GLASDEGIB Drug Interactions: What You Need to Know

INTERACTIONS Table 5.

Drug

Interactions with DAURISMO Strong CYP3A Inhibitors Clinical Impact

• Co-administration of DAURISMO with strong CYP3A inhibitors increased glasdegib plasma concentrations [see Clinical Pharmacology (12.3) ].
• Increased glasdegib concentrations may increase the risk of adverse reactions including QTc interval prolongation [see Warnings and Precautions (5.2) ] . Prevention or Management
• Consider alternative therapies that are not strong CYP3A4 inhibitors during treatment with DAURISMO.
• Monitor patients for increased risk of adverse reactions including QTc interval prolongation [see Warnings and Precautions (5.2) ]. Strong and Moderate CYP3A Inducers Clinical Impact Co-administration of DAURISMO with strong and moderate CYP3A inducers decreased glasdegib plasma concentrations [see Clinical Pharmacology (12.3) ] .
• Decreased glasdegib concentrations may reduce efficacy. Prevention or Management
• Avoid co-administration of DAURISMO with strong and moderate CYP3A4 inducers.
• If co-administration of DAURISMO with moderate CYP3A4 inducers cannot be avoided, increase the dose of DAURISMO [see Dosage and Administration (2.3) ] . QTc Prolonging Drugs Clinical Impact Co-administration of DAURISMO with QTc prolonging drugs may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2) ]. Prevention or Management
• Avoid co-administration of QTc prolonging drugs with DAURISMO or replace with alternative therapies.
• If co-administration of a QTc prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation [see Warnings and Precautions (5.2) ].
• Strong CYP3A4 Inhibitors: Consider alternative therapies that are not strong CYP3A4 inhibitors or monitor for increased risk of adverse reactions, including QTc interval prolongation. ( 7 )
• Strong CYP3A4 Inducers: Avoid concomitant use with DAURISMO. ( 7 )
• Moderate CYP3A4 Inducers: Avoid concomitant use with DAURISMO. If, concomitant use cannot be avoided, increase the dose of DAURISMO. ( 2.3 , 7 )
• QTc Prolonging Drugs: Avoid co-administration with DAURISMO. If co-administration is unavoidable, monitor for increased risk of QTc interval prolongation. ( 7 )

None. None. ( 4 )

AND PRECAUTIONS

• Blood Donation: Advise patients not to donate blood or blood products during treatment with DAURISMO and for at least 30 days after the last dose. ( 5.1 )
• QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If QTc prolongation occurs, interrupt treatment with DAURISMO. ( 2.2 , 5.2 )
• Musculoskeletal Adverse Reactions: Obtain creatine phosphokinase (CPK) and serum creatinine levels prior to initiating DAURISMO and as indicated clinically thereafter. Temporary dose interruption, dose reduction, or discontinuation of DAURISMO may be required for musculoskeletal adverse reactions or serum CPK elevation. ( 2.2 , 5.3 )

5.1 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal embryo-fetal developmental toxicity studies, DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women. In animal embryo-fetal developmental toxicity studies, glasdegib caused embryotoxicity, fetotoxicity and teratogenicity at maternal exposures that were less than the human exposure at the recommended human dose of 100 mg <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.2) , Clinical Pharmacology (12.1) ]</span> . Advise pregnant women of the potential risk to the fetus. Females of Reproductive Potential DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating DAURISMO treatment. Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose. Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.2 , 8.3) ]</span> .

Males

Advise male patients with female partners of the potential risk of exposure through semen and to use effective contraception, including a condom, even after vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose [see Use in Specific Populations (8.3) ] .

Blood Donation

Advise patients not to donate blood or blood products while taking DAURISMO and for at least 30 days after the last dose of DAURISMO because their blood or blood products might be given to a female of reproductive potential.

5.2 QTc Interval Prolongation Patients treated with DAURISMO can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients treated with DAURISMO 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease. Monitor electrocardiograms (ECGs) and electrolytes <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . Concomitant use of DAURISMO with drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation <span class="opacity-50 text-xs">[see Drug Interactions (7) , Clinical Pharmacology (12.2) ]</span> . In patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring is recommended. Interrupt DAURISMO if QTc increases to greater than 500 ms. Discontinue DAURISMO permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

5.3 Musculoskeletal Adverse Reactions Musculoskeletal adverse reactions, which may be accompanied by CPK elevations, have occurred with DAURISMO and other drugs which inhibit the hedgehog (Hh) pathway. In BRIGHT AML 1003, musculoskeletal adverse reactions occurred in 45% of patients treated, with 2% (7/79) reported as Grade 3 or higher. The most frequent manifestations of musculoskeletal adverse reactions reported were musculoskeletal pain (30%) and muscle spasms (15%). Increased CPK laboratory values occurred in 16% of patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Obtain baseline CPK levels prior to initiating DAURISMO and as clinically indicated (e.g., if muscle symptoms are reported). Obtain CPK and serum creatinine levels at least weekly in patients with musculoskeletal adverse reactions with concurrent CPK elevation greater than 2.5 times ULN until resolution of clinical signs and symptoms. Depending on the severity of symptoms, temporary dose interruption, dose reduction, or discontinuation of DAURISMO may be required for musculoskeletal adverse reactions or serum CPK elevation <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .