Zelboraf
Generic
Name: vemurafenib
Dosage Form: tablet, film coated
Indications and Usage for ZelborafUnresectable
or Metastatic Melanoma
Zelboraf® is indicated for the
treatment of patients with unresectable or metastatic melanoma with BRAF V600E
mutation as detected by an FDA-approved test.
Limitation of Use: Zelboraf is
not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and
Precautions (5.2)].
1.2 Erdheim-Chester Disease
Zelboraf® is
indicated for the treatment of patients with Erdheim-Chester Disease (ECD) with
BRAF V600 mutation.
Zelboraf Dosage and AdministrationPatient
Selection for Treatment of Melanoma
Confirm the presence of BRAF
V600E mutation in melanoma tumor specimens prior to initiation of treatment
with Zelboraf [see Warnings
and Precautions (5.2)]. Information on FDA-approved
tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/CompanionDiagnostics.
Recommended
Dose
The recommended dose of
Zelboraf is 960 mg (four 240 mg tablets) orally every 12 hours with or without
a meal. A missed dose can be taken up to 4 hours prior to the next dose.
Treat patients with Zelboraf
until disease progression or unacceptable toxicity occurs.
Do not take an additional dose
if vomiting occurs after Zelboraf administration, but continue with the next
scheduled dose.
Do not crush or chew the
tablets.
Dose
Modifications
For New Primary Cutaneous Malignancies: No dose modifications are recommended.
For Other Adverse Reactions:
Permanently discontinue
Zelboraf for any of the following:
·
Grade 4 adverse reaction,
first appearance (if clinically appropriate) or second appearance
·
QTc prolongation > 500 ms
and increased by > 60 ms from pre-treatment values [see Warnings
and Precautions (5.5)]
Withhold Zelboraf for
NCI-CTCAE (v4.0) intolerable Grade 2 or greater adverse reactions.
Upon recovery to Grade 0–1,
restart Zelboraf at a reduced dose as follows:
·
720 mg twice daily for first
appearance of intolerable Grade 2 or Grade 3 adverse reactions
·
480 mg twice daily for second
appearance of Grade 2 (if intolerable) or Grade 3 adverse reactions or for
first appearance of Grade 4 adverse reaction (if clinically appropriate)
Do not dose reduce to below
480 mg twice daily.
2.4 Dose Modification for Strong CYP3A4 Inducers
Avoid concomitant use of strong CYP3A4
inducers during treatment with Zelboraf [see Drug Interactions (7.1) and Clinical Pharmacology
(12.3)]. If concomitant use of a strong CYP3A4
inducer is unavoidable, increase the dose of Zelboraf by 240 mg (one tablet) as
tolerated. After discontinuation of a strong CYP3A4 inducer for two weeks,
resume the Zelboraf dose that was taken prior to initiating the strong CYP3A4
inducer.
Dosage Forms and Strengths
Tablet: 240 mg.
Contraindications
None.
Warnings and Precautions5.1 New Primary Malignancies
Cutaneous Malignancies
Cutaneous squamous cell carcinoma,
keratoacanthoma, and melanoma occurred at a higher incidence in patients
receiving Zelboraf compared to those in the control arm in Trial 1. The
incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in
the Zelboraf arm was 24% compared to < 1% in the dacarbazine arm [see Adverse Reactions (6.1)]. The median time to the first appearance of cuSCC was 7 to 8
weeks; approximately 33% of patients who developed a cuSCC while receiving
Zelboraf experienced at least one additional occurrence with median time
between occurrences of 6 weeks. Potential risk factors associated with cuSCC
observed in clinical studies using Zelboraf included age (≥ 65 years), prior
skin cancer, and chronic sun exposure.
In Trial 4, in patients with ECD, the
incidence of cuSCC and/or keratoacanthomas was 40.9% (9/22). The median time to
first appearance of cuSCC amongst patients with at least one occurrence was
12.1 weeks.
In Trial 1, in patients with unresectable
or metastatic melanoma, new primary malignant melanoma occurred in 2.1% (7/336)
of patients receiving Zelboraf compared to none of the patients receiving
dacarbazine.
Perform dermatologic evaluations prior to
initiation of therapy and every 2 months while on therapy. Manage suspicious
skin lesions with excision and dermatopathologic evaluation. Consider
dermatologic monitoring for 6 months following discontinuation of Zelboraf.
Non-Cutaneous Squamous Cell Carcinoma
Non-cutaneous squamous cell carcinomas (non-cuSCC)
of the head and neck can occur in patients receiving Zelboraf [see Adverse Reactions (6.1)]. Monitor patients receiving Zelboraf closely for signs or
symptoms of new non-cuSCC.
Other Malignancies
Based on mechanism of action, Zelboraf may
promote malignancies associated with activation of RAS through mutation or
other mechanisms [see Warnings
and Precautions (5.2)]. Monitor patients receiving Zelboraf closely for signs or
symptoms of other malignancies.
Cases of myeloid neoplasms amongst
patients with ECD have been observed, including in patients who have received
Zelboraf. Monitoring complete blood count in ECD patients with co-existing
myeloid malignancies is recommended.
Tumor
Promotion in BRAF Wild-Type Melanoma
In vitro experiments have
demonstrated paradoxical activation of MAP-kinase signaling and increased cell
proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors.
Confirm evidence of BRAF V600E mutation in tumor specimens prior to initiation
of Zelboraf [see Indications
and Usage (1) and Dosage
and Administration (2.1)].
Hypersensitivity
Reactions
Anaphylaxis and other serious
hypersensitivity reactions can occur during treatment and upon re-initiation of
treatment with Zelboraf. Severe hypersensitivity reactions included generalized
rash and erythema, hypotension, and drug reaction with eosinophilia and
systemic symptoms (DRESS syndrome). Permanently discontinue Zelboraf in
patients who experience a severe hypersensitivity reaction [see Adverse Reactions (6.2)].
Dermatologic
Reactions
Severe dermatologic reactions,
including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in
patients receiving Zelboraf. Permanently discontinue Zelboraf in patients who
experience a severe dermatologic reaction [see Adverse
Reactions (6.1)].
QT
Prolongation
Concentration-dependent QT
prolongation occurred in an uncontrolled, open-label QT sub-study in previously
treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology
(12.2)]. QT prolongation may lead to an increased risk of ventricular
arrhythmias, including Torsade de Pointes.
Do not start treatment in
patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long
QT syndrome, or in patients who are taking medicinal products known to prolong
the QT interval. Prior to and following treatment initiation or after dose
modification of Zelboraf for QTc prolongation, evaluate ECG and electrolytes
(including potassium, magnesium, and calcium) after 15 days, monthly during the
first 3 months, and then every 3 months thereafter or more often as clinically
indicated.
Withhold Zelboraf in patients
who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤
2), restart at a reduced dose. Permanently discontinue Zelboraf treatment if
the QTc interval remains > 500 ms and increased > 60 ms from
pre-treatment values after controlling cardiac risk factors for QT prolongation
(e.g., electrolyte abnormalities, congestive heart failure, and
bradyarrhythmias) [see Dosage
and Administration (2.3)].
Hepatotoxicity
Liver injury leading to
functional hepatic impairment, including coagulopathy or other organ
dysfunction, can occur with Zelboraf [see Adverse
Reactions (6.1)]. Monitor transaminases, alkaline phosphatase, and bilirubin
before initiation of treatment and monthly during treatment, or as clinically
indicated. Manage laboratory abnormalities with dose reduction, treatment
interruption, or treatment discontinuation [see Dosage
and Administration (2.3)].
Concurrent Administration with Ipilimumab
The safety and effectiveness of
Zelboraf in combination with ipilimumab have not been established [see Indications and Usage
(1)]. In a dose-finding trial, Grade 3 increases in transaminases
and bilirubin occurred in a majority of patients who received concurrent
ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) [see Drug Interactions (7.3)].
