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Duration of treatment
RX Treatment with vemurafenib should continue
until disease progression or the development of
VEMURAFENIB FILM unacceptable toxicity (see tables 1 and 2 below).
COATED TABLETS Missed doses
240MG If a dose is missed, it can be taken up to 4 hours
prior to the next dose to maintain the twice daily
1.NAME OF THE MEDICINAL PRODUCT regimen. Both doses should not be taken at the
same time.
Vemurafenib 240 mg film-coated tablets.
Vomiting
2. QUALITATIVE AND QUANTITATIVE
In case of vomiting after vemurafenib
COMPOSITION
administration the patient should not take an
Each tablet contains 240 mg of vemurafenib (as additional dose of the medicinal product but the
a co-precipitate of vemurafenib and treatment should be continued as usual.
hypromellose acetate succinate).
Posology adjustments
For the full list of excipients, see section 6.1.
Management of adverse drug reactions or QTc
3. PHARMACEUTICAL FORM prolongation may require dose reduction,
temporary interruption and/or treatment
Film-coated tablet (tablet). discontinuation (see tables 1 and 2). Posology
Pinkish white to orange white, oval, biconvex adjustments resulting in a dose below 480 mg
film-coated tablets of approximately 19 mm twice daily are not recommended.
4. CLINICAL PARTICULARS Table 1
Grade (CTC-AE) (a) Recommended dose

4.1 Therapeutic indications modification
Vemurafenib is indicated in monotherapy for the
Grade 1 or Grade 2 Maintain vemurafenib at a dose of
treatment of adult patients with BRAF V600 (tolerable) 960 mg twice daily.
mutation-positive unresectable or metastatic
Grade 2 (intolerable) or
melanoma (see section 5.1). Grade 3
4.2 Posology and method of administration 1st occurrence of any Interrupt treatment until grade 0 –
grade 2 or 3 AE 1. Resume dosing at 720 mg twice
Treatment with vemurafenib should be initiated daily (or 480 mg twice daily if the
and supervised by a qualified physician dose has already been lowered).
experienced in the use of anticancer medicinal 2nd occurrence of any Interrupt treatment until grade 0 –
grade 2 or 3 AE or 1. Resume dosing at 480 mg twice
products.
persistence after treatment daily (or discontinue permanently
Before taking vemurafenib, patients must have interruption if the dose has already been
lowered to 480 mg twice daily).
BRAF V600 mutation-positive tumour status
3rd occurrence of any Discontinue permanently.
confirmed by a validated test (see sections 4.4
grade 2 or 3 AE or
and 5.1). persistence after 2nd dose
reduction
Posology
Grade 4
The recommended dose of vemurafenib is 960 1st occurrence of any Discontinue permanently or
mg (4 tablets of 240 mg) twice daily (equivalent grade 4 AE interrupt vemurafenib treatment
to a total daily dose of 1,920 mg). Vemurafenib until grade 0 – 1.
may be taken with or without food, but Resume dosing at 480 mg twice
daily (or discontinue permanently
consistent intake of both daily doses on an if the dose has already been
empty stomach should be avoided (see section lowered to 480 mg twice daily).
5.2). 2nd occurrence of any Discontinue permanently.
grade 4 AE or persistence
of any grade 4 AE after
1st dose reduction
In the event the patient develops Cutaneous No special dose adjustment is required in
Squamous Cell Carcinoma (cuSCC), it is patients aged > 65 years old.
recommended to continue the treatment without
Renal impairment
modifying the dose of vemurafenib (see sections
4.4 and 4.8). Limited data are available in patients with renal
impairment. A risk for increased exposure in
Table 1: Dose modification schedule based on
patients with severe renal impairment cannot be
the grade of any Adverse Events (AEs)
excluded. Patients with severe renal impairment
(a)
The intensity of clinical adverse events graded should be closely monitored (see sections 4.4
by the Common Terminology Criteria for and 5.2).
Adverse Events v4.0 (CTC-AE).
Hepatic impairment
Exposure-dependent QT prolongation was
Limited data are available in patients with
observed in an uncontrolled, open-label phase II
hepatic impairment. As vemurafenib is cleared
study in previously treated patients with
metastatic melanoma. Management of QTc by the liver, patients with moderate to severe
prolongation may require specific monitoring hepatic impairment may have increased
measures (see section 4.4). exposure and should be closely monitored (see
sections 4.4 and 5.2).
Table 2: Dose modification schedule based on
Paediatric population
prolongation of the QT interval
The safety and efficacy of vemurafenib in
QTc value Recommended dose
modification children less than 18 years old have not been
QTc>500 ms at baseline Treatment not recommended.
established. Currently available data are
described in sections 4.8, 5.1, and 5.2, but no
QTc increase meets values of Discontinue permanently. recommendation on a posology can be made.
both >500 ms and >60 ms
change from pre-treatment Non-Caucasian patients
values
1st occurrence of QTc>500 ms Temporarily interrupt treatment The safety and efficacy of vemurafenib has not
during treatment and change until QTc decreases below 500 been established in non-Caucasian patients. No
from pre-treatment value ms. data are available.
remains <60 ms See monitoring measures in
section 4.4. Method of administration
Resume dosing at 720 mg
twice daily (or 480 mg twice Vemurafenib is for oral use. The tablets are to be
daily if the dose has already swallowed whole with water. They should not
been lowered). be chewed or crushed.
2nd occurrence of QTc>500 ms Temporarily interrupt treatment
during treatment and change until QTc decreases below 500 4.3 Contraindications
from pre-treatment value ms. Hypersensitivity to the active substance or to
remains <60 ms See monitoring measures in any of the excipients listed in section 6.1.
section 4.4.
Resume dosing at 480 mg 4.4 Special Warnings and precautions for use
twice daily (or discontinue
permanently if the dose has Before taking vemurafenib, patients must have
already been lowered to 480
BRAF V600 mutation-positive tumour status
mg twice daily).
confirmed by a validated test. The efficacy and
3rd occurrence of QTc>500 ms Discontinue permanently.
during treatment and change
safety of vemurafenib in patients with tumours
from pre-treatment value expressing rare BRAF V600 mutations other
remains <60 ms than V600E and V600K have not been
Special population convincingly established (see section 5.1).
Vemurafenib should not be used in patients with
Elderly wild type BRAF malignant melanoma.
Hypersensitivity reaction Electrocardiogram (ECG) and electrolytes

