Employ more intensive measures (intravenous hydration, frequent
`
`
`monitoring, hospitalization) as overall risk increases. (2.3, 5.1)
`
`
`• Neutropenia: Monitor blood counts and for signs of infection; manage as
`
`
`
`
`
`medically appropriate. (2.4, 5.2)
`
`• Immunization: Do not administer live attenuated vaccines prior to, during,
`
`
`
`
`
`or after VENCLEXTA treatment. (5.3)
`
`
`
`• Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of
`
`
`
`
`reproductive potential of the potential risk to a fetus and to use effective
`
`
`contraception during treatment. (5.4)
`
`
`
`
`
`
`
`ADVERSE REACTIONS
`
`The most common adverse reactions (≥20%) were neutropenia, diarrhea,
`
`nausea, anemia, upper respiratory tract infection, thrombocytopenia, and
`
`fatigue. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc.
`
`
`
`at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
`
`DRUG INTERACTIONS
`
`
`Avoid concomitant use of VENCLEXTA with moderate CYP3A inhibitors,
`
`
`
`strong or moderate CYP3A inducers, P-gp inhibitors, or narrow therapeutic
`
`index P-gp substrates. (2.5, 7.1, 7.2)
`
`
`
`
`
`• If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the
`
`
`
`
`VENCLEXTA dose by at least 50%. (2.5, 7.1)
`
`
`
`• If a strong CYP3A inhibitor must be used after the ramp-up phase, reduce
`
`
`
`the VENCLEXTA dose by at least 75%. (2.5, 7.1)
`
`
`
`
`
`
`• If a narrow therapeutic index P-gp substrate must be used, it should be
`
`
`
`
`
`taken at least 6 hours before VENCLEXTA. (7.2)
`
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`• Lactation: Discontinue breastfeeding. (8.2)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`Revised: 4/2016
`
`
`
`
`8.2 Lactation
`
`
`8.3 Females and Males of Reproductive Potential
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed.
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
` VENCLEXTA safely and effectively. See full prescribing information for
` VENCLEXTA.
`
`
` VENCLEXTA™ (venetoclax) tablets, for oral use
`
`
`
` Initial U.S. Approval: 2016
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`
`
`VENCLEXTA is a BCL-2 inhibitor indicated for the treatment of patients
`
`
`
`
`with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by
`
`
`
`an FDA approved test, who have received at least one prior therapy.
`
`
`
`This indication is approved under accelerated approval based on overall
`
`
`response rate. Continued approval for this indication may be contingent upon
`
`
`verification and description of clinical benefit in a confirmatory trial. (1)
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`• Initiate therapy with VENCLEXTA at 20 mg once daily for 7 days,
`
`
`
`
`followed by a weekly ramp-up dosing schedule to the recommended daily
`
`
`
`dose of 400 mg. (2.2)
`
`• VENCLEXTA tablets should be taken orally once daily with a meal and
`
`
`
`
`
`
`water. Do not chew, crush, or break tablets. (2.2)
`
`• Perform prophylaxis for tumor lysis syndrome. (2.3)
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`Tablets: 10 mg, 50 mg, 100 mg (3)
`
`
`
`
`CONTRAINDICATIONS
`
`
`Concomitant use of VENCLEXTA with strong inhibitors of CYP3A at
`
`
`
`
`
`initiation and during ramp-up phase is contraindicated. (2.5, 4, 7.1)
`
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
`• Tumor Lysis Syndrome (TLS): Anticipate TLS; assess risk in all patients.
`
`
`
`
`
`Premedicate with anti-hyperuricemics and ensure adequate hydration.
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Patient Selection
`
`
`2.2 Recommended Dosage
`
`
`
`2.3 Risk Assessment and Prophylaxis for Tumor Lysis Syndrome
`
`2.4 Dose Modifications Based on Toxicities
`
`
`
`2.5 Dose Modifications for Use with CYP3A and P-gp Inhibitors
`
`2.6 Missed Dose
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Tumor Lysis Syndrome
`
`5.2 Neutropenia
`
`5.3 Immunization
`
`5.4 Embryo-Fetal Toxicity
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Trial Experience
`7 DRUG INTERACTIONS
`
`
`
`7.1 Effects of Other Drugs on VENCLEXTA
`
`
`7.2 Effects of VENCLEXTA on Other Drugs
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 1
`
`DRL EXHIBIT 1009 PAGE 1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` VENCLEXTA is indicated for the treatment of patients with chronic lymphocytic leukemia
` (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one
`
`
`
`
` prior therapy.
` This indication is approved under accelerated approval based on overall response rate [see
`
`
` Clinical Studies (14)]. Continued approval for this indication may be contingent upon
`
` verification and description of clinical benefit in a confirmatory trial.
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
` 2.1 Patient Selection
`
` Select patients for the treatment of relapsed or refractory CLL with VENCLEXTA based on the
`
`
`
`
` presence of 17p deletions in blood specimens [see Indications and Usage (1) and Clinical
`
`
`
`
`
`
` Studies (14)]. Patients without 17p deletion at diagnosis should be retested at relapse because
`
` acquisition of 17p deletion can occur. Information on FDA-approved tests for the detection of
`
`
`
` 17p deletions in CLL is available at: http://www.fda.gov/CompanionDiagnostics.
`
`
`
`
`
`2.2 Recommended Dosage
`
`
`
`Assess patient-specific factors for level of risk of tumor lysis syndrome (TLS) and provide
`
`
`
`prophylactic hydration and anti-hyperuricemics to patients prior to first dose of VENCLEXTA to
`
`
`
`reduce risk of TLS [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`Administer the VENCLEXTA dose according to a weekly ramp-up schedule over 5 weeks to the
`
`
`recommended daily dose of 400 mg as shown in Table 1. The 5-week ramp-up dosing schedule
`
`is designed to gradually reduce tumor burden (debulk) and decrease the risk of TLS.
`
`
`
`Instruct patients to take VENCLEXTA tablets with a meal and water at approximately the same
`
`
`
`
`time each day. VENCLEXTA tablets should be swallowed whole and not chewed, crushed, or
`
`broken prior to swallowing.
`
`
`Table 1. Dosing Schedule for Ramp-Up Phase
`
`Week
`
`
` 1
`
` 2
`
` 3
`
` 4
` 5 and beyond
`
`
`
`
`
`
`
`
`
` VENCLEXTA
`Daily Dose
`
`
` 20 mg
`
` 50 mg
`
` 100 mg
`
` 200 mg
`
` 400 mg
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 2
`
`DRL EXHIBIT 1009 PAGE 2
`
`

`

` The Starting Pack provides the first 4 weeks of VENCLEXTA according to the ramp-up
`
`
`
` schedule. Once the ramp-up phase is completed, the 400 mg dose is achieved using 100 mg
` tablets supplied in bottles [see How Supplied/Storage and Handling (16)].
`
`
`
`
` VENCLEXTA should be taken orally once daily until disease progression or unacceptable
`toxicity is observed.
`
`
`
`
` 2.3 Risk Assessment and Prophylaxis for Tumor Lysis Syndrome
`
`
`
`
` VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-
` week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt
`
`
`
`
`
`
` management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at
`
` each dose increase.
`
`
` The risk of TLS is a continuum based on multiple factors, including tumor burden and
`
`
` comorbidities. Perform tumor burden assessments, including radiographic evaluation (e.g., CT
` scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in all
`
` patients and correct pre-existing abnormalities prior to initiation of treatment with
`
` VENCLEXTA. Reduced renal function (creatinine clearance [CrCl] <80 mL/min) further
`
` increases the risk. The risk may decrease as tumor burden decreases [see Warnings and
`
`
`
` Precautions (5.1) and Use in Specific Populations (8.6)].
`
`
`
`
`
` Table 2 below describes the recommended TLS prophylaxis and monitoring during
`
` VENCLEXTA treatment based on tumor burden determination from clinical trial data.
`
`
`
`
`
`
`
`
`
`
`
`
` Table 2. Recommended TLS Prophylaxis Based on Tumor Burden From Clinical Trial
`
`
`
`
`
` Data (consider all patient co-morbidities before final determination of prophylaxis and
`monitoring schedule)
`
`
`Blood Chemistry
`
` Monitoringc,d
`Setting and
` Frequency of
`
`
` Assessments
` Outpatient
`
` • Pre-dose, 6 to 8
`
`
`
` hours, 24 hours at
`
` first dose of 20
`
` mg and 50 mg
`
` • Pre-dose at
`
`subsequent ramp-
`
` up doses
`
`
`
`
`
` Tumor Burden
`
`
`
` Prophylaxis
`
` Hydrationa Anti-
` hyperuricemics
`
`
`
`Low
`
`
`
`All LN <5 cm AND
`
` ALC <25 x109/L
`
`
`
` Oral
`
` (1.5-2 L)
`
`
`
`
`
` Allopurinolb
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 3
`
`DRL EXHIBIT 1009 PAGE 3
`
`

`

`
`
`
`
` Medium Any LN 5 cm to <10 cm
`
` OR
` ALC ≥25 x109/L
`
`
`
`
`
` High
`
`
`
` Any LN ≥10 cm
`
` OR
`ALC ≥25 x109/L
`
`
`
` AND any LN ≥5 cm
`
`
`
`
`
` Allopurinol
`
` Oral (1.5-2
`
`
`
` L) and
` consider
`
` additional
`
` intravenous
`
`
`
`
`
` Oral (1.5-2
`
`L) and
` intravenous
`(150-200
`
` mL/hr as
` tolerated)
`
`
`
`
` Allopurinol;
`
` consider
`rasburicase if
`baseline uric
`
`
`acid is elevated
`
`
`
`Outpatient
`
` • Pre-dose, 6 to 8
`
`
`
` hours, 24 hours at
`
` first dose of 20
`
` mg and 50 mg
`
` • Pre-dose at
`
`subsequent ramp-
`up doses
`
`• Consider
`
`
`hospitalization for
`
`patients with CrCl
`<80ml/min at first
`
`
`
`dose of 20 mg and
`
`50 mg; see below
`
`for monitoring in
`
`
` hospital
`In hospital at first
`
` dose of 20 mg and
` 50 mg
`
`• Pre-dose, 4, 8,12
`
`
` and 24 hours
`Outpatient at
`subsequent ramp-up
`
`doses
`
`• Pre-dose, 6 to 8
`
`
`hours, 24 hours
`
` ALC = absolute lymphocyte count; LN = lymph node.
`
`
`
`
`
` aAdminister intravenous hydration for any patient who cannot tolerate oral hydration.
`
`
`bStart allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of VENCLEXTA.
`
`
`
`
`cEvaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine);
`review in real time.
`
`dFor patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and at 24 hours at each
`
`
`
`
` subsequent ramp-up dose.
`
` 2.4 Dose Modifications Based on Toxicities
`
`
`
`
` Interrupt dosing or reduce dose for toxicities. See Table 3 for dose modifications for hematologic
`
` and other toxicities related to VENCLEXTA, and Table 4 for dose. For patients who have had a
`
`
`
` dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than
`
`
` 2 weeks when at the daily dose of 400 mg, reassess for risk of TLS to determine if reinitiation
`
`
` with a reduced dose is necessary (e.g., all or some levels of the dose ramp-up schedule) [see
`
`
`
`
`
` Dosage and Administration (2.2, 2.3)].
`
`
`
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 4
`
`DRL EXHIBIT 1009 PAGE 4
`
`

`

`
`
`
`
`
`
`
`
`Grade 3 or 4 non-
` hematologic toxicities
`
`
`
`
`
` 2nd and subsequent
`
`
` occurrences
`
`
`
`
`
` 2nd and subsequent
`
`
` occurrences
`
`
`
`
`
` Table 3. Recommended Dose Modifications for Toxicitiesa
`Event
`Occurrence
`
`
`
` Tumor Lysis Syndrome
`
` Withhold the next day’s dose. If resolved
`
`
`
`
` within 24 to 48 hours of last dose, resume at the
` same dose.
`
` For any blood chemistry changes requiring
`
`
`
` more than 48 hours to resolve, resume at a
`reduced dose (see Table 4) [see Dosage and
`
` Administration (2.3)].
` For any events of clinical TLS,b resume at a
`
`
`
`
`
` reduced dose following resolution (see Table 4)
` [see Dosage and Administration (2.3)].
`
`
` Non-Hematologic Toxicities
` 1st occurrence
` Interrupt VENCLEXTA.
`
`
`
` Once the toxicity has resolved to Grade 1 or
`
`
`
` baseline level, VENCLEXTA therapy may be
` resumed at the same dose. No dose
`
`
`modification is required.
`
` Interrupt VENCLEXTA.
`
`
`
` Follow dose reduction guidelines in Table 4
` when resuming treatment with VENCLEXTA
`
`
`
` after resolution. A larger dose reduction may
`
` occur at the discretion of the physician.
`
`
` Hematologic Toxicities
` 1st occurrence
` Interrupt VENCLEXTA.
`
`
`
`To reduce the infection risks associated with
`
`neutropenia, granulocyte-colony stimulating
`factor (G-CSF) may be administered with
`
`
`
`VENCLEXTA if clinically indicated. Once the
`
`toxicity has resolved to Grade 1 or baseline
`
`
`
`level, VENCLEXTA therapy may be resumed
` at the same dose.
`
`
` Interrupt VENCLEXTA.
`
` Consider using G-CSF as clinically indicated.
`
` Follow dose reduction guidelines in Table 4
`
` when resuming treatment with VENCLEXTA
`
` after resolution. A larger dose reduction may
`
`
`
` occur at the discretion of the physician.
`
` Consider discontinuing VENCLEXTA for patients who require dose reductions to less than 100
`
`
`
`
` mg for more than 2 weeks.
` aAdverse reactions were graded using NCI CTCAE version 4.0.
`
`
` bClinical TLS was defined as laboratory TLS with clinical consequences such as acute renal
`
`
` failure, cardiac arrhythmias, or sudden death and/or seizures.
`
`Grade 3 or 4
`neutropenia with
`infection or fever; or
`Grade 4 hematologic
`
`toxicities (except
`
`lymphopenia) [see
`Warnings and
`
`Precautions (5.2)]
`
`
`
`Action
`
`
` Blood chemistry
`
` changes or symptoms
`
` suggestive of TLS
`
`
`
`
`
` Any
`
`
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 5
`
`DRL EXHIBIT 1009 PAGE 5
`
`