Photosensitivity
Mild to severe
photosensitivity can occur in patients treated with Zelboraf [see Adverse Reactions (6.1)]. Advise patients to avoid sun
exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen
and lip balm (SPF ≥ 30) when outdoors.
Institute dose modifications
for intolerable Grade 2 or greater photosensitivity [see Dosage
and Administration (2.2)].
Ophthalmologic
Reactions
Uveitis, blurry vision, and
photophobia can occur in patients treated with Zelboraf. In Trial 1, uveitis,
including iritis, occurred in 2.1% (7/336) of patients receiving Zelboraf
compared to no patients in the dacarbazine arm. Treatment with steroid and
mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients
for signs and symptoms of uveitis.
Embryo-Fetal
Toxicity
Based on its mechanism of
action, Zelboraf can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during treatment with
Zelboraf and for 2 weeks after the final dose [see Use in
Specific Populations (8.1, 8.3) and Clinical Pharmacology
(12.1)].
Radiation
Sensitization and Radiation Recall
Radiation sensitization and
recall, in some cases severe, involving cutaneous and visceral organs have been
reported in patients treated with radiation prior to, during, or subsequent to
vemurafenib treatment. Fatal cases have
been reported in patients with visceral organ involvement. [see Adverse Reactions (6.2)].
Monitor patients closely when
vemurafenib is administered concomitantly or sequentially with radiation
treatment.
Renal Failure
Renal failure, including acute
interstitial nephritis and acute tubular necrosis, can occur with Zelboraf. In
Trial 1, in patients with metastatic melanoma, 26% of Zelboraf-treated patients
and 5% of dacarbazine-treated patients experienced Grade 1-2 creatinine
elevations [greater than 1 and up to 3 times upper limit of normal (ULN)]; 1.2%
of Zelboraf-treated patients and 1.1% of dacarbazine-treated patients
experienced Grade 3-4 creatinine elevations (greater than 3 times ULN).
In Trial 4, in patients with
ECD, 86% (19/22) of patients experienced Grade 1/2 creatinine elevations and
9.1% (2/22) of patients experienced Grade 3 creatinine elevations.
Measure serum creatinine
before initiation of Zelboraf and periodically during treatment.
5.12 Dupuytren's Contracture and Plantar Fascial Fibromatosis
Dupuytren's contracture and plantar
fascial fibromatosis have been reported with Zelboraf. The majority of cases
were mild to moderate, but severe, disabling cases of Dupuytren's contracture
have also been reported [see Dosage and
Administration (2.3), Adverse Reactions (6.1, 6.2)].
Adverse Reactions
The following adverse
reactions are discussed in greater detail in other sections of the label:
·
New Primary Malignancies [see Warnings and
Precautions (5.1)]
·
Hypersensitivity
Reactions [see Warnings
and Precautions (5.3)]
·
Dermatologic Reactions [see Warnings and
Precautions (5.4)]
·
QT Prolongation [see Warnings and
Precautions (5.5)]
·
Hepatotoxicity [see Warnings and
Precautions (5.6)]
·
Photosensitivity [see Warnings and
Precautions (5.7)]
·
Ophthalmologic Reactions [see Warnings and
Precautions (5.8)]
·
Radiation Sensitization and
Radiation Recall [see Warnings
and Precautions (5.10)]
·
Renal Failure [see Warnings and
Precautions (5.11)]
·
Dupuytren's Contracture and
Plantar Fascial Fibromatosis [see Warnings
and Precautions (5.12)]
Clinical
Trials Experience
Because clinical studies are
conducted under widely varying conditions, adverse reaction rates observed in
the clinical studies of a drug cannot be directly compared to rates in the
clinical studies of another drug and may not predict the rates observed in a
broader patient population in clinical practice.
Unresectable or Metastatic
Melanoma with BRAF V600E Mutation This section describes adverse drug reactions
(ADRs) identified from analyses of Trial 1 and Trial 2 [see Clinical Studies (14)]. Trial 1 randomized (1:1) 675
treatment-naive patients with unresectable or metastatic melanoma to receive
Zelboraf 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3
weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at
least one prior systemic therapy received treatment with Zelboraf 960 mg orally
twice daily.
Table 1 presents adverse reactions reported in at least 10% of
unresectable or metastatic melanoma patients treated with Zelboraf. The most
common adverse reactions of any grade (≥ 30% in either study) in
Zelboraf-treated patients were arthralgia, rash, alopecia, fatigue,
photosensitivity reaction, nausea, pruritus, and skin papilloma. The most
common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of
Grade 4 adverse reactions was ≤ 4% in both studies.
The incidence of adverse
events resulting in permanent discontinuation of study medication in Trial 1
was 7% for the Zelboraf arm and 4% for the dacarbazine arm. In Trial 2, the
incidence of adverse events resulting in permanent discontinuation of study
medication was 3% in Zelboraf-treated patients. The median duration of study
treatment was 4.2 months for Zelboraf and 0.8 months for dacarbazine in Trial
1, and 5.7 months for Zelboraf in Trial 2.
Table 1 Adverse Reactions Reported in ≥ 10% of Unresectable or
Metastatic Melanoma Patients Treated with Zelboraf*
|
|
|
ADRs
|
Trial 1: Treatment-Naïve Patients
|
Trial 2: Patients with Failure of at
Least One Prior Systemic Therapy
|
|
|
Zelboraf
n=336
|
Dacarbazine
n=287
|
Zelboraf
n=132
|
|
|
All Grades
(%)
|
Grade 3†
(%)
|
All Grades
(%)
|
Grade 3
(%)
|
All Grades (%)
|
Grade 3† (%)
|
|
|
*
Adverse drug
reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI
common toxicity criteria) for assessment of toxicity.
†
Grade 4 adverse
reactions limited to gamma-glutamyltransferase increased (< 1% in Trial 1
and 4% in Trial 2).
‡
Includes both
squamous cell carcinoma of the skin and keratoacanthoma.
§
Cases of cutaneous squamous cell carcinoma were
required to be reported as Grade 3 per protocol.
