HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`COMETRIQ safely and effectively. See full prescribing
`information for COMETRIQ.
`COMETRIQ™ (cabozantinib) capsules, for oral use
`Initial U.S. Approval: 2012
`WARNING: PERFORATIONS AND FISTULAS, and
`HEMORRHAGE
`See full prescribing information for complete boxed warning.
` Perforations and Fistulas: Gastrointestinal perforations
`occurred in 3% and fistula formation in 1% of COMETRIQ-
`treated patients. Discontinue COMETRIQ in patients with
`perforation or fistula. (5.1)
` Hemorrhage: Severe, sometimes fatal, hemorrhage including
`hemoptysis and gastrointestinal hemorrhage occurred in 3% of
`COMETRIQ-treated patients. Monitor patients for signs and
`symptoms of bleeding. Do not administer COMETRIQ to
`patients with severe hemorrhage. (5.2)
`
`
`
` Wound Complications: Withhold COMETRIQ for dehiscence or
`complications requiring medical intervention. (5.4)
` Hypertension: Monitor blood pressure regularly. Discontinue
`COMETRIQ for hypertensive crisis. (5.5)
` Osteonecrosis of the jaw: Discontinue COMETRIQ. (5.6)
` Palmar-plantar Erythrodysesthesia syndrome (PPES): Interrupt
`COMETRIQ, decrease dose. (5.7)
` Proteinuria: Monitor urine protein. Discontinue for nephrotic
`syndrome. (5.8)
` Reversible posterior leukoencephalopathy syndrome (RPLS):
`Discontinue COMETRIQ. (5.9)
` Embryofetal toxicity: Can cause fetal harm. Advise women of
`potential risk to a fetus. (5.11, 8.1)
`
`_________________ADVERSE REACTIONS_________________
`The most commonly reported adverse drug reactions (≥25%) are
`diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome
`(PPES), decreased weight, decreased appetite, nausea, fatigue, oral
`pain, hair color changes, dysgeusia, hypertension, abdominal pain,
`and constipation. The most common laboratory abnormalities (≥25%)
`are increased AST, increased ALT, lymphopenia, increased alkaline
`phosphatase, hypocalcemia, neutropenia, thrombocytopenia,
`hypophosphatemia, and hyperbilirubinemia. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Exelixis, Inc. at 1-855-500-3935 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`_________________DRUG INTERACTIONS_________________
`Cabozantinib is a CYP3A4 substrate (5.10, 7.1, 7.2). Co-
`administration of strong CYP3A4 inhibitors can increase
`cabozantinib exposure (2.1, 5.10, 7.1). Chronic co-administration of
`strong CYP3A4 inducers can reduce cabozantinib exposure. (2.1,
`5.10, 7.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling
`
`
`_______________INDICATIONS AND USAGE_______________
`COMETRIQ is a kinase inhibitor indicated for the treatment of
`patients with progressive, metastatic medullary thyroid cancer
`(MTC). (1)
`
`____________DOSAGE AND ADMINISTRATION____________
` Recommended Dose: 140 mg orally, once daily. (2.1)
` Instruct patients not to eat for at least 2 hours before and at least 1
`hour after taking COMETRIQ. (2.1).
`
`___________DOSAGE FORMS AND STRENGTHS___________
`20 mg and 80 mg capsules. (3)
`
`________________ CONTRAINDICATIONS ________________
`None (4)
`
`____________ WARNINGS AND PRECAUTIONS ____________
` Thrombotic Events: Discontinue COMETRIQ for myocardial
`infarction, cerebral infarction, or other serious arterial
`thromboembolic events. (5.3)
`________________________________________________________________________________________________________________________
`7 DRUG INTERACTIONS
`FULL PRESCRIBING INFORMATION: CONTENTS*
`7.1 Effect of CYP3A4 Inhibitors
`WARNING: PERFORATIONS AND FISTULAS and
`7.2 Effect of CYP3A4 Inducers
`HEMORRHAGE
`8 USE IN SPECIFIC POPULATIONS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`8.1 Pregnancy
`2.1. Recommended Dose
`8.2 Nursing Mothers
`2.2 Dosage Adjustments
`8.3 Pediatric Use
`3 DOSAGE FORMS AND STRENGTHS
`8.4 Geriatric Use
`4 CONTRAINDICATIONS
`8.5
` Females and Males of Reproductive Potential
`5 WARNINGS AND PRECAUTIONS
`8.6 Hepatic Impairment
`5.1 Perforations and Fistulas
`8.7 Renal Impairment
`5.2 Hemorrhage
`10 OVERDOSAGE
`5.3 Thrombotic Events
`11 DESCRIPTION
`5.4 Wound Complications
`12 CLINICAL PHARMACOLOGY
`5.5 Hypertension
`12.1 Mechanism of Action
`5.6 Osteonecrosis of the Jaw
`12.3 Pharmacokinetics
`5.7 Palmar-Plantar Erythrodysesthesia Syndrome
`12.6 Cardiac Electrophysiology
`5.8 Proteinuria
`13 NONCLINICAL TOXICOLOGY
`5.9 Reversible Posterior Leukoencephalopathy
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Syndrome
`Fertility
`5.10 Drug Interactions
`14 CLINICAL STUDIES
`5.11 Hepatic Impairment
`16 HOW SUPPLIED/STORAGE AND HANDLING
`5.12 Embryo-fetal Toxicity
`17 PATIENT COUNSELING INFORMATION
`6 ADVERSE REACTIONS
`*Sections or subsections omitted from the Full Prescribing
`6.1 Clinical Trial Experience
`information are not listed.
`
`Revised: 11/2012
`
`Reference ID: 3223542
`
`Ex. 1111-0001
`
`