`

`
`
`
`
`
`
`
` Table 4. Dose Modification for Toxicity During VENCLEXTA Treatment
` Restart Dose, mga
`
`Dose at Interruption, mg
`
`
` 300
`
` 400
`
` 200
`
` 300
`
` 100
`
` 200
`
` 50
`
` 100
`
` 20
`
` 50
`
` 10
`
` 20
` aDuring the ramp-up phase, continue the reduced dose for 1 week before
`
` increasing the dose.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.5 Dose Modifications for Use with CYP3A and P-gp Inhibitors
`
`
` Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-
`
`
`
` up phase is contraindicated. Concomitant use of VENCLEXTA with strong CYP3A inhibitors
`
`
`
`increases venetoclax exposure (i.e., Cmax and AUC) and may increase the risk for TLS at
`
`
`
`
`
`initiation and during ramp-up phase [see Contraindications (4)]. For patients who have
`
`
`completed the ramp-up phase and are on a steady daily dose of VENCLEXTA, reduce the
`
`VENCLEXTA dose by at least 75% when strong CYP3A inhibitors must be used concomitantly.
`
`
`
`
`Avoid concomitant use of VENCLEXTA with moderate CYP3A inhibitors or P-gp inhibitors.
`
`
`
`
`
`Consider alternative treatments. If a moderate CYP3A inhibitor or a P-gp inhibitor must be used,
`
`
`
`
`reduce the VENCLEXTA dose by at least 50%. Monitor these patients more closely for signs of
`
`
`
`
`
`toxicities [see Dosage and Administration (2.4)].
`
`
`Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor or P-gp
`
`
`
`inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Administration (2.4)
`
`
`
`and Drug Interactions (7.1)].
`
`
`
`The recommendations for managing drug-drug interactions are summarized in Table 5.
`
`
`
`
`
`
`Table 5. Management of Potential VENCLEXTA Interactions with CYP3A and P-gp
`
`
`
`
`Inhibitors
`
`Inhibitors
`
`
`Initiation and Ramp-Up
`
`Phase
`
`
`
`
` Contraindicated
`
`
`
` Strong CYP3A inhibitor
`
`
`
` Moderate CYP3A inhibitor
`
`P-gp inhibitor
`
`
`Reference ID: 3915259
`
`Steady Daily Dose
`
`
`
` (After Ramp-Up Phase)
`
`
` Avoid inhibitor use or reduce
`
`
` the VENCLEXTA dose by at
`
`
` least 75%
`
` Avoid inhibitor use or reduce the VENCLEXTA dose by at
`
` least 50%
`
`
`
`
`
`
`
`
`DRL EXHIBIT 1009 PAGE 6
`
`DRL EXHIBIT 1009 PAGE 6
`
`

