Vemurafenib

Vemurafenib moderately inhibited CYP2C8 in vitro. The in vivo relevance of this finding is unknown, but a risk for a clinically relevant effect on concomitantly administered CYP2C8 substrates cannot be excluded. Concomitant administration of CYP2C8 substrates with a narrow therapeutic window should be made with caution since vemurafenib may increase their concentrations.

In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

The effects of vemurafenib on medicinal products that are substrates of BCRP are unknown. It cannot be excluded that vemurafenib may increase the exposure of medicines transported by BCRP (e.g. methotrexate, mitoxantrone, rosuvastatin). Many anticancer medicinal products are substrates of BCRP and therefore there is a theoretical risk for an interaction with vemurafenib.

Treatment with vemurafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT interval.

Electrocardiogram (ECG) and electrolytes (including magnesium) must be monitored in all patients before treatment with vemurafenib, after one month of treatment and after dose modification. Further monitoring is recommended in particular in patients with moderate to severe hepatic impairment monthly during the first 3 months of treatment followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with vemurafenib is not recommended in patients with QTc>500 milliseconds (ms). If during treatment the QTc exceeds 500 ms, vemurafenib treatment should be temporarily interrupted, electrolyte abnormalities (including magnesium) 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 once the QTc decreases below 500 ms and at a lower dose as described in table below. Permanent discontinuation of vemurafenib treatment is recommended if the QTc increase meets values of both >500 ms and >60 ms change from pre-treatment values.

Exposure-dependent QT prolongation was observed in an uncontrolled, open-label phase II study in previously treated patients with metastatic melanoma. Management of QTc prolongation may require specific monitoring measures.

Dose modification schedule based on prolongation of the QT interval:

Results from an in vivo drug-drug interaction study in metastatic melanoma patients demonstrated that vemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer.

Concomitant use of vemurafenib with agents metabolized by CYP1A2 with narrow therapeutic windows (e.g. agomelatine, alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, theophylline) is not recommended. If co-administration cannot be avoided, exercise caution, as vemurafenib may increase plasma exposure of CYP1A2 substrate drugs. Dose reduction of the concomitant CYP1A2 substrate drug may be considered, if clinically indicated. Co-administration of vemurafenib increased the plasma exposure (AUC) of caffeine (CYP1A2 substrate) 2.6-fold. In another clinical trial, vemurafenib increased C_max and AUC of a single 2 mg dose of tizanidine (CYP1A2 substrate) approximately 2.2-fold and 4.7-fold, respectively.

In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

A clinical drug interaction study demonstrated that multiple oral doses of vemurafenib (960 mg twice daily) increased the exposure of a single oral dose of the P-gp substrate digoxin, approximately 1.8 and 1.5 fold for digoxin AUC_last and C_max, respectively.

Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates (e.g. aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, sirolimus, sitagliptin, talinolol, topotecan) and dose reduction of the concomitant medicinal product may be considered, if clinically indicated. Consider additional drug level monitoring for P-gp substrate medicinal products with a narrow therapeutic index (NTI) (e.g. digoxin, dabigatran etexilate, aliskiren).

Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate). Exercise caution and consider additional INR (international normalized ratio) monitoring when vemurafenib is used concomitantly with warfarin.

Results from an in vivo drug-drug interaction study in metastatic melanoma patients demonstrated that vemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer.

Concomitant use of vemurafenib with agents metabolized by CYP3A4 with narrow therapeutic windows is not recommended. If co-administration cannot be avoided, it needs to be considered that vemurafenib may decrease plasma concentrations of CYP3A4 substrates and thereby their efficacy may be impaired. On this basis, the efficacy of contraceptive pills metabolized by CYP3A4 used concomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates with narrow therapeutic window may be considered, if clinically indicated. In a clinical trial, co-administration of vemurafenib decreased the AUC of midazolam (CYP3A4 substrate) by an average 39% (maximum decrease up to 80%).

Mild induction of CYP2B6 by vemurafenib was noted in vitro at a vemurafenib concentration of 10 μM. It is currently unknown whether vemurafenib at a plasma level of 100 μM observed in patients at steady state (approximately 50 μg/ml) may decrease plasma concentrations of concomitantly administered CYP2B6 substrates, such as bupropion.

