Zelboraf 240mg Film-coated Tablets
*Company:
Roche Registration GmbHStatus:
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*Additional information is available within the SPC or upon request to the company

Updated on 20 March 2024
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Zelboraf IA-IG-1730_PIL.pdf
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- Change to section 4 - possible side effects
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EMEA/H/C/xxxx/IG/1730. Implementation of PRAC recommendation (EPITT Np. 19961) - "Stomatitis" added to section 4.8 Undesirable effects and IIIB Leaflet Section 4.
Updated on 20 March 2024
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- Change to Section 4.8 – Undesirable effects - how to report a side effect
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EMEA/H/C/xxxx/IG/1730. Implementation of PRAC recommendation (EPITT Np. 19961) - "Stomatitis" added to section 4.8 Undesirable effects and IIIB Leaflet Section 4.
Updated on 20 March 2024
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EMEA/H/C/xxxx/IG/1730. Implementation of PRAC recommendation (EPITT Np. 19961) - "Stomatitis" added to Leaflet Section 4.
Updated on 28 June 2023
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PIL Zelboraf PSUSA 202208_26Jun2023.pdf
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- Change to section 4 - possible side effects
- Change to section 6 - date of revision
- Change to date of revision
Updated on 28 June 2023
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PIL Zelboraf PSUSA 202208_26Jun2023.pdf
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- Change to section 4 - possible side effects
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- Change to date of revision
Updated on 28 June 2023
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SmPC Zelboraf PSUSA 202208_26Jun2023.pdf
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- Change to section 4.8 - Undesirable effects
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Updated on 07 February 2023
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SmPC clean Zelboraf_10-Aug-2021.pdf
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- Document format updated
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Updated on 11 November 2021
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PIL Zelboraf 04-Nov-2021 Clean.pdf
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- Change to section 6 - date of revision
Updated on 13 August 2021
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PIL clean Zelboraf_10-Aug-2021.pdf
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- Change to section 4 - how to report a side effect
- Change to section 6 - marketing authorisation number
Updated on 13 August 2021
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- Change to Section 4.8 – Undesirable effects - how to report a side effect
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Updated on 17 February 2021
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Zelboraf_SmPC_11 Feb 2021 Clean.pdf
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- Change to section 5 - Pharmacological properties
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Updated on 18 December 2019
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PIL_Zelboraf II-54 - clean.pdf
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- Change to section 2 - interactions with other medicines, food or drink
- Change to section 2 - driving and using machines
Updated on 18 December 2019
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SmPC_Zelboraf II-54 - clean.pdf
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- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 10 - Date of revision of the text
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Updated on 20 August 2018
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uk-ie-mt-pil-zelboraf-clean-180814-240mg-tabs.pdf
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- Change to section 4 - possible side effects
- Change to section 6 - date of revision
Updated on 20 August 2018
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uk-ie-mt-spc-zelboraf-clean-180814-240mg-tabs.pdf
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- Change to section 4.8 - Undesirable effects
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Updated on 14 August 2018
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- Change to other sources of information section
Updated on 29 June 2018
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uk-ie-mt-spc-zelboraf-clean-180517-240mg-tab.docx
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- Change to section 5.2 - Pharmacokinetic properties
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Submission of 2 CSRs for study GO27826 and GO28053 to fulfill 2 PACs. CSR of study GO28053 triggers a label update to section 5.2 of the SmPC.
Updated on 06 June 2018
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- Change to section 4.8 - Undesirable effects
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Updated on 30 April 2018
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MAH Licence transfer from RRL (UK) to RRG (GER).
Updated on 13 April 2018
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uk-ie-mt-pil-zelboraf-clean-180406-240mg-tabs.pdf
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- Change to section 6 - marketing authorisation holder
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Updated on 26 February 2018
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- New SPC for new product
Legal category:Product subject to medical prescription which may not be renewed (A)
Updated on 26 February 2018
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.6 - Pregnancy and lactation
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
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4.4 Special warnings and precautions for use
[…]
Effects of vemurafenib on other medicinal products
Vemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer. Vemurafenib may increase the plasma exposure of medicinal products predominantly metabolised by CYP1A2 and decrease the plasma exposure of medicines predominantly metabolised by CYP3A4, including oral contraceptives. Concomitant use of vemurafenib with agents metabolized by CYP1A2 and CYP3A4 with narrow therapeutic windows is not recommended. Dose adjustments for medicinal products predominantly metabolised via CYP1A2 or CYP3A4 should be considered based on their therapeutic windows before concomitantly treating with vemurafenib (see sections 4.5 and 4.6).
Exercise caution and consider additional INR (International Normalised Ratio) monitoring when vemurafenib is used concomitantly with warfarin.
Vemurafenib is an inhibitor of the efflux transporters P-glycoprotein (P-gp). Vemurafenib may increase the plasma exposure of medicinal products that are P-gp substrates. Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates., dDose reduction and/or additional drug level monitoring for P-gp substrate medicinal products with narrow therapeutic index (NTI) (e.g. digoxin, dabigatran etexilate, aliskiren) may be considered if these medicinal products are used concomitantly with vemurafenib (see section 4.5).
Effect of other medicinal products on vemurafenib
Vemurafenib pharmacokinetics could be affected by medicines that inhibit or influence P-gp (e.g. verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine) (see section 4.5).
Concomitant administration of strong inducers of CYP3A4, P-gp and glucuronidation (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericin]) might lead to decreased exposure of vemurafenib and should be avoided when possible (see section 4.5). Alternative treatment with less inducing potential should be considered to maintain the efficacy of vemurafenib.
As vemurafenib is a substrate of CYP3A4, the Cconcomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir) or inducers of P-gp, glucuronidation, CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericin]) may alter vemurafenib concentrations. Potent CYP3A4 inhibitors and inducers should be used with caution when co-administered with vemurafenib should be avoided when possible (see section 4.5). Alternative treatment with less inhibiting/inducing potential should be considered to maintain the efficacy of vemurafenib.
[…]
4.5 Interaction with other medicinal products and other forms of interaction
Effects of vemurafenib on Drug Metabolizing EnzymesCYP substrates
Results from an in vivo drug-drug interaction study in metastatic melanoma patients demonstrated that Vvemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer.
Concomitant use of vemurafenib with agents metabolized by CYP1A2 (e.g. agomelatine, alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, theophylline) and CYP3A4 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 and decrease plasma exposure of CYP3A4 substrate drugs. Dose reduction of the concomitant CYP1A2 substrate drug may be considered, if clinically indicated.
Co-administration of vemurafenib increased the plasma exposure (AUCAUC) of caffeine (CYP1A2 substrate) 2.6-fold, while it decreased the AUC of midazolam (CYP3A4 substrate) by 39% in a clinical trial. In another clinical trial, vemurafenib Repeated doses of 960 mg BID vemurafenib increased Cmax and AUCinf of a single 2 mg dose of tizanidine (a CYP1A2 sensitive substrate) approximately 2.2-fold (geometric mean ratio, range 0.7-4.9-fold) and 4.7-fold (geometric mean ratio, range 0.9-16-fold), respectively. In another clinical trial when a single dose of caffeine was co-administered after repeat dosing
with vemurafenib for 15 days, an average 2.6-fold (maximum up to 10-fold) increase in caffeine plasma exposure after vemurafenib treatment was observed. Vemurafenib may thus
increase the plasma exposure of substances predominantly metabolised by CYP1A2 (e.g. agomelatine, alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, theophylline) and dose adjustments may be considered, if clinically indicated.
