Daurismo Drug Information

DAURISMO is indicated, in combination with low-dose cytarabine, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

Monitoring and Dosage Modifications

Assess complete blood counts, electrolytes, renal, and hepatic function prior to the initiation of DAURISMO and at least once weekly for the first month. Monitor electrolytes and renal function once monthly for the duration of therapy. Obtain creatine phosphokinase (CPK) levels prior to initiating DAURISMO and as indicated clinically thereafter (e.g., if muscle symptoms are reported).

Monitor electrocardiograms (ECGs) prior to the initiation of DAURISMO, approximately one week after initiation, and then once monthly for the next two months to assess for QTc prolongation. Repeat ECG if abnormal. Certain patients may require more frequent and ongoing ECG monitoring.

Manage any abnormalities promptly. See Table 1 for dosage modification guidelines for patients who develop an adverse reaction. Table 1.

Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Recommended Action Abbreviations: CPK = creatine phosphokinase, ULN = upper limit of normal. QTc interval prolongation on at least 2 separate electrocardiograms (ECGs) QTc interval greater than 480 ms to 500 ms Assess electrolyte levels and supplement as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects.

Interrupt DAURISMO. Consider re-escalating the dosage of DAURISMO to 100 mg daily if an alternative etiology for the QTc prolongation can be identified.

Dosage Modification for Concomitant Use with Moderate CYP3A4 Inducers Avoid concomitant use of DAURISMO with moderate CYP3A4 inducers. If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage as tolerated as shown in Table 2. After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the DAURISMO dose taken prior to initiating the moderate CYP3A4 inducer.

Table 2.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety profile of DAURISMO is based on experience in the BRIGHT AML 1003 study for 111 adults with newly-diagnosed AML and 14 adults with other conditions for which DAURISMO is not indicated. Patients were treated with DAURISMO 100 mg daily in combination with low-dose cytarabine (N=84) or low-dose cytarabine alone (N=41).

The median exposure to DAURISMO in the DAURISMO with low-dose cytarabine arm was 76 days (range 3 to 954 days). Serious adverse reactions were reported in 79% of patients treated in the DAURISMO with low-dose cytarabine arm. Adverse reactions reported in the first 90 days of therapy on the BRIGHT AML 1003 study are shown in Table 3.

Table 3. Adverse Reactions Occurring in ≥10% of Patients Adverse reactions with ≥10% incidence in the DAURISMO with low-dose cytarabine arm or the low-dose cytarabine arm are included. No Grade 5 events in the DAURISMO with low-dose cytarabine or low-dose cytarabine alone arm.

Additional clinically-significant adverse reactions occurring in <10% of patients treated with DAURISMO and low-dose cytarabine in BRIGHT AML 1003 include: • Dental disorders: loose tooth and toothache • Skin and subcutaneous tissue disorders: alopecia • Cardiac disorders: QT interval prolonged Changes in selected post-baseline laboratory values that were observed in patients with newly-diagnosed AML and other conditions for which DAURISMO is not indicated in the clinical trial are shown in Table 4. Table 4. Selected Laboratory Abnormalities (≥15%) Maximum severity based on the number of patients with available on-study laboratory data.

• Table 5. Drug Interactions with DAURISMO Strong CYP3A Inhibitors Clinical Impact
• Co-administration of DAURISMO with strong CYP3A inhibitors increased glasdegib plasma concentrations.
• Increased glasdegib concentrations may increase the risk of adverse reactions including QTc interval prolongation. 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. Strong and Moderate CYP3A Inducers Clinical Impact Co-administration of DAURISMO with strong and moderate CYP3A inducers decreased glasdegib plasma concentrations.
• 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. QTc Prolonging Drugs Clinical Impact Co-administration of DAURISMO with QTc prolonging drugs may increase the risk of QTc interval prolongation. 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.
• Strong CYP3A4 Inhibitors: Consider alternative therapies that are not strong CYP3A4 inhibitors or monitor for increased risk of adverse reactions, including QTc interval prolongation.
• Strong CYP3A4 Inducers: Avoid concomitant use with DAURISMO.
• Moderate CYP3A4 Inducers: Avoid concomitant use with DAURISMO. If, concomitant use cannot be avoided, increase the dose of DAURISMO.
• QTc Prolonging Drugs: Avoid co-administration with DAURISMO. If co-administration is unavoidable, monitor for increased risk of QTc interval prolongation.

Pregnancy Risk Summary Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, DAURISMO can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. DAURISMO is not recommended for use during pregnancy.

Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with DAURISMO. Report pregnancy exposures to Pfizer at 1-800-438-1985. In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of DAURISMO during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity and teratogenicity in rats and rabbits (see Data ).

Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data In embryo-fetal developmental toxicity studies, glasdegib was orally administered to pregnant rats and rabbits at doses up to 100 mg/kg/day during the period of organogenesis. Glasdegib resulted in embryo-fetal lethality (e.g., increased postimplantation loss and decreased numbers of live fetuses) in rats and rabbits at 50 mg/kg/day and 5 mg/kg/day, respectively, at maternal exposures approximately 4-times and 3-times the human exposure at the recommended dose.

Doses of ≥10 mg/kg in rat and ≥5 mg/kg in rabbit resulted in fetal developmental abnormalities and malformations consisting of craniofacial malformations, malformed limbs, paws/digits, trunk and tail, dilation of brain, malpositioned/malformed eyes, misshapen head, small tongue, absent palate, teeth and viscera, diaphragmatic hernia, edema, heart defects, rib and vertebral abnormalities, malformed or absent structures in the appendicular skeleton.

Pediatric Use The safety and effectiveness of DAURISMO have not been established in pediatric patients. In repeat-dose toxicity studies in rats, oral administration of DAURISMO resulted in adverse changes in growing bone, teeth, and testis. Effects on bone consisted of partial to complete closure of the epiphyseal plate.

Effects in growing incisor teeth included degeneration/necrosis of ameloblasts, and complete tooth loss with oral ulceration. Reproductive tissue toxicity was evidenced by testicular degeneration and hypospermatogenesis. These effects in bone, teeth and testis were observed after administration of DAURISMO for 26 weeks at greater than or equal to 50 mg/kg/day corresponding to approximately 6.6-times the steady-state AUC in patients at the recommended human dose.

There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day.

At the highest dosage, the adverse reactions that were dose limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness.