|
近日，美国FDA批准Cotellic（Cobimetinib）与威罗菲尼合并用于治疗已扩散至身体其它部位或不能手术切除，以及有某种形式异常基因（BRAF V600E或V600K 突变）的晚期黑色素瘤治疗。
黑色素瘤在美国是最具侵袭性及危险性的皮肤癌。它形成于生成皮肤色素的皮肤细胞中，如果早期未得到诊断，这种癌症可能会扩散到身体其它部位。美国癌症研究所预测，今年将有7.387万名美国人被诊断有黑色素瘤，有9940人会死于这种疾病。
随着我们继续推进我们肿瘤生物学知识，我们得知癌症细胞有适应靶向治疗药物并对其耐药的不寻常能力。结合两种或更多种治疗药物解决不同的致癌靶点或许能帮助解决这一挑战，FDA药物评价与研究中心血液及肿瘤产品办公室主任、医学博士 Pazdur称。
今天的批准提供了一种新的靶向治疗药物，当添加到威罗菲尼中时，这一方案在 BRAF 突变阳性黑色素瘤患者中与威罗菲尼单药治疗相比证明有更大的受益。Cotellic通过阻断一种叫MEK酶的活性而发挥作用，MEK是一个较大信号传导通路的一部分。该信号传导的异常活动可导致癌症。Cotellic可阻止或延缓癌细胞生长。
威罗菲尼在美国以Zelboraf为商品名上市，该药物是一款 BRAF抑制剂，它影响该相同信号传导通路的不同部分，其于2011年获批用于治疗已扩散到身体其它部位或不能手术切除、肿瘤表达一种叫 BRAF V600E基因（以一种FDA批准的检测手段进行检测）的黑色素瘤患者。卫生保健提供者在开始使用 Cotellic与威罗菲尼合并治疗之前，应利用一种FDA批准的检测手段证实其患者肿瘤样本存在BRAF V600 E或V600K突变。
Cotellic与威罗菲尼合并用药的安全性与有效性在一项有495名既往未治疗的、BRAF V600突变呈阳性的晚期或不能手术切除的黑色素瘤患者参与的随机临床研究中得到证明。所有研究受试者接受威罗菲尼治疗，然后随机选择同时使用Cotellic或安慰剂。
通常来说，使用Cotellic加威罗菲尼的患者从治疗开始到疾病恶化所花费时间延长（开始治疗后大约12.3个月），相比之下，那些仅使用威罗菲尼的患者开始治疗后经过大约7.2个月疾病恶化。
此外，使用Cotellic加威罗菲尼的患者生存的更久，在开始治疗后大约有65%的患者生存了17个月，而仅使用威罗菲尼的患者达到这一生存时间的人数只有一半。另外，使用 Cotellic加威罗菲尼的患者中有70%的人经历了肿瘤完全或部分缩小，相比之下，威罗菲尼加安慰剂患者中达到这一标准的人数为50%。
以Cotellic与威罗菲尼合并用药治疗最常见的副作用是腹泻、对紫外光敏感（光敏感反应）、恶心、发烧（发热）及呕吐。Cotellic可能引起严重的副作用，包括心肌或其它肌肉损伤（横纹肌溶解）、新的皮肤肿瘤（原发性皮肤恶性肿瘤）、眼科疾病（视网膜脱离）、严重皮疹、肝损伤（肝毒性）、出血及因对阳光敏感性增强而导致的严重皮疹（光敏性）。
使用Cotellic的患者应避免阳光暴露，应该穿防护服及使用广谱的紫外线A/紫外线 B遮光剂来防止晒伤。使用Cotellic的女性应采取有效避孕，因为这款药物可对正在发育的胎儿导致伤害。
Cotellic在FDA优先审评下完成审评，优先审评可以为严重疾病治疗中在安全性或有效性上有可能带来显著改善的药物提供一个加快的审评，即从提交上市申请开始6个月内完成审评。
Cotellic也获得了孤儿药资格，这一资格可以提供激励措施，如税收抵免、申请者费用减免及孤儿药市场专营权资格，从而资助及鼓励罕见病药物的开发。Cotellic 与威罗菲尼均由加利福尼亚洲旧金山的基因泰克上市销售
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use COTELLIC safely and effectively. See full prescribing information for COTELLIC.
COTELLIC (cobimetinib) tablets, for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
COTELLIC is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. (1, 14)
Limitation of Use: COTELLIC is not indicated for treatment of patients with wild-type BRAF melanoma.
