Zelboraf™ is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test.
Limitation of Use: Zelboraf is not recommended for use in patients with wild-type BRAF melanoma.
Zelboraf Dosage and Administration
Recommended Dose
The recommended dose of Zelboraf is 960 mg (four 240 mg tablets) twice daily. The first dose should be taken in the morning and the second dose should be taken in the evening approximately 12 hours later. Each dose can be taken with or without a meal.
Zelboraf tablets should be swallowed whole with a glass of water. Zelboraf tablets should not be chewed or crushed.
Duration of treatment
It is recommended that patients are treated with Zelboraf until disease progression or unacceptable toxicity occurs.
Missed doses
If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice daily regimen. Both doses should not be taken at the same time.
Dose Modifications
Management of symptomatic adverse drug reactions or prolongation of QTc may require dose reduction, treatment interruption, or treatment discontinuation of Zelboraf (Table 1). Dose modifications or interruptions are not recommended for cutaneous squamous cell carcinoma (cuSCC) adverse reactions [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Dose reductions resulting in a dose below 480 mg twice daily are not recommended.
Table 1 Dose Modification Information
| Grade (CTC-AE) |
Recommended Zelboraf Dose Modification |
|---|
|
| Grade 1 or Grade 2 (tolerable) |
Maintain Zelboraf at a dose of 960 mg twice daily. |
| Grade 2 (Intolerable) or Grade 3 |
|
| 1st Appearance |
Interrupt treatment until grade 0 – 1. Resume dosing at 720 mg twice daily. |
| 2nd Appearance |
Interrupt treatment until grade 0 – 1. Resume dosing at 480 mg twice daily. |
| 3rd Appearance |
Discontinue permanently |
| Grade 4 |
|
| 1st Appearance |
Discontinue permanently or interrupt Zelboraf treatment until grade 0 – 1.
Resume dosing at 480 mg twice daily. |
| 2nd Appearance |
Discontinue permanently |
Dosage Forms and Strengths
Film-coated tablet: 240 mg
Contraindications
None
Warnings and Precautions
Cutaneous Squamous Cell Carcinoma (cuSCC)
Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with Zelboraf [see Adverse Reactions (6.1)]. The incidence of cuSCC in Zelboraf-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in Zelboraf clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment.
It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of Zelboraf.
Hypersensitivity Reactions
Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with Zelboraf and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, Zelboraf treatment should be permanently discontinued.
Dermatologic Reactions
Severe dermatologic reactions have been reported in patients receiving Zelboraf, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, Zelboraf treatment should be permanently discontinued.
QT Prolongation
Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAFV600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with Zelboraf is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval.
ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with Zelboraf and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with Zelboraf is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), Zelboraf treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of Zelboraf treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values.
Liver Laboratory Abnormalities
Liver laboratory abnormalities have occurred with Zelboraf (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)].
Photosensitivity
Mild to severe photosensitivity was reported in patients treated with Zelboraf in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking Zelboraf. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.
For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)].
Ophthalmologic Reactions
In Trial 1, five cases of uveitis have been reported in patients treated with Zelboraf. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2.
New Primary Malignant Melanoma
There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)].
Use in Pregnancy
Pregnancy Category D
Zelboraf may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
BRAFV600E Testing
Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for Zelboraf therapy because these are the only patients studied and for whom benefit has been shown. For patients in Zelboraf clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAFV600E mutations in DNA isolated from formalin-fixed, paraffin-embedded human melanoma tissue. The safety and efficacy of Zelboraf have not been evaluated in patients whose melanoma tested negative by the cobas® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits, for detailed information.
Adverse Reactions
The following adverse reactions are discussed in greater detail in another section of the label:
- Cutaneous Squamous Cell Carcinoma [see Warnings and Precautions (5.1)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.2)]
- Dermatologic Reactions [see Warnings and Precautions (5.3)]
- QT Prolongation [see Warnings and Precautions (5.4)]
- Liver Laboratory Abnormalities [see Warnings and Precautions (5.5)]
- Photosensitivity [see Warnings and Precautions (5.6)]
- Ophthalmologic Reactions [see Warnings and Precautions (5.7)]
- New Primary Malignant Melanoma [see Warnings and Precautions (5.8)]
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.
