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.

COTELLIC (NDA-206192)

(COBIMETINIB FUMARATE)

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

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10/28/2022 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Hemorrhage

Additions and/or revisions underlined:

… Gastrointestinal tract hemorrhage (3.6% vs 1.2%), reproductive system hemorrhage (2.0% vs 0.4%), and hematuria (2.4% vs 0.8%) also occurred at a higher incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib.

In Trial 2, in patients with histiocytic neoplasms, 19% of patients experienced hemorrhage events (all were of grade 1 severity).

Withhold COTELLIC for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume COTELLIC at a lower dose level …

5.3 Cardiomyopathy

Additions and/or revisions underlined:

… Decreased LVEF resolved to above the LLN or within 10% of baseline in 62% of patients receiving COTELLIC with a median time to resolution of 3 months (range: 4 days to 12 months).

In Trial 2, in patients with histiocytic neoplasms, 8% of patients experienced grade 2 ejection fraction decreased and 12% experienced grade 3-4 events. The median time to first onset of LVEF decrease was 29 days (range 22 days to 114 days). Of the patients with decreased LVEF, all had dose interruption and/or reduction and none required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 60% of patients receiving COTELLIC with a median time to resolution of 31 days (range: 13 days to 126 days).

Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of COTELLIC …

5.4 Severe Dermatologic Reactions

Additions and/or revisions underlined:

… Among patients with Grade 3 or 4 rash events, 95% experienced complete resolution with the median time to resolution of 21 days (range 4 days to 17 months).

In Trial 2, in patients with histiocytic neoplasms, 81% of patients experienced rash events (all were of grade 1-2 severity).

Interrupt, reduce the dose, or discontinue COTELLIC [see Dosage and Administration (2.3)] …

5.5 Serious Retinopathy and Retinal Vein Occlusion

Additions and/or revisions underlined:

… The reported duration of serous retinopathy ranged between 1 day to 15 months. One patient in each arm developed retinal vein occlusion.

In Trial 2, in patients with histiocytic neoplasms, 4% experienced grade 2 retinopathy and 4% experienced grade 3 retinal vascular disorder.

Perform an ophthalmological evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt COTELLIC until visual symptoms improve …

5.6 Hepatoxicity

Additions and/or revisions underlined:

… Concurrent elevation in ALT >3 times the upper limit of normal (ULN) and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >2 X ULN occurred in one patient (0.4%) receiving COTELLIC with vemurafenib and no patients receiving single-agent vemurafenib.

In Trial 2, in patients with histiocytic neoplasms, 9% of the patients receiving COTELLIC experienced grade 3 or 4 aspartate aminotransferase increased and 5% of the patients experienced grade 3 or 4 alanine aminotransferase increased.

Monitor liver laboratory tests before initiation of COTELLIC and monthly during treatment, or more frequently as clinically indicated …

5.7 Rhabdomyolysis

Additions and/or revisions underlined:

… Obtain baseline serum CPK and creatinine levels prior to initiating COTELLIC, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of COTELLIC may be required [see Dosage and Administration (2.3)].

In Trial 2, in patients with histiocytic neoplasms, 27% of patients experienced grade 2 CPK elevation and 27% of patients experienced grade 3-4 CPK elevation.

6 Adverse Reactions

6.1 Clinical Trial Experiences

Additions and/or revisions underlined:

… Unresectable or Metastatic Melanoma

The safety of COTELLIC was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma [see Clinical Studies (14)] …

Table 3. Incidence of Adverse Drug Reactions Occurring in greater than or equal to 10% (All Grades) of Unresectable or Metastatic Melanoma Patients Receiving COTELLIC with Vemurafenib and at a Higher Incidence* than Patients Receiving Vemurafenib in Trial 1

The following clinically relevant adverse reactions (all grades) of COTELLIC were reported with <10% incidence in Trial 1:

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Table 4. Incidence of Laboratory Abnormalities Occurring in greater than or equal to 10% (All Grades) or greater than or equal to 2% (Grades 3–4) of Patients with Unresectable or Metastatic Melanoma in Trial 1*

Histiocytic Neoplasms

The safety of COTELLIC was evaluated in Trial 2, a single-center single-arm trial in patients with histiocytic neoplasms [see Clinical Studies (14)]. In Trial 2, 26 patients with histiocytic neoplasms received COTELLIC 60 mg once daily for 21 days on, then 7 days off, in a 28-day treatment cycle. The median treatment duration was 10.7 months. Table 5 presents adverse reactions in at least 15% of patients reported with histiocytic neoplasms treated with COTELLIC. Table 6 presents laboratory abnormalities of grades greater than or equal to 3 reported in patients with histiocytic neoplasms treated COTELLIC.