`
`FULL PRESCRIBING INFORMATION
`
`WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE
`Perforations and fistulas: Gastrointestinal perforations occurred in 3% and fistula
`formation in 1% of COMETRIQ™-treated patients. Discontinue COMETRIQ for
`perforation or for fistula formation [See Warnings and Precautions (5.1)].
`Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and
`gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor
`patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients
`with severe hemorrhage [See Warnings and Precautions (5.2)].
`
`INDICATIONS AND USAGE
`1
`COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary
`thyroid cancer (MTC).
`
`DOSAGE AND ADMINISTRATION
`
`2
`1.1.
`Recommended Dose
`The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules).
`Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before
`and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or
`unacceptable toxicity occurs.
`Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules.
`Do not take a missed dose within 12 hours of the next dose.
`Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known
`to inhibit cytochrome P450 during COMETRIQ.
`
`Dosage Adjustments
`
`2.2
`
`For Adverse Reactions
`Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or
`greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions.
`Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to
`Grade 1), reduce the dose as follows:
`
`If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and
`one 20-mg capsule)
`
`Reference ID: 3223542
`
`Ex. 1111-0002
`
`

`
`
`
`
`
`If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg
`capsules)
`If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue
`COMETRIQ
`Permanently discontinue COMETRIQ for any of the following:
` development of visceral perforation or fistula formation
` severe hemorrhage
` serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction)
` nephrotic syndrome
` malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite
`optimal medical management
` osteonecrosis of the jaw
`
`reversible posterior leukoencephalopathy syndrome
`
`In Patients with Hepatic Impairment
`COMETRIQ is not recommended for use in patients with moderate and severe hepatic
`impairment [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)].
`
`In Patients Taking CYP3A4 Inhibitors
`Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole,
`clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir,
`voriconazole) in patients receiving COMETRIQ [see Warnings and Precautions (5.10) and Drug
`Interactions (7.1)].
`For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily
`COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60
`mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days
`after discontinuation of the strong inhibitor.
`
`In Patients Taking Strong CYP3A4 Inducers
`Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine,
`rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available [see Warnings
`and Precautions (5.10) and Drug Interactions (7.2)].
`Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum))
`that are known to induce cytochrome P450 activity.
`For patients who require treatment with a strong CYP3A4 inducer, increase the daily
`COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140
`
`Reference ID: 3223542
`
`Ex. 1111-0003
`
`