DOSAGE AND ADMINISTRATION
Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of COTELLIC. (2.1)
The recommended dose is 60 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take COTELLIC with or without food. (2.2)
DOSAGE FORMS AND STRENGTHS
Tablets: 20 mg (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
New primary malignancies, cutaneous and non-cutaneous: Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose of COTELLIC. (5.1)
Hemorrhage: Major hemorrhagic events can occur with COTELLIC. Monitor for signs and symptoms of bleeding. (5.2, 2.4)
Cardiomyopathy: The risk of cardiomyopathy is increased in patients receiving COTELLIC with vemurafenib compared with vemurafenib as a single agent. The safety of COTELLIC has not been established in patients with decreased left ventricular ejection fraction (LVEF). Evaluate LVEF before treatment, after one month of treatment, then every 3 months thereafter during treatment with COTELLIC. (5.3, 2.4)
Severe Dermatologic Reactions: Monitor for severe skin rashes. Interrupt, reduce, or discontinue COTELLIC. (5.4, 2.4)
Serous Retinopathy and Retinal Vein Occlusion: Perform an ophthalmological evaluation at regular intervals and for any visual disturbances. Permanently discontinue COTELLIC for retinal vein occlusion (RVO). (5.5, 2.4)
Hepatotoxicity: Monitor liver laboratory tests during treatment and as clinically indicated. (5.6, 2.4)
Rhabdomyolysis: Monitor creatine phosphokinase periodically and as clinically indicated for signs and symptoms of rhabdomyolysis. (5.7, 2.4)
Severe Photosensitivity: Advise patients to avoid sun exposure. (5.8, 2.4)
Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.9, 8.1, 8.3)
ADVERSE REACTIONS
Most common adverse reactions for COTELLIC (≥20%) are diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting. The most common (≥5%) Grade 3-4 laboratory abnormalities are increased GGT, increased CPK, hypophosphatemia, increased ALT, lymphopenia, increased AST, increased alkaline phosphatase, hyponatremia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Avoid concomitant administration of COTELLIC with strong or moderate CYP3A inducers or inhibitors. (2.3, 7.1, 7.2)
USE IN SPECIFIC POPULATIONS
Lactation: Do not breastfeed while taking COTELLIC. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
COTELLIC is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib.
Limitation of Use: COTELLIC is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with COTELLIC with vemurafenib. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.
2.2 Recommended Dose
The recommended dosage regimen of COTELLIC is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity [see Clinical Studies (14)].
Take COTELLIC with or without food [see Clinical Pharmacology (12.3)].
If a dose of COTELLIC is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose.
2.3 Dose Modification for Concurrent CYP3A Inhibitors
Do not take strong or moderate CYP3A inhibitors while taking COTELLIC.
If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking COTELLIC 60 mg, reduce COTELLIC dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume previous dose of COTELLIC 60 mg [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
2.4 Dose Modifications
Review the Full Prescribing Information for vemurafenib for recommended dose modifications.
Table 1. Recommended Dose Reductions for COTELLIC
| First Dose Reduction |
40 mg orally once daily |
| Second Dose Reduction |
20 mg orally once daily |
| Subsequent Modification |
Permanently discontinue COTELLIC if unable to tolerate 20 mg orally once daily | Table 2. Recommended Dose Modifications for COTELLIC for Adverse Reactions
| Severity of Adverse Reaction* |
Dose Modification for COTELLIC |
|
|
| New Primary Malignancies (cutaneous and non-cutaneous) |
No dose modification is required. |
| Hemorrhage |
| Grade 3 |
Withhold COTELLIC for up to 4 weeks.
- If improved to Grade 0 or 1, resume at the next lower dose level.
- If not improved within 4 weeks, permanently discontinue.
|
| Grade 4 |
Permanently discontinue. |
| Cardiomyopathy |
| Asymptomatic, absolute decrease in LVEF from baseline of greater than 10% and less than institutional lower limit of normal (LLN) |
Withhold COTELLIC for 2 weeks; repeat LVEF. |
Resume at next lower dose if all of the following are present
- LVEF is at or above LLN and
- Absolute decrease from baseline LVEF is 10% or less.
|
Permanently discontinue if any of the following are present
- LVEF is less than LLN or
- Absolute decrease from baseline LVEF is more than 10%.
|
| Symptomatic LVEF decrease from baseline |
Withhold COTELLIC for up to 4 weeks, repeat LVEF. |
|
Resume at next lower dose if all of the following are present:
- Symptoms resolve and
- LVEF is at or above LLN and
- Absolute decrease from baseline LVEF is 10% or less.
|
|
Permanently discontinue if any of the following are present
- Symptoms persist, or
- LVEF is less than LLN, or
- Absolute decrease from baseline LVEF is more than 10%.
|
| Dermatologic Reactions |
| Grade 2 (intolerable), Grade 3 or 4 |
Withhold or reduce dose. |
| Serous Retinopathy or Retinal Vein Occlusion |
| Serous retinopathy |
Withhold COTELLIC for up to 4 weeks.
- If signs and symptoms improve, resume at the next lower dose level.
- If not improved or symptoms recur at the lower dose within 4 weeks, permanently discontinue.
|
| Retinal vein occlusion |
Permanently discontinue COTELLIC. |
| Liver Laboratory Abnormalities and Hepatotoxicity |
| First Occurrence Grade 4 |
Withhold COTELLIC for up to 4 weeks.
- If improved to Grade 0 or 1, then resume at the next lower dose level.
- If not improved to Grade 0 or 1 within 4 weeks, permanently discontinue.
|
| Recurrent Grade 4 |
Permanently discontinue COTELLIC. |
| Rhabdomyolysis and Creatine Phosphokinase (CPK) elevations |
- Grade 4 CPK elevation
- Any CPK elevation and myalgia
|
Withhold COTELLIC for up to 4 weeks.