|
|
|
Skin and subcutaneous tissue disorders
|
|
|
|
|
|
|
|
|
Rash
|
37
|
8
|
2
|
0
|
52
|
7
|
|
|
Photosensitivity
reaction
|
33
|
3
|
4
|
0
|
49
|
3
|
|
|
Alopecia
|
45
|
< 1
|
2
|
0
|
36
|
0
|
|
|
Pruritus
|
23
|
1
|
1
|
0
|
30
|
2
|
|
|
Hyperkeratosis
|
24
|
1
|
< 1
|
0
|
28
|
0
|
|
|
Rash
maculo-papular
|
9
|
2
|
< 1
|
0
|
21
|
6
|
|
|
Actinic
keratosis
|
8
|
0
|
3
|
0
|
17
|
0
|
|
|
Dry skin
|
19
|
0
|
1
|
0
|
16
|
0
|
|
|
Rash papular
|
5
|
< 1
|
0
|
0
|
13
|
0
|
|
|
Erythema
|
14
|
0
|
2
|
0
|
8
|
0
|
|
|
Musculoskeletal and connective tissue disorders
|
|
|
|
|
|
|
|
|
Arthralgia
|
53
|
4
|
3
|
< 1
|
67
|
8
|
|
|
Myalgia
|
13
|
< 1
|
1
|
0
|
24
|
< 1
|
|
|
Pain in
extremity
|
18
|
< 1
|
6
|
2
|
9
|
0
|
|
|
Musculoskeletal
pain
|
8
|
0
|
4
|
< 1
|
11
|
0
|
|
|
Back pain
|
8
|
< 1
|
5
|
< 1
|
11
|
< 1
|
|
|
General disorders and administration site conditions
|
|
|
|
|
|
|
|
|
Fatigue
|
38
|
2
|
33
|
2
|
54
|
4
|
|
|
Edema peripheral
|
17
|
< 1
|
5
|
0
|
23
|
0
|
|
|
Pyrexia
|
19
|
< 1
|
9
|
< 1
|
17
|
2
|
|
|
Asthenia
|
11
|
< 1
|
9
|
< 1
|
2
|
0
|
|
|
Gastrointestinal disorders
|
|
|
|
|
|
|
|
|
Nausea
|
35
|
2
|
43
|
2
|
37
|
2
|
|
|
Diarrhea
|
28
|
< 1
|
13
|
< 1
|
29
|
< 1
|
|
|
Vomiting
|
18
|
1
|
26
|
1
|
26
|
2
|
|
|
Constipation
|
12
|
< 1
|
24
|
0
|
16
|
0
|
|
|
Nervous system disorders
|
|
|
|
|
|
|
|
|
Headache
|
23
|
< 1
|
10
|
0
|
27
|
0
|
|
|
Dysgeusia
|
14
|
0
|
3
|
0
|
11
|
0
|
|
|
Neoplasms benign, malignant and unspecified (includes cysts and
polyps)
|
|
|
|
|
|
|
|
|
Skin papilloma
|
21
|
< 1
|
0
|
0
|
30
|
0
|
|
|
Cutaneous SCC‡§
|
24
|
22
|
< 1
|
< 1
|
24
|
24
|
|
|
Seborrheic
keratosis
|
10
|
< 1
|
1
|
0
|
14
|
0
|
|
|
Investigations
|
|
|
|
|
|
|
|
|
Gamma-glutamyltransferase
increased
|
5
|
3
|
1
|
0
|
15
|
6
|
|
|
Metabolism and nutrition disorders
|
|
|
|
|
|
|
|
|
Decreased
appetite
|
18
|
0
|
8
|
< 1
|
21
|
0
|
|
|
Respiratory, thoracic and mediastinal disorders
|
|
|
|
|
|
|
|
|
Cough
|
8
|
0
|
7
|
0
|
12
|
0
|
|
|
Injury, poisoning and procedural complications
|
|
|
|
|
|
|
|
|
Sunburn
|
10
|
0
|
0
|
0
|
14
|
0
|
|
Clinically relevant adverse
reactions reported in < 10% of unresectable or metastatic melanoma patients
treated with Zelboraf in the Phase 2 and Phase 3 studies include:
Skin and subcutaneous tissue disorders: palmar-plantar
erythrodysesthesia syndrome, keratosis pilaris, panniculitis, erythema nodosum,
Stevens-Johnson syndrome, toxic epidermal necrolysis
Musculoskeletal
and connective tissue disorders: arthritis,
Dupuytren's contracture
Nervous
system disorders: neuropathy peripheral,
VIIth nerve
paralysis
Neoplasms
benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell
carcinoma
Infections
and infestations: folliculitis
Eye
disorders: retinal vein occlusion
Vascular
disorders: vasculitis
Cardiac
disorders: atrial fibrillation
Table 2 shows the incidence of worsening liver laboratory
abnormalities in Trial 1 summarized as the proportion of patients who
experienced a shift from baseline to Grade 3 or 4.
Table 2 Change from Baseline to Grade 3/4 Liver Laboratory
Abnormalities in Trial 1*
|
|
|
Parameter
|
Change From Baseline to Grade 3/4
|
|
|
Zelboraf (%)
|
Dacarbazine (%)
|
|
|
*
For ALT, alkaline phosphatase, and bilirubin, there
were no patients with a change to Grade 4 in either treatment arm.
|
|
|
GGT
|
11.5
|
8.6
|
|
|
AST
|
0.9
|
0.4
|
|
|
ALT
|
2.8
|
1.9
|
|
|
Alkaline
phosphatase
|
2.9
|
0.4
|
|
|
Bilirubin
|
1.9
|
0
|
|
Erdheim-Chester Disease (ECD)
This section describes adverse
reactions identified from analyses of Trial 4 [see Clinical
Studies (14)]. In Trial 4, 22 patients with BRAF V600 mutation-positive ECD
received Zelboraf 960 mg twice daily.
The median treatment duration
for ECD patients in this study was 14.2 months. Table 3 presents adverse reactions reported in at least 20% of
BRAF V600 mutation-positive ECD patients treated with Zelboraf.
In Trial 4, the most commonly
reported adverse reactions (> 50%) in patients with BRAF V600 mutation-
positive ECD treated with Zelboraf were arthralgia, rash maculo-papular,
alopecia, fatigue, electrocardiogram QT interval prolonged, and skin papilloma.
The most common (≥ 10%) Grade ≥3 adverse reactions were squamous cell carcinoma
of the skin, hypertension, rash maculo-papular, and arthralgia.
The incidence of adverse
reactions resulting in permanent discontinuation of study medication was 32%.
Table 3 Adverse Reactions Reported in ≥ 20% of ECD Patients Treated
with Zelboraf*
|
|
Trial 4: Patients with ECD
|
|
|
n=22
|
|
Body System
Adverse Reactions
|
All Grades (%)
|
Grade 3-4 (%)
|
|
*
Adverse drug
reactions, graded using NCI-CTCAE v 4.0 (NCI common toxicity criteria) for
assessment of toxicity.
†
Cases of cutaneous squamous cell carcinoma were
required to be reported as Grade 3 per protocol.
|
|
Skin and subcutaneous tissue disorders
|
|
|
|
Rash
maculo-papular
|
59
|
18
|
|
Alopecia
|
55
|
-
|
|
Hyperkeratosis
|
50
|
5
|
|
Dry skin
|
45
|
-
|
|
Photosensitivity
reaction
|
41
|
-
|
|
Palmar-plantar
erythrodysaesthesia syndrome
|
41
|
-
|
|
Pruritus
|
36
|
-
|
|
Actinic
keratosis
|
32
|
5
|
|
Keratosis
pilaris
|
32
|
-
|
|
Rash papular
|
23
|
-
|
|
Musculoskeletal and connective tissue disorders
|
|
|
|
Arthralgia
|
82
|
14
|
|
General disorders and administration site conditions
|
|
|
|
Fatigue
|
55
|
5
|
|
Gastrointestinal disorders
|
|
|
|
Diarrhea
|
50
|
-
|
|
Nausea
|
32
|
-
|
|
Vomiting
|
23
|
-
|
|
Nervous system disorders
|
|
|
|
Peripheral
sensory neuropathy
|
36
|
-
|
|
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
|
|
|
|
Skin papilloma
|
55
|
-
|
|
Seborrhoeic
keratosis
|
41
|
-
|
|
SCC of skin†
|
36
|
36
|
|
Melanocytic
nevus
|
23
|
_
|
|
Cardiac disorders
|
|
|
|
Electrocardiogram
QT interval prolonged
|
55
|
5
|
|
Respiratory, thoracic and mediastinal disorders
|
|
|
|
Cough
|
36
|
-
|
|
Vascular disorders
|
|
|
|
Hypertension
|
36
|
23
|
|
Injury, poisoning and procedural complications
|
|
|
|
Sunburn
|
23
|
-
|
Clinically relevant adverse
reactions reported in < 20% of ECD patients treated with Zelboraf in Trial 4
include:
Neoplasms
benign, malignant and unspecified (includes cysts and polyps): keratoacanthoma
Musculoskeletal
and connective tissue disorders: Dupuytren's
contracture
Table 4 shows the incidence of worsening liver laboratory
abnormalities in Trial 4 summarized as the proportion of ECD patients who
experienced a shift from baseline to Grade 3 or 4.
Table 4 Change from Baseline to Grade 3 Liver Laboratory
Abnormalities in Trial 4
|
|
|
Change From Baseline to Grade 3
|
|
Parameter
|
Vemurafenib (%)
|
|
AST
|
0
|
|
ALT
|
9.1
|
|
Alkaline
phosphatase
|
4.5
|
|
Bilirubin
|
0
|
Postmarketing
Experience
The following adverse
reactions have been identified during post approval use of Zelboraf. Because
these reactions are reported voluntarily from a population of uncertain size,
it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Neoplasms
benign, malignant and unspecified (incl. cysts and polyps): Progression of pre-existing chronic myelomonocytic
leukemia with NRAS mutation [see Warnings
and Precautions (5.1)].