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 (see sections 4.4 and 4.6).
In a clinical trial, co-administration of vemurafenib decreased the AUC of midazolam (CYP3A4 substrate) by an on average 39% (maximum decrease up to 80%). CYP3A4 induction was observed in a clinical trial when a single dose of midazolam was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 39% decrease (maximum up to 80%) in midazolam plasma exposure after vemurafenib treatment. Vemurafenib may decrease the plasma exposure of substances predominantly metabolised by CYP3A4. On this basis, the efficacy of contraceptive pills metabolised by CYP3A4 used concomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates with narrow therapeutic window may be considered, if clinically indicated (see sections 4.4 and 4.6).
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.
When a single dose of warfarin was co-administered after repeat dosing with vemurafenib for 15 days, some patients exhibited increased warfarin exposure (mean 18%) (see section 4.4). Caution should be exercised when vemurafenib is co-administered with warfarin (CYP2C9) in patients with melanoma. Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) (see section 4.4). Exercise caution and consider additional INR (international normalized ratio) monitoring when vemurafenib is used concomitantly with warfarin (see section 4.4).
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.
Due to the long half-life of vemurafenib, the full inhibitory effect of vemurafenib on a concomitant medicinal product might not be observed before 8 days of vemurafenib treatment.
After cessation of vemurafenib treatment, a washout of 8 days might be necessary to avoid an interaction with a subsequent treatment.
Radiation treatment
Potentiation of radiation treatment toxicity has been reported in patients receiving vemurafenib (see sections 4.4 and 4.8). In the majority of cases, patients received radiotherapy regimens greater than or equal to 2 Gy/day (hypofractionated regimens).
Interaction Effects of vemurafenib with on drug transport systems
In vitro studies have demonstrated that vemurafenib is both a substrate and 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 AUClast and Cmax, 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) (see section 4.4).
The effects of P-gp inducers and inhibitors on vemurafenib exposure are unknown.
It is currently unknown whether vemurafenib is a substrate also to other transport proteins.
The effects of vemurafenib on medicinal products that are substrates of BCRP, and the effects of BCRP inducers and inhibitors on vemurafenib exposure 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. 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.
In vitro studies have also demonstrated that vemurafenib is an inhibitor of bile salt export pump (BSEP). The in vivo relevance of this finding is unknown.
The possible effect of vemurafenib on other transporters is currently unknown.
Effects of concomitant medicines on vemurafenib
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. Concomitant administration of strong CYP3A4 inhibitors or inducers or inhibitors/inducer of transport protein activity may alter vemurafenib concentrations.
There are no clinical data available showing the effect of strong inhibitors of CYP3A4 and/or transport protein activity on vemurafenib exposure. Vemurafenib should be used with caution in combination with potent strong inhibitors of CYP3A4, glucuronidation and/or transport proteins (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir).
Vemurafenib is a substrate of CYP3A4, and therefore, cConcomitant administration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations.
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%, resulting in an AUClast geometric mean ratio (with/without rifampicin) of 0.61 (90%CI:0.48-0.78).
Concomitant administration of potent 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.
In vitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters P-gp and BCRP. The effects of P-gp and BCRP inducers and inhibitors on vemurafenib exposure are unknown. It cannot be excluded that vemurafenib pharmacokinetics could be affected by medicines that influence P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole) or BCRP (e.g. cyclosporine, gefitinib).
It is currently unknown whether vemurafenib is a substrate also to other transport proteins.
In vitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters P-gp and BCRP. The effects of P-gp and BCRP inducers and inhibitors on vemurafenib exposure are unknown. It cannot be excluded that vemurafenib pharmacokinetics could be affected by medicines that influence P-gp (e.g. verapamil, cyclosporine, ritonavir, quinidine, itraconazole) or BCRP (e.g. cyclosporine, gefitinib).
It is currently unknown whether vemurafenib is a substrate also to other transport proteins.
4.6 Fertility, pregnancy and lactation
[…]
Pregnancy
There are no data regarding the use of vemurafenib in pregnant women.
Vemurafenib revealed no evidence of teratogenicity in rat or rabbit embryo/foetuses (see section 5.3). 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.
[…]
4.8 Undesirable effects
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, alopecia diarrhea, headache, and pruritus, vomiting, skin papilloma and hyperkeratosis. The most common (≥ 5%) Grade 3 ADRs were CcuSCC, keratoacanthoma, rash, arthralgia and gamma-glutamyltransferase (GGT) increased. CuSCC was very commonly reported and was most commonly treated by local excision.
[…]
System organ class |
Very Common |
Common |
Uncommon |
Rare |
Infections and infestations |
|
Folliculitis |
|
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) |
SCC of the skin (d), keratoacanthoma, seborrhoeic keratosis, skin papilloma |
Basal cell carcinoma, new primary melanoma(3) |
Non-cuSCC(1)(3) |
Chronic myelomonocytic leukaemia(2)(4), pancreatic adenocarcinoma(5) |
Blood and lymphatic system disorders |
|
Neutropenia |
|
|
Metabolism and nutrition disorders |
Decreased appetite |
|
|
|
Nervous system disorders |
Headache, dysgeusia, dizziness |
7th nerve paralysis |
|
|
Eye disorders |
|
Uveitis, |
Retinal vein occlusion, iridocyclitis |
|
Vascular disorders |
|
Vasculitis |
|
|
Respiratory, thoracic and mediastinal disorders |
Cough |
|
|
|
Gastrointestinal disorders |
Diarrhoea, vomiting, nausea, constipation |
|
Pancreatitis(2) |
|
Hepatobiliary disorders |
|
|
Liver injury(1)(2) (g) |
|
Skin and subcutaneous tissue disorders |
Photosensitivity reaction, actinic keratosis, rash, rash maculo-papular |
|
Toxic epidermal necrolysis (e), Stevens-Johnson syndrome (f) |
Drug reaction with eosinophilia and systemic symptoms(1)(2) |
Musculoskeletal and connective tissue disorders |
Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain |
Arthritis, |
Plantar fascial fibromatosis(1)(2) Dupuytren’s contracture(1)(2) |
|
Renal and urinary |
|
|
|
Acute interstitial nephritis(1)(2) (h), acute tubular necrosis(1)(2) (h) |
General disorders and administration site conditions |
Fatigue, pyrexia, oedema peripheral, asthenia |
|
|
|
Investigations |
|
ALT increased (c), alkaline phosphatase increased (c), AST increased (c),bilirubin increased (c) GGT increased (c, weight decreased, electrocardiogram QT |
|
|
[…]
10. DATE OF REVISION OF THE TEXT
25 January 2018
Updated on 22 February 2018
File name
PIL_15627_362.pdf
Reasons for updating
- New PIL for new product
Updated on 22 February 2018
Reasons for updating
- Change to section 4 - possible side effects
- Change to section 6 - date of revision
Updated on 31 May 2017
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
4.4 Special warnings and precautions for use
[....]
Dupuytren’s contracture and plantar fascial fibromatosis
Dupuytren’s contracture and plantar fascial fibromatosis have been reported with vemurafenib. The majority of cases were mild to moderate, but severe, disabling cases of Dupuytren’s contracture have also been reported (see section 4.8).
Events should be managed with dose reduction with treatment interruption or with treatment discontinuation (see section 4.2).
[....]
4.8 Undesirable effects
[....]
Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events originating from safety reports across all trials(1) and post-marketing sources(2).