(including magnesium) must be monitored in all
Serious hypersensitivity reactions, including patients before treatment with vemurafenib, after
anaphylaxis have been reported in association one month of treatment and after dose
with vemurafenib (see sections 4.3 and 4.8). modification.
Severe hypersensitivity reactions may include
Stevens-Johnson syndrome, generalised rash, Further monitoring is recommended in particular
erythema or hypotension. In patients who in patients with moderate to severe hepatic
experience severe hypersensitivity reactions, impairment monthly during the first 3 months of
vemurafenib treatment should be permanently treatment followed by every 3 months thereafter
discontinued. or more often as clinically indicated. Initiation
of treatment with vemurafenib is not
Dermatologic reactions
recommended in patients with QTc>500
Severe dermatologic reactions have been milliseconds (ms). If during treatment the QTc
reported in patients receiving vemurafenib, exceeds 500 ms, vemurafenib treatment should
including rare cases of Stevens-Johnson be temporarily interrupted, electrolyte
syndrome and toxic epidermal necrolysis in the abnormalities (including magnesium) should be
pivotal clinical trial. Drug reaction with corrected, and cardiac risk factors for QT
eosinophilia and systemic symptoms (DRESS) prolongation (e.g. congestive heart failure,
has been reported in association with bradyarrhythmias) should be controlled. Re-
vemurafenib in the post-marketing setting (see initiation of treatment should occur once the
section 4.8). In patients who experience a severe QTc decreases below 500 ms and at a lower
dermatologic reaction, vemurafenib treatment dose as described in table 2. Permanent
should be permanently discontinued. discontinuation of vemurafenib treatment is
recommended if the QTc increase meets values
Potentiation of radiation toxicity of both >500 ms and >60 ms change from pre-
Cases of radiation recall and radiation treatment values.
sensitization have been reported in patients Ophthalmologic reactions
treated with radiation either prior, during, or
subsequent to vemurafenib treatment. Most Serious ophthalmologic reactions, including
cases were cutaneous in nature but some cases uveitis, iritis and retinal vein occlusion, have
involving visceral organs had fatal outcomes been reported. Monitor patients routinely for
(see sections 4.5 and 4.8). ophthalmologic reactions.
Vemurafenib should be used with caution when Cutaneous Squamous Cell Carcinoma (cuSCC)
given concomitantly or sequentially with Cases of cuSCC (which include those classified
radiation treatment. as keratoacanthoma or mixed keratoacanthoma
QT prolongation subtype) have been reported in patients treated
with vemurafenib (see section 4.8).
Exposure-dependent QT prolongation was
observed in an uncontrolled, open-label phase II It is recommended that all patients receive a
study in previously treated patients with dermatologic evaluation prior to initiation of
metastatic melanoma (see section 4.8). QT therapy and be monitored routinely while on
prolongation may lead to an increased risk of therapy. Any suspicious skin lesions should be
ventricular arrhythmias including Torsade de excised, sent for dermatopathologic evaluation
Pointes. Treatment with vemurafenib is not and treated as per local standard of care. The
recommended in patients with uncorrectable prescriber should examine the patient monthly
electrolyte abnormalities (including during and up to six months after treatment for
magnesium), long QT syndrome or who are cuSCC. In patients who develop cuSCC, it is
taking medicinal products known to prolong the recommended to continue the treatment without
QT interval. dose adjustment. Monitoring should continue for
6 months following discontinuation of measurement of serum amylase and lipase).