`

`
`
`
`2.6 Missed Dose
`
`
`
`If the patient misses a dose of VENCLEXTA within 8 hours of the time it is usually taken, the
`
`patient should take the missed dose as soon as possible and resume the normal daily dosing
`
`schedule. If a patient misses a dose by more than 8 hours, the patient should not take the missed
`
`
`dose and should resume the usual dosing schedule the next day.
`
`If the patient vomits following dosing, no additional dose should be taken that day. The next
`
`prescribed dose should be taken at the usual time.
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`
`
` 10 mg
`
`
`
`
`
` 50 mg
`
`
`
`Table 6. VENCLEXTA Tablet Strength and Description
`
`
`Description of Tablet
`Tablet Strength
`
`
`
` Round, biconvex shaped, pale yellow film-coated
`
` tablet debossed with “V” on one side and “10” on the
`
` other side
` Oblong, biconvex shaped, beige film-coated tablet
`
` debossed with “V” on one side and “50” on the other
`
` side
` Oblong, biconvex shaped, pale yellow film-coated
`
`
` tablet debossed with “V” on one side and “100” on the
`
` other side
`
`
`
` 100 mg
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
`
`
` Concomitant use of VENCLEXTA with strong CYP3A inhibitors at initiation and during ramp-
` up phase is contraindicated [see Dosage and Administration (2.5) and Drug Interactions (7.1)].
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 5.1 Tumor Lysis Syndrome
`
` Tumor lysis syndrome, including fatal events and renal failure requiring dialysis, has occurred in
`
`
` previously treated CLL patients with high tumor burden when treated with VENCLEXTA [see
`
`
` Adverse Reactions (6.1)].
` VENCLEXTA can cause rapid reduction in tumor and thus poses a risk for TLS in the initial 5-
`
`
`
` week ramp-up phase. Changes in blood chemistries consistent with TLS that require prompt
` management can occur as early as 6 to 8 hours following the first dose of VENCLEXTA and at
`
`
`
`
`
` each dose increase.
` The risk of TLS is a continuum based on multiple factors, including tumor burden (see Table 2)
`
`
`
`
` and comorbidities. Reduced renal function (CrCl <80 mL/min) further increases the risk. Patients
`
`
`
`
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 7
`
`DRL EXHIBIT 1009 PAGE 7
`
`

`

`
`
`should be assessed for risk and should receive appropriate prophylaxis for TLS, including
`
`
`hydration and anti-hyperuricemics. Monitor blood chemistries and manage abnormalities
`
`promptly. Interrupt dosing if needed. Employ more intensive measures (intravenous hydration,
`
`frequent monitoring, hospitalization) as overall risk increases [see Dosage and Administration
`
`
`
`(2.3, 2.4) and Use in Specific Populations (8.6)].
`
`
`
`
`
`
`Concomitant use of VENCLEXTA with strong or moderate CYP3A inhibitors and P-gp
`
`
`
`
`
`inhibitors increases venetoclax exposure, may increase the risk of TLS at initiation and during
`
`
`
`ramp-up phase and may require VENCLEXTA dose adjustment [see Dosage and Administration
`
`
`(2.5) and Drug Interactions (7.1)].
`
`
`5.2 Neutropenia
`
`
`
`
`
`Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with VENCLEXTA [see
`
`Adverse Reactions (6.1)]. Monitor complete blood counts throughout the treatment period.
`
`
`
`Interrupt dosing or reduce dose for severe neutropenia. Consider supportive measures including
`
`
`antimicrobials for signs of infection and use of growth factors (e.g., G-CSF) [see Dosage and
`
`Administration (2.4)].
`
`
`5.3 Immunization
`
`
`
`
`Do not administer live attenuated vaccines prior to, during, or after treatment with
`
`
`
`
`VENCLEXTA until B-cell recovery occurs. The safety and efficacy of immunization with live
`
`
`
`
`attenuated vaccines during or following VENCLEXTA therapy have not been studied. Advise
`
`patients that vaccinations may be less effective.
`
`
`5.4 Embryo-Fetal Toxicity
`
`
`
`Based on its mechanism of action and findings in animals, VENCLEXTA may cause embryo-
`
`fetal harm when administered to a pregnant woman. In an embryo-fetal study conducted in mice,
`administration of venetoclax to pregnant animals at exposures equivalent to that observed in
`patients at the recommended dose of 400 mg daily resulted in post-implantation loss and
`
`
`decreased fetal weight. There are no adequate and well-controlled studies in pregnant woman
`
`
`using VENCLEXTA. Advise females of reproductive potential to avoid pregnancy during
`
`treatment. If VENCLEXTA is used during pregnancy or if the patient becomes pregnant while
`
`taking VENCLEXTA, the patient should be apprised of the potential hazard to the fetus [see Use
`
`in Specific Populations (8.1)].
`
`
`6 ADVERSE REACTIONS
`
`The following serious adverse events are discussed in greater detail in other sections of the
`
`labeling:
`
`
`
`• Tumor Lysis Syndrome [see Warnings and Precautions (5.1)]
`
`
`
`
`• Neutropenia [see Warnings and Precautions (5.2)]
`
`
`
`Because clinical trials are conducted under widely variable conditions, adverse event rates
`
`
`observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of
`
`
`another drug and may not reflect the rates observed in practice.
`
`
`
`
`
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 8
`
`DRL EXHIBIT 1009 PAGE 8
`
`