System organ class |
Very Common |
Common |
Uncommon |
Rare |
Musculoskeletal and connective tissue disorders |
Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain |
Arthritis, Dupuytren’s contracture(1)(2) |
Plantar fascial fibromatosis(1)(2) |
|
Updated on 30 May 2017
Reasons for updating
- Change to section 2 - what you need to know - warnings and precautions
- Change to section 4 - possible side effects
Updated on 28 March 2017
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Underlined text has been added, text with strike-through deleted:
4.2 Posology and method of administration
[…]
Paediatric population
The safety and efficacy of vemurafenib in children less than 18 years old have not been established. Currently available data are described in sections 4.8, 5.1, and 5.2, but no recommendation on a posology can be made.
The safety and efficacy of vemurafenib has not been yet established in children and adolescents (<18 years). No data are available.
[…]
4.8 Undesirable effects
[…]
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.
[…]
5.1 Pharmacodynamic properties
[…]
Paediatric population
Results from the phase I study (NO25390) in paediatric patients
A phase I dose-escalation study evaluating the use of vemurafenib in six adolescent patients with stage IIIC or IV BRAF V600 mutation positive melanoma was conducted. All patients treated were at least 15 years of age and weighed at least 45 kg. Three patients were treated with vemurafenib 720 mg twice daily, and three patients were treated with vemurafenib 960 mg twice daily. The maximum tolerated dose could not be determined. Although transient tumour regressions were seen, the best overall response rate (BORR) was 0% (95% CI: 0%, 46%) based on confirmed responses. The study was terminated due to low enrollment. See section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
[…]
Paediatric population
Limited pharmacokinetic data from six adolescent patients aged between 15 and 17 years with stage IIIC or IV BRAF V600 mutation positive melanoma suggest that vemurafenib pharmacokinetic characteristics in adolescents are generally similar to those in adults. See section 4.2 for information on paediatric use.
No studies have been conducted to investigate the pharmacokinetics of vemurafenib in paediatric patients.
10. DATE OF REVISION OF THE TEXT
23 February 2017
Updated on 02 March 2017
Reasons for updating
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Underlined text has been added, text with strike-through deleted:
4.5 Interaction with other medicinal products and other forms of interaction
[…]
Effects of concomitant medicines on vemurafenib
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. There are no clinical data available showing the effect of strong inducers or inhibitors of CYP3A4 and/or transport protein activity on vemurafenib exposure. Vemurafenib should be used with caution in combination with potent inhibitors of CYP3A4, glucuronidation and/or transport proteins (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir).
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%, resulting in an AUClastAUClast geometric mean ratio (with/without rifampinrifampicin) of 0.61 (90%CI:0.48-0.78).
Concomitant administration of potent 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.
[…]
10. DATE OF REVISION OF THE TEXT
15 December 2016
Updated on 03 October 2016
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.7 - Effects on ability to drive and use machines
- Change to section 6.1 - List of excipients
- Change to section 9 - Date of renewal of authorisation
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Removal of black triangle:
SUMMARY OF PRODUCT CHARACTERISTICS
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
4.2 Posology and method of administration
[...]
Method of administration
Vemurafenib is for oral use. The tablets are to be swallowed whole with water. Vemurafenib tabletsThey should not be chewed or crushed.
4.5 Interaction with other medicinal products and other forms of interaction
[...]
The effects of vemurafenib on medicinal productsdrugs 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 drugs are substrates of BCRP and therefore there is a theoretical risk for an interaction with vemurafenib.
[...]
4.7 Effects on ability to drive and use machines
The effects of vemurafenib Vemurafenib has minor influence on the ability to drive and use machines have not been studied. Patients should be made aware of the potential fatigue or eye problems that could be a reason for not driving.
6.1 List of excipients
Tablet Ccore
Croscarmellose sodium
Colloidal anhydrous silica
Magnesium stearate
Hydroxypropylcellulose
[...]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 17 February 2012
Date of latest renewal: 22 September 2016
10. DATE OF REVISION OF THE TEXT
22 September 2016
Updated on 28 September 2016
Reasons for updating
- Change to warnings or special precautions for use
- Change to information about driving or using machinery
- Change to further information section
- Change to date of revision
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Updated on 04 May 2016
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
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4.4 Special warnings and precautions for use
[…]
Renal Toxicity
Renal toxicity, ranging from serum creatinine elevations to acute interstitial nephritis and acute tubular necrosis, has been reported with vemurafenib. Serum creatinine should be measured before initiation of treatment and monitored during treatment as clinically indicated (see sections 4.2 and 4.8).
[…]
4.8 Undesirable effects
[…]
Renal and Urinary Disorders |
|
|
|
Acute interstitial nephritis(1)(2) (h), acute tubular necrosis(1)(2) (h) |
General disorders and administration site conditions |
Fatigue, pyrexia, oedema peripheral, asthenia |
|
|
|
Investigations |
GGT increase (c) |
ALT increase (c), alkaline phosphatase increase (c), bilirubin increase (c), weight decreased, QT prolongation, blood creatinine increased(1)(2) (h) |
AST increase (c) |
|
[…]
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 4).
Table 4: Creatinine changes from baseline in the phase III study
|
Vemurafenib (%) |
Dacarbazine (%) |
Change ³ 1 grade from baseline to any grade |
27.9 |
6.1 |
Change ³ 1 grade from baseline to grade 3 or higher |
1.2 |
1.1 |
|
0.3 |
0.4 |
|
0.9 |
0.8 |
Table 5: Acute kidney injury cases in the phase III study
|
Vemurafenib (%) |
Dacarbazine (%) |
Acute kidney injury cases* |
10.0 |
1.4 |
Acute kidney injury cases associated with dehydration events |
5.5 |
1.0 |
Dose modified for acute kidney injury |
2.1 |
0 |
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.
[…]
10. DATE OF REVISION OF THE TEXT
01 April 2016
Updated on 29 April 2016
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to date of revision
Updated on 05 November 2015
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 10 - Date of revision of the text
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4.4 Special warnings and precautions for use
[ … ]
Dermatologic reactions
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. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with vemurafenib in the post marketing setting (see section 4.8). In patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently discontinued.
Potentiation of radiation toxicity
Cases of radiation recall and radiation sensitization have been reported in patients treated with radiation either prior, during, or subsequent to vemurafenib treatment. Most cases were cutaneous in nature but some cases involving visceral organs had fatal outcomes (see sections 4.5 and 4.8).
Vemurafenib should be used with caution when given concomitantly or sequentially with radiation treatment.
[ … ]
Vemurafenib may increase the plasma exposure of medicinal products that are P-gp substrates. Caution should be exercised, dose reduction and/or additional drug level monitoring for P-gp substrate medicinal products with narrow therapeutic index (NTI) (e.g. digoxin, dabigatran etexilate, aliskiren) may be considered if these medicinal products are used concomitantly with vemurafenib (see section 4.5).
Effect of other medicinal products on vemurafenib
Vemurafenib pharmacokinetics could be affected by medicines that inhibit or influence P-gp (e.g. verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine) (see section 4.5).
[ … ]
4.5 Interaction with other medicinal products and other forms of interaction
Effects of vemurafenib on CYP substrates
CYP1A2 inhibition was observed in a clinical trial when a single dose of caffeine was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 2.52.6-fold increase (maximum up to 10-fold) in caffeine plasma exposure after vemurafenib treatment. Vemurafenib may increase the plasma exposure of substances predominantly metabolised by CYP1A2 and dose adjustments may be considered, if clinically indicatedshould be considered.