vemurafenib or until initiation of another anti- Patients should be closely monitored when re-
neoplastic therapy. Patients should be instructed starting vemurafenib after an episode of
to inform their physicians upon the occurrence pancreatitis.
of any skin changes.
Liver injury
Non-Cutaneous Squamous Cell Carcinoma
(non-cuSCC) Liver injury, including cases of severe liver
injury, has been reported with vemurafenib (see
Cases of non-cuSCC have been reported in section 4.8). Liver enzymes (transaminases and
clinical trials where patients received alkaline phosphatase) and bilirubin should be
vemurafenib. Patients should undergo a head measured before initiation of treatment and
and neck examination, consisting of at least a monitored monthly during treatment, or as
visual inspection of oral mucosa and lymph node clinically indicated. Laboratory abnormalities
palpation prior to initiation of treatment and should be managed with dose reduction,
every 3 months during treatment. treatment interruption or with treatment
discontinuation (see sections 4.2 and 4.8).
In addition, patients should undergo a chest
Computerised Tomography (CT) scan, prior to Renal toxicity
treatment and every 6 months during treatment.
Renal toxicity, ranging from serum creatinine
Anal examinations and pelvic examinations (for elevations to acute interstitial nephritis and acute
women) are recommended before and at the end tubular necrosis, has been reported with
of treatment or when considered clinically vemurafenib. Serum creatinine should be
indicated. measured before initiation of treatment and
monitored during treatment as clinically
Following discontinuation of vemurafenib, indicated (see sections 4.2 and 4.8).
monitoring for non-cuSCC should continue for
up to 6 months or until initiation of another anti- Hepatic impairment
neoplastic therapy. Abnormal findings should be
managed according to clinical practices. No adjustment to the starting dose is needed for
patients with hepatic impairment. Patients with
New primary melanoma mild hepatic impairment due to liver metastases
without hyperbilirubinaemia may be monitored
New primary melanomas have been reported in according to the general recommendations.
clinical trials. Cases were managed with
There are only very limited data available in
excision and patients continued treatment patients with moderate to severe hepatic
without dose adjustment. Monitoring for skin impairment. Patients with moderate to severe
lesions should occur as outlined above for hepatic impairment may have increased
cutaneous squamous cell carcinoma.
exposure (see section 5.2). Thus close
Other malignancies monitoring is warranted especially after the first
few weeks of treatment as accumulation may
Based on mechanism of action, vemurafenib occur over an extended period of time (several
may cause progression of cancers associated weeks). In addition ECG monitoring every
with RAS mutations (see section 4.8). Carefully month during the first three months is
consider benefits and risks before administering recommended.
vemurafenib to patients with a prior or
concurrent cancer associated with RAS Renal impairment
mutation. No adjustment to the starting dose is needed for
Pancreatitis patients with mild or moderate renal impairment.
There are only limited data available in patients
Pancreatitis has been reported in vemurafenib- with severe renal impairment (see section 5.2).
treated subjects. Unexplained abdominal pain Vemurafenib should be used with caution in
should be promptly investigated (including
patients with severe renal impairment and when vemurafenib is used concomitantly with
patients should be closely monitored. warfarin.
Photosensitivity Vemurafenib may increase the plasma exposure
of medicinal products that are P-gp substrates.
Mild to severe photosensitivity was reported in Caution should be exercised when dosing
patients who received vemurafenib in clinical vemurafenib concurrently with P-gp substrates.
studies (see section 4.8). All patients should be Dose reduction and/or additional drug level
advised to avoid sun exposure while taking monitoring for P-gp substrate medicinal
vemurafenib. While taking the medicinal
products with narrow therapeutic index (NTI)
product, patients should be advised to wear
(e.g. digoxin, dabigatran etexilate, aliskiren)
protective clothing and use a broad spectrum may be considered if these medicinal products
Ultraviolet A (UVA)/Ultraviolet B (UVB) are used concomitantly with vemurafenib (see
sunscreen and lip balm (Sun Protection Factor ≥ section 4.5).
30) when outdoors to help protect against
sunburn. Effect of other medicinal products on
vemurafenib
For photosensitivity grade 2 (intolerable) or
greater, dose modifications are recommended Concomitant administration of strong inducers
(see section 4.2). of CYP3A4, P-gp and glucuronidation (e.g.
rifampicin, rifabutin, carbamazepine, phenytoin
Dupuytren's contracture and plantar fascial or St John's Wort [hypericin]) might lead to
fibromatosis decreased exposure of vemurafenib and should
Dupuytren's contracture and plantar fascial be avoided when possible (see section 4.5).
fibromatosis have been reported with Alternative treatment with less inducing
vemurafenib. The majority of cases were mild to potential should be considered to maintain the
moderate, but severe, disabling cases of efficacy of vemurafenib.
Dupuytren's contracture have also been reported Concurrent administration with ipilimumab
(see section 4.8).
In a Phase I trial, asymptomatic grade 3
Events should be managed with dose reduction
increases in transaminases (ALT/AST >5 x
with treatment interruption or with treatment ULN) and bilirubin (total bilirubin >3x ULN)
discontinuation (see section 4.2).
were reported with concurrent administration of
Effects of vemurafenib on other medicinal ipilimumab (3 mg/kg) and vemurafenib (960 mg
products BID or 720 mg BID). Based on these
preliminary data, the concurrent administration
Vemurafenib may increase the plasma exposure of ipilimumab and vemurafenib is not
of medicinal products predominantly recommended.
metabolised by CYP1A2 and decrease the
plasma exposure of medicines predominantly 4.5 Interaction with other medicinal products
metabolised by CYP3A4. Concomitant use of and other forms of interaction
vemurafenib with agents metabolized by Effects of vemurafenib on Drug Metabolizing
CYP1A2 and CYP3A4 with narrow therapeutic Enzymes
windows is not recommended. Dose adjustments
for medicinal products predominantly Results from an in vivo drug-drug interaction
metabolised via CYP1A2 or CYP3A4 should be study in metastatic melanoma patients
considered based on their therapeutic windows demonstrated that vemurafenib is a moderate
before concomitantly treating with vemurafenib CYP1A2 inhibitor and a CYP3A4 inducer.
(see sections 4.5 and 4.6).
Concomitant use of vemurafenib with agents
Exercise caution and consider additional INR metabolized by CYP1A2 with narrow
(International Normalised Ratio) monitoring therapeutic windows (e.g. agomelatine,
alosetron, duloxetine, melatonin, ramelteon,
tacrine, tizanidine, theophylline) is not unknown, but a risk for a clinically relevant
recommended. If co-administration cannot be effect on concomitantly administered CYP2C8
avoided, exercise caution, as vemurafenib may substrates cannot be excluded. Concomitant
increase plasma exposure of CYP1A2 substrate administration of CYP2C8 substrates with a
drugs. Dose reduction of the concomitant narrow therapeutic window should be made with
CYP1A2 substrate drug may be considered, if caution since vemurafenib may increase their
clinically indicated. concentrations.
Co-administration of vemurafenib increased the Due to the long half-life of vemurafenib, the full
plasma exposure (AUC) of caffeine (CYP1A2 inhibitory effect of vemurafenib on a
substrate) 2.6-fold. In another clinical trial, concomitant medicinal product might not be
vemurafenib increased Cmax and AUC of a single observed before 8 days of vemurafenib
2 mg dose of tizanidine (CYP1A2 substrate) treatment.
approximately 2.2-fold and 4.7-fold,
respectively. After cessation of vemurafenib treatment, a
washout of 8 days might be necessary to avoid
Concomitant use of vemurafenib with agents an interaction with a subsequent treatment.
metabolized by CYP3A4 with narrow
Radiation treatment
therapeutic windows is not recommended. If co-
administration cannot be avoided, it needs to be Potentiation of radiation treatment toxicity has
considered that vemurafenib may decrease been reported in patients receiving vemurafenib
plasma concentrations of CYP3A4 substrates (see sections 4.4 and 4.8). In the majority of
