camizestrant

7 DRUG INTERACTIONS • CYP3A Inhibitors : Monitor for increased adverse reactions to ETCAMAH with strong CYP3A inhibitors and modify the dosage as recommended. ( 7.1 ) • CYP3A Inducers : Avoid concomitant use of strong and moderate CYP3A inducers. If concomitant use with a moderate CYP3A inducer cannot be avoided, dose adjustment is needed when ETCAMAH is given in combination with abemaciclib or palbociclib. ( 2.6 , 7.1 ) • CYP2C9 and/or CYP2C19 Substrates : Avoid concomitant use of ETCAMAH with CYP2C9 substrates or CYP2C19 substrates during treatment with ETCAMAH and at least 2 weeks after the last dose of ETCAMAH, unless otherwise recommended in the Prescribing Information of the CYP2C9 substrate or CYP2C19 substrate. ( 7.2 ) • CYP3A Substrates : Refer to the Prescribing Information for CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions. ( 7.2 ) 7.1 Effect of Other Drugs on ETCAMAH Table 5 describes drug interactions where concomitant use of another drug affects ETCAMAH. Table 5. Drug Interactions involving ETCAMAH and Other Drug Products Strong CYP3A Inhibitors Prevention or Management • Monitor for increased adverse reactions to ETCAMAH and modify the dosage as recommended [see Dosage and Administration ( 2.4 )]. Mechanism and Clinical Effect • Camizestrant is a CYP3A substrate. Concomitant use with strong CYP3A inhibitors increases camizestrant plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to ETCAMAH. • ETCAMAH is indicated to be used in combination with CDK4/6 inhibitors, including ribociclib, which is a strong CYP3A inhibitor and can prolong the QT interval [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.3 )] . Strong and Moderate CYP3A Inducers Prevention or Management • Avoid concomitant use of strong CYP3A inducers. • The co-administration of ETCAMAH and a moderate CYP3A inducer is allowed with caution. • The dosage recommendations for concomitant use of moderate CYP3A inducers differ depending on the CDK4/6 inhibitor used in combination with ETCAMAH. o Avoid concomitant use of moderate CYP3A inducers for patients who are receiving ETCAMAH in combination with abemaciclib or palbociclib. If concomitant use cannot be avoided, increase the ETCAMAH dosage from 75 mg once daily to 150 mg once daily for patients who are receiving ETCAMAH in combination with abemaciclib or palbociclib [see Dosage and Administration ( 2.6 )] . After the moderate CYP3A inducer has been discontinued for at least 14 days, resume the ETCAMAH dosage used prior to initiation of the moderate CYP3A inducer. o For patients who are receiving ETCAMAH in combination with ribociclib concomitantly with a moderate CYP3A inducer, no ETCAMAH dosage modification is recommended. Mechanism and Clinical Effect • Camizestrant is a CYP3A substrate. Concomitant use with strong or moderate CYP3A inducers decreases camizestrant plasma concentrations [see Clinical Pharmacology ( 12.3 )] which may reduce ETCAMAH effectiveness. 7.2 Effect of ETCAMAH on Other Drugs Table 6 describes drug interactions where concomitant use of ETCAMAH affects another drug. Table 6. Drug Interactions involving ETCAMAH and Other Drug Products CYP2C9 Substrates or CYP2C19 Substrates Prevention or Management • Avoid concomitant use of ETCAMAH with CYP2C9 substrates or CYP2C19 substrates during treatment with ETCAMAH and at least 2 weeks after the last dose of ETCAMAH, unless otherwise recommended in the Prescribing Information of the CYP2C9 substrate or CYP2C19 substrate. Mechanism and Clinical Effect • ETCAMAH is a strong CYP2C9 inhibitor and a strong CYP2C19 inhibitor. • ETCAMAH is predicted to increase the exposure of both CYP2C9 substrates and CYP2C19 substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Certain CYP3A Substrates Prevention or Management • Refer to the Prescribing Information for CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions. Mechanism and Clinical Effect • ETCAMAH is a CYP3A inhibitor. • ETCAMAH increases exposure of CYP3A substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. 7.3 Drugs That Prolong the QTc Interval ETCAMAH is indicated in combination with a CDK4/6 inhibitor and there is increased risk of QTc interval prolongation with ribociclib, a strong CYP3A inhibitor that can prolong the QTc interval [see Drug Interactions ( 7.1 )] . Refer to the ribociclib prescribing information for dosage modifications. Avoid concomitant use of ETCAMAH with products (other than ribociclib) known to prolong the QTc interval and/or have a known risk of Torsades de Pointes. If concomitant use with other products cannot be avoided, monitor the QTc interval more frequently [see Warnings and Precautions ( 5.1 )] . ETCAMAH in combination with a CDK4/6 inhibitor is associated with QTc interval prolongation [see Clinical Pharmacology ( 12.2 )]. 7.4 Drugs That Cause Bradycardia Avoid concomitant use of ETCAMAH with other products known to cause bradycardia. Monitor for signs and symptoms of bradycardia if concomitant use cannot be avoided [see Warnings and Precautions ( 5.2 )] . ETCAMAH causes decreases in heart rate that are dose and baseline heart rate dependent [see Clinical Pharmacology ( 12.2 )] .