- If improved to Grade 3 or lower, resume at the next lower dose level.
- If not improved within 4 weeks, permanently discontinue.
|
| Photosensitivity |
| Grade 2 (intolerable), Grade 3 or Grade 4 |
Withhold COTELLIC for up to 4 weeks.
- If improved to Grade 0 or 1, resume at the next lower dose level.
- If not improved within 4 weeks, permanently discontinue.
|
| Other |
- Grade 2 (intolerable) adverse reactions
- Any Grade 3 adverse reactions
|
Withhold COTELLIC for up to 4 weeks.
- If improved to Grade 0 or 1, resume at the next lower dose level.
- If not improved within 4 weeks, permanently discontinue.
|
| First occurrence of any Grade 4 adverse reaction |
- Withhold COTELLIC until adverse reaction improves to Grade 0 or 1. Then resume at the next lower dose level, OR
- Permanently discontinue.
|
| Recurrent Grade 4 adverse reaction |
Permanently discontinue COTELLIC. | 3 DOSAGE FORMS AND STRENGTHS
Tablets: 20 mg, white, round, film-coated, debossed on one side with "COB".
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
Review the Full Prescribing Information for vemurafenib for information on the serious risks of vemurafenib.
5.1 New Primary Malignancies
New primary malignancies, cutaneous and non-cutaneous, can occur with COTELLIC.
Cutaneous Malignancies:
In Trial 1, the following cutaneous malignancies or premalignant conditions occurred in the COTELLIC with vemurafenib arm and the vemurafenib arm, respectively: cutaneous squamous cell carcinoma (cuSCC) or keratoacanthoma (KA) (6% and 20%), basal cell carcinoma (4.5% and 2.4%), and second primary melanoma (0.8% and 2.4%). Among patients receiving COTELLIC with vemurafenib, the median time to detection of first cuSCC/KA was 4 months (range: 2 to 11 months), and the median time to detection of basal cell carcinoma was 4 months (range: 27 days to 13 months). The time to onset in the two patients with second primary melanoma was 9 months and 12 months.
Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. No dose modifications are recommended for COTELLIC [see Dosage and Administration (2.4)]. Conduct dermatologic monitoring for 6 months following discontinuation of COTELLIC when administered with vemurafenib.
Non-Cutaneous Malignancies:
Based on its mechanism of action, vemurafenib may promote growth and development of malignancies [refer to the Full Prescribing Information for vemurafenib]. In Trial 1, 0.8% of patients in the COTELLIC with vemurafenib arm and 1.2% of patients in the vemurafenib arm developed non-cutaneous malignancies.
Monitor patients receiving COTELLIC, when administered with vemurafenib, for signs or symptoms of non-cutaneous malignancies.
5.2 Hemorrhage
Hemorrhage, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with COTELLIC.
In Trial 1, the incidence of Grade 3–4 hemorrhages was 1.2% in patients receiving COTELLIC with vemurafenib and 0.8% in patients receiving vemurafenib. Hemorrhage (all grades) was 13% in patients receiving COTELLIC with vemurafenib and 7% in patients receiving vemurafenib. Cerebral hemorrhage occurred in 0.8% of patients receiving COTELLIC with vemurafenib and in none of the patients receiving vemurafenib. Gastrointestinal tract hemorrhage (3.6% vs 1.2%), reproductive system hemorrhage (2.0% vs 0.4%), and hematuria (2.4% vs 0.8%) also occurred at a higher incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib.
Withhold COTELLIC for Grade 3 hemorrhagic events. If improved to Grade 0 or 1 within 4 weeks, resume COTELLIC at a lower dose level. Discontinue COTELLIC for Grade 4 hemorrhagic events and any Grade 3 hemorrhagic events that do not improve [see Dosage and Administration (2.4)].
5.3 Cardiomyopathy
Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with COTELLIC. The safety of COTELLIC has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%.
In Trial 1, patients were assessed for decreases in LVEF by echocardiograms or MUGA at baseline, Week 5, Week 17, Week 29, Week 43, and then every 4 to 6 months thereafter while receiving treatment. Grade 2 or 3 decrease in LVEF occurred in 26% of patients receiving COTELLIC with vemurafenib and 19% of patients receiving vemurafenib. The median time to first onset of LVEF decrease was 4 months (range 23 days to 13 months). Of the patients with decreased LVEF, 22% had dose interruption and/or reduction and 14% required permanent discontinuation. Decreased LVEF resolved to above the LLN or within 10% of baseline in 62% of patients receiving COTELLIC with a median time to resolution of 3 months (range: 4 days to 12 months).
Evaluate LVEF prior to initiation, 1 month after initiation, and every 3 months thereafter until discontinuation of COTELLIC. Manage events of left ventricular dysfunction through treatment interruption, reduction, or discontinuation [see Dosage and Administration (2.4)]. In patients restarting COTELLIC after a dose reduction or interruption, evaluate LVEF at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated.
5.4 Severe Dermatologic Reactions
Severe rash and other skin reactions can occur with COTELLIC.