and thereby their efficacy may be impaired. On cases, patients received radiotherapy regimens
this basis, the efficacy of contraceptive pills greater than or equal to 2 Gy/day
metabolized by CYP3A4 used concomitantly (hypofractionated regimens).
with vemurafenib might be decreased. Dose
adjustments for CYP3A4 substrates with narrow Effects of vemurafenib on drug transport
therapeutic window may be considered, if systems
clinically indicated (see sections 4.4 and 4.6). In vitro studies have demonstrated that
In a clinical trial, co-administration of vemurafenib is an inhibitor of the efflux
vemurafenib decreased the AUC of midazolam transporters P-glycoprotein (P-gp) and breast
(CYP3A4 substrate) by an average 39% cancer resistance protein (BCRP).
(maximum decrease up to 80%). A clinical drug interaction study demonstrated
Mild induction of CYP2B6 by vemurafenib was that multiple oral doses of vemurafenib (960 mg
noted in vitro at a vemurafenib concentration of twice daily) increased the exposure of a single
10 µM. It is currently unknown whether oral dose of the P-gp substrate digoxin,
vemurafenib at a plasma level of 100 µM approximately 1.8 and 1.5 fold for digoxin
observed in patients at steady state AUClast and Cmax, respectively.
(approximately 50 µg/ml) may decrease plasma Caution should be exercised when dosing
concentrations of concomitantly administered vemurafenib concurrently with P-gp substrates
CYP2B6 substrates, such as bupropion. (e.g. aliskiren, ambrisentan, colchicine,
Co-administration of vemurafenib resulted in an dabigatran etexilate, digoxin, everolimus,
18% increase in AUC of S-warfarin (CYP2C9 fexofenadine, lapatinib, maraviroc, nilotinib,
substrate). Exercise caution and consider posaconazole, ranolazine, sirolimus, sitagliptin,
additional INR (international normalized ratio) talinolol, topotecan) and dose reduction of the
monitoring when vemurafenib is used concomitant medicinal product may be
concomitantly with warfarin (see section 4.4). considered, if clinically indicated. Consider
additional drug level monitoring for P-gp
Vemurafenib moderately inhibited CYP2C8 in substrate medicinal products with a narrow
vitro. The in vivo relevance of this finding is
therapeutic index (NTI) (e.g. digoxin, dabigatran In vitro studies have demonstrated that
etexilate, aliskiren) (see section 4.4). vemurafenib is a substrate of the efflux
transporters P-gp and BCRP. The effects of P-gp
The effects of vemurafenib on medicinal and BCRP inducers and inhibitors on
products that are substrates of BCRP are vemurafenib exposure are unknown. It cannot be
unknown. It cannot be excluded that excluded that vemurafenib pharmacokinetics
vemurafenib may increase the exposure of could be affected by medicines that influence P-
medicines transported by BCRP (e.g.
gp (e.g. verapamil, cyclosporine, ritonavir,
methotrexate, mitoxantrone, rosuvastatin).
quinidine, itraconazole) or BCRP (e.g.
Many anticancer medicinal products are cyclosporine, gefitinib).
substrates of BCRP and therefore there is a It is currently unknown whether vemurafenib is
theoretical risk for an interaction with a substrate also to other transport proteins.
vemurafenib.
4.6 Fertility, Pregnancy and lactation
The possible effect of vemurafenib on other
transporters is currently unknown. Women of childbearing potential /
Contraception in females
Effects of concomitant medicines on
vemurafenib Women of childbearing potential have to use
effective contraception during treatment and for
In vitro studies suggest that CYP3A4 at least 6 months after treatment.
metabolism and glucuronidation are responsible
for the metabolism of vemurafenib. Biliary Vemurafenib might decrease the efficacy of
excretion appears to be another important hormonal contraceptives (see section 4.5).
elimination pathway. Concomitant
administration of strong CYP3A4 inhibitors or Pregnancy
inducers or inhibitors/inducer of transport There are no data regarding the use of
protein activity may alter vemurafenib vemurafenib in pregnant women.
concentrations.
Vemurafenib revealed no evidence of
There are no clinical data available showing the teratogenicity in rat or rabbit embryo/foetuses
effect of strong inhibitors of CYP3A4 and/or (see section 5.3). In animal studies, vemurafenib
transport protein activity on vemurafenib was found to cross the placenta. Based on its
exposure. Vemurafenib should be used with mechanism of action, vemurafenib could cause
caution in combination with strong inhibitors of fetal harm when administered to a pregnant
CYP3A4, glucuronidation and/or transport woman. Vemurafenib should not be
proteins (e.g. ritonavir, saquinavir, administered to pregnant women unless the
telithromycin, ketoconazole, itraconazole, possible benefit to the mother outweighs the
voriconazole, posaconazole, nefazodone, possible risk to the foetus.
atazanavir).
Breast-feeding
In a clinical study, co-administration of a single
dose 960 mg of vemurafenib with rifampicin, It is not known whether vemurafenib is excreted
significantly decreased the plasma exposure of in human milk. A risk to the newborns/infants
vemurafenib by approximately 40%. cannot be excluded. A decision must be made
whether to discontinue breast-feeding or to
Concomitant administration of strong inducers discontinue vemurafenib therapy taking into
of P-gp, glucuronidation, and/or CYP3A4 (e.g. account the benefit of breast-feeding for the
rifampicin, rifabutin, carbamazepine, phenytoin child and the benefit of therapy for the woman.
or St John's Wort [Hypericum perforatum]) may
lead to suboptimal exposure to vemurafenib and Fertility
should be avoided. No specific studies with vemurafenib have been
conducted in animals to evaluate the effect on
fertility. However, in repeat-dose toxicity studies observed among phase II and phase III clinical
in rats and dogs, no histopathological findings trials. Within each frequency grouping, ADRs
were noted in reproductive organs in males and are presented in order of decreasing severity and
females (see section 5.3). were reported using NCI-CTCAE v 4.0
(common toxicity criteria) for assessment of
4.7 Effects on ability to drive and use toxicity.
machines
Vemurafenib has minor influence on the ability Table 3: ADRs occurring in patients treated
to drive and use machines. Patients should be with vemurafenib in the phase II or phase III
made aware of the potential fatigue or eye study and events originating from safety
problems that could be a reason for not driving. reports across all trials(1) and post-marketing
sources(2).
4.8 Undesirable Effects
Summary of the safety profile
System Very Common Uncomm Rare
The most common adverse drug reactions organ Common on
(ADR) of any grade (> 30%) reported with class
vemurafenib include arthralgia, fatigue, rash, Infections Folliculitis
photosensitivity reaction, alopecia, nausea and
diarrhea, headache, pruritus, vomiting, skin infestatio
papilloma and hyperkeratosis. The most ns
common (≥ 5%) Grade 3 ADRs were cuSCC, Neoplas SCC of the
(d)
Basal cell Non-
(1)(3
Chronic
keratoacanthoma, rash, arthralgia and gamma- ms skin , carcinoma, cuSCC myelomon
)
benign, keratoacan new ocytic
glutamyltransferase (GGT) increased. CuSCC malignan thoma, primary leukaemia
was most commonly treated by local excision. t and seborrhoei melanoma
( (2)(4)
,
3)
unspecifi c keratosis, pancreatic
Tabulated summary of adverse reactions ed skin adenocar
(5)
(including papilloma cinoma
ADRs which were reported in melanoma cysts and
patients are listed below by MedDRA body polyps)
system organ class, frequency and grade of Blood Neutropeni
severity. The following convention has been and a
used for the classification of frequency: lymphatic
system
Very common ≥ 1/10 disorders
Immune Sarcoidos
Common ≥ 1/100 to < 1/10 System is
(1)(2)(j)
Disorders
Uncommon ≥ 1/1,000 to < 1/100
Metabolis Decreased
Rare ≥ 1/10,000 to < 1/1,000 m and appetite
nutrition
Very rare < 1/10,000 disorders
th
Nervous Headache, 7 nerve
In this section, ADRs are based on results in 468 system dysgeusia, paralysis,
patients from a phase III randomised open label disorders dizziness neuropathy
study in adult patients with BRAF V600 peripheral
mutation-positive unresectable or stage IV Eye Uveitis, Retinal
melanoma, as well as a phase II single-arm study disorders vein
in patients with BRAF V600 mutation-positive occlusion,
iridocycliti
stage IV melanoma who had previously failed at s
least one prior systemic therapy (see section
Vascular Vasculitis
5.1). In addition ADRs originating from safety disorders
reports across all clinical trials and post-
Respirato Cough
marketing sources are reported. All terms ry,
included are based on the highest percentage
thoracic Investigat , ALT