`
`mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2
`to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not
`exceed 180 mg.
`
`DOSAGE FORMS AND STRENGTHS
`3
`COMETRIQ 20-mg gelatin capsules are grey with “XL184 20mg” printed in black on the body
`of the capsule.
`COMETRIQ 80-mg gelatin capsules are Swedish orange with “XL184 80mg” printed in black
`on the body of the capsule.
`
`CONTRAINDICATIONS
`
`4
`None
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Perforations and Fistulas
`5.1
`Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-
`treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non-GI
`fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two
`(1%) of these were fatal.
`Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients
`who experience a perforation or a fistula.
`
`Hemorrhage
`5.2
`Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3
`hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs.
`1%).
`Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.
`
`Thrombotic Events
`5.3
`COMETRIQ treatment results in an increased incidence of thrombotic events (venous
`thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated
`and placebo-treated patients, respectively).
`Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other
`clinically significant arterial thromboembolic complication.
`
`Wound Complications
`5.4
`Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at
`least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on
`
`Reference ID: 3223542
`
`Ex. 1111-0004
`
`

`
`clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence
`or wound healing complications requiring medical intervention.
`
`Hypertension
`5.5
`COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension
`with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High
`Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in
`COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized
`trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment.
`Withhold COMETRIQ for hypertension that is not adequately controlled with medical
`management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ
`for severe hypertension that cannot be controlled with anti-hypertensive therapy.
`
`Osteonecrosis of the Jaw
`5.6
`Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can
`manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection,
`toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw
`after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and
`periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices.
`For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to
`scheduled surgery, if possible.
`
`Palmar-Plantar Erythrodysesthesia Syndrome
`5.7
`Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with
`cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients
`who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1;
`resume COMETRIQ at a reduced dose.
`
`Proteinuria
`5.8
`Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with
`nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine
`protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who
`develop nephrotic syndrome.
`
`Reversible Posterior Leukoencephalopathy Syndrome
`5.9
`Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical
`vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient.
`Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual
`disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who
`develop RPLS.
`
`Reference ID: 3223542
`
`Ex. 1111-0005
`
`

`
`Drug Interactions
`5.10
`Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors
`[see Dosage and Administration (2.1) and Drug Interactions (7.1, 7.2)].
`
`Hepatic Impairment
`5.11
`COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment
`[see Use in Specific Populations (8.6)].
`
`
`Embryo-fetal Toxicity
`5.12
`COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was
`embryolethal in rats at exposures below the recommended human dose, with increased
`incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If
`this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the
`patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations
`(8.1)].
`
`ADVERSE REACTIONS
`6
`The following serious adverse reactions are discussed elsewhere in the label:
` Perforations and Fistula [see Boxed Warning, Warnings and Precautions (5.1)]
` Hemorrhage [see Boxed Warning, Warnings and Precautions (5.2)]
` Thromboembolic Events [see Warnings and Precautions (5.3)]
` Wound Complications [see Warnings and Precautions (5.4)]
` Hypertension [see Warnings and Precautions (5.5)]
` Osteonecrosis of the Jaw [see Warnings and Precautions (5.6)]
` Palmar-plantar erythrodysesthesia syndrome [see Warnings and Precautions (5.7)]
` Proteinuria [see Warnings and Precautions (5.8)]
` Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions
`(5.9)]
`
`
`
`Clinical Trial Experience
`6.1
`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 COMETRIQ was evaluated in 330 patients with progressive metastatic medullary
`thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109)
`administered daily until disease progression or intolerable toxicity in a randomized, double-
`blind, controlled trial. [See Clinical Studies (14).] The data described below reflect a median
`exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male,
`90% white, and had a median age of 55 years.
`
`Reference ID: 3223542
`
`Ex. 1111-0006
`
`

`
`Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more
`frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of
`decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES),
`decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia,
`hypertension, abdominal pain, and constipation. The most common laboratory abnormalities
`(>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia,
`neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse
`reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients
`occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2%
`included, in order of decreasing frequency; diarrhea, PPES, lymphopenia, hypocalcemia, fatigue,
`hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see
`Table 1, Table 2).
`Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from
`hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified
`death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from
`septicemia, pneumonia, and general deterioration.
`The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients
`receiving placebo. The median number of dosing delays was one in patients receiving
`COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study
`treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients
`receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in
`patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue,
`hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting.
`Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients
`receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo
`(regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had
`a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose.
`
`Reference ID: 3223542
`
`Ex. 1111-0007
`
`