1 INDICATIONS AND USAGE ETCAMAH in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer upon detection of ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy, based on an FDA-authorized test [see Dosage and Administration ( 2.1 )] . This indication is approved under accelerated approval based on progression-free survival as measured from detection of ESR1 mutation [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ETCAMAH is an estrogen receptor antagonist indicated: • in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) for the treatment of adult patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative, locally advanced or metastatic breast cancer upon detection of ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy, based on an FDA authorized test. ( 1 , 2.1 ) This indication is approved under accelerated approval based on progression-free survival as measured from detection of ESR1 mutation. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

2 DOSAGE AND ADMINISTRATION • Select patients for treatment with ETCAMAH based on the detection of ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy. ( 2.1 ) • Recommended Dosage: 75 mg orally once daily with or without food. ( 2.3 ) • See Full Prescribing Information for dosage modifications for adverse reactions ( 2.4 ). • Recommended dosage for patients with hepatic impairment differs depending on the CDK4/6 inhibitor used in combination with ETCAMAH. ( 2.5 ) 2.1 Patient Selection Select patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer who have received at least 6 months of an aromatase inhibitor and CDK4/6 inhibitor therapy for treatment with ETCAMAH in combination with a CDK4/6 inhibitor based on the presence of an ESR1 mutation in plasma specimens, using an FDA-authorized test performed every 3 months until an ESR1 mutation has been detected [see Indications and Usage ( 1 ) and Clinical Studies ( 14 )] . Information on FDA-authorized tests for the detection of an ESR1 mutation in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Cardiac Evaluation Perform an electrocardiogram (ECG) prior to initiating ETCAMAH, then every week for the first 2 weeks of treatment, and periodically during treatment as clinically indicated [see Warnings and Precautions ( 5.1 )] . Monitor heart rate more frequently during the first 30 days of treatment with ETCAMAH in patients with bradycardia (resting heart rate less than 60 bpm) at baseline and those on concomitant medications known to lower heart rate (e.g., beta-blockers) [see Warnings and Precautions ( 5.2 )] . 2.3 Recommended Dosage and Administration The recommended dosage of ETCAMAH is 75 mg orally once daily, with or without food, until disease progression or unacceptable toxicity [see Clinical Pharmacology ( 12.3 )] . Administer ETCAMAH in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib). Continue the CDK4/6 inhibitor at the same dosage as when the ESR1 mutation was detected. Refer to the Prescribing Information of the CDK4/6 inhibitor for additional dosing information [see Clinical Studies ( 14 )] . Take ETCAMAH at approximately the same time each day. Swallow tablets whole. Do not cut, crush, or chew tablets prior to swallowing. Do not take broken, cracked, or otherwise not intact tablets. If a dose is missed within 6 hours, take the missed dose. If a dose of ETCAMAH is missed for more than 6 hours, skip the dose for the day and take the next dose at the usual time. If a dose is vomited, do not take an additional dose and take the next dose at the usual time. 2.4 Dosage Modifications for Adverse Reactions The recommended dosage modifications for ETCAMAH for adverse reactions are provided in Table 1. No dose reductions of ETCAMAH are recommended. Table 1. Recommended Dosage Modifications for ETCAMAH Adverse Reaction Severity Severity as defined by NCI CTCAE version 5.0. ETCAMAH Dosage Modifications QTc Interval Prolongation [see Warnings and Precautions ( 5.1 )] QTc > 500 msec or QTc > 480 msec and prolongation from baseline > 60 msec Withhold ETCAMAH. If other contributing causes are identified, then treat or correct the contributing causes. Resume ETCAMAH when QTc returns to < 480 msec. Re-assess ECGs weekly for the first 2 weeks of treatment, and periodically during treatment as clinically indicated. Permanently discontinue ETCAMAH if QTc interval prolongation is either > 500 msec or > 60 msec change from baseline AND associated with any of the following: Torsades de Pointes, polymorphic ventricular tachycardia, syncope, or signs/symptoms of serious arrhythmia. Bradycardia Bradycardia includes bradycardia and sinus bradycardia. [see Warnings and Precautions ( 5.2 )] Symptomatic, Grade 2 or above Withhold ETCAMAH until symptoms resolve. Obtain ECG to evaluate etiology of symptomatic bradycardia. If a contributing concomitant medication is identified, modify the dosage or discontinue this medication as appropriate until bradycardia symptoms resolve and then resume ETCAMAH. Consider reassessing the heart rate after restart of ETCAMAH. Permanently discontinue ETCAMAH for persistent symptomatic bradycardia. Visual Disturbances Visual disturbances include: photopsia, blurred vision, visual field defect, decreased visual acuity, visual impairment, diplopia, photophobia and visual perseveration. [see Adverse Reactions ( 6.1 )] Grade 2 or above/limiting instrumental ADLs Withhold ETCAMAH until symptoms resolve to Grade 1 or below. Refer patients to an eye care professional for an ophthalmic examination and treatment. Reassess visual disturbances at the next visit. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or higher Withhold ETCAMAH until resolution to Grade 2 or below, then resume ETCAMAH. Permanently discontinue ETCAMAH for recurrence of Grade 3 or higher adverse reactions. ADL = Activities of daily living; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute. Refer to the Prescribing Information for the co-administered CDK4/6 inhibitor for dosage modification guidelines related to adverse reactions, organ impairment, and drug-drug interactions. 2.5 Dosage in Patients with Hepatic Impairment The recommended dosage for patients with hepatic impairment differs depending on the CDK4/6 inhibitor used in combination with ETCAMAH. For patients with severe (Child-Pugh C) hepatic impairment who are receiving ETCAMAH in combination with ribociclib, the recommended dosage of ETCAMAH is 75 mg once every other day. For patients with severe (Child-Pugh C) hepatic impairment who are receiving ETCAMAH in combination with abemaciclib or palbociclib, no dosage modification of ETCAMAH is recommended. Monitor patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment receiving ETCAMAH in combination with any CDK4/6 inhibitor for increased adverse reactions and modify the dosage as recommended [see Dosage and Administration ( 2.4 )]. 2.6 Dosage Modifications for Strong and Moderate CYP3A Inducers Avoid concomitant use of strong CYP3A inducers. Dosage modifications for concomitant use of moderate CYP3A inducers differ depending on the CDK4/6 inhibitor used in combination with ETCAMAH. Avoid concomitant use of moderate CYP3A inducers for patients who are receiving ETCAMAH in combination with abemaciclib or palbociclib. If concomitant use of a moderate CYP3A inducer cannot be avoided, increase the ETCAMAH dosage from 75 mg once daily to 150 mg once daily for patients who are receiving ETCAMAH in combination with abemaciclib or palbociclib [see Drug Interactions ( 7.1 )] . After the moderate CYP3A inducer has been discontinued for at least 14 days, resume the ETCAMAH dosage used prior to initiation of the moderate CYP3A inducer. For patients who are receiving ETCAMAH in combination with ribociclib concomitantly with a moderate CYP3A inducer, no ETCAMAH dosage modification is recommended.