(
and ions increased
c)
mediastin , alkaline
al phosphata
disorders se
(
Gastroint Diarrhoea, Pancreatit increased
c)
estinal vomiting, is
(2) , AST
(
disorders nausea, increased
c),
constipatio bilirubin
(
n increased
c)
GGT
Hepatobil Liver increased
(
(1)(2)
iary injury c
, weight
(g)
disorders decreased,
Skin and Photosensi Rash Toxic Drug electrocard
subcutan tivity papular, epidermal reaction iogram QT
eous reaction, panniculitis necrolysis with prolonged,
(e)
tissue actinic (including , eosinophil blood
disorders keratosis, erythema Stevens- ia and creatinine
(1)
rash, rash nodosum), Johnson systemic increased
(2) (h)
maculo- keratosis syndrome symptoms
(f) (1)(2)
papular, pilaris Injury, Potentiatio
pruritus, Poisonin n of
hyperkerat g, and Radiation
osis, Procedur toxicity
(1) (2)
erythema, al
(i)
palmar- Complica
plantar tions
erythrodys
aesthesia
syndrome, (1)
alopecia, Events originating from safety reports across
dry skin, all trials
sunburn
(2)
Musculos Arthralgia, Arthritis, Plantar Events originating from post-marketing
keletal myalgia, fascial sources.
and pain in fibromato (3)
connectiv extremity, sis
(1)(2)
Du A causal relationship between the medicinal
e tissue musculosk puytren's product and the adverse event is at least a
disorders eletal pain, contractur reasonable possibility.
(1)(2)
back pain e
(4)
Renal Acute Progression of pre-existing chronic
and interstitial myelomonocytic leukaemia with NRAS
(1)
urinary nephritis mutation.
(2) (h)
disorders ,
(5)
acute Progression of pre-existing pancreatic
tubular adenocarcinoma with KRAS mutation.
(1)
necrosis
(2) (h)
Description of selected adverse reactions
General Fatigue,
disorders pyrexia, Hepatic enzyme increase (c)
and oedema
administr peripheral, Liver enzyme abnormalities reported in the
ation site asthenia phase III clinical study are expressed below as
condition the proportion of patients who experienced a
s shift from baseline to a grade 3 or 4 liver
enzyme abnormalities:
• Very common: GGT
• Common: ALT, alkaline phosphatase, bilirubin New primary melanomas have been reported in
clinical trials. These cases were managed with
• Uncommon: AST
excision, and patients continued treatment
There were no increases to Grade 4 ALT, without dose adjustment. Monitoring for skin
alkaline phosphatase or bilirubin. lesions should occur as outlined in section 4.4.
Liver injury (g) Potentiation of radiation toxicity(i)
Based on the criteria for drug induced liver Cases reported include recall phenomenon,
injury developed by an international expert radiation skin injury, radiation pneumonitis,
working group of clinicians and scientists, liver radiation esophagitis, radiation proctitis,
injury was defined as any one of the following radiation hepatitis, cystitis radiation, and
laboratory abnormalities: radiation necrosis.
• ≥ 5x ULN ALT In a phase III clinical trial (MO25515, N=
3219), a higher incidence of potentiation of
• ≥ 2x ULN ALP (without other cause for ALP radiation toxicity was reported when
elevation) vemurafenib patients received radiation prior to
• ≥ 3x ULN ALT with simultaneous elevation of and during vemurafenib therapy (9.1%)
bilirubin concentration > 2x ULN compared to those patients who received
radiation and vemurafenib concomitantly (5.2
Cutaneous squamous cell carcinoma (d) (cuSCC) %) or to those whose radiation treatment was
Cases of cuSCC have been reported in patients prior to vemurafenib (1.5%).
treated with vemurafenib. The incidence of Hypersensitivity reactions (e)
cuSCC in vemurafenib-treated patients across
studies was approximately 20%. The majority of Serious hypersensitivity reactions, including
the excised lesions reviewed by an independent anaphylaxis have been reported in association
central dermatopathology laboratory were with vemurafenib. Severe hypersensitivity
classified as SCC-keratoacanthoma subtype or reactions may include Stevens-Johnson
with mixed-keratoacanthoma features (52%). syndrome, generalised rash, erythema or
Most lesions classified as “other” (43%) were hypotension. In patients who experience severe
benign skin lesions (e.g. verruca vulgaris, actinic hypersensitivity reactions, vemurafenib
keratosis, benign keratosis, cyst/benign cyst). treatment should be permanently discontinued
CuSCC usually occurred early in the course of (see section 4.4).
treatment with a median time to the first Dermatologic reactions (f)
appearance of 7 to 8 weeks. Of the patients who
experienced cuSCC, approximately 33% Severe dermatologic reactions have been
experienced > 1 occurrence with median time reported in patients receiving vemurafenib,
between occurrences of 6 weeks. Cases of including rare cases of Stevens-Johnson
cuSCC were typically managed with simple syndrome and toxic epidermal necrolysis in the
excision, and patients generally continued on pivotal clinical trial. In patients who experience
treatment without dose modification (see a severe dermatologic reaction, vemurafenib
sections 4.2 and 4.4). treatment should be permanently discontinued.
Non-cutaneous squamous cell carcinoma (non- QT prolongation
cuSCC)
Analysis of centralised ECG data from an open-
Cases of non-cuSCC have been reported in label uncontrolled phase II QT sub-study in 132
patients receiving vemurafenib while enrolled in patients dosed with vemurafenib 960 mg twice
clinical trials. Surveillance for non-cuSCC daily (NP22657) showed an exposure-dependent
should occur as outlined in section 4.4. QTc prolongation. The mean QTc effect
remained stable between 12-15 ms beyond the
New primary melanoma first month of treatment, with the largest mean
QTc prolongation (15.1 ms; upper 95% CI: 17.7 involving the skin, lung and eye. In majority of
ms) observed within the first 6 months (n=90 the cases, vemurafenib was maintained and the
patients). Two patients (1.5%) developed event of sarcoidosis either resolved or persisted.
treatment-emergent absolute QTc values >500
Special populations
ms (CTC Grade 3), and only one patient (0.8%)
exhibited a QTc change from baseline of >60 ms Elderly
(see section 4.4).
In the phase III study, ninety-four (28%) of 336
Acute kidney injury (h) patients with unresectable or metastatic
Cases of renal toxicity have been reported with melanoma treated with vemurafenib were ≥ 65
years. Older patients (≥ 65 years) may be more
vemurafenib ranging from creatinine elevations
likely to experience adverse reactions, including
to acute interstitial nephritis and acute tubular
necrosis, some observed in the setting of cuSCC, decreased appetite, and cardiac
disorders.
dehydration events. Serum creatinine elevations
were mostly mild (>1-1.5x ULN) to moderate Gender
(>1.5-3x ULN) and observed to be reversible in
nature (see table 4). During clinical trials with vemurafenib, grade 3
adverse reactions reported more frequently in
Table 4: Creatinine changes from baseline in females than males were rash, arthralgia and
the phase III study photosensitivity.
Vemurafenib Dacarbazine Paediatric population
(%) (%)
The safety of vemurafenib in children and
Change ≥ 1 grade from 27.9 6.1
baseline to any grade
adolescents has not been established. No new
safety signals were observed in a clinical study
Change ≥ 1 grade from 1.2 1.1 with six adolescent patients.
baseline to grade 3 or higher
• To grade 3 0.3 0.4 Reporting of suspected adverse reactions
• To grade 4 0.9 0.8 Reporting suspected adverse reactions after
authorisation of the medicinal product is
Table 5: Acute kidney injury cases in the
important. It allows continued monitoring of the
phase III study
benefit/risk balance of the medicinal product.
Vemurafenib Dacarbazine
4.9 Overdose
(%) (%)
There is no specific antidote for overdose of
Acute kidney injury cases* 10.0 1.4
vemurafenib. Patients who develop adverse
Acute kidney injury cases reactions should receive appropriate
associated with dehydration 5.5 1.0 symptomatic treatment. No cases of overdose
events have been observed with vemurafenib in clinical
Dose modified for acute trials. In case of suspected overdose,
2.1 0
kidney injury vemurafenib should be withheld and supportive
All percentages are expressed as cases out of care initiated.
total patients exposed to each medicinal product.
5. PHARMACOLOGICAL PROPERTIES
* Includes acute kidney injury, renal
5.1 Pharmacodynamic properties
impairment, and laboratory changes consistent
with acute kidney injury.
Pharmacotherapeutic group: Antineoplastic
Sarcoidosis (j) agents, protein kinase inhibitor
Cases of sarcoidosis have been reported in Mechanism of action and pharmacodynamic
patients treated with vemurafenib, mostly effects
Vemurafenib is an inhibitor of BRAF serine- used to assess the BRAF mutation status of
threonine kinase. Mutations in the BRAF gene DNA isolated from formalin-fixed, paraffin-
result in constitutive activation of BRAF embedded (FFPE) tumour tissue. It was
proteins, which can cause cell proliferation designed to detect the predominant BRAF
without associated growth factors. V600E mutation with high sensitivity (down to
5% V600E sequence in a background of wild
Preclinical data generated in biochemical assays type sequence from FFPE-derived DNA). Non-
demonstrated that vemurafenib can potently
clinical and clinical studies with retrospective
inhibit BRAF kinases with activating codon 600
sequencing analyses have shown that the test
mutations (table 6).
also detects the less common BRAF V600D
Table 6: Kinase inhibitory activity of mutations and V600K mutations with lower
vemurafenib against different BRAF kinases sensitivity. Of the specimens available from the
non-clinical and clinical studies (n=920), that
Kinase Anticipated frequency in Inhibitory were mutation-positive by the cobas test and
V600 mutation-positive Concentration 50 (nM)
melanoma (t)
additionally analyzed by sequencing, no
specimen was identified as being wild type by
BRAFV600E 87.3% 10
both Sanger and 454 sequencing.
BRAFV600K 7.9% 7
Clinical efficacy and safety
V600R
BRAF 1% 9
The efficacy of vemurafenib has been evaluated
BRAFV600D <0.2% 7 in 336 patients from a phase III clinical trial
BRAFV600G <0.1% 8 (NO25026) and 278 patients from two phase II
clinical trials (NP22657 and MO25743). All
V600M
BRAF <0.1% 7 patients were required to have advanced
BRAFV600A <0.1% 14 melanoma with BRAF V600 mutations
according to the cobas 4800 BRAF V600
BRAFWT N/A 39 Mutation Test.
(t)
Estimated from 16,403 melanomas with Results from the Phase III study (NO25026) in
annotated BRAF codon 600 mutations in the previously untreated patients
public COSMIC database, release 71 (November
2014). An open-label, multicentre, international,
randomised phase III study supports the use of
This inhibitory effect was confirmed in the ERK vemurafenib in previously untreated patients
phosphorylation and cellular anti-proliferation with BRAF V600E mutation-positive
assays in available melanoma cell lines unresectable or metastatic melanoma. Patients
expressing V600-mutant BRAF. In cellular anti- were randomised to treatment with vemurafenib
proliferation assays the inhibitory concentration (960 mg twice daily) or dacarbazine (1000
50 (IC50) against V600 mutated cell lines mg/m2 on day 1 every 3 weeks).
(V600E, V600R, V600D and V600K mutated
cell lines) ranged from 0.016 to 1.131 μM A total of 675 patients were randomised to
whereas the IC50 against BRAF wild type cell vemurafenib (n=337) or dacarbazine (n=338).
lines were 12.06 and 14.32 μM, respectively. Most patients were male (56%) and Caucasian
(99%), the median age was 54 years (24% were
Determination of BRAF mutation status ≥ 65 years), all patients had ECOG performance
Before taking vemurafenib, patients must have status of 0 or 1, and the majority of patients had
BRAF V600 mutation-positive tumour status stage M1c disease (65%). The co-primary
confirmed by a validated test. In the phase II and efficacy endpoints of the study were overall
phase III clinical trials, eligible patients were survival (OS) and progression-free survival
identified using a real-time polymerase chain (PFS).
reaction assay (the cobas 4800 BRAF V600
Mutation Test). This test has CE marking and is
At the pre-specified interim analysis with a