`
`
`
`
`MedDRA System Organ Class/ Preferred Terms
`
`GASTROINTESTINAL DISORDERS
`Diarrhea
`Stomatitis2
`Nausea
`Oral pain3
`Constipation
`Abdominal pain4
`Vomiting
`Dysphagia
`Dyspepsia
`Hemorrhoids
`GENERAL DISORDERS AND
`ADMINISTRATION SITE CONDITIONS
`Fatigue
`Asthenia
`INVESTIGATIONS
`Decreased weight
`METABOLISM AND NUTRITION DISORDERS
`Decreased appetite
`Dehydration
`MUSCULOSKELETAL AND CONNECTIVE
`TISSUE DISORDERS
`Arthralgia
`Muscle spasms
`Musculoskeletal chest pain
`NERVOUS SYSTEM DISORDERS
`Dysgeusia
`Headache
`Dizziness
`Paresthesia
`Peripheral sensory neuropathy
`Peripheral neuropathy
`PSYCHIATRIC DISORDERS
`Anxiety
`RESPIRATORY, THORACIC AND
`MEDIASTINAL DISORDERS
`Dysphonia
`SKIN AND SUBCUTANEOUS TISSUE
`DISORDERS
`PPES5
`Hair color changes/ depigmentation, graying
`
`Table 1
` Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301
`Occurring at a Higher Incidence in COMETRIQ-Treated Patients
`[Between Arm Difference of ≥ 5% (All Grades)1or ≥ 2% (Grades 3-4)]
`Cabozantinib
`Placebo
`(n=214)
`(n=109)
`All
`Grades
`All
`Grades
`Grades
`3-4
`Grades
`3-4
`
`63
`51
`43
`36
`27
`27
`24
`13
`11
`9
`
`41
`21
`
`48
`
`46
`7
`
`14
`12
`9
`
`34
`18
`14
`7
`7
`5
`
`9
`
`20
`
`50
`34
`
`16
`5
`1
`2
`0
`3
`2
`4
`0
`0
`
`9
`6
`
`5
`
`5
`2
`
`1
`0
`1
`
`0
`0
`0
`0
`0
`0
`
`0
`
`0
`
`13
`0
`
`33
`6
`21
`6
`6
`13
`2
`6
`0
`3
`
`28
`15
`
`10
`
`16
`2
`
`7
`5
`4
`
`6
`8
`7
`2
`0
`0
`
`2
`
`9
`
`2
`1
`
`2
`0
`0
`0
`0
`1
`1
`1
`0
`0
`
`3
`1
`
`0
`
`1
`1
`
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`
`0
`
`0
`
`0
`0
`
`Reference ID: 3223542
`
`Ex. 1111-0008
`
`

`
`
`
`
`MedDRA System Organ Class/ Preferred Terms
`
`Table 1
` Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301
`Occurring at a Higher Incidence in COMETRIQ-Treated Patients
`[Between Arm Difference of ≥ 5% (All Grades)1or ≥ 2% (Grades 3-4)]
`Cabozantinib
`Placebo
`(n=214)
`(n=109)
`All
`Grades
`All
`Grades
`Grades
`3-4
`Grades
`3-4
`19
`1
`10
`0
`19
`0
`3
`0
`16
`0
`2
`0
`11
`1
`2
`0
`7
`0
`0
`0
`
`Rash
`Dry skin
`Alopecia
`Erythema
`Hyperkeratosis
`VASCULAR DISORDERS
`4
`8
`33
`Hypertension
`0
`1
`7
`Hypotension
`1 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0
`2 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation
`3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome,
`glossodynia
`4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal
`rigidity, abdominal tenderness, esophageal pain
`5 Palmar-plantar erythrodysesthesia syndrome
`
`0
`0
`
`
`
`Reference ID: 3223542
`
`Ex. 1111-0009
`
`