Skin
and subcutaneous tissue disorders: Drug
reaction with eosinophilia and systemic symptoms (DRESS syndrome) [see Warnings and
Precautions (5.3)].
Blood
and lymphatic systems disorder: Neutropenia
Injury,
poisoning and procedural complications: Radiation
sensitization and recall [see Warnings
and Precautions (5.10)].
Gastrointestinal
disorders: Pancreatitis
Renal
and urinary disorders: Acute interstitial nephritis, acute tubular necrosis [see Warnings
and Precautions (5.11)].
Musculoskeletal
and connective tissue disorders: Dupuytren's contracture and plantar fascial
fibromatosis [see Warnings and
Precautions (5.12)].
Drug InteractionsEffect of
Strong CYP3A4 Inhibitors or Inducers on Vemurafenib
Strong CYP3A4 Inhibitors
Vemurafenib is a substrate of
CYP3A4; therefore, coadministration of strong CYP3A4 inhibitors may increase
vemurafenib plasma concentrations and may lead to increased toxicity. Avoid
coadministration of Zelboraf with strong CYP3A4 inhibitors (e.g., ketoconazole,
itraconazole, clarithromycin, saquinavir, ritonavir, indinavir, nelfinavir,
voriconazole) and replace these drugs with alternative drugs when
possible [see Clinical
Pharmacology (12.3)].
Strong CYP3A4 Inducers
Coadministration of Zelboraf
with rifampin, a strong CYP3A4 inducer, decreased vemurafenib plasma
concentrations and may result in decreased efficacy. Avoid coadministration of
Zelboraf with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine,
rifampin), and replace these drugs with alternative drugs when possible. If
coadministration of a strong CYP3A4 inducer is unavoidable, increase the dose
of Zelboraf by 240 mg (one tablet) as tolerated [see Dosage
and Administration (2.4), Clinical Pharmacology
(12.3)].
Effect of
Vemurafenib on CYP1A2 Substrates
Coadministration of Zelboraf
with tizanidine, a sensitive CYP1A2 substrate, increased tizanidine systemic
exposure by 4.7-fold. Avoid concomitant use of Zelboraf with drugs having a
narrow therapeutic window that are predominantly metabolized by CYP1A2 [see Clinical Pharmacology
(12.3)]. If coadministration cannot be avoided, monitor closely for
toxicities and consider a dose reduction of concomitant CYP1A2 substrates.
Concurrent
Ipilimumab
Increases in transaminases and
bilirubin occurred in a majority of patients who received concurrent ipilimumab
and Zelboraf [see Warnings
and Precautions Section 5.6].
Effect of
Vemurafenib on P-gp Substrates
Coadministration of Zelboraf
with digoxin, a sensitive P-glycoprotein (P-gp) substrate, increased digoxin
systemic exposure by 1.8-fold. Avoid concurrent use of P-gp substrates known to
have narrow therapeutic indices. If use of these medications is unavoidable,
consider dose reduction of P-gp substrates with narrow therapeutic indices.
USE IN SPECIFIC POPULATIONSPregnancy
Risk Summary
Based on its mechanism of
action, Zelboraf can cause fetal harm when administered to a pregnant
woman [see Clinical Pharmacology
(12.1)]. There are no available data on the use of Zelboraf in pregnant
women to determine the drug-associated risk; however, placental transfer of
vemurafenib to a fetus has been reported. Exposure to vemurafenib could not be
achieved in animals at levels sufficient to fully address its potential
toxicity in pregnant women. Advise pregnant women of the potential harm to a
fetus.
The estimated background risks
of major birth defects and miscarriage for the indicated population(s) are
unknown. 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
Vemurafenib showed no evidence
of developmental toxicity in rat fetuses at doses up to 250 mg/kg/day
(approximately 1.3 times the clinical exposure at 960 mg twice daily based on
AUC) or rabbit fetuses at doses up to 450 mg/kg/day (approximately 0.6 times
the clinical exposure at 960 mg twice daily based on AUC). Fetal drug levels
were 3–5% of maternal levels, indicating that vemurafenib has the potential to
be transmitted from the mother to the developing fetus.
Lactation
There is no information
available regarding the presence of vemurafenib 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, including malignancy, severe
dermatologic reactions, QT prolongation, hepatotoxicity, photosensitivity, and
ophthalmologic toxicity, [see Warnings
and Precautions (5)], advise women not to
breastfeed during treatment with Zelboraf and for 2 weeks after the final dose.
Females and
Males of Reproductive Potential
Contraception
Based on its mechanism of
action, Zelboraf 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 Zelboraf and for 2 weeks after the final
dose.
Pediatric Use
The safety and effectiveness
of Zelboraf in pediatric patients have not been established. Vemurafenib was
studied in 6 adolescent patients 15 to 17 years of age with unresectable or
metastatic melanoma with BRAF V600 mutation. A maximum tolerated dose was not
reached with doses up to vemurafenib 960 mg twice daily. No new safety signals were
observed. Vemurafenib steady-state exposure in these 6 adolescent patients was
generally similar to that in adults.
Geriatric Use
Clinical studies of Zelboraf
did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects.
Hepatic
Impairment
No formal clinical study has
been conducted to evaluate the effect of hepatic impairment on the
pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients
with mild and moderate hepatic impairment based on a population pharmacokinetic
analysis [see Clinical
Pharmacology (12.3)]. The appropriate dose of
Zelboraf has not been established in patients with severe hepatic impairment.
Renal
Impairment
No formal clinical study has
been conducted to evaluate the effect of renal impairment on the
pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients
with mild and moderate renal impairment based on a population pharmacokinetic
analysis [see Clinical
Pharmacology (12.3)]. The appropriate dose of
Zelboraf has not been established in patients with severe renal impairment.
Overdosage
There is no information on
overdosage of Zelboraf.
Zelboraf Description
Zelboraf (vemurafenib) is a
kinase inhibitor available as 240 mg tablets for oral use. Vemurafenib has the
chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-
2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of
489.9. Vemurafenib has the following chemical structure:
Vemurafenib is a white to
off-white crystalline solid. It is practically insoluble in aqueous media.
Tablets of Zelboraf are for
oral administration. Each tablet contains 240 mg of vemurafenib.
The inactive ingredients of
Zelboraf are: Tablet core: hypromellose
acetate succinate, croscarmellose sodium, colloidal silicon dioxide, magnesium
stearate, and hydroxypropyl cellulose. Coating: pinkish
white: poly (vinyl alcohol), titanium dioxide, polyethylene glycol 3350, talc,
and iron oxide red.
Zelboraf - Clinical PharmacologyMechanism of
Action
Vemurafenib is a low molecular
weight, orally available inhibitor of some mutated forms of BRAF serine-
threonine kinase, including BRAF V600E. Vemurafenib also inhibits other kinases
in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at
similar concentrations. Some mutations in the BRAF gene including V600E result
in constitutively activated BRAF proteins, which can cause cell proliferation
in the absence of growth factors that would normally be required for proliferation.
Vemurafenib has anti-tumor effects in cellular and animal models of melanomas
with mutated BRAF V600E.
Pharmacodynamics
Cardiac Electrophysiology
In a multi-center, open-label,
single-arm study in 132 patients with BRAF V600E mutation-positive metastatic
melanoma, patients administered vemurafenib 960 mg orally twice daily did not
experience large changes in mean QTc interval (i.e., > 20 ms) from baseline.
Vemurafenib is associated with concentration- dependent QTc interval
prolongation. The largest mean change from baseline in the first month of
treatment occurred at 2 hours post-dose on Day 15—an increase of 12.8 ms (upper
boundary of the two-sided 90% confidence interval of 14.9 ms). In the first 6
months of treatment, the largest observed mean change from baseline occurred at
a pre-dose time point—an increase of 15.1 ms (upper boundary of the two-sided
90% confidence interval of 17.7 ms).