December 30, 2010 data cut-off, significant
improvements in the co-primary endpoints of
OS (p<0.0001) and PFS (p<0.0001) (unstratified
log-rank test) were observed. Upon Data Safety
Monitoring Board (DSMB) recommendation,
those results were released in January 2011 and
the study was modified to permit dacarbazine
patients to cross over to receive vemurafenib.
Post-hoc survival analyses were undertaken
thereafter as described in table 7.
Table 7: 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 Treatment Number of Hazard Ratio Number of Table 8 shows the treatment effect for all pre-
dates deaths (%) (95% CI) cross-over
patients (%)
specified stratification variables which are
established as prognostic factors.
December dacarbazine 75 (22) 0.37 (0.26, 0 (not
30, 2010 0.55) applicable) Table 8: Overall survival in previously
vemurafenib 43 (13)
untreated patients with BRAF V600
March 31, dacarbazine 122 (36) 0.44 (0.33, 50 (15%) mutation-positive melanoma by LDH,
2011 0.59) (w)
tumour stage and ECOG status (post hoc
vemurafenib 78 (23)
analysis, December 20, 2012 cut-off, censored
October dacarbazine 175 (52) 0.62 (0.49, 81 (24%) results at time of cross over)
3, 2011 0.77) (w)
vemurafenib 159 (47) Stratification N Hazard Ratio 95% Confidence
February dacarbazine 200 (59) 0.70 (0.57, 83 (25%) variable Interval
1, 2012 0.87) (w) LDH normal 391 0.88 0.67; 1.16
vemurafenib 199 (59)
December dacarbazine 236 (70) 0.78 (0.64, 84 (25%) LDH >ULN 284 0.57 0.44; 0.76
20, 2012 0.94) (w)
vemurafenib 242 (72) Stage 234 1.05 0.73; 1.52
IIIc/M1A/M1B
Stage MIC 441 0.64 0.51; 0.81
(w)
Censored results at time of cross-over
ECOG PS=0 459 0.86 0.67; 1.10
Non-censored results at time of cross-over:
March 31 2011: HR (95% CI) = 0.47 (0.35, ECOG PS=1 216 0.58 0.42; 0.9
0.62); October 3 2011: HR (95% CI) = 0.67
(0.54, 0.84); February 1 2012: HR (95% CI) = LDH: Lactate Dehydrogenase, ECOG PS:
0.76 (0.63, 0.93); December 20 2012: HR (95% Eastern Cooperative Oncology Group
CI) = 0.79 (0.66, 0.95) Performance Status
Figure 1: Kaplan-Meier curves of overall Table 9 shows the overall response rate and
survival – previously untreated patients progression-free survival in previously untreated
(December 20, 2012 cut-off) patients with BRAF V600 mutation-positive
melanoma.
Table 9: Overall response rate and
progression-free survival in previously
untreated patients with BRAF V600 Results from the phase II study (NP22657) in
mutation-positive melanoma patients who failed at least one prior therapy
vemurafenib dacarbazine p-value (x) A phase II single-arm, multi-centre,
multinational study was conducted in 132
December 30, 2010 data cut-off date (y) patients who had BRAF V600E mutation-
Overall Response 48.4% positive metastatic melanoma according to the
Rate (41.6%, 5.5% cobas 4800 BRAF V600 Mutation Test and had
(95% CI) 55.2%) (2.8%, 9.3%) <0.0001 received at least one prior therapy. The median
Progression-free age was 52 years with 19% of patients being
survival older than 65 years. The majority of patients was
Hazard Ratio 0.26 male (61%), Caucasian (99%), and had stage
(95% CI) (0.20, 0.33) <0.0001 M1c disease (61%). Forty-nine percent of
Number of patients failed ≥ 2 prior therapies.
events (%) 104 (38%) 182 (66%)
Median PFS With a median follow-up of 12.9 months (range,
(months) 5.32 1.61 0.6 to 20.1), the primary endpoint of confirmed
(95% CI) (4.86, 6.57) (1.58, 1.74) best overall response rate (CR + PR) as assessed
February 01, 2012 data cut-off date (z) by an independent review committee (IRC) was
53% (95% CI: 44%, 62%). Median overall
Progression-free survival was 15.9 months (95% CI: 11.6, 18.3).
survival
Hazard Ratio 0.38
The overall survival rate at 6 months was 77%
(95% CI) (0.32, 0.46) <0.0001 (95% CI: 70%, 85%) and at 12 months was 58%
Number of
(95% CI: 49%, 67%).
events (%) 277 (82%) 273 (81%)
Nine of the 132 patients enrolled into NP22657
Median PFS had V600K mutation-positive tumours
(months) 6.87 1.64
(95% CI) (6.14, 6.97) (1.58, 2.07) according to retrospective Sanger sequencing.
(x) Amongst these patients, 3 had a PR, 3 had SD, 2
Unstratified log-rank test for PFS and Chi-
had PD and one was not evaluable.
squared test for Overall Response Rate.
(y) Results from the phase II study (MO25743) in
As of December 30, 2010, a total of 549
patients with brain metastases
patients were evaluable for PFS and 439 patients
were evaluable for overall response rate. A single-arm, multicentre study (N = 146) of
(z) vemurafenib was conducted in adult patients
As of February 01, 2012, a total of 675
with histologically confirmed metastatic
patients were evaluable for the post-hoc analysis
melanoma harbouring the BRAF V600 mutation
update of PFS.
(according to the cobas 4800 BRAF V600
A total of 57 patients out of 673 whose tumours Mutation Test) and with brain metastases. The
were analysed retrospectively by sequencing study included two simultaneously enrolling
were reported to have BRAF V600K mutation- cohorts:
positive melanoma in NO25026. Although
- Cohort 1 with previously untreated patients (N
limited by the low number of patients, efficacy
= 90): Patients who had not received previous
analyses among these patients with V600K-
treatment for brain metastases; prior systemic
positive tumours suggested similar treatment
therapy for metastatic melanoma was allowed,
benefit of vemurafenib in terms of OS, PFS and
excluding BRAF inhibitors and MEK inhibitors.
confirmed best overall response. No data are
available in patients with melanoma harbouring - Cohort 2 with previously treated patients (N =
rare BRAF V600 mutations other than V600E 56): Patients who had been previously treated
and V600K. for their brain metastases and had progressed
following this treatment. For patients treated
with stereotactic radiotherapy (SRT) or surgery,
a
a new RECIST-assessable brain lesion must Best overall confirmed response rate as
have developed following this prior therapy. assessed by independent review committee,
number of responders n (%)
A total of 146 patients were enrolled. The
b
majority of patients were male (61.6%), and Two-sided 95% Clopper-Pearson Confidence
Caucasian (92.5%), and the median age was 54 Interval (CI)
years (range 26 to 83 years), similarly c
distributed between the two cohorts. The median Duration of response as assessed by an
number of brain target lesions at baseline was 2 Independent Review Committee
(range 1 to 5), in both cohorts. d
Kaplan-Meier estimate
e
The primary efficacy objective of the study was Assessed by investigator
best overall response rate (BORR) in the brain
of metastatic melanoma patients with previously Paediatric population
untreated brain metastases, as assessed by an Results from the phase I study (NO25390) in
independent review committee (IRC). paediatric patients
Secondary objectives included an evaluation of A phase I dose-escalation study evaluating the
the efficacy of vemurafenib using BORR in the use of vemurafenib in six adolescent patients
brain of previously treated patients, duration of with stage IIIC or IV BRAF V600 mutation
response (DOR), progression-free survival (PFS) positive melanoma was conducted. All patients
and overall survival (OS) in patients with treated were at least 15 years of age and weighed
melanoma metastatic to the brain (see table 10). at least 45 kg. Three patients were treated with
Table 10: Efficacy of vemurafenib in patients vemurafenib 720 mg twice daily, and three
with brain metastases patients were treated with vemurafenib 960 mg
twice daily. The maximum tolerated dose could
Cohort 1 Cohort 2 Total not be determined. Although transient tumour
No previous Previously regressions were seen, the best overall response
treatment treated n = 146
n = 90 n = 56
rate (BORR) was 0% (95% CI: 0%, 46%) based
on confirmed responses. The study was
BORRa in brain
Responders n (%) terminated due to low enrollment. See section
(95% CI)b 16 (17.8%) 10 (17.9%) 26 (17.8%) 4.2 for information on paediatric use.
(10.5, 27.3) (8.9, 30.4) (12.0, 25.0)
5.2 Pharmacokinetic properties
DORc in brain (n)
Median (months) (n = 16) (n = 10) (n = 26) Vemurafenib is a Class IV substance (low
(95% CI)d 4.6 6.6 5.0
solubility and permeability), using the criteria
(2.9, 6.2) (2.8, 10.7) (3.7, 6.6)
described in the Biopharmaceutics Classification
BORR extra-
cranial n (%)a 26 (32.9%) 9 (22.5%) 35 (29.4%)
System. The pharmacokinetic parameters for
vemurafenib were determined using non-
PFS - overall
Median (months)e compartmental analysis in a phase I and phase
(95% CI)d 3.7 3.7 3.7 III studies (20 patients after 15 days of dosing at
(3.6, 3.7) (3.6, 5.5) (3.6, 3.7) 960 mg twice daily, and 204 patients in steady
PFS - brain only state day 22) as well as by population PK
Median (months)e analysis using pooled data from 458 patients.
(95% CI)d 3.7 4.0 3.7 Among these patients, 457 were Caucasians.
(3.6, 4.0) (3.6, 5.5) (3.6, 4.2)
OS Absorption
Median (months)
(95% CI)d 8.9 9.6 9.6 The bioavailability at steady state ranged
(6.1, 11.5) (6.4, 13.9) (6.9, 11.5) between 32 and 115% (mean 64%) relative to an
intravenous microdose, in a phase I study with
uncontrolled food conditions in 4 patients with
BRAF V600 positive malignancies.
Vemurafenib is absorbed with a median Tmax of Distribution