6 ADVERSE REACTIONS The most common adverse reactions (≥ 20%), including laboratory abnormalities, with ETCAMAH in combination with a CDK4/6 inhibitor were decreased neutrophils, decreased leukocytes, decreased hemoglobin, decreased lymphocytes, decreased platelets, visual disturbances, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The following clinically significant adverse reactions are described elsewhere in the labeling: • QTc interval prolongation [see Warnings and Precautions ( 5.1 )] • Bradycardia [see Warnings and Precautions ( 5.2 )] 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. HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer The safety of ETCAMAH was evaluated in 155 patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with detectable ESR1 mutation without disease progression during first line treatment with an aromatase inhibitor (AI) in combination with a CDK4/6 inhibitor in SERENA-6 [see Clinical Studies ( 14 )] . Patients received ETCAMAH 75 mg orally once daily in combination with a CDK4/6 inhibitor (N = 157) or AI in combination with a CDK4/6 inhibitor (N = 158). The median duration of exposure to ETCAMAH in combination with a CDK4/6 inhibitor was 10.1 months. Serious adverse reactions occurred in 10% of patients who received ETCAMAH in combination with a CDK4/6 inhibitor. Serious adverse reactions in > 1% of patients included urinary tract infection, pneumonia, and osteonecrosis of jaw (1.3% each). Fatal adverse reactions occurred in 1.3% of patients who received ETCAMAH in combination with a CDK4/6 inhibitor, including acute respiratory distress syndrome and sudden death (0.6% each). Permanent discontinuation of ETCAMAH due to adverse reactions occurred in 1.3% of patients. Adverse reactions that resulted in permanent discontinuation of ETCAMAH included gastroesophageal reflux disease, cholestasis and hepatic cytolysis (0.6% each). Dosage interruption of ETCAMAH due to adverse reactions occurred in 22% of patients. Adverse reactions which required dosage interruption of ETCAMAH in ≥ 2% of patients included bradycardia (3.9%) and visual disturbances (2.6%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophils, decreased leukocytes, decreased hemoglobin, decreased lymphocytes, decreased platelets, visual disturbances, and fatigue. Tables 2 and 3 summarize the adverse reactions and laboratory abnormalities, respectively, in SERENA-6. Table 2. Adverse Reactions in ≥ 10% (All Grades) of Patients with HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer Who Received ETCAMAH in SERENA-6 Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse Reaction ETCAMAH with a CDK4/6 Inhibitor N = 155 Aromatase Inhibitor with a CDK4/6 Inhibitor N = 155 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Eye Disorders Visual disturbances Visual disturbances include: photopsia, blurred vision, visual field defect, decreased visual acuity, visual impairment, diplopia, photophobia, and visual perseveration. 34 0.6 16 0 Dry eye 12 0 7 0 General Disorders and Administration Site Conditions Fatigue Fatigue includes: fatigue and asthenia. 23 0 19 0.6 Musculoskeletal and Connective Tissue Disorders Arthralgia 16 0 17 0.6 Back pain 10 0.6 10 0 Gastrointestinal Disorders Nausea 10 0 14 0.6 Clinically relevant adverse reactions (< 10%) in patients who received ETCAMAH included: vitreous floaters, bradycardia, and QTc prolongation. Table 3. Select Laboratory Abnormalities ≥ 10% that Worsened from Baseline in Patients with HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer Who Received ETCAMAH in SERENA-6 Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Includes patients with at least one baseline and one post-baseline result. Laboratory Abnormality ETCAMAH with a CDK4/6 Inhibitor N = 155 Aromatase Inhibitor with a CDK4/6 Inhibitor N = 155 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Neutrophils decreased 68 42 66 39 Leukocytes decreased 66 23 58 17 Hemoglobin decreased 47 3.9 38 5 Lymphocyte decreased 39 9 37 8 Platelets decreased 36 2.6 30 1.3 Chemistry Aspartate aminotransferase increased 17 2.6 29 1.3 Corrected calcium decreased 17 0 12 0.7 Creatinine