VEPPANU Film-coated tablet Ref.[116672] Active ingredients: Vepdegestrant

5.1 QTc Interval Prolongation

VEPPANU can cause QT (QTc) interval prolongation [see Clinical Pharmacology (12.2)].

In VERITAC-2, QTc interval prolongation was reported in 10% of patients; Grade 3 occurred in 1.6% of patients. The heart-rate corrected QTc interval using Fridericia's method was greater than 500 msec in 1.6% of patients, and the increase from baseline QTc was greater than 60 msec in 2.6% of patients. VEPPANU dose reduction was required for 0.3% of patients due to QTc interval prolongation [see Adverse Reactions (6.1)].

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to and during treatment with VEPPANU. Perform an ECG prior to initiation of treatment with VEPPANU, and do not initiate VEPPANU in patients with QTc >470 msec. Repeat ECG approximately 4 weeks after initiating treatment and as clinically indicated. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, additional ECG monitoring may be necessary. Avoid concomitant use of VEPPANU with strong CYP3A inhibitors or drugs known to prolong the QTc interval. Reduce VEPPANU dose when concomitant use with strong CYP3A inhibitors cannot be avoided [see Dosage and Administration (2.4), Drug Interactions (7.1, 7.3), and Clinical Pharmacology (12.2)]. If concomitant use with other QTc-prolonging agents cannot be avoided, increase the frequency of ECG monitoring.

Withhold, reduce dose, or permanently discontinue based on severity [see Dosage and Administration (2.3)].

5.2 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, VEPPANU can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of vepdegestrant to pregnant rats during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at maternal exposures below the recommended dose based on area under the curve (AUC).

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

The following clinically significant adverse reaction is described elsewhere in the labeling:

• QTc Interval Prolongation [see Warnings and Precautions (5.1)]

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 of VEPPANU was evaluated in patients with ER-positive, HER2-negative, advanced or metastatic breast cancer following endocrine therapy in VERITAC-2 [see Clinical Studies (14)].

Patients received VEPPANU 200 mg orally once daily (N=312) or fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each subsequent 28-day cycle (N=307). Among patients who received VEPPANU, 33% were exposed for 6 months or longer and 6% were exposed for greater than one year.

Serious adverse reactions occurred in 9% of patients who received VEPPANU. The serious adverse reactions included any fracture (1.3%), fall, hypercalcemia, hepatic injury, pneumonia, musculoskeletal pain (0.6% each), and QTc prolonged (0.3%). Fatal adverse reactions occurred in 1.0% of patients who received VEPPANU, including dyspnea, cerebral ischemia, and unknown cause (one patient each).

Permanent discontinuation of VEPPANU due to an adverse reaction occurred in 2.9% of patients. Adverse reactions that resulted in permanent discontinuation of VEPPANU included increased alanine aminotransferase (ALT) and dyspnea (0.6% each).

Dosage interruptions of VEPPANU due to an adverse reaction occurred in 14% of patients. Adverse reactions which required dosage interruption in >1% of patients included neutropenia (1.9%), anemia, hepatic injury, nausea, fatigue, and musculoskeletal pain (1.3% each).

Dosage reductions of VEPPANU due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage reductions of VEPPANU included electrocardiogram QT prolonged, fatigue and musculoskeletal pain (0.3% each).

The most common (≥10%) adverse reactions, including laboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation.

Table 3 and Table 4 summarize adverse reactions and laboratory abnormalities in VERITAC-2, respectively.

Table 3. Adverse Reactions (≥10%) in Patients with ER+, HER2-, Advanced or Metastatic Breast Cancer Who Received VEPPANU in VERITAC-2^a:

^a Adverse reactions were graded using NCI CTCAE version 5.0
^b No Grade 4 events were reported.
^c Includes multiple related terms.

Clinically relevant adverse reactions in <10% of patients who received VEPPANU included headache, hot flush, diarrhea, vomiting, bradycardia, and urinary tract infection.

Table 4. Select Laboratory Abnormalities (≥10%) that Worsened from Baseline in Patients with ER+, HER2-, Advanced or Metastatic Breast Cancer Who Received VEPPANU in VERITAC-2:

^a The denominator used to calculate the rate varied between 308 and 310 based on the number of patients with a baseline value and at least one post-treatmen value.
^b The denominator used to calculate the rate varied between 302 and 303 based on the number of patients with a baseline value and at least one post-treatment value.

7.1 Effect of Other Drugs on VEPPANU

Table 5 describes drug interactions where concomitant use of another drug affects VEPPANU.

Table 5. Drug Interactions that Affect VEPPANU:

7.2 Effect of VEPPANU on Other Drugs

Table 6 describes drug interactions where concomitant use of VEPPANU affects another drug.

Table 6. VEPPANU Drug Interactions that Affect Other Drugs:

7.3 Drugs that Prolong QTc Interval

Avoid concomitant use of VEPPANU with other drugs with a known potential to prolong the QTc interval.

If concomitant use cannot be avoided:

• Obtain ECGs when initiating and during concomitant use, and as clinically indicated [see Warnings and Precautions (5.1)].
• Withhold VEPPANU if the QTc interval is >480 ms or the change from baseline is >60 ms [see Dosage and Administration (2.3)].

Vepdegestrant causes QTc interval prolongation [see Clinical Pharmacology (12.2)]. Concomitant use of VEPPANU with other drugs that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de Pointes, other serious arrythmias, and sudden death [see Warnings and Precautions (5.1)].

Risk Summary

Based on findings in animals and its mechanism of action, VEPPANU can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on the use of VEPPANU in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of vepdegestrant to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal exposures below the recommended dose based on AUC (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study in pregnant rats, administration of oral doses of vepdegestrant up to 300 mg/kg/day during the period of organogenesis resulted in embryo-fetal mortality (increased resorptions, post-implantation loss and reduced number of live fetuses) at ≥30 mg/kg/day (approximately 0.3 times the human AUC at the recommended dose). Additional adverse effects at ≥30 mg/kg/day included reduced fetal weight and skeletal abnormalities including delays in skeletal ossification (reduced number of ossification sites, incompletely ossified cervical arches or thoracic centra), skeletal malformations (fusion of sacral centra, hemivertebrae of the sacrum), and/or increased incidence of fetal variations (short cervical ribs, misaligned caudal vertebrae, misshapen cervical arches, and misaligned sacral vertebrae).

Risk Summary

There are no data on the presence of vepdegestrant or its metabolites in human milk, or its effects on milk production or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with VEPPANU and for 2 weeks after the last dose.

VEPPANU can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating VEPPANU treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose.

Infertility

Based on findings from animal studies, VEPPANU may impair fertility in females and males of reproductive potential. The effects of vepdegestrant on fertility were reversible in female animals [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of VEPPANU in pediatric patients have not been established.

Of 313 patients who received VEPPANU in the VERITAC-2 study, 39% were 65 years of age or older and 13% were 75 years of age or older. No overall differences in safety or effectiveness of VEPPANU were observed between patients 65 years of age or older compared to younger patients. There is an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or effectiveness.