Retevmo (selpercatinib)

The most common side effects of Retevmo include:

• increased levels ofliver enzymes
• increased bloodsugarlevels
• decrease in white blood cell count
• decreased protein levels (albumin) in the blood
• decreased levels of calcium in the blood
• dry mouth
• diarrhea
• increasedcreatinine(kidney function test)
• high blood pressure
• tiredness
• swelling of your arms, legs, hands, andfeet(peripheraledema)
• decrease inplatelet count
• increasedcholesterol levels
• rash
• decreased levels of salt (sodium) in the blood
• constipation

Retevmo may affectfertilityin females and males, which may affect your ability to have children. Talk to your healthcare provider if this is a concern for you.

These are not all the possible side effects with Retevmo.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Patient Selection

Select patients for treatment with Retevmo based on the presence of a RET gene fusion (NSCLC or thyroidcancer) or specific RET gene mutation (MTC) intumorspecimens or plasma. An FDA-approved test for the detection of RET gene fusions and RET gene mutations is not currently available.

Important Administration Instructions

Retevmo may be taken with or without food unless coadministrated with a proton pump inhibitor (PPI).

Recommended Dosage

The recommended dosage of Retevmo based on body weight is:

• Less than 50 kg: 120 mg
• 50 kg or greater: 160 mg

Take Retevmo orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity.

Swallow the capsules whole. Do not crush or chew the capsules.

Do not take a missed dose unless it is more than 6 hours until next scheduled dose.

Ifvomitingoccurs after Retevmo administration, do not take an additional dose and continue to the next scheduled time for the next dose.

Dosage Modifications For Concomitant Use Of Acid-Reducing Agents

Avoid concomitant use of a PPI, a histamine-2 (H2) receptor antagonist, or a locally-acting antacid with Retevmo. If concomitant use cannot be avoided:

• Take Retevmo with food when coadministered with a PPI.
• Take Retevmo 2 hours before or 10 hours after administration of an H2 receptor antagonist.
• Take Retevmo 2 hours before or 2 hours after administration of a locally-acting antacid.

Dosage Modifications For Adverse Reactions

The recommended dose reductions for adverse reactions are provided in Table 1.

Table 1: Recommended Retevmo Dose Reductions for Adverse Reactions

Dose Reduction	Patients Weighing Less Than 50 kg	Patients Weighing 50 kg or Greater
First	80 mg orally twice daily	120 mg orally twice daily
Second	40 mg orally twice daily	80 mg orally twice daily
Third	40 mg orally once daily	40 mg orally twice daily

Permanently discontinue Retevmo in patients unable to tolerate three dose reductions.

The recommended dosage modifications for adverse reactions are provided in Table 2.

Table 2: Recommended Retevmo Dosage Modifications for Adverse Reactions

Adverse Reaction	Severity	Dosage Modification
Hepatotoxicity	Grade 3 or Grade 4	Withhold Retevmo and monitor AST/ALT once weekly until resolution to Grade 1 or baseline. Resume at reduced dose by 2 dose levels and monitor AST and ALT once weekly until 4 weeks after reaching dose taken prior to the onset of Grade 3 or 4 increased AST or ALT. Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence.
Hypertension	Grade 3	Withhold Retevmo for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled.
	Grade 4	Discontinue Retevmo.
QT Interval Prolongation	Grade 3	Withhold Retevmo until recovery to baseline or Grade 0 or 1. Resume at a reduced dose.
	Grade 4	Discontinue Retevmo
Hemorrhagic Events	Grade 3 or Grade 4	Withhold Retevmo until recovery to baseline or Grade 0 or 1. Discontinue Retevmo for severe or life-threatening hemorrhagic events.
Hypersensitivity Reactions	All Grades	Withhold Retevmo until resolution of the event. Initiate corticosteroids. Resume at a reduced dose by 3 dose levels while continuing corticosteroids. Increase dose by 1 dose level each week until the dose taken prior to the onset of hypersensitivity is reached, then taper corticosteroids.

Dosage Modifications For Concomitant Use Of Strong And Moderate CYP3A Inhibitors

Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the Retevmo dose as recommended in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume Retevmo at the dose taken prior to initiating the CYP3A inhibitor.

Table 2: Recommended Retevmo Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors

Current Retevmo Dosage	Recommended Retevmo Dosage
	Moderate CYP3A Inhibitor	Strong CYP3A Inhibitor
120 mg orally twice daily	80 mg orally twice daily	40 mg orally twice daily
160 mg orally twice daily	120 mg orally twice daily	80 mg orally twice daily

Dosage Modification For Severe Hepatic Impairment

Reduce the recommended dosage of Retevmo for patients with severe hepatic impairment as recommended in Table 4 [seeUse In Specific Populations].

Table 3: Recommended Retevmo Dosage for Severe Hepatic Impairment

Current Retevmo Dosage	Recommended Retevmo Dosage
120 mg orally twice daily	80 mg orally twice daily
160 mg orally twice daily	80 mg orally twice daily

Effects Of Other Drugs On Retevmo

Acid-Reducing Agents

• Concomitant use of Retevmo with acid-reducing agents decreases selpercatinib plasma concentrations, which may reduce Retevmo anti-tumor activity.
• Avoid concomitant use ofPPIs, H2 receptor antagonists, and locally-acting antacids with Retevmo. If coadministration cannot be avoided, take Retevmo with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid).

Strong And Moderate CYP3A Inhibitors

• Concomitant use of Retevmo with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations, which may increase the risk of Retevmo adverse reactions, including QTc interval prolongation.
• Avoid concomitant use of strong and moderate CYP3A inhibitors with Retevmo. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the Retevmo dosage and monitor the QT interval with ECGs more frequently.

Strong And Moderate CYP3A Inducers

• Concomitant use of Retevmo with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations, which may reduce Retevmo anti-tumor activity.
• Avoid coadministration of strong or moderate CYP3A inducers with Retevmo.

Effects Of Retevmo On Other Drugs

CYP2C8 And CYP3A Substrates

• Retevmo is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor.
• Concomitant use of Retevmo with CYP2C8 and CYP3A substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates.
• 避免共同服用Retevmo CYP2C8和的CYP3A substrates where minimal concentration changes may lead to increased adverse reactions.
• If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

Drugs That Prolong QT Interval

• 间隔prolongati Retevmo与高职院校学前教育专业on.
• Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

• Based on findings from animal studies, and its mechanism of action, Retevmo can cause fetal harm when administered to apregnantwoman.
• There are no available data on Retevmo use in pregnant women to inform drug-associated risk.
• There are no data on the presence of selpercatinib or its metabolites inhuman milkor on their effects on thebreastfedchild or on milk production.
• Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Retevmo and for 1 week after the final dose.