Safety Profile

Adverse Reactions

A WELL-ESTABLISHED SAFETY PROFILE

Adverse reactions occurring in ≥20% (all grades) of patients treated with TAFINLAR + MEKINIST^1,2,a

	TAFINLAR + MEKINIST (N=93)
Adverse reactions	All grades, %	Grades 3 and 4, %
General
Pyrexia	55	5
Fatigue^b	51	5
Edema^c	28	0
Chills	23	1.1
Gastrointestinal
Nausea	45	0
Vomiting	33	3.2
Diarrhea	32	2.2
Decreased appetite	29	0
Skin
Dry skin	31	1.1
Rash^d	28	3.2
Vascular
Hemorrhage^e	23	3.2
Respiratory system
Cough	22	0
Dyspnea	20	5

^aNational Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
^bIncludes fatigue, malaise, and asthenia.
^cIncludes peripheral edema, edema, and generalized edema.
^dIncludes rash, rash generalized, rash papular, rash macular, rash maculopapular, and rash pustular.
^eIncludes hemoptysis, hematoma, epistaxis, purpura, hematuria, subarachnoid hemorrhage, gastric hemorrhage, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, and retroperitoneal hemorrhage.

Other clinically important adverse reactions for TAFINLAR observed in <10% of patients with NSCLC receiving TAFINLAR administered with MEKINIST were:

Gastrointestinal: Pancreatitis

Renal and Urinary: Tubulointerstitial nephritis

Treatment-Emergent Laboratory Abnormalities

Treatment-emergent laboratory abnormalities occurring at ≥20% (all grades) of patients receiving TAFINLAR + MEKINIST^1,2

	TAFINLAR + MEKINIST (N=93)
	All grades, %	Grades 3 and 4, %
Chemistry^a
Hyperglycemia	71	9
Hyponatremia	57	17
Hypophosphatemia	36	7
Increased creatinine	21	1.1
Hepatic^a
Increased blood alkaline phosphatase	64	0
Increased AST	61	4.4
Increased ALT	32	6
Hematology^b
Leukopenia	48	8
Anemia	46	10
Neutropenia	44	8
Lymphopenia	42	14

ALT, alanine aminotransferase; AST, aspartate aminotransferase.
^aFor these laboratory tests the denominator is 90.
^bFor these laboratory tests the denominator is 91.

Discontinuation Rates

PERCENTAGES OF PATIENTS WHOSE DOSE OF TAFINLAR + MEKINIST WAS DISCONTINUED, REDUCED, OR INTERRUPTED DUE TO ADVERSE REACTIONS

TAFINLAR

18% TAFINLAR discontinuation rate due to adverse reactions; the most common were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%)¹
Adverse reactions leading to dose reductions of TAFINLAR occurred in 35% of patients receiving TAFINLAR + MEKINIST; the most common were pyrexia (10%), diarrhea (4.3%), nausea (4.3%), vomiting (4.3%), and neutropenia (3.2%)¹
Adverse reactions leading to dose interruptions of TAFINLAR occurred in 62% of patients; the most common were pyrexia (27%), vomiting (11%), neutropenia (8%), and chills (6%)¹

MEKINIST

19% MEKINIST discontinuation rate due to adverse reactions; the most common were pyrexia (2.2%), ejection fraction decreased (2.2%), and respiratory distress (2.2%)²
Adverse reactions leading to dose reductions of MEKINIST occurred in 30% of patients receiving MEKINIST + TAFINLAR; the most common were pyrexia (5%), nausea (4.3%), vomiting (4.3%), diarrhea (3.2%), and neutropenia (3.2%)²
Adverse reactions leading to dose interruptions of MEKINIST occurred in 57% of patients receiving MEKINIST + TAFINLAR; the most common were pyrexia (16%), vomiting (10%), neutropenia (8%), nausea (5%), and ejection fraction decreased (5%)²