In vitro studies suggest that CYP3A4 metabolism and glucuronidation are responsible for the metabolism of vemurafenib. Biliary excretion appears to be another important elimination pathway. In vitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters P-gp and BCRP. It is currently unknown whether vemurafenib is a substrate also to other transport proteins. Concomitant administration of strong CYP3A4 inhibitors or inducers or inhibitors/inducer of transport protein activity may alter vemurafenib concentrations.

Co-administration of itraconazole, a strong CYP3A4/P-gp inhibitor, increased steady state vemurafenib AUC by approximately 40%. Vemurafenib should be used with caution in combination with strong inhibitors of CYP3A4, glucuronidation and/or transport proteins (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir). Patients co-treated with such agents should be carefully monitored for safety and dose modifications applied if clinically indicated.

In a clinical study, co-administration of a single dose 960 mg of vemurafenib with rifampicin, significantly decreased the plasma exposure of vemurafenib by approximately 40%. Concomitant administration of strong inducers of P-gp, glucuronidation, and/or CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [Hypericum perforatum]) may lead to suboptimal exposure to vemurafenib and should be avoided.

The effects of P-gp and BCRP inhibitors that are not also strong CYP3A4 inhibitors are unknown. It cannot be excluded that vemurafenib pharmacokinetics could be affected by such medicines through influence on P-gp (e.g. verapamil, cyclosporine, quinidine) or BCRP (e.g. cyclosporine, gefitinib).

No adjustment to the starting dose is needed for patients with mild or moderate renal impairment. There are only limited data available in patients with severe renal impairment. Vemurafenib should be used with caution in patients with severe renal impairment and patients should be closely monitored.

No adjustment to the starting dose is needed for patients with hepatic impairment. Patients with mild hepatic impairment due to liver metastases without hyperbilirubinaemia may be monitored according to the general recommendations. There are only very limited data available in patients with moderate to severe hepatic impairment. Patients with moderate to severe hepatic impairment may have increased exposure. Thus close monitoring is warranted especially after the first few weeks of treatment as accumulation may occur over an extended period of time (several weeks). In addition ECG monitoring every month during the first three months is recommended.

In a Phase I trial, asymptomatic grade 3 increases in transaminases (ALT/AST >5 x ULN) and bilirubin (total bilirubin >3x ULN) were reported with concurrent administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). Based on these preliminary data, the concurrent administration of ipilimumab and vemurafenib is not recommended.

Cases of radiation recall and radiation sensitization have been reported in patients treated with radiation either prior, during, or subsequent to vemurafenib treatment. Inthe majority of cases, patients received radiotherapy regimens greater than or equal to 2 Gy/day (hypofractionated regimens). Most cases were cutaneous in nature but some cases involving visceral organs had fatal outcomes. Vemurafenib should be used with caution when given concomitantly or sequentially with radiation treatment.

There are no data regarding the use of vemurafenib in pregnant women. Vemurafenib revealed no evidence of teratogenicity in rat or rabbit embryo/foetuses. In animal studies, vemurafenib was found to cross the placenta. Based on its mechanism of action, vemurafenib could cause fetal harm when administered to a pregnant woman. Vemurafenib should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus.

It is not known whether vemurafenib is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue vemurafenib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential / Contraception in females

Women of childbearing potential have to use effective contraception during treatment and for at least 6 months after treatment. Vemurafenib might decrease the efficacy of hormonal contraceptives.

Fertility

No specific studies with vemurafenib have been conducted in animals to evaluate the effect on fertility. However, in repeat-dose toxicity studies in rats and dogs, no histopathological findings were noted in reproductive organs in males and females.

Vemurafenib has minor influence on the ability to drive and use machines. Patients should be made aware of the potential fatigue or eye problems that could be a reason for not driving.

Summary of the safety profile

The most common adverse drug reactions (ADR) of any grade (> 30%) reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, alopecia, nausea diarrhea, headache, pruritus, vomiting, skin papilloma and hyperkeratosis. The most common (≥5%) Grade 3 ADRs were cuSCC, keratoacanthoma, rash, arthralgia and gamma-glutamyltransferase (GGT) increased. CuSCC was most commonly treated by local excision.