The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to Zelboraf 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with Zelboraf 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with Zelboraf are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported 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 2 Adverse Reactions Reported in ≥ 10% of Patients Treated with Zelboraf
|
Trial 1: Treatment Naive Patients |
Trial 2: Patients with Failure of at Least One Prior Systemic Therapy |
|---|
|
Zelboraf
n= 336 |
Dacarbazine
n= 287 |
Zelboraf
n= 132 |
|---|
| ADRs |
All Grades (%) |
Grade 3 (%) |
Grade 4 (%) |
All Grades (%) |
Grade 3 (%) |
Grade 4 (%) |
All Grades (%) |
Grade 3 (%) |
Grade 4 (%) |
|---|
|
| Skin and subcutaneous tissue disorders |
|
|
|
|
|
|
|
|
|
| Rash |
37 |
8 |
- |
2 |
- |
- |
52 |
7 |
- |
| Photosensitivity reaction |
33 |
3 |
- |
4 |
- |
- |
49 |
3 |
- |
| Alopecia |
45 |
<1 |
- |
2 |
- |
- |
36 |
- |
- |
| Pruritus |
23 |
1 |
- |
1 |
- |
- |
30 |
2 |
- |
| Hyperkeratosis |
24 |
1 |
- |
<1 |
- |
- |
28 |
- |
- |
| Rash maculo-papular |
9 |
2 |
- |
<1 |
- |
- |
21 |
6 |
- |
| Actinic keratosis |
8 |
- |
- |
3 |
- |
- |
17 |
- |
- |
| Dry skin |
19 |
- |
- |
1 |
- |
- |
16 |
- |
- |
| Rash papular |
5 |
<1 |
- |
- |
- |
- |
13 |
- |
- |
| Erythema |
14 |
- |
- |
2 |
- |
- |
8 |
- |
- |
| Musculoskeletal and connective tissue disorders |
|
|
|
|
|
|
|
|
|
| Arthralgia |
53 |
4 |
- |
3 |
<1 |
- |
67 |
8 |
- |
| Myalgia |
13 |
<1 |
- |
1 |
- |
- |
24 |
<1 |
- |
| Pain in extremity |
18 |
<1 |
- |
6 |
2 |
- |
9 |
- |
- |
| Musculoskeletal pain |
8 |
- |
- |
4 |
<1 |
- |
11 |
- |
- |
| 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 |
- |
- |
23 |
- |
- |
| Pyrexia |
19 |
<1 |
- |
9 |
<1 |
- |
17 |
2 |
- |
| Asthenia |
11 |
<1 |
- |
9 |
<1 |
- |
2 |
- |
- |
| 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 |
- |
- |
16 |
- |
- |
| Nervous system disorders |
|
|
|
|
|
|
|
|
|
| Headache |
23 |
<1 |
- |
10 |
- |
- |
27 |
- |
- |
| Dysgeusia |
14 |
- |
- |
3 |
- |
- |
11 |
- |
- |
| Neoplasms benign, malignant and unspecified (includes cysts and polyps) |
|
|
|
|
|
|
|
|
|
| Skin papilloma |
21 |
<1 |
- |
- |
- |
- |
30 |
- |
- |
| Cutaneous SCC |
24 |
22 |
- |
<1 |
<1 |
- |
24 |
24 |
- |
| Seborrheic keratosis |
10 |
<1 |
- |
1 |
- |
- |
14 |
- |
- |
| Investigations |
|
|
|
|
|
|
|
|
|
| Gamma-glutamyltransferase increased |
5 |
3 |
<1 |
1 |
- |
- |
15 |
6 |
4 |
| Metabolism and nutrition disorders |
|
|
|
|
|
|
|
|
|
| Decreased appetite |
18 |
- |
- |
8 |
<1 |
- |
21 |
- |
- |
| Respiratory, thoracic and mediastinal disorders |
|
|
|
|
|
|
|
|
|
| Cough |
8 |
- |
- |
7 |
- |
- |
12 |
- |
- |
| Injury, poisoning and procedural complications |
|
|
|
|
|
|
|
|
|
| Sunburn |
10 |
- |
- |
- |
- |
- |
14 |
- |
- |
Clinically relevant adverse events reported in < 10% of patients treated with Zelboraf in the Phase 2 and Phase 3 studies include:
Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome
Musculoskeletal and connective tissue disorders: arthritis
Nervous system disorders: dizziness, neuropathy peripheral, VIIth nerve paralysis
Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma
Infections and infestations: folliculitis
Investigations: weight decreased
Eye disorders: retinal vein occlusion, uveitis
Vascular disorders: vasculitis
Cardiac disorders: atrial fibrillation
Table 3 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 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities
|
Change From Baseline to Grade 3/4 |
|---|
| Parameter |
Zelboraf (%) |
Dacarbazine (%) |
|---|
|
| GGT |
11.5 |
8.6 |
| AST |
0.9 |
0.4 |
| ALT |
2.8 |
1.9 |
| Alkaline phosphatase |
2.9 |
0.4 |
| Bilirubin |
1.9 |
- |
Drug Interactions
Effects of Vemurafenib on Drug Metabolizing Enzymes
Results from an in vivo drug-drug interaction study in patients with cancer demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)].
Coadministration of vemurafenib increased the AUC of caffeine (CYP1A2 substrate) 2.6-fold and increased the AUC of dextromethorphan (CYP2D6 substrate) by 47%, while it decreased the AUC of midazolam (CYP3A4 substrate) by 39% [see Clinical Pharmacology (12.3)]. Concomitant use of Zelboraf with agents with narrow therapeutic windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is not recommended as Zelboraf may alter their concentrations. If coadministration cannot be avoided, exercise caution and consider a dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug.
Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology (12.3)]. Exercise caution and consider additional INR monitoring when Zelboraf is used concomitantly with warfarin.
Drugs that Inhibit or Induce CYP3A4
Based on in vitro data, vemurafenib is a substrate of CYP3A4, and therefore, concomitant administration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) should be used with caution when coadministered with Zelboraf.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [see Warnings and Precautions (5.9)].
Zelboraf may cause fetal harm when administered to a pregnant woman based on its mechanism of action.
Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure 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. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during Zelboraf therapy and for at least 2 months after discontinuation of Zelboraf. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Nursing Mothers
It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Zelboraf in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and efficacy in pediatric patients below the age of 18 have not been established.
Geriatric Use
Ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with Zelboraf in Trial 1 were ≥ 65 years. Elderly patients (≥ 65 years) may be more likely to experience some adverse reactions, including cutaneous squamous cell carcinoma, nausea, decreased appetite, peripheral edema, keratoacanthoma and atrial fibrillation. The effects of Zelboraf on overall survival, progression-free survival and best overall response rate were similar in the elderly as compared to younger patients.
Gender
The Grade 3 adverse events reported more frequently in females than males were rash, arthralgia, photosensitivity and increased creatinine. The Grade 3 adverse events reported more frequently in males than females were keratoacanthoma, increased alkaline phosphatase and increased total bilirubin.
Hepatic Impairment
No adjustment to the starting dose is needed for patients with pre-existing mild and moderate hepatic impairment. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, pre-existing mild and moderate hepatic impairment did not influence the apparent clearance of vemurafenib. Clinical and pharmacokinetic data from only three patients with pre-existing severe hepatic impairment are available from clinical trials, and based on the limited data, the potential need for starting dose adjustment cannot be determined. Zelboraf should be used with caution in patients with pre-existing severe hepatic impairment [see Clinical Pharmacology (12.3)].
Renal Impairment
No adjustment to the starting dose is needed for patients with pre-existing mild and moderate renal impairment. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, pre-existing mild and moderate renal impairment did not influence the apparent clearance of vemurafenib. Clinical and pharmacokinetic data from one patient with pre-existing severe renal impairment are available from clinical trials, and based on the limited data, the potential need for starting dose adjustment cannot be determined. Zelboraf should be used with caution in patients with pre-existing severe renal impairment [see Clinical Pharmacology (12.3)].
Drug Abuse and Dependence
No studies on the potential for Zelboraf to cause dependence have been performed. However, there is no evidence from the available data that Zelboraf treatment can result in dependence.
Overdosage
There is no specific antidote for overdosage of Zelboraf. Patients who develop adverse reactions should receive appropriate symptomatic treatment. In case of suspected overdose, Zelboraf should be withheld and supportive care instituted.
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 Pharmacology
Mechanism of Action
Vemurafenib is a low molecular weight, orally available, inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E. 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 BRAFV600E.
Pharmacokinetics
The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of dosing at 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. A one-compartment disposition model with first-order absorption and first-order elimination adequately describes the vemurafenib concentration-time profile. 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. Following oral administration of vemurafenib at 960 mg twice daily for 15 days to patients with metastatic melanoma, the median Tmax was approximately 3 hours.
Following 15 days of dosing at 960 mg twice daily, the mean (± SD) Cmax and AUC0-12 were 62 µg/mL ± 17 and 601 ± 170 µg*h/mL, respectively. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice daily regimen is 7.36, with steady state achieved at approximately 15 to 22 days following dosing at 960 mg twice daily. At steady state, the mean vemurafenib exposure in plasma is stable (concentrations before and 2-4 hours after the morning dose) as indicated by the mean ratio of 1.13.
The potential effect of food on vemurafenib absorption has not been studied. In clinical trials, vemurafenib was administered without regard to food.
Distribution
Vemurafenib is highly bound (> 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The population apparent volume of distribution for vemurafenib in metastatic melanoma patients is estimated to be 106 L (with 66% inter-patient variability).
Metabolism
Following oral administration of 14C-vemurafenib 960 mg in the tablet formulation, plasma samples were analyzed over 48 hours for vemurafenib and its metabolites. Mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma, respectively.
Elimination
Following oral administration of 14C-vemurafenib 960 mg in the tablet formulation, approximately 94% of the radioactive dose was recovered in feces and approximately 1% was recovered in the urine. The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimated to be 31 L/day (with 32% inter-patient variability). The median of the individual elimination half-life estimates for vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours).
Pharmacokinetics in Special 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 pre-existing 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 pre-existing mild and moderate hepatic impairment was similar to that in patients with normal hepatic function. The potential need for dose adjustment in patients with severe hepatic impairment cannot be determined as clinical and pharmacokinetic data were available for only three patients [see Use in Specific Populations (8.7)].
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 pre-existing 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 vemurafeni
