Zelboraf

Take the missed dose as soon as you remember it. However, if it is within 4 hours of your next scheduled dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Contraindications

None

Cautions

Cutaneous squamous cell carcinomas (cuSCC) occurred in 24% of patients; perform dermatologic evaluations prior to treatment initiation and q2Months while on therapy; manage with excision and continue treatment without dose adjustment

Anaphylaxis and other serious hypersensitivity reactions reported during treatment and upon reinitiation, including generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); permanently discontinue

Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis reported; discontinue treatment

Elevated liver enzymes may occur; monitor liver enzymes and bilirubin before treatment initiation and then monthly or as clinically indicated

Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with vemurafenib

Mild-to-moderate photosensitivity reported; advise patients to avoid sun exposure and wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF >30) when outdoors

Serious ophthalmologic reactions, including uveitis, iritis, blurry vision, photophobia, and retinal vein occlusion reported

New primary malignant melanomas reported; manage with excision, and continue treatment without dose modification

Avoid in pregnancy; based on mechanism of action, therapy can cause fetal harm when administered to pregnant woman; advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose

Severe cases of radiation sensitization and recall reported

Renal failure, including acute interstitial nephritis and acute tubular necrosis reported

Dupuytren’s contracture and plantar fascial fibromatosis reported; majority of cases, mild to moderate, but severe disabling cases of Dupuytren’s contracture also reported

BRAF mutation test required to confirm eligibility for treatment; has not been studied with wild-type BRAF melanoma

QT prolongation

• QT prolongation reported
• Monitor ECG and electrolytes before treatment initiation and after dose modification
• Monitor ECGs at day 15, monthly during the first 3 months of treatment, and then q3Months thereafter, or more often as clinically indicated
• If the QTc exceeds 500 ms, temporarily interrupt treatment, correct electrolyte abnormalities, and control for cardiac risk factors for QT prolongation (see Dosage Modifications)
• Permanently discontinue if QTc interval remains >500 ms and increased >60 ms from pretreatment values after controlling cardiac risk factors for QT prolongation (eg, electrolyte abnormalities, congestive heart failure, and bradyarrhythmias)

Mechanism of Action

Inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF-V600E

Also inhibits other kinases in vitro (eg, CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, 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

Absorption

Bioavailability: Not determined

Peak Plasma Time: 3 hr

Peak Plasma Concentration: 62 mcg/mL

AUC: 610 mcg•h/mL

Distribution

Protein Bound: >99% to human albumin and alpha-1 acid glycoprotein plasma proteins

Vd: 106 L (66% inter-patient variability

Metabolism

Mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma, respectively

Metabolized by CYP3A4

Moderate CYP1A2 inhibitor, weak CYP2D6 inhibitor, and a CYP3A4 inducer

Substrate and an inhibitor of the efflux transporter P-glycoprotein

Elimination

Half-life: 57 hr (range 30-120 hr)

Total body clearance: 31 L/day (32% inter-patient variability)

Excretion: Feces (94%), urine (1%)

Pharmacogenomics

Vemurafenib is indicated only for patients with melanoma who have the V600E mutation of the BRAF gene (50% of patients with melanoma have this type of BRAF mutation, which does not occur in normal cells)

Genetic test

• Vemurafenib approved with companion diagnostic test known as the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems)

• Cotellic
• Opdivo

• Proleukin

© Zelboraf Patient Information is supplied by Cerner Multum, Inc. and Zelboraf Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially, tell your healthcare provider if you take:

• the blood thinner warfarin sodium (Coumadin, Jantoven)
• antifungal medicines, such as ketoconazole (Nizoral), itraconazole (Sporanox, Onmel), or voriconazole (Vfend)
• certain antibiotic medicines, such as telithromycin (Ketek), clarithromycin (Biaxin, Biaxin XL), rifampin (Rifater, Rifimate, Rimactane, Rifadin), rifabutin (Mycobutin), rifapentine (Prifin)
• HIV medicines, such as atazanavir sulfate (Reyataz), saquinavir mesylate (Invirase), ritonavir (Kaletra), indinavir sulfate (Crixivan), nelfinavir mesylate (Viracept)
• seizure medicines, such as phenytoin (Dilantin-125, Dilantin, phenobarbital (Solfoton), or carbamazepine (Carbitrol, Equetro, Tegretol, Tegretol-XR, Teril, Epitol)
• the anti-depressant medicine, nafazodone hydrochloride
• medicines to treat irregular heart beat
• ipilimumab (Yervoy)

Know the medicines you take. Keep a list to show your healthcare provider and pharmacist when you get a new medicine.

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of vemurafenib is restricted.1 (See General under Dosage and Administration.)

Vemurafenib is used to treat melanoma (a type of skin cancer) that has spread or that cannot be removed by surgery. It is only used if the melanoma cells have the BRAF V600E mutation. Your doctor will use a special test to look for this mutation. Vemurafenib belongs to the group of medicines called antineoplastics (cancer medicines).

This medicine is available only with your doctor's prescription.

• If you have an allergy to vemurafenib or any other part of Zelboraf (vemurafenib).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Low calcium levels, low magnesium levels, or low potassium levels.
• If you have a long QT on ECG.
• If you are taking any drugs that can cause a certain type of heartbeat that is not normal (prolonged QT interval). There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you take any drugs (prescription or OTC, natural products, vitamins) that must not be taken with this medicine, like certain drugs that are used for HIV, infections, or seizures. There are many drugs that must not be taken with Zelboraf.
• If you are breast-feeding. Do not breast-feed while you take this medicine and for 2 weeks after your last dose.

This is not a list of all drugs or health problems that interact with Zelboraf.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Hair loss.
• Muscle or joint pain.
• Back pain.
• Itching.
• Headache.
• Upset stomach or throwing up.
• Loose stools (diarrhea).
• Hard stools (constipation).
• Change in taste.
• Feeling tired or weak.
• Not hungry.
• Cough.
• Dry skin.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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 1, 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.

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. Twenty-six percent 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).

Measure serum creatinine before initiation of Zelboraf and periodically during treatment.

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 Dose Modifications (2.3), Postmarketing Experience (6.2)].

There is no information on overdosage of Zelboraf.

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.