CYP3A4 induction was observed in a clinical trial when a single dose of midazolam was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 3239% decrease (maximum up to 80%) in midazolam plasma exposure after vemurafenib treatment. Vemurafenib may decrease the plasma exposure of substances predominantly metabolised by CYP3A4. On this basis, the efficacy of contraceptive pills metabolised by CYP3A4 used concomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates with narrow therapeutic window may be considered, if clinically indicatedshould be considered (see sections 4.4 and 4.6).
[ … ]
When a single dose of warfarin was co-administered after repeat dosing with vemurafenib for 15 days, some patients exhibited increased warfarin exposure (mean 2018%) (see section 4.4). Caution should be exercised when vemurafenib is co-administered with warfarin (CYP2C9) in patients with melanoma.
[ … ]
Radiation treatment
Potentiation of radiation treatment toxicity has been reported in patients receiving vemurafenib (see sections 4.4 and 4.8). In the majority of cases, patients received radiotherapy regimens greater than or equal to 2 Gy/day (hypofractionated regimens).
Effects of vemurafenib on substance transport systems
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 AUClast and Cmax, 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) (see section 4.4).
The effects of vemurafenib on drugs that are substrates of BCRP, and the effects of BCRP inducers and inhibitors on vemurafenib exposure are unknown. The clinical relevance of this finding is unknown. It cannot be excluded that vemurafenib may increase the exposure of other medicines transported by P-gp (e.g. aliskiren, colchicine, digoxin, everolimus, fexofenadine) or BCRP (e.g. methotrexate, mitoxantrone, rosuvastatin).
Many anticancer drugs are substrates of P-gp and/or BCRP and therefore there is a theoretical risk for an interaction with vemurafenib.
The possible effect of vemurafenib on other transporters is currently unknown.
[ … ]
4.8 Undesirable effects
Summary of the safety profile
The most common adverse drug reactions (ADR) (> 30%) reported with vemurafenib include arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. CuSCC was very commonly reported and was most commonly treated by local excision.
Potentiation of radiation toxicity: Radiation recall and radiation sensitization have been observed from postmarketing sources. However the frequency of this adverse reaction is unknown since radiation treatment information including radiation dosage information is not routinely collected in spontaneous safety reports.
[ … ]
Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events originating from safety reports across all trials(1)* and post-marketing sources(2)#.
System organ class |
Very Common |
Common |
Uncommon |
Rare |
Infections and infestations |
|
Folliculitis |
|
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) |
SCC of the skin ( |
Basal cell carcinoma, new primary melanoma(3) |
Non-cuSCC(1)(3) |
Chronic myelomonocytic leukaemia(2)(4) |
[ … ] |
|
|
|
|
Gastrointestinal disorders |
Diarrhoea, vomiting, nausea, constipation |
|
Pancreatitis |
|
Hepatobiliary disorders |
|
|
Liver injury(1)(2) |
|
Skin and subcutaneous tissue disorders |
Photosensitivity reaction, actinic keratosis, rash, rash maculo-papular, rash papular, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn |
Palmar-plantar erythrodysaesthesia syndrome, panniculitis (including erythema nodosum), keratosis pilaris |
Toxic epidermal necrolysis ( |
Drug reaction with eosinophilia and systemic symptoms(1)(2) |
[ … ] |
|
|
|
|
Investigations |
GGT increase ( |
ALT increase ( |
AST increase ( |
|
* Events originating from safety reports across all trials
# Events originating from post-marketing sources.
§ Progression of pre-existing chronic myelomonocytic leukaemia with NRAS mutation.
+ A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.
(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 (bc)
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 (fg)
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 (cd) (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 (see sections 4.2 and 4.4).
[ … ]
Potentiation of radiation toxicity
Cases reported include recall phenomenon, radiation skin injury, radiation pneumonitis, radiation esophagitis, radiation proctitis, radiation hepatitis, cystitis radiation, and radiation necrosis.
Hypersensitivity reactions (de)
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 (see section 4.4).
Dermatologic Reactions (ef)
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.
[ … ]
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE15
Mechanism of action and pharmacodynamic effects
Vemurafenib is an inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene result in constitutive activation of BRAF proteins, which can cause cell proliferation without associated growth factors.
Preclinical data generated in biochemical assays demonstrated that vemurafenib can potently inhibit BRAF kinases with activating codon 600 mutations (table 4).
Vemurafenib is a low molecular weight, orally available, inhibitor of BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation.
Preclinical data generated in biochemical assays demonstrated that vemurafenib can potently inhibit BRAF kinases with activating codon 600 mutations (table 4).
Table 4: Kinase inhibitory activity of vemurafenib against different BRAF kinases
Kinase |
Anticipated frequency in V600 mutation-positive melanoma ( |
Inhibitory Concentration 50 (nM) |
BRAFV600E |
|
10 |
BRAFV600K |
|
7 |
BRAFV600R |
1% |
9 |
BRAFV600D |
< |
7 |
BRAFV600G |
<0.1% |
8 |
BRAFV600M |
<0.1% |
7 |
BRAFV600A |
|
14 |
BRAFWT |
N/A |
39 |
(ft) Estimated from 209916403 melanomas with annotated BRAF codon 600 mutations in the public COSMIC database, release 5471 (July 2011November 2014).
This inhibitory effect was confirmed in the ERK phosphorylation and cellular anti-proliferation assays in available melanoma cell lines expressing V600-mutant BRAF. In cellular anti-proliferation assays the inhibitory concentration 50 (IC50) against V600 mutated cell lines (V600E, V600R, V600D and V600K mutated cell lines) ranged from 0.016 to 1.131 mM whereas the inhibitory concentration IC50 against BRAF wild type cell lines were 12.06 and 14.32 mM, respectively.
[ … ]
Table 5: Overall survival in previously untreated patients with BRAF V600 mutation-positive melanoma by study cut-off date (N=338 dacarbazine, N=337 vemurafenib)
Cut-off dates |
Treatment |
Number of deaths (%) |
Hazard Ratio (95% CI) |
Number of cross-over patients (%) |
December 30, 2010 |
dacarbazine |
75 (22) |
0.37 (0.26, 0.55) |
0 (not applicable) |
vemurafenib |
43 (13) |
|||
March 31, 2011 |
dacarbazine |
122 (36) |
0.44 (0.33, 0.59) ( |
50 (15%) |
vemurafenib |
78 (23) |
|||
October 3, |
dacarbazine |
175 (52) |
0.62 (0.49, 0.77) ( |
81 (24%) |
vemurafenib |
159 (47) |
|||
February 1, 2012 |
dacarbazine |
200 (59) |
0.70 (0.57, 0.87) ( |
83 (25%) |
vemurafenib |
199 (59) |
|||
December 20, 2012 |
dacarbazine |
236 (70) |
0.78 (0.64, 0.94) ( |
84 (25%) |
vemurafenib |
242 (72) |
(gw) Censored results at time of cross-over
Non-censored results at time of cross-over: March 31 2011: HR (95% CI) = 0.47 (0.35, 0.62); October 3 2011: HR (95% CI) = 0.67 (0.54, 0.84); February 1 2012: HR (95% CI) = 0.76 (0.63, 0.93); December 20 2012: HR (95% CI) = 0.79 (0.66, 0.95)
[ … ]
Table 7: Overall response rate and progression-free survival in previously untreated patients with BRAF V600 mutation-positive melanoma
|
vemurafenib |
dacarbazine |
p-value ( |
December 30, 2010 data cut-off date ( |
|||
Overall Response Rate (95% CI) |
48.4% (41.6%, 55.2%) |
5.5% (2.8%, 9.3%) |
<0.0001 |
Progression-free survival Hazard Ratio (95% CI) |
0.26 (0.20, 0.33) |
<0.0001 |
|
Number of events (%) |
104 (38%) |
182 (66%) |
|
Median PFS (months) (95% CI) |
5.32 (4.86, 6.57) |
1.61 (1.58, 1.74) |
|
February 01, 2012 data cut-off date ( |
|||
Progression-free survival Hazard Ratio (95% CI) |
0.38 (0.32, 0.46) |
<0.0001 |
|
Number of events (%) |
277 (82%) |
273 (81%) |
|
Median PFS (months) (95% CI) |
6.87 (6.14, 6.97) |
1.64 (1.58, 2.07) |
|
(hx) Unstratified log-rank test for PFS and Chi-squared test for Overall Response Rate.