Summary of adverse reactions

ADRs which were reported in melanoma patients are listed below by MedDRA body system organ class, frequency and grade of severity. The following convention has been used for the classification of frequency: Very common ≥1/10, Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1,000, Very rare <1/10,000.

ADRs are based on results in 468 patients from a phase III randomised open label study in adult patients with BRAF V600 mutation-positive unresectable or stage IV melanoma, as well as a phase II single-arm study in patients with BRAF V600 mutation-positive stage IV melanoma who had previously failed at least one prior systemic therapy. In addition ADRs originating from safety reports across all clinical trials and post-marketing sources are reported. All terms included are based on the highest percentage observed among phase II and phase III clinical trials. Within each frequency grouping, ADRs are presented in order of decreasing severity and were reported using NCI-CTCAE v 4.0 (common toxicity criteria) for assessment of toxicity.

ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events originating from safety reports across all trials¹ and post-marketing sources²:

Infections and infestations

Common: Folliculitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Very Common: SCC of the skin^d, keratoacanthoma, seborrhoeic keratosis, skin papilloma

Common: Basal cell carcinoma, new primary melanoma³

Uncommon: Non-cuSCC¹,3^

Rare: Chronic myelomonocytic leukaemia^2,4, pancreatic adenocarcinoma⁵

Blood and lymphatic system disorders

Common: Neutropenia

Immune System Disorders

Rare: Sarcoidosis^1,2,j

Metabolism and nutrition disorders

Very Common: Decreased appetite

Nervous system disorders

Very Common: Headache, dysgeusia, dizziness

Common: 7^th nerve paralysis, neuropathy peripheral

Eye disorders

Common: Uveitis

Uncommon: Retinal vein occlusion, iridocyclitis

Vascular disorders

Common: Vasculitis

Respiratory, thoracic and mediastinal disorders

Very Common: Cough

Gastrointestinal disorders

Very Common: Diarrhoea, vomiting, nausea, constipation

Uncommon: Pancreatitis²

Hepatobiliary disorders

Uncommon: Liver injury^1,2,g

Skin and subcutaneous tissue disorders

Very Common: Photosensitivity reaction, actinic keratosis, rash, rash maculo-papular, pruritus, hyperkeratosis, erythema, palmarplantar erythrodysaesthesia syndrome, alopecia, dry skin, sunburn

Common: Rash papular, panniculitis (including erythema nodosum), keratosis pilaris

Uncommon: Toxic epidermal necrolysis^e, StevensJohnson syndrome^f

Rare: Drug reaction with eosinophilia and systemic symptoms^1,2

Musculoskeletal and connective tissue disorders

Very Common: Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain

Common: Arthritis

Uncommon: Plantar fascial fibromatosis^1,2, Dupuytren’s contracture^1,2

Renal and urinary disorders

Rare: Acute interstitial nephritis^1,2,h, acute tubular necrosis^1,2,h

General disorders and administration site conditions

Very Common: Fatigue, pyrexia, oedema peripheral, asthenia

Investigations

Common: ALT increased^c, alkaline phosphatase increased^c, AST increased^c, bilirubin increased^c GGT increased^c, weight decreased, electrocardiogram QT prolonged, blood creatinine increased^1,2,h

Injury, Poisoning, and Procedural Complications

Common: Potentiation of Radiation toxicity^1,2,i

¹ Events originating from safety reports across all trials.
² Events originating from post-marketing sources.
³ A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.
⁴ Progression of pre-existing chronic myelomonocytic leukaemia with NRAS mutation.
⁵ Progression of pre-existing pancreatic adenocarcinoma with KRAS mutation.

Description of selected adverse reactions

Hepatic enzyme increase^c

Liver enzyme abnormalities reported in the phase III clinical study are expressed below as the proportion of patients who experienced a shift from baseline to a grade 3 or 4 liver enzyme abnormalities:

• Very common: GGT.
• Common: ALT, alkaline phosphatase, bilirubin.
• Uncommon: AST.

There were no increases to Grade 4 ALT, alkaline phosphatase or bilirubin.