approximately 4 hours following a single 960
mg dose (four 240 mg tablets). Vemurafenib The population apparent volume of distribution
exhibits high inter-patient variability. In the for vemurafenib in metastatic melanoma patients
phase II study, AUC0-8h and Cmax at day 1 were is estimated to be 91 L (with 64.8% between
22.1 ± 12.7 µg·h/mL and 4.1 ± 2.3 µg/mL. patient variability). It is highly bound to human
Accumulation occurs upon multiple twice daily plasma proteins in vitro (>99%).
dosing of vemurafenib. In the non- Biotransformation
compartmental analysis, after dosing with 960
mg vemurafenib twice daily the Day 15 / Day 1 The relative proportions of vemurafenib and its
ratio ranged from 15- to 17-fold for AUC, and metabolites were characterised in a human mass
13- to 14-fold for Cmax, yielding AUC0-8h and balance study with a single dose of 14C-labeled
Cmax of 380.2 ± 143.6 µg·h/mL and 56.7 ± 21.8 vemurafenib administered orally. CYP3A4 is the
µg/mL, respectively, under steady-state primary enzyme responsible for the metabolism
conditions. of vemurafenib in vitro. Conjugation metabolites
(glucuronidation and glycosylation) were also
Food (high fat meal) increases the relative identified in humans. However, the parent
bioavailability of a single 960 mg dose of compound was the predominant component
vemurafenib. The geometric mean ratios (95%) in plasma. Although metabolism does not
between the fed and fasted states for Cmax and appear to result in a relevant amount of
AUC were 2.5 and 4.6 to 5.1 fold, respectively. metabolites in plasma, the importance of
The median Tmax was increased from 4 to 7.5 metabolism for excretion cannot be excluded.
hours when a single vemurafenib dose was taken
with food. Elimination
The effect of food on steady state vemurafenib The population apparent clearance of
exposure is currently unknown. Consistent vemurafenib in patients with metastatic
intake of vemurafenib on an empty stomach may melanoma is estimated to be 29.3 L/day (with
lead to significantly lower steady state exposure 31.9% between patient variability). The
than consistent intake of vemurafenib with or a population elimination half-life estimated by the
short time after a meal. Occasional intake of population PK analysis for vemurafenib is 51.6
vemurafenib on an empty stomach is expected to hours (the 5th and 95th percentile range of the
have limited influence on steady state exposure individual half-life estimates is 29.8 - 119.5
due to the high accumulation of vemurafenib at hours).
steady state. Safety and efficacy data from In the human mass balance study with
pivotal studies were collected from patients vemurafenib administered orally, on average
taking vemurafenib with or without food. 95% of the dose was recovered within 18 days.
Variability in exposure may also occur due to The majority of vemurafenib-related material
differences in gastro-intestinal fluid content, (94%) was recovered in faeces, and <1% in
volumes, pH, motility and transition time and urine. Renal elimination does not appear to be of
bile composition. importance for vemurafenib elimiation, whereas
biliary excretion of unchanged compound may
At steady state, the mean vemurafenib exposure be an important route of elimination..
in plasma is stable during the 24-hour interval as Vemurafenib is a substrate and inhibitor of P-
indicated by the mean ratio of 1.13 between the gp in vitro.
plasma concentrations before and 2-4 hours after
the morning dose. Following oral dosing, the Special populations
absorption rate constant for the population of Elderly
metastatic melanoma patients is estimated to be
0.19 hr-1 (with 101% between patient Based on the population PK analysis, age has no
variability). statistically significant effect on vemurafenib
pharmacokinetics.
Gender dog. Reversible toxic effects (hepatocellular