(iy) As of December 30, 2010, a total of 549 patients were evaluable for PFS and 439 patients were evaluable for overall response rate.
(jz) As of February 01, 2012, a total of 675 patients were evaluable for the post-hoc analysis update of PFS.
[ … ]
5.2 Pharmacokinetic properties
[ … ]
Absorption
The absolute bioavailability of the vemurafenib 240 mg tablet is unknown.
Vemurafenib at 960 mg twice daily is absorbed with a median Tmax of approximately 4 hours following a single 960 mg dose (four 240 mg tablets). Vemurafenib exhibits high inter-patient variability. In the phase II study, AUC0-8h and Cmax at day 1 were 22.1 ± 12.7 µg×h/mL and 4.1 ± 2.3 µg/mL. Accumulation occurs upon multiple twice daily dosing of vemurafenib. In the non-compartmental analysis, after dosing with 960 mg vemurafenib twice daily the Day 15 / Day 1 ratio ranged from 15- to 17-fold for AUC, and 13- to 14-fold for Cmax, yielding AUC0-8h and Cmax of 380.2 ± 143.6 µg×h/mL and 56.7 ± 21.8 µg/mL, respectively, under steady-state conditions.
Food (high fat meal) increases the relative bioavailability of a single 960 mg dose of vemurafenib. The geometric mean ratios between the fed and fasted states for Cmax and AUC were 2.62.5 and 4.74.6 to 5.1 fold, respectively. The median Tmax was increased from 4 to 87.5 hours when a single vemurafenib dose was taken with food.
[ … ]
10. DATE OF REVISION OF THE TEXT
28 October 2015
Updated on 03 November 2015
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to date of revision
Updated on 29 April 2015
Reasons for updating
- Change to section 6.3 - Shelf life
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
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DATE OF REVISION
16 April 2015
Updated on 23 April 2015
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Underlined text has been added, text with strike-through deleted:
4.4 Special warnings and precautions for use
[…]
Pancreatitis
Pancreatitis has been reported in vemurafenib-treated subjects. Unexplained abdominal pain should be promptly investigated (including measurement of serum amylase and lipase). Patients should be closely monitored when re-starting vemurafenib after an episode of pancreatitis.
[…]
4.8 Undesirable effects
[…]
Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events originating from safety reports across all trials* and post-marketing sources#.
System organ class |
Very Common |
Common |
Uncommon |
Rare |
Infections and infestations |
|
Folliculitis |
|
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) |
SCC of the skin (c), seborrheic keratosis, skin papilloma |
Basal cell carcinoma, new primary melanoma+ |
Non-cuSCC*+ |
Chronic myelomonocytic leukaemia#§ |
Blood and lymphatic system disorders |
|
|
Neutropenia |
|
Metabolism and nutrition disorders |
Decreased appetite |
|
|
|
Nervous system disorders |
Headache, dysgeusia |
7th nerve paralysis, dizziness |
Neuropathy peripheral |
|
Eye disorders |
|
Uveitis |
Retinal vein occlusion |
|
Vascular disorders |
|
|
Vasculitis |
|
Respiratory, thoracic and mediastinal disorders |
Cough |
|
|
|
|
Diarrhoea, vomiting, nausea, constipation |
|
Pancreatitis# |
|
Hepatobiliary disorders |
|
|
Liver injury*# (f) |
|
Skin and subcutaneous tissue disorders |
Photosensitivity reaction, actinic keratosis, rash, rash maculo-papular, rash papular, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn |
Palmar-plantar erythrodysaesthesia syndrome, panniculitis (including erythema nodosum), keratosis pilaris |
Toxic epidermal necrolysis (d), Stevens-Johnson syndrome (e) |
Drug reaction with eosinophilia and systemic symptoms*# |
Musculoskeletal and connective tissue disorders |
Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain |
Arthritis |
|
|
General disorders and administration site conditions |
Fatigue, pyrexia, oedema peripheral, asthenia |
|
|
|
Investigations |
GGT increase (b) |
ALT increase (b), alkaline phosphatase increase (b), bilirubin increase (b), weight decreased, QT prolongation |
AST increase (b) |
|
* Events originating from safety reports across all trials
# Events originating from post-marketing sources.
§ Progression of pre-existing chronic myelomonocytic leukaemia with NRAS mutation.
+ A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.
[…]
10. DATE OF REVISION OF THE TEXT
26 March 2015
Updated on 22 April 2015
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to date of revision
Updated on 24 December 2014
Reasons for updating
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 23 December 2014
Reasons for updating
- Change to side-effects
- Change to date of revision
Updated on 25 July 2014
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to Section 4.8 – Undesirable effects - how to report a side effect
- Change to section 10 - Date of revision of the text
- Change to section 4.4 - Special warnings and precautions for use
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
4.4 Special warnings and precautions for use
[...]
Liver injury
Liver laboratory abnormalitiesinjury, including cases of severe liver injury, may occurhas been reported with vemurafenib (see section 4.8). 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 with treatment discontinuation (see sections 4.2 and 4.84).
[...]
4.8 Undesirable effects
[...]
Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events originating from safety reports across all trials* and post-marketing sources#.
System organ class |
Very Common |
Common |
Uncommon |
Rare |
Infections and infestations |
|
Folliculitis |
|
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) |
SCC of the skin (c), seborrheic keratosis, skin papilloma |
Basal cell carcinoma, new primary melanoma+ |
Non-cuSCC*+ |
Chronic myelomonocytic leukaemia#§ |
Blood and lymphatic system disorders |
|
|
Neutropenia |
|
Metabolism and nutrition disorders |
Decreased appetite |
|
|
|
Nervous system disorders |
Headache, dysgeusia |
7th nerve paralysis, dizziness |
Neuropathy peripheral |
|
Eye disorders |
|
Uveitis |
Retinal vein occlusion |
|
Vascular disorders |
|
|
Vasculitis |
|
Respiratory, thoracic and mediastinal disorders |
Cough |
|
|
|
Gastrointestinal disorders |
Diarrhoea, vomiting, nausea, constipation |
|
|
|
Hepatobiliary disorders |
|
|
Liver injury*# (f) |
|
Skin and subcutaneous tissue disorders |
Photosensitivity reaction, actinic keratosis, rash, rash maculo-papular, rash papular, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn |
Palmar-plantar erythrodysaesthesia syndrome, panniculitis (including erythema nodosum), keratosis pilaris |
Toxic epidermal necrolysis (d), Stevens-Johnson syndrome (e) |
Drug reaction with eosinophilia and systemic symptoms*# |
Musculoskeletal and connective tissue disorders |
Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain |
Arthritis |
|
|
General disorders and administration site conditions |
Fatigue, pyrexia, oedema peripheral, asthenia |
|
|
|
Investigations |
GGT increase (b) |
ALT increase (b), alkaline phosphatase increase (b), bilirubin increase (b), weight decreased, QT prolongation |
AST increase (b) |
|
* Events originating from safety reports across all trials
# Events originating from post-marketing sources.
§ Progression of Prepre-existing chronic myelomonocytic leukaemia with NRAS mutation.