In Trial 1, Grade 3 to 4 rash, occurred in 16% of patients receiving COTELLIC with vemurafenib and in 17% of patients receiving vemurafenib, including Grade 4 rash in 1.6% of patients receiving COTELLIC with vemurafenib and 0.8% of the patients receiving vemurafenib. The incidence of rash resulting in hospitalization was 3.2% in patients receiving COTELLIC with vemurafenib and 2.0% in patients receiving vemurafenib. In patients receiving COTELLIC, the median time to onset of Grade 3 or 4 rash events was 11 days (range: 3 days to 2.8 months). Among patients with Grade 3 or 4 rash events, 95% experienced complete resolution with the median time to resolution of 21 days (range 4 days to 17 months).
Interrupt, reduce the dose, or discontinue COTELLIC [see Dosage and Administration (2.4)].
5.5 Serous Retinopathy and Retinal Vein Occlusion
Ocular toxicities can occur with COTELLIC, including serous retinopathy (fluid accumulation under layers of the retina).
In Trial 1, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving COTELLIC with vemurafenib. The majority of these events were reported as chorioretinopathy (13%) or retinal detachment (12%). The time to first onset of serous retinopathy events ranged between 2 days to 9 months. The reported duration of serous retinopathy ranged between 1 day to 15 months. One patient in each arm developed retinal vein occlusion.
Perform an ophthalmological evaluation at regular intervals and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt COTELLIC until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation [see Dosage and Administration (2.4)].
5.6 Hepatotoxicity
Hepatotoxicity can occur with COTELLIC.
The incidences of Grade 3 or 4 liver laboratory abnormalities in Trial 1 among patients receiving COTELLIC with vemurafenib compared to patients receiving vemurafenib were: 11% vs. 6% for alanine aminotransferase, 7% vs. 2.1% for aspartate aminotransferase, 1.6% vs. 1.2% for total bilirubin, and 7% vs. 3.3% for alkaline phosphatase [see Adverse Drug Reactions (6.1)]. Concurrent elevation in ALT >3 times the upper limit of normal (ULN) and bilirubin >2 × ULN in the absence of significant alkaline phosphatase >2 × ULN occurred in one patient (0.4%) receiving COTELLIC with vemurafenib and no patients receiving single-agent vemurafenib.
Monitor liver laboratory tests before initiation of COTELLIC and monthly during treatment, or more frequently as clinically indicated. Manage Grade 3 and 4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of COTELLIC [see Dosage and Administration (2.4)].
5.7 Rhabdomyolysis
Rhabdomyolysis can occur with COTELLIC.
In Trial 1, Grade 3 or 4 CPK elevations, including asymptomatic elevations over baseline, occurred in 12% of patients receiving COTELLIC with vemurafenib and 0.4% of patients receiving vemurafenib. The median time to first occurrence of Grade 3 or 4 CPK elevations was 16 days (range: 12 days to 11 months) in patients receiving COTELLIC with vemurafenib; the median time to complete resolution was 15 days (range: 9 days to 11 months). Elevation of serum CPK increase of more than 10 times the baseline value with a concurrent increase in serum creatinine of 1.5 times or greater compared to baseline occurred in 3.6% of patients receiving COTELLIC with vemurafenib and in 0.4% of patients receiving vemurafenib.
Obtain baseline serum CPK and creatinine levels prior to initiating COTELLIC, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation of COTELLIC may be required [see Dosage and Administration (2.4)].
5.8 Severe Photosensitivity
Photosensitivity, including severe cases, can occur with COTELLIC.
In Trial 1, photosensitivity was reported in 47% of patients receiving COTELLIC with vemurafenib: 43% of patients with Grades 1 or 2 photosensitivity and the remaining 4% with Grade 3 photosensitivity. Median time to first onset of photosensitivity of any grade was 2 months (range: 1 day to 14 months) in patients receiving COTELLIC with vemurafenib, and the median duration of photosensitivity was 3 months (range: 2 days to 14 months). Among the 47% of patients with photosensitivity reactions on COTELLIC with vemurafenib, 63% experienced resolution of photosensitivity reactions.
Advise patients to avoid sun exposure, wear protective clothing and use a broad-spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors. Manage intolerable Grade 2 or greater photosensitivity with dose modifications [see Dosage and Administration (2.4)].
5.9 Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal reproduction studies, COTELLIC can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during the period of organogenesis was teratogenic and embryotoxic at doses resulting in exposures [area under the curves (AUCs)] that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with COTELLIC, and for 2 weeks following the final dose of COTELLIC [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
New Primary Cutaneous Malignancies [see Warnings and Precautions (5.1)]
Hemorrhage [see Warnings and Precautions (5.2)]
Cardiomyopathy [see Warnings and Precautions (5.3)]
Serious Dermatologic Reactions [see Warnings and Precautions (5.4)]
Serous Retinopathy and Retinal Vein Occlusion [see Warnings and Precautions (5.5)]
Hepatotoxicity [see Warnings and Precautions (5.6)]
Rhabdomyolysis [see Warnings and Precautions (5.7)]
Severe Photosensitivity [see Warnings and Precautions (5.8)]
Embryo-fetal Toxicity [see Warnings and Precautions (5.9)]
6.1 Clinical Trials 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 COTELLIC was evaluated in Trial 1, a randomized (1:1), double-blind, active-controlled trial in previously untreated patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma [see Clinical Studies (14)]. All patients received vemurafenib 960 mg twice daily on Days 1–28 and received either COTELLIC 60 mg once daily (n=247) or placebo (n=246) on Days 1–21 of each 28-day treatment cycle until disease progression or unacceptable toxicity. In the COTELLIC plus vemurafenib arm, 66% percent of patients were exposed for greater than 6 months and 24% of patients were exposed for greater than 1 year. Patients with abnormal liver function tests, history of acute coronary syndrome within 6 months, evidence of Class II or greater congestive heart failure (New York Heart Association), active central nervous system lesions, or evidence of retinal pathology were excluded from Trial 1. The demographics and baseline tumor characteristics of patients enrolled in Trial 1 are summarized in Clinical Studies [see Clinical Studies (14)].