`

`
`
`
`
`6.1 Clinical Trial Experience
`
` The safety of single agent VENCLEXTA at the 400 mg recommended daily dose following a
`
`
`
`
`
`
`
` dose ramp-up schedule is based on pooled data of 240 patients with previously treated CLL from
` two phase 2 trials and one phase 1 trial. In the pooled dataset, the median age was 66 years
`
`
`
` (range: 29 to 85 years), 95% were white, and 69% were male. The median number of prior
`
`
` therapies was 3 (range: 1 to 12). The median duration of treatment with VENCLEXTA at the
`
`
`
` time of data analysis was approximately 10.3 months (range: 0 to 34.1 months). Approximately
`
`
`
` 46% of patients received VENCLEXTA for more than 48 weeks.
` The most common adverse reactions (≥20%) of any grade were neutropenia, diarrhea, nausea,
`
`
`
`
`
` anemia, upper respiratory tract infection, thrombocytopenia, and fatigue.
` Serious adverse reactions were reported in 43.8% of patients. The most frequent serious adverse
`
`
`
`
`
` reactions (≥2%) were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia
`
`
` (AIHA), anemia, and TLS.
` Discontinuations due to adverse reactions occurred in 8.3% of patients. The most frequent
`
`
`
` adverse reactions leading to drug discontinuation were thrombocytopenia and AIHA.
` Dosage adjustments due to adverse reactions occurred in 9.6% of patients. The most frequent
`
`
` adverse reactions leading to dose adjustments were neutropenia, febrile neutropenia, and
` thrombocytopenia.
`
`
` Adverse reactions reported in 3 trials of patients with previously treated CLL using single agent
`
` VENCLEXTA are presented in Table 7.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 7. Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3 or 4) of
`
`
` Patients with CLL
`
`Body System
`
`
`
`
` Blood and lymphatic system disorders
`
`
`
` Gastrointestinal disorders
`
`
`
` General disorders and administration
`
` site conditions
`
`
`
` Infections and infestations
`
`
`
` Metabolic and nutrition disorders
`
`Reference ID: 3915259
`
`Adverse Reaction
`
`
` Neutropeniaa
`
` Anemiab
`
` Thrombocytopeniac
`
` Febrile neutropenia
` Diarrhea
`
`
` Nausea
` Vomiting
`
` Constipation
`
` Fatigue
`
` Pyrexia
` Peripheral edema
`
` Upper respiratory tract
`
` infection
` Pneumonia
`
` Hypokalemia
`
`
`
`
`
`
`
`Any Grade
`
` (%)
`N=240
`
`
` 45
`
` 29
`
` 22
`
` 5
`
` 35
`
` 33
`
` 15
`
` 14
`
` 21
`
` 16
`
` 11
`
` 22
`
` 8
` 12
`
`
`
`
` Grade 3 or 4
`
` (%)
`N=240
`
`
` 41
`
` 18
`
` 15
`
` 5
`
` <1
`
` <1
`
` <1
`
` 0
`
` 2
`
` <1
`
` <1
`
` 1
`
` 5
`
` 4
`
`DRL EXHIBIT 1009 PAGE 9
`
`DRL EXHIBIT 1009 PAGE 9
`
`