+ A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.
[...]
There were no increases to Grade 4 ALT, alkaline phosphatase or bilirubin.
Liver injury (f)
The severity of liver laboratory abnormalities observed in clinical trials and post-marketing sources are shown below: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
[...]
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).
Ireland
IMB HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imbhpra.ie
e-mail: imbpharmacovigilance@imb.ie
medsafety@hpra.ie
[...]
10. DATE OF REVISION OF THE TEXT
26 June 2014
Updated on 23 July 2014
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to date of revision
Updated on 21 March 2014
Reasons for updating
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Underlined text has been added, text with strike through deleted:
System organ class |
Very Common |
Common |
Uncommon |
Rare |
Infections and infestations |
|
Folliculitis |
|
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) |
SCC of the skin (c), seborrheic keratosis, skin papilloma |
Basal cell carcinoma, new primary melanoma+ |
Non-cuSCC*+ |
Chronic myelomonocytic leukaemia#§ |
Metabolism and nutrition disorders |
Decreased appetite |
|
|
|
Nervous system disorders |
Headache, dysgeusia |
7th nerve paralysis, dizziness |
Neuropathy peripheral |
|
Eye disorders |
|
Uveitis |
Retinal vein occlusion |
|
Vascular disorders |
|
|
Vasculitis |
|
Respiratory, thoracic and mediastinal disorders |
Cough |
|
|
|
Gastrointestinal disorders |
Diarrhoea, vomiting, nausea, constipation |
|
|
|
Skin and subcutaneous tissue disorders |
Photosensitivity reaction, actinic keratosis, rash, rash maculo-papular, rash papular, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn |
Palmar-plantar erythrodysaesthesia syndrome, panniculitis (including erythema nodosum), keratosis pilaris |
Toxic epidermal necrolysis (d), Stevens-Johnson syndrome (e |
Drug reaction with eosinophilia and systemic symptoms*# |
Musculoskeletal and connective tissue disorders |
Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain |
Arthritis |
|
|
General disorders and administration site conditions |
Fatigue, pyrexia, oedema peripheral, asthenia |
|
|
|
Investigations |
GGT increase (b) |
ALT increase (b), alkaline phosphatase increase (b), bilirubin increase (b), weight decreased, QT prolongation |
AST increase (b) |
|
Updated on 20 March 2014
Reasons for updating
- Change to side-effects
Updated on 23 January 2014
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 4.8 - Undesirable effects
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
4.4 Special warnings and precautions for use
[...]
Dermatologic reactions
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. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with vemurafenib in the post marketing setting (see section 4.8). In patients who experience a severe dermatologic reaction, vemurafenib treatment should be permanently discontinued.
[...]
Other Malignancies
Based on mechanism of action, vemurafenib may cause progression of cancers associated with RAS mutations (see section 4.8). Vemurafenib should be used with caution in patients with a prior or concurrent cancer associated with RAS mutation.Carefully consider benefits and risks before administering Zelborafvemurafenib to patients with a prior or concurrent cancer associated with RAS mutation.
[...]
4.8 Undesirable effects
[...]
In this section, ADRs are based on results in 468 patients from a phase III randomized 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 (see section 5.1). 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.
[....]
Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events* originating from safety reports across all trials* and post-marketing sources#.
System organ class |
Very Common |
Common |
Uncommon |
Rare |
Infections and infestations |
|
Folliculitis |
|
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) |
SCC of the skin (c), seborrheic keratosis, skin papilloma |
Basal cell carcinoma, new primary melanoma+ |
Non-cuSCC*+ |
Chronic myelomonocytic leukaemia#§ |
Metabolism and nutrition disorders |
Decreased appetite |
|
|
|
[...]
Skin and subcutaneous tissue disorders |
Photosensitivity reaction, actinic keratosis, rash, rash maculo-papular, rash papular, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn |
Palmar-plantar erythrodysaesthesia syndrome,erythema nodosum, keratosis pilaris |
Toxic epidermal necrolysis (d), Stevens-Johnson syndrome (e) |
Drug reaction with eosinophilia and systemic symptoms*# |
[...]
* Events originating from safety reports across all trials.
# Events originating from post-marketing sources.
§ Pre-existing chronic myelomonocytic leukaemia with NRAS mutation.
+ A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.
10. DATE OF REVISION OF THE TEXT
18 December 2013
Updated on 20 January 2014
Reasons for updating
- Change to warnings or special precautions for use
- Change to side-effects
- Change to date of revision
Updated on 27 November 2013
Reasons for updating
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor, ATC code: L01XE15
[...]
Table 5: Overall survival in previously untreated patients with BRAF V600 mutation positive melanoma by study cut-off date (N=338 dacarbazine, N=337 vemurafenib)
Cut-off dates |
Treatment |
Number of deaths (%) |
Hazard Ratio (95% CI) |
Number of cross-over patients (%) |
December 30, 2010 |
dacarbazine |
75 (22) |
0.37 (0.26, 0.55) |
0 (not applicable) |
vemurafenib |
43 (13) |
|||
March 31, 2011 |
dacarbazine |
122 (36) |
0.44 (0.33, 0.59) (g) |
50 (15%) |
vemurafenib |
78 (23) |
|||
October 3, |
dacarbazine |
175 (52) |
0.62 (0.49, 0.77) (g) |
81 (24%) |
vemurafenib |
159 (47) |
|||
February 1, 2012 |
dacarbazine |
200 (59) |
0.70 (0.57, 0.87) (g) |
83 (25%) |
vemurafenib |
199 (59) |
|||
December 20, 2012 |
dacarbazine |
236 (70) |
0.78 (0.64, 0.94) (g) |
84 (25%) |
vemurafenib |
242 (72) |
(g) Censored results at time of cross-over
Non-censored results at time of cross-over: March 31 2011: HR (95% CI) = 0.47 (0.35, 0.62); October 3 2011: HR (95% CI) = 0.67 (0.54, 0.84); February 1 2012: HR (95% CI) = 0.76 (0.63, 0.93); December 20 2012: HR (95% CI) = 0.79 (0.66, 0.95)
Figure 1: Kaplan-Meier curves of overall survival – previously untreated patients (December 20,February 1, 2012 cut-off)
(Figures in original published version)
Table 6 shows the treatment effect for all pre-specified stratification variables which are established as prognostic factors.
Table 6: Overall survival in previously untreated patients with BRAF V600 mutation positive melanoma by LDH, tumour stage and ECOG status (post hoc analysis, December 20February 1, 2012 cut-off, censored results at time of cross over)
Stratification variable |
N |
Hazard Ratio |
95% Confidence Interval |
LDH normal |
391 |
0.88 |
0.67 |
LDH >ULN |
284 |
0.57 |
0.44 |
Stage IIIc/M1A/M1B |
234 |
1.05 |
0. |
Stage MIC |
441 |
0.64 |
0.51 |
ECOG PS=0 |
459 |
0. |
0. |
ECOG PS=1 |
216 |
0. |
0. |
LDH: Lactate Dehydrogenase, ECOG PS: Eastern Cooperative Oncology Group Performance Status
Table 7 shows the overall response rate and progression-free survival in previously untreated patients with BRAF V600 mutation positive melanoma.