In Trial 1, 15% of patients receiving COTELLIC experienced an adverse reaction that resulted in permanent discontinuation of COTELLIC. The most common adverse reactions resulting in permanent discontinuation were liver laboratory abnormalities defined as increased aspartate aminotransferase (AST) (2.4%), increased gamma glutamyltransferase (GGT) (1.6%) and increased alanine aminotransferase (ALT) (1.6%); rash (1.6%); pyrexia (1.2%); and retinal detachment (2%). Among the 247 patients receiving COTELLIC, adverse reactions led to dose interruption or reductions in 55%. The most common reasons for dose interruptions or reductions of COTELLIC were rash (11%), diarrhea (9%), chorioretinopathy (7%), pyrexia (6%), vomiting (6%), nausea (5%), and increased creatine phosphokinase (CPK) (4.9%). The most common (≥20%) adverse reactions with COTELLIC were diarrhea, photosensitivity reaction, nausea, pyrexia, and vomiting.
Table 3. Incidence of Adverse Drug Reactions Occurring in ≥10% (All Grades) of Patients Receiving COTELLIC with Vemurafenib and at a Higher Incidence* than Patients Receiving Vemurafenib in Trial 1
| Adverse reactions |
COTELLIC + Vemurafenib
(n=247) |
Placebo + Vemurafenib
(n=246) |
All Grades
(%) |
Grades 3–4
(%) |
All Grades
(%) |
Grades 3–4
(%) |
|
|
| GASTROINTESTINAL DISORDERS |
|
|
|
|
| Diarrhea |
60 |
6 |
31 |
1 |
| Nausea |
41 |
1 |
25 |
1 |
| Vomiting |
24 |
1 |
13 |
1 |
| Stomatitis‡ |
14 |
1 |
8 |
0 |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS |
|
|
|
|
| Photosensitivity reaction |
46 |
4 |
35 |
0 |
| Acneiform dermatitis |
16 |
2 |
11 |
1 |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS |
|
|
|
|
| Pyrexia |
28 |
2 |
23 |
0 |
| Chills |
10 |
0 |
5 |
0 |
| VASCULAR DISORDERS |
|
|
|
|
| Hypertension |
15 |
4 |
8 |
2 |
| Hemorrhage |
13 |
1 |
7 |
<1 |
| EYE DISORDERS |
|
|
|
|
| Vision impaired |
15 |
<1 |
4 |
0 |
| Chorioretinopathy |
13 |
<1 |
<1 |
0 |
| Retinal detachment |
12 |
2 |
<1 |
0 | Adverse reactions of vemurafenib which occurred at a lower rate in patients receiving COTELLIC plus vemurafenib were alopecia (15%), hyperkeratosis (11%), and erythema (10%).
The following adverse reactions (all grades) of COTELLIC were reported with <10% incidence in Trial 1:
Respiratory, thoracic and mediastinal disorders: Pneumonitis
Table 4. Incidence of Laboratory Abnormalities Occurring in ≥10% (All Grades) or ≥2% (Grades 3–4) of Patients in Trial 1*
| Laboratory |
COTELLIC + Vemurafenib |
Placebo + Vemurafenib |
| All Grades† |
Grades 3–4† |
All Grades† |
Grades 3–4† |
| % |
% |
% |
% |
| AST - aspartate aminotransferase, ALT - alanine aminotransferase, GGT - gamma-glutamyltransferase |
|
|
| Chemistry |
|
|
|
|
| Increased creatinine |
99.6 |
3.3 |
99.6 |
0.4 |
| Increased AST |
73 |
8 |
44 |
2.1 |
| Increased ALT |
68 |
11 |
55 |
5 |
| Increased alkaline phosphatase |
71 |
7 |
56 |
3.3 |
| Increased creatine phosphokinase‡ |
79 |
14 |
16 |
0.5 |
| Hypophosphatemia |
68 |
12 |
38 |
6 |
| Increased GGT |
65 |
21 |
61 |
17 |
| Hyponatremia |
38 |
6 |
33 |
2.1 |
| Hypoalbuminemia |
42 |
0.8 |
20 |
0.4 |
| Hyopkalemia |
25 |
4.5 |
17 |
3.3 |
| Hyperkalemia |
26 |
2.9 |
15 |
0.4 |
| Hypocalcemia |
24 |
0.4 |
10 |
1.7 |
| Hematology |
|
|
|
|
| Anemia |
69 |
2.5 |
57 |
3.3 |
| Lymphopenia |
73 |
10 |
55 |
8 |
| Thrombocytopenia |
18 |
0 |
10 |
0 | 7 DRUG INTERACTIONS
7.1 Effect of Strong or Moderate CYP3A Inhibitors on Cobimetinib
Coadministration of COTELLIC with itraconazole (a strong CYP3A4 inhibitor) increased cobimetinib systemic exposure by 6.7-fold. Avoid concurrent use of COTELLIC and strong or moderate CYP3A inhibitors. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable for patients who are taking COTELLIC 60 mg, reduce COTELLIC dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume COTELLIC at the previous dose [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
7.2 Effect of Strong or Moderate CYP3A Inducers on Cobimetinib
Coadministration of COTELLIC with a strong CYP3A inducer may decrease cobimetinib systemic exposure by more than 80% and reduce its efficacy. Avoid concurrent use of COTELLIC and strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. John's Wort [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on findings from animal reproduction studies and its mechanism of action, COTELLIC can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of COTELLIC during pregnancy. In animal reproduction studies, oral administration of cobimetinib in pregnant rats during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 0.9 to 1.4-times those observed in humans at the recommended human dose of 60 mg [see Data]. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Data