Incidence of Pyrexia

PYREXIA WAS ONE OF THE MOST COMMON ADVERSE REACTIONS WITH TAFINLAR + MEKINIST, LEADING TO DISCONTINUATION IN 2.2% OF PATIENTS^1,2

Incidence of pyrexia in the NSCLC study (N=93)³

55% of patients experienced pyrexia

Incidence of pyrexia in metastatic NSCLC with TAFINLAR + MEKINIST

Pyrexia occurred in patients taking TAFINLAR + MEKINIST in the NSCLC study

No patients experienced grade 4 pyrexia
2.2% of patients discontinued TAFINLAR + MEKINIST due to pyrexia

In patients receiving the combination who experienced fever^3,4

Instances, duration, and time to first occurrence of pyrexia in metastatic NSCLC with TAFINLAR + MEKINIST

Grade 1: Temperature of 100.4 °F to 102.2 °F
Grade 2: Temperature of 102.3 °F to 104 °F
Grade 3: Temperature of >104 °F for ≤24 hours
Grade 4: Temperature of >104 °F for >24 hours

PATIENT COUNSELING

Inform patients that fever is common during treatment with TAFINLAR + MEKINIST but may also be serious. When taking TAFINLAR + MEKINIST, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever
Advise patients to tell their health care provider right away if they get a fever during treatment with TAFINLAR + MEKINIST

DON'T LET PYREXIA GET IN THE WAY OF YOUR PATIENT'S TREATMENT

In patients treated with combination therapy across clinical studies, fever occurred in 58% of patients receiving TAFINLAR with MEKINIST. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in <1% of patients.^1,2

THREE SIMPLE STEPS TOWARDS PYREXIA MANAGEMENT^1,2,a

PYREXIA (≥100.4 °F)	1	Interrupt TAFINLAR + MEKINIST at the onset of pyrexia (≥100.4 °F) OR first symptom in case of recurrence.
	2	Manage until pyrexia (100.4 °F-104 °F) resolves until febrile reactions resolve for at least 24 hours for pyrexia >104 °F or fever complicated by rigors, hypotension, dehydration, or renal failure, OR discontinue permanently
	3	Restart at same or lower dose for pyrexia (100.4 °F-104 °F) at a lower dose for pyrexia >104 °F or fever complicated by rigors, hypotension, dehydration, or renal failure
Manage pyrexia with antipyretics or corticosteroids, depending on episode and severity
Antipyretics can be used to help manage pyrexia, including as secondary prophylaxis when resuming TAFINLAR + MEKINIST if patient had a prior episode of severe febrile reaction or fever associated with complications.		Corticosteroids can be considered and administered for at least 5 days for second or subsequent pyrexia if temperature doesn't return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications, such as dehydration, hypotension, renal failure, or severe chills/rigors, and there is no evidence of active infection.	Monitor renal function and serum creatinine during and following severe pyrexia.

^aSee the Prescribing Information for TAFINLAR and Prescribing Information for MEKINIST for additional details.