Liver injury^g

Based on the criteria for drug induced liver injury developed by an international expert working group of clinicians and scientists, liver injury was defined as any one of the following laboratory abnormalities:

• ≥5x ULN ALT.
• ≥2x ULN ALP (without other cause for ALP elevation).
• ≥3x ULN ALT with simultaneous elevation of bilirubin concentration >2x ULN.

Cutaneous squamous cell carcinoma^d (cuSCC)

Cases of cuSCC have been reported in patients treated with vemurafenib. The incidence of cuSCC in vemurafenib-treated patients across studies was approximately 20%. The majority of the excised lesions reviewed by an independent central dermatopathology laboratory were classified as SCC-keratoacanthoma subtype or with mixed-keratoacanthoma features (52%). Most lesions classified as “other” (43%) were benign skin lesions (e.g. verruca vulgaris, actinic keratosis, benign keratosis, cyst/benign cyst). 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. Cases of cuSCC were typically managed with simple excision, and patients generally continued on treatment without dose modification.

Non-cutaneous squamous cell carcinoma (non-cuSCC)

Cases of non-cuSCC have been reported in patients receiving vemurafenib while enrolled in clinical trials.

New primary melanoma

New primary melanomas have been reported in clinical trials. These cases were managed with excision, and patients continued treatment without dose adjustment.

Potentiation of radiation toxicityⁱ

Cases reported include recall phenomenon, radiation skin injury, radiation pneumonitis, radiation esophagitis, radiation proctitis, radiation hepatitis, cystitis radiation, and radiation necrosis.

In a phase III clinical trial (MO25515, N=3219), a higher incidence of potentiation of radiation toxicity was reported when vemurafenib patients received radiation prior to and during vemurafenib therapy (9.1%) compared to those patients who received radiation and vemurafenib concomitantly (5.2%) or to those whose radiation treatment was prior to vemurafenib (1.5%).

Hypersensitivity reactions^e

Serious hypersensitivity reactions, including anaphylaxis have been reported in association with vemurafenib. Severe hypersensitivity reactions may include Stevens-Johnson syndrome, generalised rash, erythema or hypotension. In patients who experience severe hypersensitivity reactions, vemurafenib treatment should be permanently discontinued.

Dermatologic reactions^f

Severe dermatologic reactions have been reported in patients receiving vemurafenib, including rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis in the pivotal clinical trial. In patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently discontinued.

QT prolongation

Analysis of centralised ECG data from an open-label uncontrolled phase II QT sub-study in 132 patients dosed with vemurafenib 960 mg twice daily (NP22657) showed an exposure-dependent QTc prolongation. The mean QTc effect remained stable between 12-15 ms beyond the first month of treatment, with the largest mean QTc prolongation (15.1 ms; upper 95% CI: 17.7 ms) observed within the first 6 months (n=90 patients). Two patients (1.5%) developed treatment-emergent absolute QTc values >500 ms (CTC Grade 3), and only one patient (0.8%) exhibited a QTc change from baseline of >60 ms.

Acute kidney injury^h

Cases of renal toxicity have been reported with vemurafenib ranging from creatinine elevations to acute interstitial nephritis and acute tubular necrosis, some observed in the setting of dehydration events. Serum creatinine elevations were mostly mild (>1-1.5x ULN) to moderate (>1.5-3x ULN) and observed to be reversible in nature (see table 1).

Table 1. Creatinine changes from baseline in the phase III study:

Table 2. Acute kidney injury cases in the phase III study:

All percentages are expressed as cases out of total patients exposed to each medicinal product.
* Includes acute kidney injury, renal impairment, and laboratory changes consistent with acute kidney injury.

Sarcoidosis^j

Cases of sarcoidosis have been reported in patients treated with vemurafenib, mostly involving the skin, lung and eye. In majority of the cases, vemurafenib was maintained and the event of sarcoidosis either resolved or persisted.

Special populations

Elderly

In the phase III study, ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with vemurafenib were ≥65 years. Older patients (≥65 years) may be more likely to experience adverse reactions, including cuSCC, decreased appetite, and cardiac disorders.

Gender

During clinical trials with vemurafenib, grade 3 adverse reactions reported more frequently in females than males were rash, arthralgia and photosensitivity.

Paediatric population

The safety of vemurafenib in children and adolescents has not been established. No new safety signals were observed in a clinical study with six adolescent patients.