Animal Data
Administration of cobimetinib to pregnant rats during the period of organogenesis resulted in increased post-implantation loss, including total litter loss, at exposures (AUC) of 0.9–1.4 times those in humans at the recommended dose of 60 mg. Post-implantation loss was primarily due to early resorptions. Fetal malformations of the great vessels and skull (eye sockets) occurred at the same exposures.
8.2 Lactation
Risk Summary
There is no information regarding the presence of cobimetinib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman not to breastfeed during treatment with COTELLIC and for 2 weeks after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Females
COTELLIC can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with COTELLIC and for 2 weeks after the final dose of COTELLIC.
Infertility
Females and Males
Based on findings in animals, COTELLIC may reduce fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of COTELLIC have not been established in pediatric patients.
Juvenile Animal Data
In a 4-week juvenile rat toxicology study, daily oral doses of 3 mg/kg (approximately 0.13–0.5 times the adult human AUC at the recommended dose of 60 mg) between postnatal Days 10–17 (approximately equivalent to ages 1–2 years in humans) were associated with mortality, the cause of which was not defined.
8.5 Geriatric Use
Clinical studies of cobimetinib did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.
8.6 Hepatic Impairment
Pharmacokinetics of cobimetinib has not been studied in patients with moderate or severe hepatic impairment. Dose adjustment is not recommended for patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN or total bilirubin >ULN but ≤ 1.5 times ULN and any AST) based on results of the population pharmacokinetic analysis [see Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No dedicated pharmacokinetic trial in patients with renal impairment has been conducted. Dose adjustment is not recommended for mild to moderate renal impairment (CLcr 30 to 89 mL/min) based on the results of the population pharmacokinetic analysis. A recommended dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
There is no information on overdosage of COTELLIC.
11 DESCRIPTION
Cobimetinib fumarate is a kinase inhibitor. The chemical name is (S)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl)azetidin-1-yl]methanone hemifumarate. It has a molecular formula C46H46F6I2N6O8 (2 C21H21F3IN3O2 ∙ C4H4O4) with a molecular mass of 1178.71 as a fumarate salt. Cobimetinib fumarate has the following chemical structure:
Cobimetinib is a fumarate salt appearing as white to off-white solid and exhibits a pH dependent solubility.
COTELLIC (cobimetinib) tablets are supplied as white, round, film-coated 20 mg tablets for oral administration, debossed on one side with "COB". Each 20 mg tablet contains 22 mg of cobimetinib fumarate, which corresponds to 20 mg of the cobimetinib free base.
The inactive ingredients of COTELLIC are: Tablet Core: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate. Coating: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines expressing BRAF V600E, cobimetinib inhibited tumor cell growth.
Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model.
12.2 Pharmacodynamics
Cardiac Electrophysiology
Clinically relevant QT prolongation has been reported with vemurafenib, further QTc prolongation was not observed when cobimetinib 60 mg daily was co-administered with vemurafenib. Monitor ECG and electrolytes before initiating treatment and routinely during treatment with cobimetinib, when administered with vemurafenib. Review the Full Prescribing Information for vemurafenib for details.
12.3 Pharmacokinetics
The pharmacokinetics of cobimetinib was studied in healthy subjects and cancer patients. Cobimetinib exhibits linear pharmacokinetics in the dose range of 3.5 to 100 mg (i.e., 0.06 to 1.7 times the recommended dosage). Following oral administration of COTELLIC 60 mg once daily, steady-state was reached by 9 days with a mean accumulation ratio of 2.4-fold (44% CV).
Absorption
Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels (Tmax) was 2.4 (range:1–24) hours, geometric mean steady-state AUC0-24h was 4340 ng∙h/mL (61% CV) and Cmax was 273 ng/mL (60% CV). The absolute bioavailability of COTELLIC was 46% (90% CI: 40%, 53%) in healthy subjects. A high-fat meal (comprised of approximately 150 calories from protein, 250 calories from carbohydrate, and 500–600 calories from fat) had no effect on cobimetinib AUC and Cmax after a single 20 mg COTELLIC was administered to healthy subjects.