`
`Table 2
`Percent-Patient Incidence of Laboratory Abnormalities Occurring at a
`Higher Incidence in COMETRIQ-Treated Patients in Protocol
`XL184-301
`[Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)]
`COMETRIQ
`Placebo
`(n=214)
`(n=109)
`Grade
`Grade 3-4
`3-4
`
`
`Adverse Event
`
`
`All
`Grades
`
`All
`Grades
`
`Chemistries
`35
`3
`86
`Increased AST
`41
`6
`86
` Increased ALT
`35
`3
`52
`Increased ALP
`27
`12
`52
`Hypocalcemia
`10
`3
`28
`Hypophosphatemia
`14
`2
`25
`Hyperbilirubinemia
`4
`1
`19
`Hypomagnesemia
`9
`4
`18
`Hypokalemia
`5
`2
`10
`Hyponatremia
`
`
`
`Hematologic
`51
`16
`53
`Lymphopenia
`15
`3
`35
`Neutropenia
`4
`0
`35
` Thrombocytopenia
`ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate
`aminotransferase
`
`
`
`
`
`2
`2
`3
`3
`1
`5
`0
`3
`0
`
`11
`2
`3
`
`
`Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood
`pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated
`patients over placebo-treated patients (61% vs. 30%) according to modified Joint National
`Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC)
`staging criteria. No patients developed malignant hypertension.
`
`
`Reference ID: 3223542
`
`Ex. 1111-0010
`
`

`
`
`Hypertension, JNC1 Stage
`
`Table 3
`Per-Patient Incidence of Hypertension in Protocol XL184-301
`COMETRIQ
`N = 2113(%)
`
`Placebo
`N = 1073
`(%)
`15
`4
`Normal: Grade 0: Systolic < 120 mmHg and Diastolic < 80 mmHg
`54
`34
`Pre-hypertension: Systolic ≥ 120 mmHg or Diastolic ≥ 80 mmHg
`25
`46
`Stage 1: Systolic ≥ 140 mmHg or Diastolic ≥ 90 mmHg
`5
`15
`Stage 2: Systolic ≥ 160 mmHg or Diastolic ≥ 100 mmHg
`0
`0
`Malignant: Diastolic ≥ 120 mmHg
`1Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,
`JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per
`timepoint, and therefore not averaged.
`2Subjects classified by highest category based on all recorded blood pressure readings beginning after the
`first dose through 30 days after last dose.
`3Subjects with at least two blood pressure measurements after the first dose
`
`7
`
`DRUG INTERACTIONS
`
`Effect of CYP3A4 Inhibitors
`7.1
`Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to
`healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid
`taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir,
`indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking
`COMETRIQ [see Dosage and Administration (2.1) and Warnings and Precautions (5.10)].
`
`
`Effect of CYP3A4 Inducers
`7.2
`Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy
`subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic
`co-administration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine,
`rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ [see Dosage
`and Administration (2.1) and Warnings and Precautions (5.10)].
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category D
`Risk Summary
`
`Reference ID: 3223542
`
`Ex. 1111-0011
`
`

`
`Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a
`pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended
`human dose, with increased incidences of skeletal variations in rats and visceral variations and
`malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant
`while taking this drug, the patient should be apprised of the potential hazard to the fetus.
`Animal Data
`In an embryo-fetal development study in which pregnant rats were administered daily doses of
`cabozantinib during organogenesis, increased loss of pregnancy compared to controls was
`observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the
`recommended dose). Findings included delayed ossifications and skeletal variations at doses
`equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at
`the recommended dose).
`In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of
`visceral malformations and variations including reduced spleen size and missing lung lobe at 3
`mg/kg (approximately 11% of the human exposure by AUC at the recommended dose).
`
`Nursing Mothers
`8.2
`It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many
`drugs are excreted in human milk and because of the potential for serious adverse reactions in
`nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or
`to discontinue the drug, taking into account the importance of the drug to the mother.
`
`Pediatric Use
`8.3
`The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.
`
`Geriatric Use
`8.4
`Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and
`over to determine whether they respond differently from younger patients
`
`8.5 Females and Males of Reproductive Potential
`Contraception
`Use effective contraception during treatment with COMETRIQ and up to 4 months after
`completion of therapy.
`Infertility
`There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male
`and female fertility in animal studies [see Nonclinical Toxicology (13.1)].
`
`Hepatic Impairment
`8.6
`Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There
`are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the
`upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or
`
`Reference ID: 3223542
`
`Ex. 1111-0012
`
`