Pharmacokinetics
The pharmacokinetics of
vemurafenib were determined in patients with BRAF mutation-positive metastatic
melanoma following 15 days of 960 mg twice daily with dosing approximately 12
hours apart. The population pharmacokinetic analysis pooled data from 458
patients. At steady-state, vemurafenib exhibits linear pharmacokinetics within
the 240 mg to 960 mg dose range.
Absorption
The bioavailability of
vemurafenib has not been determined. The median Tmax was approximately 3
hours following multiple doses.
The mean (± SD) Cmax and AUC0-12 were 62 ± 17 µg/mL and
601 ± 170 µg*h/mL, respectively. The median accumulation ratio estimate from
the population pharmacokinetic analysis for the twice daily regimen is 7.4,
with steady-state achieved at approximately 15 to 22 days.
In clinical trials,
vemurafenib was administered without regard to food. A food effect study has
demonstrated that a single dose of vemurafenib administered with a high-fat
meal increased AUC by approximately 5-fold, increased Cmax by 2.5-fold, and delayed
Tmax by
approximately 4 hours as compared to the fasted state.
QTc prolongation may occur
with increased exposures as vemurafenib is associated with
concentration-dependent QTc interval prolongation [see Clinical
Pharmacology (12.2)].
Distribution
Vemurafenib is highly bound
(> 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The
population apparent volume of distribution is estimated to be 106 L (with 66%
inter-patient variability).
Metabolism
Following oral administration
of 960 mg of 14C-vemurafenib, mean data showed that vemurafenib and its
metabolites represented 95% and 5% of the components in plasma over 48 hours,
respectively.
Elimination
Following oral administration
of 960 mg of 14C-vemurafenib, approximately 94% of the radioactive dose was
recovered in feces and approximately 1% was recovered in the urine. The
population apparent clearance is estimated to be 31 L/day (with 32%
inter-patient variability). The median elimination half-life estimate for
vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours).
Specific Populations
Hepatic Impairment: The
pharmacokinetics of vemurafenib were examined in patients with metastatic
melanoma enrolled in the clinical trials with normal hepatic function (n=158,
total bilirubin ≤ ULN) and mild (n=58, total bilirubin 1.0–1.5 × ULN), moderate
(n=27, total bilirubin 1.5–3 × ULN), or severe (n=3, total bilirubin > 3 ×
ULN) hepatic impairment. Patients received vemurafenib 960 mg orally twice
daily. The apparent clearance of vemurafenib in patients with mild and moderate
hepatic impairment was similar to that in patients with normal hepatic
function. The appropriate dose for patients with severe hepatic impairment
cannot be determined as clinical and pharmacokinetic data were available for
only three patients [see Use in
Specific Populations (8.6)].
Renal Impairment: The
pharmacokinetics of vemurafenib were examined in patients with metastatic
melanoma enrolled in the clinical trials with normal renal function (CLcr ≥ 90
mL/min) and mild (n=94, CLcr > 60 to 89 mL/min), moderate (n=11, CLcr 30 to
59 mL/min) or severe (n=1, CLcr < 29 mL/min) renal impairment. Patients
received vemurafenib 960 mg orally twice daily. The apparent clearance of
vemurafenib in patients with mild and moderate renal impairment was similar to
that in patients with normal renal function. The appropriate dose for patients
with severe renal impairment cannot be determined as clinical and pharmacokinetic
data were available for only one patient [see Use in
Specific Populations (8.7)].
Age, Body Weight, Sex, and Race: Based on the population pharmacokinetic analysis, age, body
weight, and sex do not have a clinically important effect on the exposure of
vemurafenib. There are insufficient data to evaluate potential differences in
the pharmacokinetics of vemurafenib by race.
Drug Interaction Studies
Effect of Strong CYP3A4 Inhibitors on Vemurafenib: In vitro studies have demonstrated that vemurafenib is a
CYP3A4 substrate. The effect of strong CYP3A4 inhibitors on the systemic
exposure of vemurafenib has not been evaluated in vivo [see Drug Interactions (7.1)].
Effect of Strong CYP3A4 Inducers on Vemurafenib: Coadministration of 600 mg daily doses of rifampin (a
strong CYP3A inducer) with a single 960 mg dose of Zelboraf decreased
vemurafenib AUC by 40% (90% CI: 24%, 53%) with no effect on Cmax, relative to a 960 mg dose of
Zelboraf administered alone [see Dosage
and Administration (2.4), Drug Interactions (7.1)].
Effect of Vemurafenib on CYP Substrates: In vitro studies suggest that vemurafenib is an inhibitor
of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5.
Coadministration of tizanidine
2 mg (a sensitive CYP1A2 substrate) on day 21 with vemurafenib which was
administered 960 mg twice daily for 21 days increased tizanidine AUCinf by 4.7-fold (90% CI:
3.6, 6.3) and Cmax by 2.2-fold (90% CI: 1.7, 2.7) in 16 cancer patients [see Drug Interactions (7.2)]. In an in vivo phenotypic
cocktail drug-drug interaction study in patients with cancer, a single dose of
the CYP probe substrate cocktail (for CYP1A2, 2D6, 3A4, 2C19 and 2C9) was
administered before and concomitantly with vemurafenib (following 15 days of
dosing at 960 mg twice daily). Coadministration of vemurafenib increased the
mean AUC of caffeine (CYP1A2 substrate) by 2.6-fold [see Drug
Interactions (7.2)]. Coadministration of
vemurafenib increased the mean AUC of dextromethorphan (CYP2D6 substrate) by
47% and the AUC of S-warfarin (CYP2C9 substrate) by 18%, while it decreased the
mean AUC of midazolam (CYP3A4 substrate) by 39%. Coadministration of
vemurafenib did not change the mean systemic exposure to omeprazole (CYP2C19
substrate).
Effect of Vemurafenib on Transporters: In vitro studies suggest that vemurafenib is both a
substrate and an inhibitor of the efflux transporters P-glycoprotein (P-gp) and
Breast Cancer Resistance Protein (BCRP).
Administration of vemurafenib
960 mg twice daily for 22 days increased digoxin AUC by 1.8-fold (90% CI:1.6,
2.0) and Cmax by 1.5-fold (90% CI:1.3, 1.7) in 26 cancer patients who
were coadministered a single dose of digoxin 0.25 mg (sensitive P-gp
substrate) [see Drug
Interactions (7.4)].
Nonclinical ToxicologyCarcinogenesis,
Mutagenesis, Impairment of Fertility
There have been no formal
studies conducted assessing the carcinogenic potential of vemurafenib. Zelboraf
increased the development of cutaneous squamous cell carcinomas in patients in
clinical trials.
Vemurafenib did not cause genetic
damage when tested in in vitro assays (bacterial mutation [AMES Assay], human
lymphocyte chromosome aberration) or in the in vivo rat bone marrow
micronucleus test.
No specific studies with
vemurafenib have been conducted in animals to evaluate the effect on fertility;
nevertheless, no histopathological findings were noted in reproductive organs
in males and females in repeat-dose toxicology studies in rats at doses up to
450 mg/kg/day (approximately 0.6 and 1.6 times the human exposure based on AUC
in males and females, respectively) and dogs at doses up to 450 mg/kg/day
(approximately 0.3 times the human clinical exposure based on AUC in both males
and females, respectively).
Animal
Toxicology and/or Pharmacology
Consistent with the increased
incidence of cutaneous squamous cell carcinomas in patients treated with
vemurafenib, the treatment of mice implanted with human cuSCC cells with
vemurafenib caused a dose- dependent acceleration of the growth of the
implanted tumors.
Clinical Studies
Treatment-Naïve Patients with BRAF V600E Mutation-Positive
Unresectable or Metastatic Melanoma
Trial 1, an international,
open-label, randomized controlled trial, equally allocated 675 patients with
treatment-naive, BRAF V600E mutation-positive unresectable or metastatic
melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, to receive Zelboraf 960 mg
by mouth twice daily (n=337) or dacarbazine 1000 mg/m2 intravenously on Day 1
every 3 weeks (n=338). Randomization stratification factors were disease stage,
lactate dehydrogenase (LDH), ECOG performance status, and geographic region.