necrosis and degeneration) in the liver at
The population pharmacokinetic analysis exposures below the anticipated clinical
indicated a 17% greater apparent clearance exposure (based on AUC comparisons) were
(CL/F) and a 48% greater apparent volume of noted in the 13-week dog study. Focal bone
distribution (V/F) in males than in females. It is marrow necrosis was noted in one dog in a
unclear whether this is a gender or a body size prematurely terminated 39-week BID dog study
effect. However, the differences in exposure are
at exposures similar to the anticipated clinical
not large enough to warrant dose adjustment
exposure (based on AUC comparisons). In an in
based on body size or gender.
vitro bone marrow cytotoxicity study, slight
Renal impairment cytotoxicity was observed in some lympho-
haematopoietic cell populations of rat, dog and
In the population pharmacokinetic analysis using human at clinically relevant concentrations.
data from clinical trials in patients with
metastatic melanoma, mild and moderate renal Vemurafenib was shown to be phototoxic, in
impairment did not influence the apparent vitro, on cultured murine fibroblasts after UVA
clearance of vemurafenib (creatinine clearance irradiation, but not in vivo in a rat study at doses
>40 ml/min). There are no data in patients with up to 450 mg/kg/day (at exposures below the
severe renal impairment (see sections 4.2 and anticipated clinical exposure (based on AUC
4.4). comparison). No specific studies with
vemurafenib have been conducted in animals to
Hepatic impairment evaluate the effect on fertility. However, in
Based on preclinical data and the human mass repeat-dose toxicity studies, no histopathological
balance study, major part of vemurafenib is findings were noted on reproductive organs in
eliminated via the liver. In the population males and females in rats and dogs at doses up
pharmacokinetic analysis using data from to 450 mg/kg/day (at exposures below the
clinical trials in patients with metastatic anticipated clinical exposure based on AUC
melanoma, increases in AST and ALT up to comparison). No teratogenicity was observed in
three times the upper limit of normal did not embryofoetal development studies in rats and
influence the apparent clearance of vemurafenib. rabbits at doses up to respectively 250
Data are insufficient to determine the effect of mg/kg/day and 450 mg/kg/day leading to
metabolic or excretory hepatic impairment on exposures below the anticipated clinical
vemurafenib pharmacokinetics (see sections 4.2 exposure (based on AUC comparison).
and 4.4). However, exposures in the embryofoetal
development studies were below the clinical
Paediatric population exposure based on AUC comparison, it is
Limited pharmacokinetic data from six therefore difficult to define to what extent these
adolescent patients aged between 15 and 17 results can be extrapolated to humans. Therefore
years with stage IIIC or IV BRAF V600 an effect of vemurafenib on the foetus cannot be
mutation positive melanoma suggest that excluded. No studies were performed regarding
vemurafenib pharmacokinetic characteristics in pre- and postnatal development.
adolescents are generally similar to those in No signs of genotoxicity were identified in in
adults. See section 4.2 for information on vitro assays (bacterial mutation [AMES Assay],
paediatric use. human lymphocyte chromosome aberration) nor
5.3 Preclinical safety data in the in vivo rat bone marrow micronucleus test
conducted with vemurafenib.
The preclinical safety profile of vemurafenib
was assessed in rats, dogs, and rabbits. Carcinogenicity studies have not been conducted
with vemurafenib.
Repeat-dose toxicology studies identified the
liver and bone marrow as target organs in the
6. PHARMACEUTICAL PARTICULARS Dist- Ahmedabad. Gujarat (India)

MFG. LIC NO: G/25A/4795-A
6.1 List of excipients
Tablet core
Croscarmellose sodium
Colloidal anhydrous silica
Magnesium stearate
Hydroxypropylcellulose
Film-coating
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogol 3350
Talc
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Store in the original package in order to protect
from moisture.
6.5 Nature and contents of container
Aluminium/Aluminium perforated unit dose
blisters.
Pack-size: 56 x 1 film-coated tablets (7 blisters
of 8 x 1 tablet)
6.6 Special precautions for disposal and
other handling
Any unused medicinal product or waste material
should be disposed of in accordance with local
requirements.
7. MANUFACTURER:
Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
At:388/34, Changodar Industrial Estate
Changodar- 382 210

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Grade (CTC-AE) (a) Recommended dose

Hypersensitivity reaction Electrocardiogram (ECG) and electrolytes

6 months following discontinuation of measurement of serum amylase and lipase).

thoracic Investigat , ALT

At the pre-specified interim analysis with a

Vemurafenib is absorbed with a median Tmax of Distribution

Gender dog. Reversible toxic effects (hepatocellular

6. PHARMACEUTICAL PARTICULARS Dist- Ahmedabad. Gujarat (India)

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