and/or revisions underlined below:

There are no data regarding the presence of eltrombopag or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. However, eltrombopag was detected in the pups of lactating rats 10 days postpartum suggesting the potential for transfer during lactation. Due to the potential for serious adverse reactions in a breastfed child from PROMACTA, breastfeeding is not recommended during treatment.

8.3 Females and Males of Reproductive Potential

Newly added subsection:

Contraception

Based on animal reproduction studies, PROMACTA can cause fetal harm when administered to a pregnant woman. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using PROMACTA during treatment and for at least 7 days after stopping treatment with PROMACTA.

8.5 Geriatric Use

Additions and/or revisions underlined:

… Of the 1439 patients in two randomized clinical trials of PROMACTA in patients with chronic hepatitis C and thrombocytopenia, 7% were 65 years of age and over, while less than 1% were 75 years of age and over. Of 43 patients in a single-arm, open-label trial of PROMACTA in patients with severe aplastic anemia, 33% were 65 years of age and over, while 5% were 75 years of age and older. No overall differences in safety …

8.6 Hepatic Impairment

Additions and/or revisions underlined:

… No dosage adjustment is recommended in patients with chronic hepatitis C and hepatic impairment.

8.7 Ethnicity

Additions and/or revisions underlined:

Reduce the initial dose of PROMACTA for patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, or Korean) with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia. No reduction in the initial dose of PROMACTA is recommended in patients of Asian ethnicity with chronic hepatitis C.

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

PATIENT COUNSELING INFORMATION

Addition of the following:

Lactation

Advise women not to breastfeed during treatment with PROMACTA

05/25/2018 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Increased Risk of Death and Progression of Myelodysplastic Syndromes (MDS) to Acute Myeloid Leukemia (AML)

(Newly Added Subsection)

A randomized, double-blind, placebo-controlled, multicenter trial in patients with International Prognostic Scoring System (IPSS) intermediate-1, intermediate-2 or high risk MDS with thrombocytopenia, receiving azacitidine in combination with either PROMACTA (n=179) or placebo (n=177) was terminated due to lack of efficacy and safety reasons, including increased progression to AML. Patients received PROMACTA or placebo at a starting dose of 200 mg once daily, up to a maximum of 300 mg once daily, in combination with azacitidine for at least six cycles. The incidence of death (overall survival) was 32% (57/179) in the PROMACTA arm versus 29% (51/177) in the placebo arm (HR [95% CI] = 1.42 [0.97, 2.08], showing an increased relative risk of death in this trial by 42% in the PROMACTA arm). The incidence of progression to AML was 12% (21/179) in the PROMACTA arm versus 6% (10/177) in the placebo arm (HR [95% CI] = 2.66 [1.31, 5.41], showing an increased relative risk of progression to AML in this trial by 166% in the PROMACTA arm.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions associated with PROMACTA are described in other sections.

Increased Risk of Death and Progression of Myelodysplastic Syndromes to Acute Myeloid Leukemia

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Administration of PROMACTA

Inform patients or caregivers to use a new oral dosing syringe to prepare each dose of PROMACTA for oral suspension.

07/05/2017 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Chronic Immune (Idiopathic) Thrombocytopenia: Adults:…

In the three controlled chronic ITP trials, cataracts developed or worsened in 7% of patients treated with PROMACTA and 7% of patients in the placebo group. All patients had documented, preexisting risk factors for cataractogenesis including corticosteroid use. In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with PROMACTA. Seventy-two percent of patients had preexisting risk factors, including corticosteroid use.

Pediatric Patients:…

In the two controlled clinical chronic ITP trials, cataracts developed or worsened in 2 (1%) patients treated with PROMACTA. Both patients had received chronic oral corticosteroids, a risk factor for cataractogenesis.

Chronic Hepatitis C-associated Thrombocytopenia:…

In the two controlled clinical trials in patients with chronic hepatitis C, cataracts developed or worsened in 8% of patients treated with PROMACTA and 5% of patients treated with placebo.

Severe Aplastic Anemia:…

Rash was reported in 7% of patients; cataract was reported in 2% of patients.

03/09/2017 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

Chronic Hepatitis C-associated Thrombocytopenia: In the two placebo-controlled trials, 955 patients with chronic hepatitis C-associated thrombocytopenia received PROMACTA….

Rash was reported in 9% and 7% of patients receiving PROMACTA and placebo, respectively.

In the two controlled clinical trials in patients with chronic hepatitis C, hyperbilirubinemia was reported in 8%

of patients receiving PROMACTA compared with 3% for placebo. Total bilirubin greater than or equal to

1.5 x ULN was reported in 76% and 50% of patients receiving PROMACTA and placebo, respectively. ALT or AST greater than or equal to 3 x ULN was reported in 34% and 38% of patients for PROMACTA and placebo, respectively.