Distribution
Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. No preferential binding to human red blood cells was observed (blood to plasma ratio of 0.93). The estimated apparent volume of distribution was 806 L in cancer patients based on a population PK analysis.
Elimination
Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean elimination half-life (t1/2) was 44 (range: 23–70) hours and the mean apparent clearance (CL/F) was 13.8 L/h (61% CV).
Metabolism
CYP3A oxidation and UGT2B7 glucuronidation were the major pathways of cobimetinib metabolism in vitro. Following oral administration of a single 20 mg radiolabeled cobimetinib dose, no oxidative metabolites >10% of total circulating radioactivity were observed.
Excretion
Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76% of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was recovered in the urine (with 1.6% as unchanged drug).
Specific Populations
Age, Sex, and Race/Ethnicity: Based on the population pharmacokinetic analysis, age (19–88 years), sex, or race/ethnicity does not have a clinically important effect on the systemic exposure of cobimetinib.
Hepatic Impairment
The pharmacokinetics of cobimetinib has not been studied in patients with moderate to severe hepatic impairment. As cobimetinib is metabolized and eliminated via the liver, patients with moderate to severe hepatic impairment may have increased exposure. Cobimetinib exposures were similar between 80 patients with mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin >ULN but ≤ 1.5 times ULN and any AST) and 388 patients with normal hepatic function (total bilirubin ≤ ULN and AST ≤ ULN) [see Use in Specific Populations (8.6)].
Renal Impairment
Cobimetinib undergoes minimal renal elimination. Cobimetinib exposures were similar in 151 patients with mild renal impairment (CLcr 60 to 89 mL/min), 48 patients with moderate renal impairment (CLcr 30 to 59 mL/min) and 286 patients with normal renal function (CLcr ≥90 mL/min) [see Use in Specific Populations (8.7)].
Drug Interaction Studies
Vemurafenib: Coadministration of COTELLIC 60 mg once daily and vemurafenib 960 mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions.
Effect of Strong and Moderate CYP3A Inhibitors on Cobimetinib: In vitro studies show that cobimetinib is a substrate of CYP3A. Coadministration of itraconazole (a strong CYP3A inhibitor) 200 mg once daily for 14 days with a single 10 mg cobimetinib dose increased mean cobimetinib AUC (90% CI) by 6.7-fold (5.6, 8.0) and mean Cmax (90% CI) by 3.2-fold (2.7, 3.7) in 15 healthy subjects. Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib at the 60 mg dose alone [see Drug Interactions (7.1)].
Effect of Strong and Moderate CYP3A Inducers on Cobimetinib: Based on simulations, cobimetinib exposures would decrease by 83% when coadministered with a strong CYP3A inducer and by 73% when coadministered with a moderate CYP3A inducer [see Drug Interactions (7.2)].
Effect of Cobimetinib on CYP Substrates: Coadministration of cobimetinib 60 mg once daily for 15 days with a single 30 mg dose of dextromethorphan (sensitive CYP2D6 substrate) or a single 2 mg dose of midazolam (sensitive CYP3A substrate) to 20 patients with solid tumors did not change dextromethorphan or midazolam systemic exposure. In vitro data indicated that cobimetinib may inhibit CYP3A and CYP2D6. Cobimetinib at clinically relevant concentrations is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9 and 2C19 or inducer of CYP1A2, 2B6 and 3A4.
Effect of Transporters on Cobimetinib: Cobimetinib is a substrate of efflux transporter P-glycoprotein (P-gp), but is not a substrate of Breast Cancer Resistance Protein (BCRP), Organic Anion Transporting Polypeptide (OATP1B1 or OATP1B3) or Organic Cation Transporter (OCT1) in vitro. Drugs that inhibit P-gp may increase cobimetinib concentrations.
Effect of Cobimetinib on Transporters: In vitro data suggest that cobimetinib at clinically relevant concentrations does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, or OCT1.
Effect of Gastric Acid Reducing Drugs on Cobimetinib: Coadministration of a proton pump inhibitor, rabeprazole 20 mg once daily for 5 days, with a single dose of 20 mg COTELLIC under fed and fasted conditions did not result in a clinically important change in cobimetinib exposure.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with cobimetinib have not been conducted. Cobimetinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in bone marrow of rats.
No dedicated fertility studies have been performed with cobimetinib in animals; however, effects on reproductive tissues observed in general toxicology studies conducted in animals suggest that there is potential for cobimetinib to impair fertility. In female rats, degenerative changes included increased apoptosis/necrosis of corpora lutea and vaginal epithelial cells at cobimetinib doses approximately twice those in humans at the clinically recommended dose of 60 mg based on body surface area. In male dogs, testicular degeneration occurred at exposures as low as approximately 0.1 times the exposure in humans at the clinically recommended dose of 60 mg.