Treatment continued until disease progression, unacceptable toxicity, and/or
consent withdrawal. The major efficacy outcome measures of the trial were
overall survival (OS) and investigator-assessed progression-free survival
(PFS). Other outcome measures included confirmed investigator-assessed best
overall response rate.
Baseline characteristics were
balanced between treatment groups. Most patients were male (56%) and Caucasian
(99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG
performance status of 0 or 1, and the majority of patients had metastatic
disease (95%).
Trial 1 demonstrated
statistically significant increases in overall survival and progression-free
survival in the Zelboraf arm compared to the dacarbazine control arm. Table
5 and Figure 1 summarize the efficacy results.
Table 5 Efficacy of Zelboraf in Treatment-Naïve Patients with BRAF
V600E Mutation-Positive Melanoma*
|
|
|
Zelboraf
(n=337)
|
Dacarbazine
(n=338)
|
p-value†
|
|
*
As detected by
the cobas® 4800 BRAF V600 Mutation Test
†
Unstratified
log-rank test
‡
Total of 200
deaths (Zelboraf median follow-up 6.2 months)
§
Hazard ratio
estimated using Cox model; a hazard ratio of < 1 favors Zelboraf
¶
Kaplan-Meier
estimate
#
Updated based on 478 deaths (Zelboraf median
follow-up 13.4 months)
|
|
Overall Survival
|
|
Number
of Deaths‡
|
78 (23%)
|
122 (36%)
|
|
|
Hazard
Ratio
(95% CI)§
|
0.47
(0.35, 0.62)
|
< 0.0001
|
|
Updated
Median Survival (months)
(95 % CI) ¶, #
|
13.6
(12.0, 15.3)
|
10.3
(9.1, 12.8)
|
-
|
|
Progression-Free Survival
|
|
Hazard
Ratio
(95% CI)§
|
0.26
(0.20, 0.33)
|
< 0.0001
|
|
Median
PFS (months)
(95% CI)¶
|
5.3
(4.9, 6.6)
|
1.6
(1.6, 1.7)
|
-
|
Figure
1 Kaplan-Meier Curves of Overall Survival – Treatment-Naïve Patients
The confirmed,
investigator-assessed best overall response rate was 48.4% (95% CI: 41.6%,
55.2%) in the Zelboraf arm compared to 5.5% (95% CI: 2.8%, 9.3%) in the
dacarbazine arm. There were 2 complete responses (0.9%) and 104 partial
responses (47.4%) in the Zelboraf arm and all 12 responses were partial
responses (5.5%) in the dacarbazine arm.
Patients with BRAF V600E Mutation-Positive Metastatic Melanoma
Who Received Prior Systemic Therapy
In a single-arm, multicenter,
multinational trial (Trial 2), 132 patients with BRAF V600E mutation-positive
metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation
Test, who had received at least one prior systemic therapy, received Zelboraf
960 mg by mouth twice daily. The median age was 52 years with 19% of patients
being older than 65 years. The majority of patients were male (61%) and
Caucasian (99%). Forty-nine percent of patients received ≥ 2 prior therapies.
The median duration of follow-up was 6.87 months (range, 0.6 to 11.3).
The confirmed best overall
response rate as assessed by an independent review committee (IRC) was 52% (95%
CI: 43%, 61%). There were 3 complete responses (2.3%) and 66 partial responses
(50.0%). The median time to response was 1.4 months with 75% of responses
occurring by month 1.6 of treatment. The median duration of response by IRC was
6.5 months (95% CI: 5.6, not reached).
Patients with BRAF V600E Mutation-Positive Melanoma with Brain
Metastases
The activity of Zelboraf for
the treatment of BRAF V600E mutation-positive melanoma, metastatic to the brain
was evaluated in an open-label, multicenter, single-arm, two cohort trial
(Trial 3). All patients received Zelboraf 960 mg orally twice daily until disease
progression or unacceptable toxicity. Patients were required to have at least
one measurable brain lesion of 0.5 cm or greater on contrast-enhanced MRI, a
stable or decreasing corticosteroid dose and no prior treatment with a BRAF or
MEK inhibitor. Patients in Cohort A had received no prior local therapy for
brain metastases. Patients in Cohort B had received at least one prior local
therapy for brain metastases (surgical resection, whole brain radiotherapy, or
stereotactic radiotherapy) with CNS progression following this therapy.
Patients were followed until death, disease progression, withdrawal, or up to
24 months. The primary efficacy outcome measure was the confirmed best overall
response rate in the brain in Cohort A, as assessed by an independent radiology
review committee using Response Evaluation Criteria in Solid Tumors (RECIST
v1.1). Secondary efficacy outcome measures included duration of response in
Cohort A, and confirmed best overall response rate and duration of response in
Cohort B.
A total of 146 patients
(Cohort A: n=90; Cohort B: n=56) were enrolled and received at least one dose
of Zelboraf. In Cohort A, the median age of patients was 56 years, 62% were
male, 47% had a pre- treatment ECOG performance status (PS) of 0, 57% had an
elevated LDH value at baseline, and 20% received one or more systemic regimens
for the treatment of metastatic disease. In Cohort B, the median age of
patients was 53 years, 61% were male, 38% had a pre-treatment ECOG PS of 0, 55%
had an elevated LDH value at baseline, and 39% received one or more systemic
regimens for the treatment of metastatic disease. All patients enrolled on
Trial 3 whose race was identified were White. The efficacy results are
summarized in Table 6.
Table 6 Efficacy Results in Patients with BRAF V600E Melanoma Brain
Metastases
|
|
|
Cohort A
(n=90)
|
Cohort B
(n=56)
|
|
*
Two-sided 95%
Clopper-Pearson Confidence Interval (CI)
†
Kaplan-Meier estimate
|
|
Confirmed Best
Overall Response Rate in Brain, 95%CI*
|
18% (11%, 27%)
|
18% (9%, 30%)
|
|
Complete
response
|
2%
|
0
|
|
Partial
response
|
16%
|
18%
|
|
Median of
Duration of Response, months (95%CI†)
|
4.6 (2.9, 6.2)
|
6.6 (2.8, 10.7)
|
Patients with Wild-Type BRAF Melanoma
Zelboraf has not been studied
in patients with wild-type BRAF melanoma [see Warnings
and Precautions (5.2)].
Patients with Erdheim-Chester Disease (ECD)
An open-label, multicenter,
single-arm, multiple cohort study of Zelboraf (Trial 4) was conducted in
patients ≥ 16 years of age with non-melanoma BRAF V600 mutation–positive
diseases.
The trial included 22 patients
with ECD. Fifteen patients (68.2%) had received prior systemic therapies. The
median age was 58.5 years (range, 34 to 77 years). Fifty-five percent of
patients were men.
All 22 patients received a
starting dose of 960 mg orally twice daily with or without food. For 8
patients, the dose was reduced to 720 mg twice daily. For the remaining 14
patients, the dose was ultimately reduced to 480 mg. The median duration of
treatment following a dose reduction to 720 mg was 77 days (range, 4 to 1325)
and to 480 mg was 236 days (range, 21 to 924). The efficacy was maintained in
these patients based on the overall response rate.
The efficacy of Zelboraf in
ECD was based on best overall response rate maintained on two occasions at
least four weeks apart, as assessed by the investigator using RECIST v 1.1, and
is presented in Table 7below. The median duration of follow up was 26.6 months in ECD
patients (range, 3.0 to 44.3 months). The median time to response was 11 months
(95% CI: 3.7, 14.6). The median DOR was not estimable.
