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.

TIBSOVO (NDA-211192)

(IVOSIDENIB)

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

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10/24/2023 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Differentiation Syndrome in AML and MDS

Additions and/or revisions underlined:

Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal.

Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased.

In the combination study AG120-C-009, 15% (11/71) patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome [see Adverse Reactions (6.1)]. Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment.

In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1)]. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

In the monotherapy clinical trial AG120-C-001, 11% (2/19) of patients with relapsed or refractory MDS treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1)]. Of the 2 patients who experienced differentiation syndrome, both recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

…

5.2 QTc Interval Prolongation

Additions and/or revisions underlined:

…

Of the 265 patients with hematological malignancies, including patients with AML and MDS, treated with TIBSOVO monotherapy in the clinical trial (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1)]. One patient developed ventricular fibrillation attributed to TIBSOVO. The clinical trial excluded patients with baseline QTc of ? 450 msec (unless the QTc ? 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.

…

5.3 Guillain-Barré Syndrome

Additions and/or revisions underlined:

Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Guillain-Barré syndrome occurred in 0.8% (2/265) of patients treated with TIBSOVO in study AG120-C-001 [see Adverse Reactions (6.1)].

Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain- Barré syndrome [see Dosage and Administration (2.3)].

6 Adverse Reactions

Additions and/or revisions underlined:

The following clinically significant adverse reactions are described elsewhere in the labeling:

Differentiation Syndrome in AML and MDS [see Warnings and Precautions (5.1)]
QTc Interval Prolongation [see Warnings and Precautions (5.2)]
Guillain-Barré Syndrome [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 304 patients who received TIBSOVO in the clinical studies for AML and MDS, 75% were 65 years of age or older and 35% were 75 years or older.

Of the 124 patients with cholangiocarcinoma treated with TIBSOVO in Study AG120-C-005, 37% were 65 years of age or older and 11% were 75 years or older.

No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about TIBSOVO? TIBSOVO may cause serious side effects, including:

Differentiation Syndrome. Differentiation syndrome is a common condition that affects your blood cells and may be life-threatening or lead to death. Differentiation syndrome in adults with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has happened as early as 1 day and up to 3 months after starting TIBSOVO. Call your healthcare provider or go to the nearest hospital emergency room right away if you develop any of the following symptoms of differentiation syndrome during treatment with TIBSOVO:

…

What is TIBSOVO?

TIBSOVO is a prescription medicine used to treat adults with an isocitrate dehydrogenase-1 (IDH1) mutation with:

acute myeloid leukemia (AML):
- with newly diagnosed AML treated in combination with azacitidine, or alone, who are 75 years or older or who have health problems that prevent the use of certain chemotherapy treatments.
- when the disease has come back or has not improved after previous treatment(s).
myelodysplastic syndrome (MDS):
- when the disease has come back or has not improved after previous treatment(s).
bile duct cancer (cholangiocarcinoma):

with bile duct cancer that has spread and
who have already received previous treatment(s).

Your healthcare provider will perform a test to make sure that TIBSOVO is right for you. It is not known if TIBSOVO is safe and effective in children.

…

What are the possible side effects of TIBSOVO? TIBSOVO may cause serious side effects, including:

See “What is the most important information I should know about TIBSOVO?”

Changes in the electrical activity of your heart called QTc prolongation. QTc prolongation can cause irregular heartbeats that can be life-threatening. Your healthcare provider will check the electrical activity of your heart with a test called an electrocardiogram (ECG) before and during treatment

…

The most common side effects of TIBSOVO when used in adults with Myelodysplastic Syndromes (MDS) include:

changes in certain kidney function tests
decreased levels of sodium in the blood
changes in certain blood cell counts
pain or sores in your mouth or throat
joint pain, back pain, or neck pain
decreased appetite
decreased levels of albumin in the blood
muscle pain
changes in liver function tests
decreased levels of phosphorus in the blood
fatigue
itchy skin
diarrhea
rash
cough

…

How should I store TIBSOVO?

Store TIBSOVO at room temperature between 68°F to 77°F (20°C to 25°C).
Do not remove the desiccant canister from the bottle.

Keep TIBSOVO and all medicines out of the reach of children.

…

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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

Differentiation Syndrome in AML and MDS

…

Dosing and Storage Instructions

Advise patients to swallow tablets whole and to not split, crush, or chew TIBSOVO tablets.
Advise patients to avoid taking TIBSOVO with a high-fat meal.
Instruct patients that if a dose of TIBSOVO is vomited, not to take an additional dose, and wait until the next scheduled dose is due. If a dose of TIBSOVO is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 12 hours. Patients can return to the normal schedule the following day.
Store TIBSOVO at room temperature from 20°C to 25°C (68°F to 77°F).
Advise patients not to remove the desiccant canister from the bottle.

05/25/2022 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Differentiation Syndrome in AML

Additions underlined

In the combination study AG120-C-009, 15% (11/71) patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome [see Adverse Reactions (6.1)]. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment.

…

5.2 QTc Interval Prolongation

Additions underlined

Patients treated with TIBSOVO can develop QT (QTc) prolongation [see Clinical Pharmacology (12.2)] and ventricular arrhythmias.

Of the 71 patients with newly diagnosed AML treated with TIBSOVO in combination with azacitidine in the clinical trial (Study AG120-C-009), 10 (14%) were found to have a heart-rate corrected QT interval (using Fridericia’s method) (QTcF) greater than 500 msec and 15 out of 69 (22%) had an increase from baseline QTcF greater than 60 msec [see Adverse Reactions (6.1)]. The clinical trial excluded patients with a QTcF greater than or equal to 470 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g. NYHA Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome).

Of the 258 patients with hematological malignancies treated with TIBSOVO monotherapy in the clinical trial (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and14% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1)]. One patient developed ventricular fibrillation attributed to TIBSOVO. The clinical trial excluded patients with baseline QTc of greater than or equal to 450 msec (unless the QTc greater than or equal to 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive additions and/or revisions; please refer to label for complete information.

8 Use in Specific Populations

8.5 Geriatric Use

Additions underlined

Of the 72 patients with newly diagnosed AML treated with TIBSOVO in combination with azacitidine, 94% were 65 years of age or older, and 54% were 75 years or older. Of the 34 patients with newly diagnosed AML treated with TIBSOVO monotherapy, 97% were 65 years of age or older, and 56% were 75 years or older. Of the 179 patients with relapsed or refractory AML treated with TIBSOVO monotherapy, 63% were 65 years of age or older and 22% were 75 years or older. Of the 124 patients with cholangiocarcinoma treated with TIBSOVO in Study AG120-C-005, 37% were 65 years of age or older and 11% were 75 years or older.

No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.

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

MEDICATION GUIDE

Additions underlined

…

TIBSOVO may cause serious side effects, including:

Differentiation Syndrome. Differentiation syndrome is a serious condition that affects your blood cells and may be life-threatening or lead to death.

…

What is TIBSOVO?

TIBSOVO is a prescription medicine used to treat:

acute myeloid leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation in:
- adults with newly diagnosed AML treated in combination with TIBSOVO and azacitidine who are 75 years or older or who have health problems that prevent the use of certain chemotherapy treatments.
  …
  The most common side effects of TIBSOVO when used in combination with azacitidine or alone in adults with AML include:

changes in certain blood cell counts
shortness of breath
diarrhea
uric acid increased
increased blood sugar
stomach (abdominal) pain
fatigue
changes in certain kidney function tests
changes in certain liver function tests
pain or sores in your mouth or throat
swelling of arms or legs
rash
decreased levels of electrolytes in the blood
irregular heart rhythm or heartbeat (QTc prolongation)
nausea
vomiting
differentiation syndrome
decreased appetite
muscle pain
joint pain
…

08/25/2021 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Differentiation Syndrome in AML

5.2 QTc Interval Prolongation

Of the 258 patients with hematological malignancies treated with TIBSOVO in the clinical trial (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec … The clinical trial excluded patients with baseline QTc of greater than or equal to 450 msec (unless the QTc greater than or equal to 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.

Of the 123 patients with cholangiocarcinoma treated with TIBSOVO in the clinical trial (Study AG120-C-005), 2% were found to have a QTc interval greater than 500 msec. and 5% of patients had an increase from baseline QTc greater than 60 msec. The clinical trial excluded patients with a heart-rate corrected QT interval (using Fridericia’s formula) (QTcF) greater than or equal to 450 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g. heart failure, hypokalemia, family history of long QT interval syndrome).

5.3 Guillain-Barre Syndrome

Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in study AG120-C-001.

6 Adverse Reactions

Addition and/or revisions to bulleted line listing:

