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. 

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. 

EMEA/H/C/xxxx/IG/1730. Implementation of PRAC recommendation (EPITT Np. 19961) - "Stomatitis" added to Leaflet Section 4. 

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.

MAH Licence transfer from RRL (UK) to RRG (GER).

Underlined text has been added, text with strike-through deleted

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 C_max and AUC_inf 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 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) (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 AUC_last 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.

[…]

[…]

10.       DATE OF REVISION OF THE TEXT

25 January 2018

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⁾.

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

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 AUClastAUC_last 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

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

Underlined text has been added, text with strike through has been deleted:

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

[…]

[…]

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

Table 5:  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.

[…]

10.       DATE OF REVISION OF THE TEXT

01 April 2016

Underlined Text = New Text

Strike through Text = Deleted Text

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 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) (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)#.

 * 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

^(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)

^(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

^(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, AUC_0-8h and C_max 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 C_max, yielding AUC_0-8h and C_max 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 C_max and AUC were 2.62.5 and 4.74.6 to 5.1 fold, respectively. The median T_max 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

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^#.

* 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

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^#.

* 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

Underlined text has been added, text with strike through deleted:

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.