[...]
10. DATE OF REVISION OF THE TEXT
24 October 2013
Updated on 25 November 2013
Reasons for updating
- Change to date of revision
- Correction of spelling/typing errors
Updated on 30 July 2013
Reasons for updating
- Change to section 4.2 - Posology and method of administration
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.8 - Undesirable effects
- Change to section 5.2 - Pharmacokinetic properties
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
SUMMARY OF PRODUCT CHARACTERISTICS
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals
are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
4.2 Posology and method of administration
[….]
ElderlyOlder people
No special dose adjustment is required in patients aged > 65 years old.
4.5 Interaction with other medicinal products and other forms of interaction
[….]
Effects of vemurafenib on substance transport systems
In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporters (P-gp). and BCRP. The clinical relevance of this finding
s unknown. It cannot be excluded that vemurafenib may increase the exposure of other medicines transported by P-gp (e.g. aliskiren, colchicine,
digoxin, everolimus, fexofenadine) or BCRP (e.g. methotrexate, mitoxantrone, rosuvastatin).
Many anticancer drugs are substrates of P-gp and/or BCRP and therefore there is a theoretical risk for an interaction with vemurafenib.
The possible effect of vemurafenib on other transporters (e.g. BCRP) is currently unknown.
[….]
In vitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters, P-gp and BCRP. The effects of P-gp and BCRP inducers
and inhibitors on vemurafenib exposure are unknown. It cannot be excluded that vemurafenib pharmacokinetics could be affected by medicines that
inhibit or influence P-gp (e.g. verapamil, clarithromycin, cyclosporine, ritonavir, quinidine, dronedarone, amiodarone, itraconazole, ranolazine) or
BCRP (e.g. cyclosporine, gefitinib).
It is currently unknown whether vemurafenib is a substrate also to other transport proteins.
4.8 Undesirable effects
[….]
Special populations
ElderlyOlder people
In the phase III study, ninety-four (28%) of 336 patients with unresectable or metastatic melanoma treated with vemurafenib were ≥ 65 years.
Elderly 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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk
balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system (see details below).
listed in Appendix V
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Malta
ADR Reporting
The Medicines Authority
Post-Licensing Directorate
203 Level 3, Rue D'Argens
GŻR-1368 Gżira
Website: www.medicinesauthority.gov.mt
e-mail: postlicensing.medicinesauthority@gov.mt
Ireland
Pharmacovigilance Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 67678362517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
5.2 Pharmacokinetic properties
[….]
Special populations
ElderlyOlder people
Based on the population PK analysis, age has no statistically significant effect on vemurafenib pharmacokinetics.
[….]
10. DATE OF REVISION OF THE TEXT
27 June 2013
Updated on 26 July 2013
Reasons for updating
- Change to drug interactions
- Change to date of revision
Updated on 01 July 2013
Reasons for updating
- Change to section 4.4 - Special warnings and precautions for use
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
4.4 Special warnings and precautions for use
[...]
Concurrent administration with ipilimumab
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.
[...]
10. DATE OF REVISION OF THE TEXT
30 May 2013
Updated on 28 June 2013
Reasons for updating
- Change to drug interactions
- Change to date of revision
Updated on 19 February 2013
Reasons for updating
- Change to section 4.1 - Therapeutic indications
- Change to section 4.2 - Posology and method of administration
- Change to section 4.3 - Contraindications
- Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
- Change to section 4.8 - Undesirable effects
- Change to section 5.1 - Pharmacodynamic properties
- Change to section 10 - Date of revision of the text
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
4.1 Therapeutic indicationindications
Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma (see section 5.1).
4.2 4.2 Posology and method of administration
[.....]
Duration of treatment
Treatment with vemurafenib should continue until disease progression or the development of unacceptable toxicity (see tabletables 1 and 2 below).
[....]
Posology adjustments
Management of adverse drug reactions or QTc prolongation may require dose reduction, temporary interruption and/or treatment discontinuation (see tabletables 1 and 2). Posology adjustments resulting in a dose below 480 mg twice daily are not recommended.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
[...]
QT prolongation
[....]
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 1.2. 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.
[....]
Non-Cutaneous Squamous Cell Carcinoma (non-cuSCC)
No casesCases of non-cuSCC have been reported in clinical trials withwhere patients received vemurafenib in melanoma. Patients should undergo a head and neck examination, consisting of at least a visual inspection of oral mucosa and lymph node palpation prior to initiation of treatment and every 3 months during treatment.
4.5 Interaction with other medicinal products and other forms of interaction
[....]
Concomitant administration of potent inducers of P-gp, glucuronidation, and/or CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [hypericum perforatum]) may lead to supoptimalsuboptimal exposure to vemurafenib and should be avoided.
[...]
4.6 Fertility, pregnancy and lactation
Breastfeeding
Breast-feeding
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 breastfeeding for the child and the benefit of therapy for the woman.
[...]
4.8 4.8 Undesirable effects
[...]
In this section, ADRs are based on results in 500468 patients from a phase III randomized 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 (see section 5.1). In addition ADRs originating from safety reports across all clinical trials 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.
Table 3: ADRs occurring in patients treated with vemurafenib in the phase II or phase III study and events* originating from safety reports across all trials
System organ class |
Very Common |
Common |
Uncommon |
Infections and infestations |
|
Folliculitis |
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) |
SCC of the skin (c), seborrheic keratosis, skin papilloma |
Basal cell carcinoma, new primary melanoma+ |
Non-cuSCC*+ |
Metabolism and nutrition disorders |
Decreased appetite |
|
|
Nervous system disorders |
Headache, dysgeusia |
7th nerve paralysis, dizziness |
Neuropathy peripheral |
Eye disorders |
|
Uveitis |
Retinal vein occlusion |
Vascular disorders |
|
|
Vasculitis |
Respiratory, thoracic and mediastinal disorders |
Cough |
|
|
Gastrointestinal disorders |
Diarrhoea, vomiting, nausea, constipation |
|
|
Skin and subcutaneous tissue disorders |
Photosensitivity reaction, actinic keratosis, rash, rash maculo-papular, rash papular, pruritus, hyperkeratosis, erythema, alopecia, dry skin, sunburn |
Palmar-plantar erythrodysaesthesia syndrome,erythema nodosum, keratosis pilaris |
Toxic epidermal necrolysis (d), Stevens-Johnson syndrome (e) |
Musculoskeletal and connective tissue disorders |
Arthralgia, myalgia, pain in extremity, musculoskeletal pain, back pain |
Arthritis |
|
General disorders and administration site conditions |
Fatigue, pyrexia, oedema peripheral, asthenia |
|
|
Investigations |
GGT increase (b) |
ALT increase (b), alkaline phosphatase increase (b), bilirubin increase (b), weight decreased, QT prolongation |
AST increase (b) |
* Events originating from safety reports across all trials
+ A causal relationship between the medicinal product and the adverse event is at least a reasonable possibility.
[....]
Non-cutaneous squamous cell carcinoma (non-cuSCC)
Cases of non-cuSCC have been reported in patients receiving vemurafenib while enrolled in clinical trials. Surveillance for non-cuSCC should occur as outlined in section 4.4.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
[...]