Differentiation Syndrome in AML [see Warnings and Precautions (5.1)]
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
Acute Myeloid Leukemia
The safety of TIBSOVO as a single agent at 500 mg daily was evaluated in 213 patients with AML in Study AG120-C-001 [see Clinical Studies (14.1 and 14.2)] …
Newly added information:
Locally Advanced or Metastatic Cholangiocarcinoma
The safety of TIBSOVO was studied in patients with previously treated, locally advanced or metastatic cholangiocarcinoma in Study AG120-C-005 [see Clinical Studies (14.3)]. Patients received at least one dose of either TIBSOVO 500 mg daily (N=123) or placebo (N=59). The median duration of treatment was 2.8 months (range 0.1 to 34.4 months) with TIBSOVO.
Serious adverse reactions occurred in 34% of patients receiving TIBSOVO. Serious adverse reactions in greater than or equal to 2% of patients in the TIBSOVO arm were pneumonia, ascites, hyperbilirubinemia, and jaundice cholestatic. Fatal adverse reactions occurred in 4.9% of patients receiving TIBSOVO, including sepsis (1.6%) and pneumonia, intestinal obstruction, pulmonary embolism, and hepatic encephalopathy (each 0.8%) TIBSOVO was permanently discontinued in 7% of patients. The most common adverse reactions leading to permanent discontinuation was acute kidney injury (1.6%).
Dose interruptions due to adverse reactions occurred in 29% of patients treated with TIBSOVO. The most common (>2%) adverse reactions leading to dose interruption were hyperbilirubinemia, alanine aminotransferase increased, aspartate aminotransferase increased, ascites, and fatigue.
Dose reductions of TIBSOVO due to an adverse reaction occurred in 4.1% of patients. Adverse reactions leading to dose reduction were electrocardiogram QT prolonged (3.3%) and neuropathy peripheral (0.8%).
The most common adverse reactions (greater than or equal to 15%) were fatigue, nausea, abdominal pain, diarrhea, cough, decreased appetite, ascites, vomiting, anemia, and rash.
Adverse reactions and laboratory abnormalities observed in Study AG120-C-005 are shown in Tables 6 and 7.
Table 6: Adverse Reactions Occurring in greater than or equal to 10% of Patients Receiving TIBSOVO in Study AG120-C-005 Newly added table; please refer to label for complete information.
Table 7: Selected Laboratory Abnormalities Occurring in greater than or equal to 10% of Patients Receiving TIBSOVO in Study AG120-C-0051 Newly added table; please refer to label for complete information.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 34 patients with newly diagnosed AML treated with TIBSOVO, 97% were 65 years of age or older, and 56% were 75 years or older. Of the 179 patients with relapsed or refractory AML treated with TIBSOVO, 63% were 65 years of age or older and 22% were 75 years or older. Of the 124 patients with cholangiocarcinoma treated with TIBSOVO in Study

AG120-C-005, 37% were 65 years of age or older and 11% were 75 years or older.

No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.

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

MEDICATION GUIDE

additions and/or revisions underlined:

What is the most important information I should know about TIBSOVO?

TIBSOVO may cause serious side effects, including:

Differentiation Syndrome. Differentiation syndrome is a condition that affects your blood cells and may be life-threatening or lead to death if not treated. Differentiation syndrome in adults with acute myeloid leukemia (AML) has happened as early as 1 day and up to 3 months after starting TIBSOVO.
What is TIBSOVO?
TIBSOVO is a prescription medicine used to treat:
adults with bile duct cancer (cholangiocarcinoma) that has spread:
- who have already received previous treatment(s) and
- whose tumor has a certain type of abnormal IDH1 mutation

What are the possible side effects of TIBSOVO?

TIBSOVO may cause serious side effects, including:

The most common side effects of TIBSOVO in adults with AML include: …

Newly added information:

The most common side effects of TIBSOVO in adults with Cholangiocarcinoma include:

fatigue
nausea
abdominal pain
diarrhea
cough
decreased appetite
fluid and swelling in your stomach area
vomiting
hemoglobin decreased (anemia)
rash
changes in liver function tests

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Differentiation Syndrome in AML

Advise patients with AML being treated with TIBSOVO of the risks of developing

differentiation syndrome as early as 1 day after start of therapy and during the first 3 months on treatment.

Gastrointestinal Adverse Reactions

Advise patients on the risks of experiencing gastrointestinal reactions such as diarrhea, nausea, mucositis, constipation, vomiting, decreased appetite, ascites and abdominal pain.

05/02/2019 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Differentiation Syndrome

(additions underlined)

In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. …

5.2 QTc Interval Prolongation

(additions underlined)

Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. Of the 258 patients with hematological malignancies treated with TIBSOVO in the clinical trial, 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec. One patient developed ventricular fibrillation attributed to TIBSOVO. The clinical trial excluded patients with baseline QTc of greater than or equal to 450 msec (unless the QTc greater than or equal to450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.

…

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions, please refer to label for more information)

8 Use in Specific Populations

8.5 Geriatric Use

(additions underlined)

Thirty-three (97%) of the 34 patients with newly diagnosed AML in the clinical study were 65 years of age or older, and 19 patients (56%) were 75 years or older. One hundred and twelve (63%) of the 179 patients with relapsed or refractory AML in the clinical study were 65 years of age or older and 40 patients (22%) were 75 years or older. No overall differences in effectiveness or safety were observed between patients with relapsed or refractory AML who were 65 years and older and younger patients.

8.6 Renal Impairment

(new subsection added)

No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73m2, MDRD). The pharmacokinetics and safety of ivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis are unknown. For patients with pre-existing severe renal impairment or who are requiring dialysis, consider the risks and potential benefits before initiating treatment with TIBSOVO.

8.7 Hepatic Impairment

(new subsection added)

No modification of the starting dose is recommended for patients with mild or moderate (Child- Pugh A or B) hepatic impairment .The pharmacokinetics and safety of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) are unknown. For patients with pre-existing severe hepatic impairment, consider the risks and potential benefits before initiating treatment with TIBSOVO.