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2012年11月29日，美国食品药品监督管理局(FDA)批准Cometriq(cabozantinib)治疗已播散至身体其他部分(转移的)甲状腺髓样癌。
甲状腺制造一种有助于维持血中钙健康水平的激素被称为降钙素[calcitonin]细胞中发生甲状腺髓样癌。这性癌自发发生或在有某些基因突变家族，导致内分泌系统1种或更多癌症，包括甲状腺。
美国国立癌症研究所估计在2012年56,460 美国人将诊断有甲状腺癌和1,780将死于此病。约4%甲状腺癌是甲状腺髓癌，为罕见甲状腺癌之一。
FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur，M.D.说：“在过去2年中Cometriq是第二个被批准治疗甲状腺髓样癌和反映FDA承诺发展和批准为治疗罕见病药物，”“在2011年4月批准Caprelsa，有此罕见和难治疾病患者的治疗选择有限。”
美国FDA在其优先审评程序下在6个月内完成Cometriq的申请审评。这个程序为可能提供治疗重要进展或当前没有治疗存在的药物提供一个加快6个月审评。Cometriq因为意向治疗罕见病或情况还获得孤儿产品指定。
Cometriq是激酶抑制剂阻断涉及髓样癌细胞的发育和生长的异常激酶蛋白。在服用Cometriq前至少2小时和后1小时患者不应进食。
在一项涉及330例有甲状腺髓样癌患者临床研究确定Cometriq的安全性和有效性。用Cometriq治疗增加无癌进展生存患者生存时间长度(无进展生存) 而，有些患者，肿瘤大小减小(缓解率)。
被给予Cometriq患者无肿瘤生长生存平均11.2个月与之比较接受糖丸(安慰剂)患者平均4个月。结果还显示用Cometriq治疗患者27%肿瘤大小减小平均持续接近15个月，而who 接受安慰剂患者未见减小。用Cometriq治疗不延长 患者生命。
Cometriq处方资料包括黑框警告警告患者和卫生保健专业人员严重和在有些患者中结肠内发生致命性出血和孔(穿孔和瘘管)。
最常见副作用是腹泻；炎症或口腔痛；发红，疼痛，或指趾肿胀(手足综合征)；体重减轻；食欲不振；恶心；疲乏；口疼；头发灰或色消失；难闻味；高血压新发作或恶化；腹痛和便秘。最常见实验室异常包括肝酶增加，低钙和磷，白血细胞和血小板减低。
Cometriq由Exelixis上市，位于南旧金山，加州。Caprelsa (vandetanib)由Wilmington，Del.-based AstraZeneca药业上市
COMETRIQ(cabozantinib)胶囊获美国FDA批准为口服使用
适应症和用途
COMETRIQ是激酶抑制剂适用为进展性，转移甲状腺髓样癌(MTC)患者的治疗。
剂量和给药方法
● 推荐剂量：140mg口服，每天1次。
● 指导患者服用COMETRIQ前至少2小时和后至少1小时不要进食。
剂型和规格
20mg和80mg胶囊。
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)
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
20mg and 80mg 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)
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). Coadministration 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.
Revised: 12/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).
2 DOSAGE AND ADMINISTRATION
2.1 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 treatment.
2.2 Dosage Adjustments
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)
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 Interactions7.1)].
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 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.
3 DOSAGE FORMS AND STRENGTHS
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.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Perforations and Fistulas
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.
5.2 Hemorrhage
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.
5.3 Thrombotic Events
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.
5.4 Wound Complications
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 clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.
5.5 Hypertension
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.
5.6 Osteonecrosis of the Jaw
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.
5.7 Palmar-Plantar Erythrodysesthesia Syndrome
Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with COMETRIQ 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.
5.8 Proteinuria
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.
5.9 Reversible Posterior Leukoencephalopathy Syndrome
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.
5.10 Drug Interactions
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)].
5.11 Hepatic Impairment
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.6)].
5.12 Embryo-fetal Toxicity
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)].
6 ADVERSE REACTIONS
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)]
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety 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, doubleblind, 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.
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.