`

`
`
`
`
`
`
`
`
` Grade 3 or 4
`Any Grade
`
`
` (%)
` (%)
`Body System
`N=240
`N=240
`Adverse Reaction
`
`
`
`
`Musculoskeletal and connective tissue
`
` <1
`
` 10
`
` Back pain
`
` disorders
` Nervous system disorders
`
` <1
`
` 15
`
` Headache
`
`Respiratory, thoracic, and mediastinal
`
`
` 13
`
` Cough
` 0
`
` disorders
` Adverse Reactions graded using NCI Common Terminology Criteria for Adverse Events version
`
`
` 4.0.
` aNeutropenia/neutrophil count decreased.
`
`
` bAnemia/hemoglobin decreased.
` cThrombocytopenia/platelet count decreased.
`
` Tumor Lysis Syndrome
`
` Tumor lysis syndrome is an important identified risk when initiating VENCLEXTA. In the initial
`
`
`
`
`
`
` Phase 1 dose-finding trials, which had shorter (2-3 week) ramp-up phase and higher starting
` dose, the incidence of TLS was 12% (9/77; 4 laboratory TLS, 5 clinical TLS), including 2 fatal
`
`
`events and 3 events of acute renal failure, 1 requiring dialysis.
`The risk of TLS was reduced after revision of the dosing regimen and modification to
`
`
`
` prophylaxis and monitoring measures [see Dosage and Administration (2.2, 2.3)]. In venetoclax
`
`clinical trials, patients with any measurable lymph node ≥10 cm or those with both an ALC ≥25
` x 109/L and any measurable lymph node ≥5 cm were hospitalized to enable more intensive
`
`
`hydration and monitoring for the first day of dosing at 20 mg and 50 mg during the ramp-up
`
`phase.
`
`In 66 patients with CLL starting with a daily dose of 20 mg and increasing over 5 weeks to a
`
`
`
`
`daily dose of 400 mg, the rate of TLS was 6%. All events either met laboratory TLS criteria
`
`
`
`(laboratory abnormalities that met ≥2 of the following within 24 hours of each other: potassium
`
`
`>6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5 mmol/L); or
`
`
`
`were reported as TLS events. The events occurred in patients who had a lymph node(s) ≥5 cm or
`
`
`
`
`ALC ≥25 x 109/L. No TLS with clinical consequences such as acute renal failure, cardiac
`
`
`arrhythmias or sudden death and/or seizures was observed in these patients. All patients had
`CrCl ≥50 mL/min.
`
`Laboratory abnormalities relevant to TLS observed in 66 patients with CLL who followed the
`
`
`
`dose ramp-up schedule and TLS prophylaxis measures are presented in Table 8.
`
`
`
`
`
`
`Table 8. Adverse Reactions of TLS and Relevant Laboratory Abnormalities Reported in
`
`
`Patients with CLL
`
`
`
` All Grades (%)
`N=66
`
`
` 6
`
`
`
` Grade ≥3 (%)
`N=66
`
`
` 6
`
`
`
`
`
`Parameter
`
`
` Laboratory TLSa
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 10
`
`DRL EXHIBIT 1009 PAGE 10
`
`

`

`
`
`
`
`
`
`
`
` Grade ≥3 (%)
` All Grades (%)
`N=66
`N=66
`Parameter
`
`
`
`
` Hyperkalemiab
`
` 2
`
` 20
` Hyperphosphatemiac
`
` 3
`
` 15
`
` Hypocalcemiad
`
` 3
`
` 9
`
` Hyperuricemiae
`
` 2
`
` 6
` aLaboratory abnormalities that met ≥2 of the following criteria within 24 hours of each other:
`potassium >6 mmol/L, uric acid >476 µmol/L, calcium <1.75 mmol/L, or phosphorus >1.5
`
`
`
` mmol/L; or were reported as TLS events.
`bHyperkalemia/blood potassium increased.
`
`cHyperphosphatemia/blood phosphorus increased.
`dHypocalcemia/blood calcium decreased.
`
`eHyperuricemia/blood uric acid increased.
`
`
`
`
`
`
`
`
`
`
`
` 7 DRUG INTERACTIONS
`
`
`
`
`
` 7.1 Effects of Other Drugs on VENCLEXTA
`
`
`Venetoclax is predominantly metabolized by CYP3A4/5.
`
`
` Strong CYP3A Inhibitors
` Concomitant use of VENCLEXTA with strong CYP3A inhibitors (e.g., ketoconazole,
`
`
` conivaptan, clarithromycin, indinavir, itraconazole, lopinavir, ritonavir, telaprevir, posaconazole
`
`
` and voriconazole) at initiation and during ramp-up phase is contraindicated [see
` Contraindications (4) and Clinical Pharmacology (12.3)].
`
`
`
`
` For patients who have completed the ramp-up phase and are on a steady daily dose of
` VENCLEXTA, reduce the VENCLEXTA dose by at least 75% when used concomitantly with
`
`
`
`
`
`
` strong CYP3A inhibitors. Resume the VENCLEXTA dose that was used prior to initiating the
` CYP3A inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and
`
`
`
` Administration (2.4, 2.5) and Clinical Pharmacology (12.3)].
`
`Co-administration of ketoconazole increased venetoclax Cmax by 2.3-fold and AUC∞ by 6.4-fold.
`
`
`
`Moderate CYP3A Inhibitors and P-gp Inhibitors
`
`
`
`Avoid concomitant use of moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin,
`
`
`
`
` diltiazem, dronedarone, fluconazole, verapamil) or P-gp inhibitors (e.g., amiodarone,
`azithromycin, captopril, carvedilol, cyclosporine, felodipine, quercetin, quinidine, ranolazine,
`
`
`
`ticagrelor) with VENCLEXTA. Consider alternative treatments. If a moderate CYP3A inhibitor
`
`
`
`
`
`
`or a P-gp inhibitor must be used, reduce the VENCLEXTA dose by at least 50%. Monitor
`
`
`
`
`patients more closely for signs of VENCLEXTA toxicities [see Dosage and Administration (2.4,
`
`2.5) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`Resume the VENCLEXTA dose that was used prior to initiating the CYP3A inhibitor or P-gp
`
`
`inhibitor 2 to 3 days after discontinuation of the inhibitor [see Dosage and Administration (2.5)
`
`
`and Clinical Pharmacology (12.3)].
`
`
`
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 11
`
`DRL EXHIBIT 1009 PAGE 11
`
`