`
`severe hepatic impairment, as safety and efficacy have not been established [see Dosage and
`Administration (2.1) and Warnings and Precautions (5.11)].
`
`Renal Impairment
`8.7
`No dose adjustment is recommended for patients with mild or moderate renal impairment. There
`is no experience with COMETRIQ in patients with severe renal impairment.
`
`OVERDOSAGE
`10
`One case of overdosage was reported in a patient who inadvertently took twice the intended dose
`(200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental
`status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in
`BUN. The extent of recovery was not documented.
`
`DESCRIPTION
`11
`COMETRIQ is the (S)-malate salt of cabozantinib. Cabozantinib (S)-malate is described
`chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4-fluorophenyl)cyclopropane-
`1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5.C4H6O5
`and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib
`(S)-malate salt is:
`
`
`F
`
`HN
`
`O
`
`O
`
`O
`
`OH
`
`O
`
`OH
`
`HN
`
`HO
`
`O
`
`N
`
`
`
`MeO
`
`MeO
`
`
`
`Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous
`media.
`COMETRIQ (cabozantinib) capsules are supplied as printed hard gelatin capsules containing
`cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib and the following inactive
`ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate,
`fumed silica, and stearic acid.
`The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish
`orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink
`contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol,
`and ammonium hydroxide.
`
`Reference ID: 3223542
`
`Ex. 1111-0013
`
`

`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1. Mechanism of Action
`In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine
`kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2.
`These receptor tyrosine kinases are involved in both normal cellular function and pathologic
`processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor
`microenvironment.
`
`Pharmacokinetics
`12.3
`A population pharmacokinetic analysis of cabozantinib was performed using data collected from
`289 patients with solid tumors including MTC following oral administration of 140 mg daily
`doses. The predicted effective half-life is approximately 55 hours, the oral volume of distribution
`(V/F) is approximately 349 L, and the clearance (CL/F) at steady-state is estimated to be 4.4
`L/hr.
`Absorption and Distribution
`Following oral administration of COMETRIQ, median time to peak cabozantinib plasma
`concentrations (Tmax) ranged from 2 to 5 hours post-dose. Repeat daily dosing of COMETRIQ at
`140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC)
`compared to a single dose administration; steady state was achieved by Day 15. Cabozantinib is
`highly protein bound in human plasma (≥ 99.7%).
`A high-fat meal increased Cmax and AUC values by 41% and 57%, respectively relative to fasted
`conditions in healthy subjects administered a single 140 mg oral COMETRIQ dose.
`Metabolism and Elimination
`Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition of CYP3A4 reduced the formation of
`the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on
`cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6,
`CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite
`formation.
`Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy subjects,
`approximately 81% of the total administered radioactivity was recovered with 54% in feces and
`27% in urine.
`
`
`Reference ID: 3223542
`
`Ex. 1111-0014
`
`

`
`Specific Populations
`Renal Impairment: No formal pharmacokinetic study of cabozantinib has been conducted in
`patients with renal impairment. The results of a population pharmacokinetic analysis suggested
`that mild to moderate renal impairment (creatinine clearance value ≥30 mL/min) does not have a
`clinically relevant effect on the clearance of cabozantinib.
`Hepatic Impairment: The pharmacokinetics of cabozantinib has not been studied in patients with
`hepatic impairment [see Dosage and Administration (2.1), Warnings and Precautions (5.11) and
`Use in Specific Populations (8.6)].
`Pediatric Population: The pharmacokinetics of cabozantinib has not been studied in the pediatric
`population [see Use in Specific Populations (8.3)].
`Effects of Age, Gender and Race: A population PK analysis did not identify clinically relevant
`differences in clearance of cabozantinib between females and males or between Whites (89%)
`and non-Whites (11%). Cabozantinib pharmacokinetics was not affected by age (20-86 years).
`Drug Interactions
`CYP Enzyme Inhibition and Induction: Cabozantinib is a noncompetitive inhibitor of CYP2C8
`(Kiapp = 4.6 µM), a mixed-type inhibitor of both CYP2C9 (Kiapp = 10.4 µM) and CYP2C19
`(Kiapp = 28.8 µM), and a weak competitive inhibitor of CYP3A4 (estimated Kiapp = 282 µM) in
`human liver microsomal (HLM) preparations. IC50 values >20 μM were observed for CYP1A2,
`CYP2D6, and CYP3A4 isozymes in both recombinant and HLM assay systems.
`Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (i.e., 75-100%
`of CYP1A1 positive control β-