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)* or ≥ 2% (Grades 3-4)]
| MedDRA System Organ Class/Preferred Terms |
COMETRIQ
(n=214) |
Placebo
(n=109) |
All
Grades |
Grades
3-4 |
All
Grades |
Grades
3-4 |
|
|
| GASTROINTESTINAL DISORDERS |
| Diarrhea |
63 |
16 |
33 |
2 |
| Stomatitis |
51 |
5 |
6 |
0 |
| Nausea |
43 |
1 |
21 |
0 |
| Oral pain |
36 |
2 |
6 |
0 |
| Constipation |
27 |
0 |
6 |
0 |
| Abdominal pain |
27 |
3 |
13 |
1 |
| Vomiting |
24 |
2 |
2 |
1 |
| Dysphagia |
13 |
4 |
6 |
1 |
| Dyspepsia |
11 |
0 |
0 |
0 |
| Hemorrhoids |
9 |
0 |
3 |
0 |
GENERAL DISORDERS AND
ADMINISTRATION SITE CONDITIONS |
| Fatigue |
41 |
9 |
28 |
3 |
| Asthenia |
21 |
6 |
15 |
1 |
| INVESTIGATIONS |
| Decreased weight |
48 |
5 |
10 |
0 |
| METABOLISM AND NUTRITION DISORDERS |
| Decreased appetite |
46 |
5 |
16 |
1 |
| Dehydration |
7 |
2 |
2 |
1 |
MUSCULOSKELETAL AND CONNECTIVE
TISSUE DISORDERS |
| Arthralgia |
14 |
1 |
7 |
0 |
| Muscle spasms |
12 |
0 |
5 |
0 |
| Musculoskeletal chest pain |
9 |
1 |
4 |
0 |
| NERVOUS SYSTEM DISORDERS |
| Dysgeusia |
34 |
0 |
6 |
0 |
| Headache |
18 |
0 |
8 |
0 |
| Dizziness |
14 |
0 |
7 |
0 |
| Paresthesia |
7 |
0 |
2 |
0 |
| Peripheral sensory neuropathy |
7 |
0 |
0 |
0 |
| Peripheral neuropathy |
5 |
0 |
0 |
0 |
| PSYCHIATRIC DISORDERS |
| Anxiety |
9 |
0 |
2 |
0 |
RESPIRATORY, THORACIC AND
MEDIASTINAL DISORDERS |
| Dysphonia |
20 |
0 |
9 |
0 |
SKIN AND SUBCUTANEOUS TISSUE
DISORDERS |
| PPES |
50 |
13 |
2 |
0 |
Hair color changes/
depigmentation, graying |
34 |
0 |
1 |
0 |
| Rash |
19 |
1 |
10 |
0 |
| Dry skin |
19 |
0 |
3 |
0 |
| Alopecia |
16 |
0 |
2 |
0 |
| Erythema |
11 |
1 |
2 |
0 |
| Hyperkeratosis |
7 |
0 |
0 |
0 |
| VASCULAR DISORDERS |
| Hypertension |
33 |
8 |
4 |
0 |
| Hypotension |
7 |
1 |
0 |
0 | National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0
Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation
Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia
Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain
Palmar-plantar erythrodysesthesia syndrome
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)]
| Adverse Event |
COMETRIQ
(n=214) |
Placebo
(N=109) |
| |
All
Grades |
Grade
3-4 |
All
Grades |
Grade
3-4 |
| Chemistries |
|
|
|
|
| Increased AST |
86 |
3 |
35 |
2 |
| Increased ALT |
86 |
6 |
41 |
2 |
| Increased ALP |
52 |
3 |
35 |
3 |
| Hypocalcemia |
52 |
12 |
27 |
3 |
| Hypophosphatemia |
28 |
3 |
10 |
1 |
| Hyperbilirubinemia |
25 |
2 |
14 |
5 |
| Hypomagnesemia |
19 |
1 |
4 |
0 |
| Hypokalemia |
18 |
4 |
9 |
3 |
| Hyponatremia |
10 |
2 |
5 |
0 |
| Hematologic |
|
|
|
|
| Lymphopenia |
53 |
16 |
51 |
11 |
| Neutropenia |
35 |
3 |
15 |
2 |
| Thrombocytopenia |
35 |
0 |
4 |
3 |
| |
| ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase | 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.
Table 3 Per-Patient Incidence of Hypertension in Protocol XL184-301
| Hypertension, JNCStage |
COMETRIQ
N=211(%) |
Placebo
N=107(%) |
| Normal: Grade 0: Systolic < 120 mmHg and Diastolic < 80 mmHg |
4 |
15 |
| Pre-hypertension: Systolic ≥ 120 mmHg or Diastolic ≥ 80 mmHg |
34 |
54 |
| Stage 1: Systolic ≥ 140 mmHg or Diastolic ≥ 90 mmHg |
46 |
25 |
| Stage 2: Systolic ≥ 160 mmHg or Diastolic ≥ 100 mmHg |
15 |
5 |
| Malignant: Diastolic ≥ 120 mmHg |
0 |
0 |
Joint 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.
Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.
Subjects with at least two blood pressure measurements after the first dose
7 DRUG INTERACTIONS
7.1 Effect of CYP3A4 Inhibitors
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)].
7.2 Effect of CYP3A4 Inducers
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
8.1 Pregnancy
Pregnancy Category D
Risk Summary
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).
8.2 Nursing Mothers
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.
8.3 Pediatric Use
The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.
8.4 Geriatric Use
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)].
