VEMURAFENIB Drug Interactions: What You Need to Know

INTERACTIONS Avoid concomitant administration of ZELBORAF with strong CYP3A4 inhibitors or inducers. ( 7.1 ) CYP1A2 Substrates: ZELBORAF can increase concentrations of CYP1A2 substrates. Avoid concomitant use of ZELBORAF with CYP1A2 substrates with a narrow therapeutic window. If coadministration cannot be avoided, monitor closely for toxicities and consider dose reduction of CYP1A2 substrates. ( 7.2 ).

7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib Strong CYP3A4 Inhibitors Coadministration of a strong CYP3A4 inhibitor increased vemurafenib plasma concentrations and may lead to increased toxicity. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors. If coadministration of a strong CYP3A4 inhibitor is unavoidable, consider dose reduction of ZELBORAF, if clinically indicated. <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) , Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ]</span> .

7.2 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

7.3 Concurrent Ipilimumab Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent ipilimumab and ZELBORAF <span class="opacity-50 text-xs">[see Warnings and Precautions Section 5.6 ]</span>.

7.4 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.

None. None

AND PRECAUTIONS New Primary Cutaneous Malignancies: Perform dermatologic evaluations prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation of ZELBORAF. Manage with excision and continue treatment without dose adjustment. ( 5.1 )

New

Non-Cutaneous Squamous Cell Carcinoma: Evaluate for symptoms or clinical signs of new non-cutaneous SCC before initiation of treatment and periodically during treatment. ( 5.1 )

Other

Malignancies: Monitor patients receiving ZELBORAF closely for signs or symptoms of other malignancies ( 5.1 ).

Tumor

Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors ( 5.2 ).

Serious Hypersensitivity

Reactions including anaphylaxis and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome): Discontinue ZELBORAF for severe hypersensitivity reactions. ( 5.3 )

Severe Dermatologic

Reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Discontinue ZELBORAF for severe dermatologic reactions. ( 5.4 ) QT Prolongation: Monitor ECG and electrolytes before and during treatment. Withhold ZELBORAF for QTc of 500 ms or greater. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. ( 5.5 ) Hepatotoxicity: Measure liver enzymes and bilirubin before initiating ZELBORAF and monitor monthly during treatment. ( 5.6 ) Photosensitivity: Advise patients to avoid sun exposure. ( 5.7 )

Serious Ophthalmologic

Reactions: Monitor for signs and symptoms of uveitis. ( 5.8 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of the potential risk to the fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 )

Radiation

Sensitization and Radiation Recall: Severe cases have been reported. ( 5.10 ).

Renal

Failure: Measure serum creatinine before initiating ZELBORAF and monitor periodically during treatment ( 5.11 ). Dupuytren's Contracture and plantar fascial fibromatosis: Events should be managed with dose reduction, treatment interruption, or treatment discontinuation. ( 5.12 ).

5.1 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 &lt; 1% in the dacarbazine arm <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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.

5.2 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 <span class="opacity-50 text-xs">[see Indications and Usage (1) and Dosage and Administration (2.1) ]</span> .

5.3 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

5.4 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>.

5.5 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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 &gt; 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 &gt; 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 &gt; 500 ms and increased &gt; 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias) <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.6 Hepatotoxicity Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with ZELBORAF <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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) ].

5.7 Photosensitivity Mild to severe photosensitivity can occur in patients treated with ZELBORAF <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> .

5.8 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.

5.9 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ]</span> .

5.10 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. <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Monitor patients closely when vemurafenib is administered concomitantly or sequentially with radiation treatment.

5.11 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&apos;s Contracture and Plantar Fascial Fibromatosis Dupuytren&apos;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&apos;s contracture have also been reported <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) , Adverse Reactions (6.1 , 6.2) ]</span>.