In Trial 2, 4 patients (15%) receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. One patient discontinued due to worsening of underlying dyspnea and hypoxia; one patient discontinued due to retinal vascular disorder; one patient discontinued due to hyponatremia; and the other patient discontinued due to pneumonia.

Table 5 Incidence of Adverse Reactions Reported Occurring in greater than or equal to 15% (All Grades) or Any Percentage (Grade greater than or equal to 3) in Patients with Histiocytic Neoplasms Treated with COTELLIC in Trial 2 Newly added table; please refer to label for complete information.

The following clinically relevant adverse reactions (all grades) of COTELLIC were reported with <15% incidence in Trial 2:

Eye disorders: Vision blurred (12%), retinal vascular disorder (4%) and retinopathy (4%).

Gastrointestinal disorders: Stomatitis (12%)

Nervous system disorders: Headache (12%)

Respiratory, thoracic, and mediastinal disorders: Hypoxia (12%), pulmonary edema (4%), and respiratory failure (8%).

Table 6. Incidence of Grade greater than or equal to 3 Laboratory Abnormalities Occurring in Patients with Histiocytic Neoplasms Treated with COTELLIC in Trial 2* Newly added table; please refer to label for complete information.

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

PATIENT INFORMATION

What is COTELLIC?

COTELLIC is a prescription medicine that is used:

Newly added information:

alone to treat adults with a group of blood cancers called histiocytic neoplasms

See “What should I avoid during treatment with COTELLIC?” for information on protecting your skin during treatment with COTELLIC.

The most common side effects of COTELLIC in adults with unresectable or metastatic melanoma include:

Newly added information:

sensitivity to sunlight

The most common side effects of COTELLIC in adults with histiocytic neoplasms include:

acne-like (red and pus filled) bumps on face, scalp, chest or upper back
diarrhea
any infection
tiredness
nausea
swelling of arms, legs or feet or any other parts of your body
dry skin
rash with both flat and raised reddened areas on your skin
itching
indigestion or heartburn
vomiting
urinary tract infection
lung problems

Your healthcare provider will do blood tests during treatment with COTELLIC. The most common changes to blood tests include:

Additions and/or revisions underlined:

increased blood level of creatinine
decreased blood level of phosphate, albumin, sodium, potassium or calcium
decreased blood level of red blood counts
increased blood level of potassium

COTELLIC may cause fertility problems in males and females, which may affect your ability to have a child. Talk to your healthcare provider if this is a concern for you.

These are not all of the possible side effects of COTELLIC.

07/28/2022 (SUPPL-4)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

The safety and effectiveness of COTELLIC have not been established in pediatric patients.

The safety and effectiveness of cobimetinib were assessed, but not established, in a multi-center, open-label, dose-escalation study in 55 pediatric patients aged 2 to 17 years with solid tumors [NCT02639546]. No new safety events were observed in pediatric patients in this trial.

Exposure in pediatric patients who received cobimetinib at the maximum tolerated dosage were lower than those previously observed in adults who received the approved recommended dosage.

…

05/31/2016 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

Hepatic Impairment (update)

Adjustment in the starting dose of COTELLIC is not required in patients with mild (Child-Pugh score A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

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

MG - Severe rash (renamed subsection)

Muscle problems (rhabdomyolysis). COTELLIC can cause muscle problems that can be severe.

Skin Sensitivity to sunlight (photosensitivity). Skin sensitivity to sunlight during treatment with COTELLIC is common and can sometimes be severe.

MG - What are the possible side effects of COTELLIC?

COTELLIC may cause serious side effects, including:

Check your skin regularly and tell your healthcare provider right away if you have any skin changes including:
Your healthcare provider should also check for cancers that may not occur on the skin. Tell our healthcare provider about any new symptoms that develop during treatment with COTELLIC and vemurafenib.
Bleeding problems. COTELLIC can cause serious bleeding problems. Call your healthcare provider and get medical attention right away if you get any signs of bleeding, including:
- cough up or vomit blood
- stomach (abdominal) pain