14 CLINICAL STUDIES
The safety and efficacy of cobimetinib was established in a multicenter, randomized (1:1), double-blinded, placebo-controlled trial conducted in 495 patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic, melanoma. The presence of BRAF V600 mutation was detected using the cobas® 4800 BRAF V600 mutation test. All patients received vemurafenib 960 mg orally twice daily on days 1–28 and were randomized to receive COTELLIC 60 mg or matching placebo orally once daily on days 1–21 of an every 28-day cycle. Randomization was stratified by geographic region (North America vs. Europe vs. Australia/New Zealand/others) and disease stage (unresectable Stage IIIc, M1a, or M1b vs. Stage M1c). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive placebo were not offered COTELLIC at the time of disease progression.
The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Additional efficacy outcomes were investigator-assessed confirmed objective response rate, overall survival, PFS as assessed by blinded independent central review, and duration of response.
The median age of the study population was 55 years (range 23 to 88 years), 58% of patients were male, 93% were White and 5% had no race reported, 60% had stage M1c disease, 72% had a baseline ECOG performance status of 0, 45% had an elevated baseline serum lactate dehydrogenase (LDH), 10% had received prior adjuvant therapy, and <1% had previously treated brain metastases. Patients with available tumor samples were retrospectively tested using next generation sequencing to further classify mutations as V600E or V600K; test results were obtained on 81% of randomized patients. Of these, 86% were identified as having a V600E mutation and 14% as having a V600K mutation.
Efficacy results are summarized in Table 5 and Figure 1.
Table 5 Efficacy Results from Trial 1
COTELLIC + Vemurafenib
(n=247) |
Placebo + Vemurafenib
(n=248) |
| CI - Confidence Intervals; NE - not estimable |
|
|
| Progression-free Survival (Investigator-Assessed) |
| Number of Events (%) |
143 (58%) |
180 (73%) |
| Progression |
131 |
169 |
| Death |
12 |
11 |
| Median PFS, months (95% CI) |
12.3 (9.5, 13.4) |
7.2 (5.6,7.5) |
| Hazard Ratio (95% CI) |
0.56 (0.45, 0.70) |
| p-value (stratified log-rank test) |
<0.001 |
| Overall Survival |
| Number of Deaths (%) |
79 (32%) |
109 (44%) |
| Median OS, months (95% CI) |
NE (20.7, NE) |
17.0 (15.0, NE) |
| Hazard Ratio (95% CI) |
0.63 (0.47, 0.85) |
| p -value (stratified log-rank test) |
0.0019 * |
| Objective Response Rate |
| Objective Response Rate |
70% |
50% |
| (95% CI) |
(64%, 75%) |
(44%, 56%) |
| Complete Response |
16% |
10% |
| Partial Response |
54% |
40% |
| P-value |
<0.001 |
| Median Duration of Response, months (95% CI) |
13.0 (11.1, 16.6) |
9.2 (7.5, 12.8) | Figure 1 Kaplan-Meier Curves of Overall Survival
The effect on PFS was also supported by analysis of PFS based on the assessment by blinded independent review. A trend favoring the cobimetinib with vemurafenib arm was observed in exploratory subgroup analyses of PFS, OS, and ORR in both BRAF V600 mutation subtypes (V600E or V600K) in the 81% of patients in this trial where BRAF V600 mutation type was determined.
16 HOW SUPPLIED/STORAGE AND HANDLING
COTELLIC (cobimetinib) is supplied as 20 mg film-coated tablets debossed on one side with "COB". COTELLIC tablets are available in bottles of 63 tablets.
NDC 50242-717-01
Storage and Stability: Store at room temperature below 30°C (86°F).
17 PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Patient Information).
Inform patients of the following:
New primary cutaneous malignancies: Advise patients to contact their health care provider immediately for change in or development of new skin lesions [see Warnings and Precautions (5.1)].
Hemorrhage: Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage [see Warnings and Precautions (5.2)].
Cardiomyopathy: Advise patients to report any history of cardiac disease and of the requirement for cardiac monitoring prior to and during COTELLIC administration. Instruct patients to immediately report any signs or symptoms of left ventricular dysfunction to their healthcare provider [see Warnings and Precautions (5.3)].
Serious dermatologic reactions: Instruct patients to contact their healthcare provider to immediately report severe skin changes [see Warnings and Precautions (5.4)].
Serous retinopathy and retinal vein occlusion: Instruct patients to immediately contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.5)].
Hepatotoxicity: Advise patients that treatment with COTELLIC requires monitoring of their liver function. Instruct patients to report any signs or symptoms of liver dysfunction [see Warnings and Precautions (5.6)].
Rhabdomyolysis: Instruct patients to report any signs and symptoms of muscle pain or weakness to their healthcare provider [see Warnings and Precautions (5.7)].
Severe photosensitivity: Advise patients to avoid sun exposure, wear protective clothing, and use broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30) when outdoors [see Warnings and Precautions (5.8)].
Embryo-fetal toxicity: Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with COTELLIC [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)].
Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with COTELLIC and for at least 2 weeks after the final dose of COTELLIC [see Use in Specific Populations (8.3)].
Lactation: Advise females not to breastfeed during treatment with COTELLIC and for 2 weeks after the final dose [see Use in Specific Populations (8.2)].
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c387579e-cee0-4334-bd1e-73f93ac1bde6
|