increased 16 0.6 20 1.3 Gamma glutamyl transferase increased 12 2.7 23 8 Alanine aminotransferase increased 12 1.3 20 0 Creatine kinase increased 12 0 6 0 Alkaline phosphatase increased 10 0.7 22 0.7 Patient-Reported Outcomes Patient-reported blurred vision was assessed using the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) at baseline, every week through Week 12, and then every 8 weeks until treatment discontinuation. For post-baseline time points, completion rates for the patient-reported symptom of blurred vision (severity) ranged between 65% to 80% for patients on ETCAMAH in combination with a CDK4/6 inhibitor and 58% to 72% for patients on AI in combination with a CDK4/6 inhibitor up to Week 52. PRO-CTCAE blurred vision (severity) results are summarized in Table 4. Table 4. Patient-Reported Symptom of Blurred Vision Assessed by PRO-CTCAE Number of Patients The number of patients with score before study treatment and at least one on treatment up to week 52 ETCAMAH in combination with a CDK4/6 inhibitor (N = 102) AI in combination with a CDK4/6 inhibitor (N = 88) Symptoms Any symptoms before study treatment (%) The percentage of patients whose symptom score at baseline assessment (before study treatment) was 1-4 Any Worsening on treatment (%) The percentage of patients whose symptom score increased with respect to their score at baseline assessment (before study treatment) Any Worsening to Score 3 or 4 (%) The percentage of patients whose symptom score increased to 3 or 4 with respect to their score at baseline assessment (before study treatment) ETCAMAH in combination with a CDK4/6 inhibitor (%) AI in combination with a CDK4/6 inhibitor (%) ETCAMAH in combination with a CDK4/6 inhibitor (%) AI in combination with a CDK4/6 inhibitor (%) ETCAMAH in combination with a CDK4/6 inhibitor (%) AI in combination with a CDK4/6 inhibitor (%) Blurred Vision (Severity) 31 25 69 50 10 4.5 The symptom attribute scoring for severity is defined as a score of 0 = ‘none’; 1 = ‘mild’; 2 = ‘moderate’; 3 = ‘severe’; 4 = ‘very severe’. Patient-reported overall impact of visual disturbances was assessed using the Visual Symptom Assessment Questionnaire [VSAQ]. The VSAQ was assessed at baseline, in Weeks 2, 6 and 24, and then every 12 weeks. For post-baseline timepoints, completion rates ranged from 69% to 81% for patients on ETCAMAH in combination with a CDK4/6 inhibitor and 60% to 73% for patients on AI in combination with a CDK4/6 inhibitor. Among patients who reported experiencing a visual disturbance and completed a baseline and at least one post baseline assessment, 12% of patients on ETCAMAH in combination with a CDK4/6 inhibitor versus 13% of patients on AI in combination with a CDK4/6 inhibitor reported “I am bothered by visual disturbances from my cancer treatment”. With respect to baseline, the proportion of patients with VSAQ responses of "quite a bit" or "extremely" bothered was 4.9% of patients on ETCAMAH in combination with a CDK4/6 inhibitor and 1.2% of patients on AI in combination with a CDK4/6 inhibitor. Among patients who reported experiencing a visual disturbance while receiving ETCAMAH in combination with a CDK4/6 inhibitor, episodes were typically < 1 minute and occurred < 3 days per week. Patient-reported overall side-effect burden was assessed using the single-item Patient Global Impression of Treatment Tolerability (PGI-TT) questionnaire at baseline, every week through Week 12, and then every 8 weeks until treatment discontinuation. For post-baseline timepoints, the completion rate for patients on ETCAMAH in combination with a CDK4/6 inhibitor ranged from 67% to 81% and for patients on AI in combination with a CDK4/6 inhibitor ranged from 59% to 73% in the first 52 weeks. In the PGI-TT questionnaire patients provided a response to “In the last 7 days, how bothered were you by the side effects of your cancer treatment?” The proportion of patients with PGI-TT responses of “not at all” bothered was > 30% across all timepoints for patients on ETCAMAH in combination with a CDK4/6 inhibitor and > 40% across all timepoints for patients on AI in combination with a CDK4/6 inhibitor.