DOSING & MONITORING GUIDELINES

Twice daily, oral dosing for at least 6 months or until unacceptable toxicity or disease progression

DOSING AND ADMINISTRATION WITH REZLIDHIA

Twice Daily Dosing¹

The recommended dose for REZLIDHIA is one 150 mg capsule taken orally twice daily until disease progression or unacceptable toxicity
Patients should take REZLIDHIA about the same time each day. Do not administer 2 doses within 8 hours

On an Empty Stomach¹

REZLIDHIA should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal
Advise patients to swallow capsules whole
Do not break, open, or chew the capsules

At Least 6 Months of Treatment¹

For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response

Missed Dose Guidance¹

If a dose is vomited, do not administer a replacement dose. Wait until the next scheduled dose is due
If a dose is missed or not taken at the usual time, administer the dose as soon as possible and at least 8 hours prior to the next scheduled dose. Return to the normal schedule the following day

MONITORING GUIDELINES

Assess blood counts and blood chemistries, including liver function tests, prior to initiation of REZLIDHIA and for the duration of therapy.¹

Manage any abnormalities promptly. Interrupt dosing or reduce dose for toxicities
See section 2.3 of the Full Prescribing Information or the table below for specific guidance on dose modifications and recommendations for adverse event management

Electrocardiogram monitoring is not required per the Prescribing Information

Recommended Assessment Schedule at Treatment Initiation and Throughout Therapy¹

Month	Frequency of Lab Tests
1	At least once weekly
2	At least once weekly
3	Once every other week
4	Once
5+	Once every other month

DRUG INTERACTIONS WITH STRONG OR MODERATE CYP3A INDUCERS

REZLIDHIA is a CYP3A substrate. Concomitant use of REZLIDHIA with a strong CYP3A inducer decreases REZLIDHIA C_max and AUC, which may reduce efficacy.¹

Concomitant use of REZLIDHIA with a moderate CYP3A inducer may also decrease C_max and AUC, which may also reduce REZLIDHIA efficacy, based on observations from concomitant use with a strong CYP3A inducer.¹

DOSING MODIFICATIONS

Modification, interruption, or discontinuation of REZLIDHIA may be necessary to manage adverse reactions.

Adverse Reactions	Recommended Action	Adverse Reactions and Recommended Actions
Differentiation Syndrome	If differentiation syndrome is suspected, withhold REZLIDHIA until signs and symptoms improve. Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days. Resume REZLIDHIA at 150 mg twice daily after resolution of differentiation syndrome. If a recurrence of differentiation syndrome is suspected, withhold REZLIDHIA and institute treatment per above guidance. After resolution of symptoms, REZLIDHIA may be resumed at a reduced dose of 150 mg once daily for a minimum of 7 days, after which it can be increased to 150 mg twice daily.
Noninfectious leukocytosis	Initiate treatment with hydroxyurea, as per standard practices. Taper hydroxyurea only after leukocytosis improves or resolves.
Grade 3* hepatotoxicity	Withhold REZLIDHIA and monitor liver function tests, twice per week, until laboratory values have returned to baseline or Grade 1* toxicity. Resume REZLIDHIA at a reduced dose of 150 mg once daily and continue monitoring; may increase to 150 mg twice daily if hepatotoxicity resolves to baseline for at least 28 days. If hepatotoxicity (Grade 3) recurs at 150 mg once daily, discontinue REZLIDHIA.
Grade 4* hepatotoxicity or AST or ALT >3x ULN and total bilirubin >2x ULN and alkaline phosphatase <2x ULN in the absence of a clear alternative explanation	Permanently discontinue REZLIDHIA.
Other Grade 3* or higher toxicity considered	Interrupt REZLIDHIA until toxicity resolves to Grade 2* or lower. Resume REZLIDHIA at 150 mg once daily; may increase to 150 mg twice daily if toxicities resolve to Grade 1* or lower for at least 1 week. If Grade 3* or higher toxicity recurs at 150 mg once daily, discontinue REZLIDHIA.

Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03).

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.

Reference:

REZLIDHIA® [package insert], South San Francisco, CA: Rigel Pharmaceuticals, Inc.

REZ_AML-24011 0424

INDICATION AND IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING

INDICATION

REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. 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 REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.

Hepatotoxicity REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.

Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia , rash, lipase increased, mucositis, diarrhea and transaminitis.

DRUG INTERACTIONS

Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.
Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

LACTATION

Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.

GERIATRIC USE

No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.

HEPATIC IMPAIRMENT

In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.

Please see Full Prescribing Information, including Boxed WARNING.