Recommended Dose Modifications for Adverse Reactions

Severity of Adverse Reaction^a	TAFINLAR^1,b	MEKINIST^2,b
Hemorrhage
Grade 3	Withhold TAFINLAR If improved to grade 0/1, resume TAFINLAR at lower dose If not improved, permanently discontinue TAFINLAR	Withhold MEKINIST If improved, resume MEKINIST at lower dose If not improved, permanently discontinue MEKINIST
Grade 4	Permanently discontinue TAFINLAR	Permanently discontinue MEKINIST
New Primary Malignancies
Noncutaneous RAS-mutation–positive malignancies	Permanently discontinue TAFINLAR	No dose modifications recommended for MEKINIST
Venous Thromboembolism
Uncomplicated DVT or PE	No dose modifications recommended for TAFINLAR	Withhold MEKINIST for up to 3 weeks If improved to grade 0/1, resume MEKINIST at a lower dose If not improved, permanently discontinue MEKINIST
Life-threatening PE	Dose modifications are not included in TAFINLAR Prescribing Information	Permanently discontinue MEKINIST
Cardiomyopathy
Asymptomatic, absolute decrease in LVEF of 10% or greater from baseline and is below institutional LLN from pretreatment value	Dose modifications are not included in TAFINLAR Prescribing Information	Withhold MEKINIST for up to 4 weeks If improved to normal LVEF value, resume MEKINIST at a lower dose If not improved to normal LVEF value, permanently discontinue MEKINIST
Symptomatic cardiomyopathy or congestive heart failure Absolute decrease in LVEF of greater than 20% from baseline that is below LLN	Withhold TAFINLAR until LVEF improves to at least the institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, then resume at same dose	Permanently discontinue MEKINIST
Ocular Toxicities
Retinal pigment epithelial detachment	No dose modifications recommended for TAFINLAR	Withhold MEKINIST for up to 3 weeks If improved, resume MEKINIST at same or lower dose If not improved, permanently discontinue MEKINIST or resume MEKINIST at lower dose
Retinal vein occlusion	No dose modifications recommended for TAFINLAR	Permanently discontinue MEKINIST
Uveitis (including iritis and iridocyclitis) that is mild or moderate but does not respond to ocular therapy Severe uveitis	Withhold TAFINLAR for up to 6 weeks If improved to grade 0/1, then resume TAFINLAR at same or lower dose If not improved, permanently discontinue TAFINLAR	No dose modifications recommended for MEKINIST
Pulmonary
Interstitial lung disease/pneumonitis	No dose modifications recommended for TAFINLAR	Permanently discontinue MEKINIST
Febrile Reactions
Fever of 100.4 °F to 104 °F (or first symptoms in case of recurrence)	Withhold TAFINLAR and MEKINIST until fever resolves, then resume TAFINLAR and MEKINIST at same or lower dose
Fever higher than 104 °F Fever complicated by rigors, hypotension, dehydration, or renal failure	Withhold TAFINLAR and MEKINIST until febrile reactions resolve for at least 24 hours, then resume at lower dose Or Permanently discontinue TAFINLAR and MEKINIST
Skin Toxicities
Intolerable grade 2 Grade 3 or 4	Withhold TAFINLAR and MEKINIST for up to 3 weeks If improved, resume TAFINLAR and MEKINIST at a lower dose If not improved, permanently discontinue TAFINLAR and MEKINIST
Severe cutaneous adverse reactions	Permanently discontinue TAFINLAR and MEKINIST
Other Adverse Reactions
Intolerable grade 2 Any grade 3	Withhold TAFINLAR and MEKINIST If improved to grade 0/1, resume TAFINLAR and MEKINIST at a lower dose If not improved, permanently discontinue TAFINLAR and MEKINIST
First occurrence of any grade 4	Withhold TAFINLAR and MEKINIST until adverse reaction improves to grade 0/1, resume at a lower dose Or Permanently discontinue TAFINLAR and MEKINIST
Recurrent grade 4	Permanently discontinue TAFINLAR and MEKINIST

DVT, deep vein thrombosis; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; PE, pulmonary embolism; RAS, monomeric G protein.

^aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^bSee recommended dose reductions of TAFINLAR and MEKINIST under Dosing and Administration tab.

Next: Dosing & Administration

References: 1. Tafinlar. Prescribing information. Novartis Pharmaceuticals Corp. 2. Mekinist. Prescribing information. Novartis Pharmaceuticals Corp. 3. Data on file. CDRB436E2201 Interim Clinical Study Report. Novartis Pharmaceuticals Corp; 2017. 4. National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Updated November 27, 2017. Accessed November 16, 2023. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf

Safety Profile

TAFINLAR

MEKINIST

PATIENT COUNSELING

DON'T LET PYREXIA GET IN THE WAY OF YOUR PATIENT'S TREATMENT

1

Interrupt

2

Manage

3

Restart

IMPORTANT SAFETY INFORMATION

INDICATION