8.6 Hepatic Impairment
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 severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration (2.1) and Warnings and Precautions (5.11)].
8.7 Renal Impairment
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.
10 OVERDOSAGE
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.
11 DESCRIPTION
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:
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.
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.
12.3 Pharmacokinetics
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 foration.
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.
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) and 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-naphthoflavone induction), but not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-associated enzyme activities.
Cabozantinib at steady-state plasma concentrations (≥100 mg/day daily for a minimum of 21 days) showed no effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) in patients with solid tumors.
P-glycoprotein Inhibition: Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-gp transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp.
12.6 Cardiac Electrophysiology
The effect of orally administered COMETRIQ 140 mg on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with MTC. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating COMETRIQ. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No COMETRIQ-treated patients had a QTcF > 500 ms [see Clinical Studies (14)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies examining the carcinogenic potential of cabozantinib have not been conducted.
Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay.
Based on nonclinical findings, male and female fertility may be impaired by treatment with COMETRIQ. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately equal to the human exposure by AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (approximately 50% of the human exposure by AUC at the recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and postimplantation losses.
Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at exposures equal to 6% and 3%, respectively, the human exposure by AUC at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately equal to the human exposure by AUC at the recommended dose) exhibited ovarian necrosis.
14 CLINICAL STUDIES
The safety and efficacy of COMETRIQ was assessed in an international, multi-center, randomized, double-blind, controlled trial (Study 1) of 330 patients with metastatic medullary thyroid carcinoma (MTC). Patients were required to have evidence of actively progressive disease within 14 months prior to study entry confirmed by an Independent Radiology Review Committee (IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were randomized (2:1) to receive COMETRIQ 140 mg (n = 219) or placebo (n = 111) orally once daily, without food, until disease progression determined by the treating physician or until intolerable toxicity. Randomization was stratified by age (≤ 65 years vs. > 65 years) and prior use of a tyrosine kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The main efficacy outcome measures of progression-free survival (PFS), objective response (OR), and response duration were based on IRRC-confirmed events using modified RECIST criteria.
Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years or older, 89% were white, 54% had a baseline ECOG performance status of 0, 92% had undergone a thyroidectomy, and 48% were reported to be RET mutation positive according to research-use assays. Twenty-five percent (25%) had two or more prior systemic therapies and 21% had been previously treated with a TKI.
A statistically significant prolongation in PFS was demonstrated among COMETRIQ-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p <0.0001], with median PFS times of 11.2 months and 4.0 months in the COMETRIQ and placebo arms, respectively.
Partial responses were observed only among patients in the COMETRIQ arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with COMETRIQ. There was no statistically significant difference in overall survival between the treatment arms at the planned interim analysis.
Figure 1: Progression-Free Survival
16 HOW SUPPLIED/STORAGE AND HANDLING
COMETRIQ 20 mg capsules are supplied as hard gelatin capsules with grey cap and grey body, printed with "XL184 20mg" in black ink and containing cabozantinib (S)-malate salt equivalent to 20 mg cabozantinib.
COMETRIQ 80 mg capsules are supplied as hard gelatin capsules with Swedish orange cap and Swedish orange body, printed with "XL184 80mg" in black ink and containing cabozantinib (S)- malate salt equivalent to 80 mg cabozantinib.
COMETRIQ capsules are supplied as follows:
Cartons
140 mg daily-dose carton NDC#42388-011-14
Containing four 140 mg daily-dose blister cards
(each blister card contains seven 80-mg and twenty-one 20-mg capsules)
100 mg daily-dose carton NDC#42388-012-14
Containing four 100 mg daily-dose blister cards
(each blister card contains seven 80-mg and seven 20-mg capsules)
60 mg daily-dose carton NDC#42388-013-14
Containing four 60 mg daily-dose blister cards
(each blister card contains twenty-one 20-mg capsules)
Bottle containing sixty 20-mg COMETRIQ capsules NDC#42388-014-25
Store COMETRIQ at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Inform patients of the following:
COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.
COMETRIQ often causes palmar plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.
COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.
COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.
To contact their healthcare provider before any planned surgeries, including dental procedures.
COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.
Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ.
Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy.
COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.
Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.
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产地国家: 美国
原产地英文商品名:
Cometriq 100MG DILY DOSE 4 BILISTER CARDS （EACH BLISTER CARD CONTAINS SEVEN 80MG AND SEVEN 20MG CAPSULES )
原产地英文药品名:
CABOZANTINIB S-MALATE
中文参考商品译名:
Cometriq 100毫克 4吸塑包 （每个吸塑包含七个80毫克和七20MG胶囊）
中文参考药品译名:
CABOZANTINIB S-MALATE
生产厂家中文参考译名:
EXELIXIS
生产厂家英文名:
EXELIXIS |