`

`
`
`
`
`
`
`
`
` Avoid grapefruit products, Seville oranges, and starfruit during treatment with VENCLEXTA, as
`
`
` they contain inhibitors of CYP3A.
` Co-administration of a single dose of rifampin, a P-gp inhibitor, increased venetoclax Cmax by
`
`
`106% and AUC∞ by 78%.
`
`CYP3A Inducers
`
`
` Avoid concomitant use of VENCLEXTA with strong CYP3A inducers (e.g., carbamazepine,
` phenytoin, rifampin, St. John’s wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz,
`
`
`
` etravirine, modafinil, nafcillin). Consider alternative treatments with less CYP3A induction [see
` Clinical Pharmacology (12.3)].
`
` Co-administration of multiple doses of rifampin, a strong CYP3A inducer, decreased venetoclax
`
` Cmax by 42% and AUC∞ by 71%.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`7.2 Effects of VENCLEXTA on Other Drugs
`
`Warfarin
` In a drug-drug interaction study in healthy subjects, administration of a single dose of venetoclax
`
`
`
`
` with warfarin resulted in an 18% to 28% increase in Cmax and AUC ∞ of R-warfarin and S-
`warfarin. Because venetoclax was not dosed to steady state, it is recommended that the
` international normalized ratio (INR) be monitored closely in patients receiving warfarin.
` P-gp substrates
`
`
` In vitro data suggest venetoclax has inhibition potential on P-gp substrates at therapeutic dose
` levels in the gut. Therefore, co-administration of narrow therapeutic index P-gp substrates (e.g.,
`
`
`
`
`
`
`
` digoxin, everolimus, and sirolimus) with VENCLEXTA should be avoided. If a narrow
` therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before
`
`
`
` VENCLEXTA.
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
` 8.1 Pregnancy
`
`
` Risk Summary
`
`
`
`
`
`There are no available human data on the use of VENCLEXTA in pregnant women. Based on
`
`
`
`
`toxicity observed in mice, VENCLEXTA may cause fetal harm when administered to pregnant
`
`
`women. In mice, venetoclax was fetotoxic at exposures 1.2 times the human clinical exposure
`
`
`
`
`based on AUC at the recommended human dose of 400 mg daily. If VENCLEXTA is used
`
`
`
`during pregnancy or if the patient becomes pregnant while taking VENCLEXTA, the patient
`
`should be apprised of the potential risk to a fetus.
`
`The background risk in the U.S. general population of major birth defects is 2% to 4% and of
`
`miscarriage is 15% to 20% of clinically recognized pregnancies.
`
`Reference ID: 3915259
`
`DRL EXHIBIT 1009 PAGE 12
`
`DRL EXHIBIT 1009 PAGE 12
`
`

`

` Data
`
` Animal data
`
` In embryo-fetal development studies, venetoclax was administered to pregnant mice and rabbits
`
`
` during the period of organogenesis. In mice, venetoclax was associated with increased post-
` implantation loss and decreased fetal body weight at 150 mg/kg/day (maternal exposures
`
`
`
`
` approximately 1.2 times the human AUC exposure at the recommended dose of 400 mg daily).
`
`No teratogenicity was observed in either the mouse or the rabbit.
`
`
`
` 8.2 Lactation
`
` Risk Summary
`
`There are no data on the presence of VENCLEXTA in human milk, the effects of VENCLEXTA
`
`
`
`
`on the breastfed child, or the effects of VENCLEXTA on milk production. Because many drugs
`
`
`
`
`are excreted in human milk and because the potential for serious adverse reactions in breastfed
`
`infants from VENCLEXTA is unknown, advise nursing women to discontinue breastfeeding
`
`
`
`during treatment with VENCLEXTA.
`
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`VENCLEXTA may cause fetal harm [see Warnings and Precautions (5.4) and Use in Specific
`
`
`
`
`Populations (8.1)].
`
`Pregnancy Testing
`
`Females of reproductive potential should undergo pregnancy testing before initiation
`
`
`
`
`of VENCLEXTA [see Use in Specific Populations (8