…

Severe Aplastic Anemia: In the single-arm, open-label trial, 43 patients with severe aplastic anemia received PROMACTA. Eleven patients (26%) were treated for greater than 6 months and 7 patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache.

Rash was reported in 7% of patients.

In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had complex changes in chromosome 7.

6.2 Postmarketing Experience

(addition underline)

The following adverse reactions have been identified during post approval use of PROMACTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Vascular Disorders: Thrombotic microangiopathy with acute renal failure.

Skin and Subcutaneous Tissue Disorders: Skin discoloration including hyperpigmentation and skin yellowing.

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

Medication Guide

(additions and revisions; please refer to label)

10/12/2016 (SUPPL-1)

Approved Drug Label (PDF)

Boxed Warning

CHRONIC HEPATITIS C (addition underlined)

PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

5 Warnings and Precautions

5.2 Hepatotoxicity (addition underlined)

PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity.

Isolated cases of severe liver injury were identified in clinical trials. The elevation of liver laboratory values occurred approximately three months after initiation of PROMACTA. In all cases, the event resolved following PROMACTA discontinuation.

5.3 Thrombotic/Thromboembolic Complications (addition underlined)

Thrombotic/thromboembolic complications may result from increases in platelet counts with PROMACTA. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts.

5.4 Cataracts (revision underlined)

… In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular examination prior to therapy with PROMACTA.

6 Adverse Reactions

6.1 Clinical Trials Experience (revision underlined)

Chronic Immune (Idiopathic) Thrombocytopenia:

…The data described below reflect exposure of PROMACTA to patients with chronic ITP aged 18 to 85 years, of whom 66% were female, in three placebo-controlled trials and one open-label extension trial. PROMACTA was administered to 330 patients for at least 6 months and 218 patients for at least 1 year.

Among 302 patients with chronic ITP who received PROMACTA in the single-arm extension trial, the adverse reactions occurred in a pattern similar to that seen in the placebo-controlled trials.

Seventeen of the patients treated with PROMACTA in the controlled trials with hepatobiliary laboratory abnormalities were re-exposed to PROMACTA in the extension trial. Eight of these patients again experienced liver test abnormalities (less than or equal to Grade 3) resulting in discontinuation of PROMACTA in one patient. In the extension chronic ITP trial, six additional patients had PROMACTA discontinued due to liver test abnormalities (less than or equal to Grade 3).

In clinical trials in patients with chronic ITP, one patient treated with PROMACTA (less than1%) experienced drug- induced liver injury.

Pediatric Patients: The data described below reflect median exposure to PROMACTA of 91 days for 107 pediatric patients (aged 1 to 17 years) with chronic ITP, of whom 53% were female, across the randomized phase of two placebo-controlled trials.

Table 6 presents the most common adverse drug reactions (experienced by greater than or equal to 3% of pediatric patients 1 year and older receiving PROMACTA) across the two placebo-controlled trials, with a higher incidence for PROMACTA versus placebo.

Table 6. Adverse Reactions (greater than or equal to 3%) with a Higher Incidence for PROMACTA versus Placebo from Two Placebo-controlled Trials in Pediatric Patients 1 Year and Older with Chronic Immune (Idiopathic) Thrombocytopenia (please refer to label)

Chronic Hepatitis C-associated Thrombocytopenia:

In clinical trials in patients with chronic hepatitis C, 11 patients treated with PROMACTA (1%) experienced drug-induced liver injury.

7 Drug Interactions

7.1 Polyvalent Cations (Chelation) (addition underlined)

Take PROMACTA at least 2 hours before or 4 hours after any medications or products containing polyvalent cations such as antacids, dairy products, and mineral supplements to avoid significant reduction in absorption of PROMACTA due to chelation.

8 Use in Specific Populations

8.4 Pediatric Use (revisions underlined)

The safety and efficacy of PROMACTA in pediatric patients 1 year and older with chronic ITP were evaluated in two double-blind, placebo-controlled trials. The pharmacokinetics of eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once daily. The safety and efficacy of PROMACTA in pediatric patients younger than 1 year with ITP have not yet been established.

8.8 Ethnicity (addition underlined)

Patients of East Asian ethnicity (i.e., Japanese, Chinese, Taiwanese, and Korean) exhibit higher eltrombopag exposures. A reduction in the initial dose of PROMACTA is recommended for patients of East Asian ancestry with ITP (adult and pediatric patients 6 years and older only) or severe aplastic anemia. No dose reduction is needed in patients of East Asian ethnicity with chronic hepatitis.

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

17 PATIENT COUNSELING INFORMATION (revised)

Please refer to label.