Table 7 Efficacy of Zelboraf in patients with ECD (investigator
assessed)
|
|
|
N=22
|
|
*
95% Confidence Interval (CI) constructed using
Clopper-Pearson method
|
|
Overall Response
|
|
|
Responders (n
[%])
|
12 (54.5%)
|
|
(95% CI)*
|
(32.2, 75.6)
|
|
Complete
Response (CR)
|
1 (4.5%)
|
|
Partial
Response (PR)
|
11 (50%)
|
How Supplied/Storage and Handling
Zelboraf (vemurafenib) is
supplied as 240 mg film-coated tablets with VEM debossed on one side. The
following packaging configurations are available:
NDC 50242-090-01 single bottle
of 120 count
NDC 50242-090-02 single bottle
of 112 count
Storage
and Stability: Store at room temperature
20°C–25°C (68°F–77°F); excursions permitted between 15°C and 30°C (59°F and
86°F), See USP Controlled Room Temperature. Store in the original container
with the lid tightly closed.
Disposal
of unused/expired medicines: The
release of pharmaceuticals in the environment should be minimized. Medicines
should not be disposed of via wastewater and disposal through household waste
should be avoided. Use established "collection systems," if available
in your location.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication
Guide).
Healthcare providers should
advise patients of the potential benefits and risks of Zelboraf and instruct
their patients to read the Medication
Guide before starting Zelboraf therapy.
Inform patients of the following:
·
Evidence of BRAF V600E
mutation in the tumor specimen with an FDA approved test is necessary to
identify patients with melanoma for whom treatment with Zelboraf is
indicated [see Dosage
and Administration (2.1)].
·
Zelboraf increases the risk of
developing new primary cutaneous malignancies. Advise patients of the
importance of contacting their healthcare provider immediately for any changes
in their skin [see Warnings
and Precautions (5.1)].
·
Anaphylaxis and other serious
hypersensitivity reactions can occur during treatment and upon re- initiation
of treatment with Zelboraf. Advise patients to stop taking Zelboraf and to seek
immediate medical attention for symptoms of anaphylaxis or hypersensitivity [see Warnings and
Precautions (5.3)].
·
Severe dermatologic reactions
can occur in patients receiving Zelboraf. Advise patients to stop taking
Zelboraf and to contact their health-care provider for severe dermatologic
reactions [see Warnings
and Precautions (5.4)].
·
Zelboraf can prolong QT
interval, which may result in ventricular arrhythmias. Advise patients of the
importance of monitoring of their electrolytes and the electrical activity of
their heart (via an ECG) during Zelboraf treatment [see Warnings
and Precautions (5.5)].
·
Liver injury leading to
functional hepatic impairment, including coagulopathy or other organ
dysfunction, can occur with Zelboraf. Advise patients of the importance of
laboratory monitoring of their liver during Zelboraf treatment and to contact
their health-care provider for relevant symptoms [see Warnings
and Precautions (5.6)].
·
Zelboraf can cause mild to
severe photosensitivity. Advise patients to avoid sun exposure, wear protective
clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30)
when outdoors to help protect against sunburn [see Warnings
and Precautions (5.7)].
·
Ophthalmologic reactions can
occur in patients treated with Zelboraf. Advise patients to contact their
health-care provider immediately for ophthalmologic symptoms [see Warnings and
Precautions (5.8)].
Embryo-fetal Toxicity
·
Advise pregnant women and
females of reproductive potential of the potential risk to a fetus [see Warnings and
Precautions (5.9) and Use in
Special Populations (8.1)].
·
Advise females of reproductive
potential to use effective contraception during treatment with Zelboraf and for
2 weeks after the final dose [see Warnings
and Precautions (5.9) and Use in Special
Populations (8.1, 8.3)].
·
Advise female patients to
contact their health-care provider immediately with a known or suspected
pregnancy [see Warnings
and Precautions (5.9) and Use in Special
Populations (8.1, 8.3)].
Lactation
·
Advise a woman not to
breastfeed during treatment with Zelboraf and for 2 weeks after the final
dose [see Use in Specific
Populations (8.2)].
·
Radiation sensitization and
recall can occur in patients treated with radiation prior to, during, or
subsequent to Zelboraf treatment. Advise patients to inform their health care
provider if they have had or are planning to receive radiation therapy [see Warnings and
Precautions (5.10), Adverse Reactions (6.2)].
·
Renal failure can occur in patients
treated with Zelboraf. Advise patients of the importance of monitoring serum
creatinine prior to and during Zelboraf treatment [see Warnings
and Precautions (5.11), Adverse Reactions (6.2)].
·
Advise patients to contact
their health care provider for symptoms of Dupuytren's contracture or plantar
fascial fibromatosis [see Warnings
and Precautions (5.12)].
Distributed by:
Genentech USA, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
Zelboraf is a registered
trademark of Genentech, Inc.
Co-promoted by: Genentech USA, Inc. and Daiichi Sankyo, Inc.
©2017 Genentech, Inc.
|
This Medication
Guide has been approved by the U.S. Food and Drug Administration
|
Revised: 11/2017
|
|
MEDICATION GUIDE
Zelboraf® (ZEL-bor-raf)
(vemurafenib)
tablet
|
|
What is the most important information I
should know about Zelboraf?
Zelboraf can
cause serious side effects, including:
Risk of new
cancers. Zelboraf
may cause certain types of skin cancer called cutaneous squamous cell
carcinoma (cuSCC) and keratoacanthoma. New melanoma lesions have occurred in
people who take Zelboraf. Zelboraf may also cause another type of cancer
called non-cutaneous squamous cell carcinoma (non-cuSCC). Talk with your
healthcare provider about your risk for these cancers.
Check your
skin and tell your healthcare provider right away about any skin changes
including a:
· new
wart
· skin
sore or reddish bump that bleeds or does not heal
· change
in size or color of a mole
Your healthcare provider should
check your skin before you start taking Zelboraf, and every 2 months during
treatment with Zelboraf, to look for any new skin cancers. Your healthcare
provider may continue to check your skin for 6 months after you stop taking
Zelboraf.
Your healthcare provider should
also check for cancers that may not occur on the skin. Tell your healthcare
provider about any new symptoms that you get while taking Zelboraf.
Other blood cell cancers have
happened in some people with Erdheim-Chester Disease (ECD) including those
who take Zelboraf. If you have other blood cell cancers and take Zelboraf for
ECD, your healthcare provider will monitor your blood cancer through routine
blood tests.
See "What are the possible side effects of
Zelboraf?" for more information about side effects.
|
|
What is Zelboraf?
Zelboraf is a prescription
medicine used to treat:
· a
type of skin cancer called melanoma that:
o has
spread to other parts of the body or cannot be removed by surgery, and
o has
a certain type of abnormal "BRAF" gene.
Zelboraf is not used to treat
melanoma with a normal BRAF gene.
Your healthcare provider will
perform a test to make sure that Zelboraf is right for you.
· a
type of blood cell cancer called Erdheim-Chester Disease (ECD) that:
o can
affect body tissues and organs, and
o has
a certain type of abnormal "BRAF" gene.
It is not known if Zelboraf is
safe and effective in children under 18 years of age.
|
|
Before you take Zelboraf, tell your
healthcare provider about all of your medical conditions, including if you:
· have
any heart problems, including a condition called long QT syndromes
· have
liver or kidney problems
· have
had or are planning to receive radiation therapy
· have
been told that you have low blood levels of potassium, calcium, or magnesium
· are
pregnant or plan to become pregnant. Zelboraf can harm your unborn baby.
o Females
who are able to become pregnant should use effective birth control during
treatment with Zelboraf and for 2 weeks after the final dose of Zelboraf.
o Talk
to your healthcare provider about birth control methods that may be right for
you.
o Tell
your healthcare provider right away if you become pregnant or think you are
pregnant during treatment with Zelboraf.
· are
breastfeeding or plan to breastfeed. It is not known if Zelboraf passes into
your breast milk. Do not breastfeed during treatment with Zelboraf and for 2
weeks after the final dose of Zelboraf. Talk to your healthcare provider
about the best way to feed your baby during this time.
Tell your
healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements. Know the
medicines you take. Keep a list of them to show your healthcare provider and
pharmacist when you get a new medicine.
|
|
How should I take Zelboraf?