Table 5: Overall survival in previously untreated patients with BRAF V600 mutation positive melanoma by study cut-off date (N=338 dacarbazine, N=337 vemurafenib)
Cut-off dates |
Treatment |
Number of deaths (%) |
Hazard Ratio (95% CI) |
Number of cross-over patients (%) |
December 30, 2010 |
dacarbazine |
75 (22) |
0.37 (0.26, 0.55) |
0 (not applicable) |
vemurafenib |
43 (13) |
|||
March 31, 2011 |
dacarbazine |
122 (36) |
0.44 (0.33, 0.59) (g) |
50 (15%) |
vemurafenib |
78 (23) |
|||
October 3, |
dacarbazine |
175 (52) |
0.62 (0.49, 0.77) (g) |
81 (24%) |
vemurafenib |
159 (47) |
|||
February 1, 2012 |
dacarbazine |
200 (59) |
0.70 (0.57, 0.87) (g) |
83 (25%) |
vemurafenib |
199 (59) |
(g) Censored results at time of cross-over
Non-censored results at time of cross-over: March 31: HR (95% CI) = 0.47 (0.35, 0.62); October 3: HR (95% CI) = 0.67 (0.54, 0.84); February 1: HR (95% CI) = 0.76 (0.63, 0.93)
Figure 1: Kaplan-Meier curves of overall survival – previously untreated patients (October 3 2011February 1, 2012 cut-off)
[Figure left out)
Table 6 shows the treatment effect for all pre-specified stratification variables which are established as prognostic factors.
Table 6: Overall survival in previously untreated patients with BRAF V600 mutation positive melanoma by LDH, tumour stage and ECOG status (October 3, 2011February 1, 2012 cut-off, censored results at time of cross over)
Stratification variable |
N |
Hazard Ratio |
95% Confidence Interval |
LDH normal |
391 |
0. |
0. |
LDH >ULN |
284 |
0. |
0. |
Stage IIIc/M1A/M1B |
234 |
0. 871.02 |
0. |
Stage MIC |
441 |
0. |
0. |
ECOG PS=0 |
459 |
0. |
0. |
ECOG PS=1 |
216 |
0. |
0. |
LDH: Lactate Dehydrogenase, ECOG PS: Eastern Cooperative Oncology Group Performance Status
Table 7 shows the overall response rate and progression-free survival in previously untreated patients with BRAF V600 mutation positive melanoma.
Table 7: Overall response rate and progression-free survival in previously untreated patients with BRAF V600 mutation positive melanoma (December 30, 2010 cut-off)
|
(N=336) |
(N=336) |
p-value (h) |
||
December 30, 2010 data cut-off date (i) |
|||||
Overall Response Rate (95% CI) |
48.4% (41.6%, 55.2%) |
5.5% (2.8%, 9.3%) |
<0.0001 |
||
Progression-free survival Hazard Ratio (95% CI) |
0.26 (0.20, 0.33) |
<0.0001 |
|||
Number of events (%) |
104 (38%) |
182 (66%) |
|
||
Median PFS (months) (95% CI) |
5.32 (4.86, 6.57) |
1.61 (1.58, 1.74) |
- |
||
(95% CI)February 01, 2012 data cut-off date (j) |
48.4% (41.6%, 55.2%) |
5.5% (2.8%, 9.3%) |
< |
||
Progression-free survival Hazard Ratio (95% CI) |
0.38 (0.32, 0.46) |
<0.0001 |
|||
Number of events (%) |
277 (82%) |
273 (81%) |
|
||
Median PFS (months) (95% CI) |
6.87 (6.14, 6.97) |
1.64 (1.58, 2.07) |
|
||
(h) Unstratified log-rank test for PFS and Chi-squared test for Overall Response Rate.
A(i) As of December 30, 2010, a total of 549 patients were evaluable for PFS and 439 patients were evaluable for overall response rate.
(j) As of February 01, 2012, a total of 675 patients were evaluable for the post-hoc analysis update of PFS.
A total of 57 patients out of 673 whose tumours were analysed retrospectively by
sequencing were reported to have BRAF V600K mutation-positive melanoma in NO25026. Although limited by the low number of patients, efficacy analyses among these patients with V600K-positive tumours suggested similar treatment benefit of vemurafenib in terms of OS, PFS and The confirmed best overall response. No data are available in patients with melanoma harboringharbouring rare BRAF V600 mutations otherother than V600E and V600K.s
Results from the phase II study (NP22657) in patients who failed at least one prior therapy
A phase II single-arm, multi-center, multinational study was conducted in 132 patients who had BRAF V600E mutation-positive metastatic melanoma according to the cobas 4800 BRAF V600 Mutation Test and had received at least one prior therapy. The median age was 52 years with 19% of patients being older than 65 years. The majority of patients was male (61%), Caucasian (99%), and had stage M1c disease (61%). Forty-nine percent of patients failed ≥ 2 prior therapies.
With a median follow-up of 12.9 months (range, 0.6 to 20.1), the primary endpoint of confirmed best overall response rate (CR + PR) as assessed by an independent review committee (IRC) was 53% (95% CI: 44%, 62%). Median overall survival was 15.9 months (95% CI: 11.6, 18.3). The overall survival rate at 6 months was 77% (95% CI: 70%, 85%) and at 12 months was 58% (95% CI: 49%, 67%).
Nine of the 132 patients enrolled into NP22657 had V600K mutation positive tumorstumours according to retrospective Sanger sequencing. Amongst these patients, 3 had a PR, 3 had SD, 2 had PD and one was not evaluable.
The European Medicines Agency has waived the obligation to submit the results of studies with vemurafenib in all subsets of the paediatric population in melanoma (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Vemurafenib is a Class IV substance (low solubility and permeability), using the criteria described in the Biopharmaceutics Classification System. The pharmacokinetic parameters for vemurafenib were determined using non compartmental analysis in a phase I and phase III studies (20 patients after 15 days of dosing at 960 mg twice daily, and 204 patients in steady state day 22) as well as by population PK analysis using pooled data from 458 patients. Among these patients, 457 were Caucasians.
Absorption
The absolute bioavailability of the vemurafenib 240 mg tablet is unknown.
Vemurafenib at 960 mg twice daily is absorbed with a median Tmax of approximately 4 hours. Vemurafenib exhibits high inter-patient variability. In the phase II study, AUC0-8h and Cmax at day 1 were 22.1 ± ± 12.7 µg×h/mL and 4.1 ± ± 2.3 µg/mL. Accumulation occurs upon multiple twice daily dosing of vemurafenib. In the non compartmental analysis, after dosing with 960 mg vemurafenib twice daily the Day 15 / Day 1 ratio ranged from 15- to 17-fold for AUC, and 13- to 14-fold for Cmax, yielding AUC0-8h and Cmax of 380.2 ± ± 143.6 µg×h/mL and 56.7 ± 21.8 µg/mL, respectively, under steady-state conditions.
[.....]
10. DATE OF REVISION OF THE TEXT
20 December 2012
17 January 2013
Updated on 18 February 2013
Reasons for updating
- Change to side-effects
- Change to information about pregnancy or lactation
- Change to date of revision
Updated on 15 February 2013
Reasons for updating
- New SPC for new product
- New SPC for medicines.ie
Legal category:Product subject to medical prescription which may not be renewed (A)
Free text change information supplied by the pharmaceutical company
Updated on 08 February 2013
Reasons for updating
- New PIL for new product
- New PIL for medicines.ie
Roche Registration GmbH

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