· Take
Zelboraf exactly as your healthcare provider tells you. Do not change your
dose or stop taking Zelboraf unless your healthcare provider tells you to.
· Take
Zelboraf every 12 hours with or without a meal.
· Do
not crush or chew Zelboraf tablets.
· Do
not take an additional dose of Zelboraf if you vomit after taking your
scheduled dose. Take your next dose at your regular time.
· If
you miss a dose of Zelboraf, take it as soon as you remember. If it is within
4 hours of your next scheduled dose, just take your next dose at your regular
time. Do not make up for the missed dose.
· If
you take too much Zelboraf, call your healthcare provider or go the nearest
hospital emergency room right away.
|
|
What should I avoid while taking
Zelboraf?
Avoid sunlight during treatment
with Zelboraf. Zelboraf can make your skin sensitive to sunlight. You may
burn more easily and get severe sunburns. To help protect against sunburn:
· When
you go outside, wear clothes that protect your skin, including your head,
face, hands, arms, and legs.
· Use
lip balm and a broad-spectrum sunscreen with SPF 30 or higher.
|
|
What are the possible side effects of
Zelboraf?
Zelboraf may
cause serious side effects, including:
· See "What is the most important information
I should know about Zelboraf?"
· Allergic reactions can happen while taking Zelboraf
and can be severe. Stop
taking Zelboraf and get medical help right away if you get any of these
symptoms of an allergic reaction:
|
|
|
o rash
or redness all over your body
o trouble
breathing or swallowing
o swelling
of the face, lips, or tongue
|
o throat
tightness or hoarseness
o feel
faint
o a
fast heartbeat
|
|
· Severe skin reactions. Stop taking Zelboraf and call your
healthcare provider right away if you get a skin rash with any of the
following symptoms because you may have a severe skin reaction:
|
|
|
o blisters
on your skin
o blisters
or sores in your mouth
o peeling
of your skin
|
o fever
o redness
or swelling of your face, hands, or soles of your feet
|
|
· Changes in the electrical activity of your heart
called QT prolongation. QT prolongation can cause irregular heartbeats that
can be life-threatening. Your
healthcare provider should do tests before you start taking Zelboraf and
during your treatment with Zelboraf to check the electrical activity of your
heart and your body salts (electrolytes). Tell your healthcare provider right
away if you feel faint, lightheaded, dizzy, or feel your heart beating
irregularly or fast while taking Zelboraf. These may be symptoms related to
QT prolongation.
· Liver injury. Your healthcare provider should do blood tests
to check your liver function before you start taking Zelboraf and during
treatment. Tell your healthcare provider right away if you get any of these
symptoms of a liver problem during treatment:
yellowing of your skin or the white
part of your eyesdark or brown (tea color) urinenausea or vomitingloss of appetitepain on the right side of your
stomach
· Eye problems. Tell your healthcare provider right away if
you get any of these symptoms during treatment with Zelboraf:
eye pain, swelling, or rednessblurred vision or other vision
changes
· Worsening side effects from radiation treatment that
can sometimes be severe or lead to death. Tell your healthcare provider if you have had
or are planning to receive radiation therapy.
· Kidney injury. Your healthcare provider should do blood tests to
check your kidney function before you start taking Zelboraf and during
treatment.
· Connective tissue disorders. Tell your healthcare provider if
you develop an unusual thickening of the palms of your hands along with
tightening of the fingers inward or any unusual thickening of the soles of
your feet which may be painful.
The
most common side effects of Zelboraf in melanoma include:
|
|
· joint
pain
· rash (see "Severe skin reactions" above)
· hair
loss
· tiredness
|
· sunburn
or sun sensitivity
· nausea
· itching
· warts
|
|
The most common side effects of Zelboraf
in Erdheim-Chester Disease include:
|
|
· joint
pain
· rash
· warts
· QT
prolongation (see "Changes in the electrical activity of
your heart called QT prolongation" above)
|
· tiredness
· hair
loss
|
|
These are not all the possible side effects of
Zelboraf.
Call your doctor for medical
advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
You may also report side effects
to Genentech at 1-888-835-2555.
|
|
How should I store Zelboraf?
· Store
Zelboraf at room temperature between 68°F to 77°F (20°C to 25°C).
· Store
Zelboraf in the original container with the lid tightly closed.
· Ask
your healthcare provider or pharmacist how to safely throw away (dispose of)
any unused or expired Zelboraf.
Keep
Zelboraf and all medicine out of the reach of children.
|
|
General information about the safe and
effective use of Zelboraf.
Medicines are sometimes
prescribed for purposes other than those listed in a Medication Guide. Do not
use Zelboraf for a condition for which it was not prescribed. Do not give
Zelboraf to other people, even if they have the same symptoms that you have.
It may harm them. You can ask your healthcare provider or pharmacist for
information about Zelboraf that is written for health professionals.
|
|
What are the ingredients in Zelboraf?
Active
ingredient: vemurafenib
Inactive
ingredients:
Tablet Core: hypromellose acetate succinate,
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and
hydroxypropyl cellulose.
Coating: pinkish white: poly (vinyl
alcohol), titanium dioxide, polyethylene glycol 3350, talc, and iron oxide
red.
Distributed by: Genentech USA,
Inc., A Member of the Roche Group,1 DNA Way, South San Francisco, CA
94080-4990
Zelboraf is a registered trademark of Genentech, Inc.
Co-promoted by: Genentech USA, Inc. and Daiichi Sankyo, Inc.
©2017 Genentech, Inc. For more information, go to www.Zelboraf.com or
call 1-877-436-3683.
|
Representative sample of
labeling (see the HOW SUPPLIED section for complete listing):
PRINCIPAL DISPLAY PANEL - 240 mg Tablet Bottle Carton
NDC 50242-090-02
Zelboraf®
(vemurafenib)
tablets
240 mg
Do not
crush or chew tablet.
Rx
only
Attention
Pharmacist: Dispense the
accompanying Medication Guide to
each patient.
112 tablets
Genentech | Daiichi Sankyo, Inc.
10158170
|
Zelboraf vemurafenib tablet, film
coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:50242-090
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Vemurafenib (Vemurafenib)
|
Vemurafenib
|
240 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
Hypromellose acetate succinate 16070722 (3
MM2/S)
|
|
|
Croscarmellose sodium
|
|
|
Hydroxypropyl cellulose (120000 MW)
|
|
|
Polyvinyl alcohol, unspecified
|
|
|
Titanium dioxide
|
|
|
Polyethylene glycol 3350
|
|
|
Talc
|
|
|
Ferric oxide red
|
|
|
|
Product
Characteristics
|
|
Color
|
ORANGE, WHITE
(Pinkish white to orange white)
|
Score
|
no score
|
|
Shape
|
OVAL (biconvex)
|
Size
|
19mm
|
|
Flavor
|
|
Imprint Code
|
VEM
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:50242-090-01
|
1 BOTTLE,
PLASTIC in 1 CARTON
|
|
|
1
|
|
120 TABLET,
FILM COATED in 1 BOTTLE, PLASTIC
|
|
|
2
|
NDC:50242-090-02
|
1 BOTTLE,
PLASTIC in 1 CARTON
|
|
|
2
|
|
112 TABLET,
FILM COATED in 1 BOTTLE, PLASTIC
|
|
|
3
|
NDC:50242-090-86
|
1 BOTTLE,
PLASTIC in 1 CARTON
|
|
|
3
|
|
112 TABLET,
FILM COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA202429
|
08/17/2011
|
|
|
|
Labeler - Genentech, Inc. (080129000)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
F. Hoffmann-La
Roche Ltd.
|
|
482242971
|
API
MANUFACTURE(50242-090), MANUFACTURE(50242-090), ANALYSIS(50242-090)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Roche S.p.A.
|
|
430351356
|
MANUFACTURE(50242-090),
ANALYSIS(50242-090)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Roche Farma SA
|
|
462083082
|
PACK(50242-090),
LABEL(50242-090)
|
Revised:
11/2017
Genentech, Inc.
