NEXAVAR®

Sorafenib (tosylate) tablets, film-coated 200 mg

Name Of The Medicine

NEXAVAR is a multikinase inhibitor targeting several serine/threonine and
receptor tyrosine kinases.

Sorafenib tosylate is
4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]-ureido}phenoxy)-N2-methylpyridine-2-carboxamide
4-methylbenzenesulfonate. The empirical formula is C₂₁H₁₆ClF₃N₄O₃
x C₇H₈O₃S and the CAS number is 28844-1-73-01
(sorafenib) and 475207-59-1 (sorafenib tosylate).

Sorafenib tosylate has the following structural formula:-

Description

Sorafenib tosylate is a white to yellowish or brownish solid with a
molecular weight of 637 g/mole. Sorafenib tosylate is practically insoluble in
aqueous media, slightly soluble in ethanol and soluble in PEG 400.

In addition to sorafenib tosylate, each NEXAVAR tablet contains the
following inactive ingredients: croscarmellose sodium, microcrystalline
cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, macrogol,
titanium dioxide, iron oxide red.

Pharmacology

Pharmacological actions

Sorafenib is a multikinase inhibitor that targets various receptor tyrosine
kinases and RAF kinases (serine/threonine kinases) associated with tumour
growth. Sorafenib inhibits the activity of targets present in tumour cells
(Raf-1 [CRAF], BRAF, V600E BRAF, KIT and FLT-3) and in the tumour vasculature
(Raf-1 [CRAF], VEGFR-2, VEGFR-3 and PDGFR-β). Sorafenib has been shown to
inhibit tumour cell proliferation in vitro, and to inhibit the growth
of mouse renal cell carcinoma (RENCA) allografts, human renal cell carcinoma
(A498) xenografts, as well as a broad range of other human tumour xenografts,
in nude mice. Inhibition of tumour growth was accompanied by a reduction in
tumour angiogenesis.

Pharmacokinetics

After administration of NEXAVAR tablets, the mean relative bioavailability
is 38 - 49% when compared to an oral solution. Absolute bioavailability has
not been determined.

The elimination half-life of sorafenib is approximately 25-48 hours.
Multiple dosing of NEXAVAR for 7 days results in a 3 to 7 fold accumulation
compared to single dose administration.

Steady state plasma sorafenib concentrations are achieved within 7 days,
with a peak to trough ratio of mean concentrations of less than 2.

Absorption and Distribution

Following oral administration, sorafenib reaches peak plasma levels in
approximately 3 hours. When given with a moderate-fat meal, bioavailability is
similar to that in the fasted state. With a high-fat meal, sorafenib
bioavailability is reduced by 29% compared to administration in the fasted
state.

Mean C_max and AUC increase less than proportionally beyond doses
of 400 mg administered orally twice daily.

In vitro binding of sorafenib to human plasma proteins is 99.5%.

Metabolism and Elimination

Sorafenib is metabolized primarily in the liver undergoing oxidative
metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9.

Sorafenib accounts for approximately 70 - 85% of the circulating analytes
in plasma at steady state. Eight metabolites of sorafenib have been
identified, of which five have been detected in plasma. The main circulating
metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro
potency similar to that of sorafenib and comprises approximately 9 - 16% of
circulating analytes at steady state.

Following oral administration of a 100 mg dose of a solution formulation of
sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose
excreted in faeces, and 19% of the dose excreted in urine as glucuronidated
metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in
faeces but not in urine.

Renal Impairment

In patients with normal renal function (N = 71) and in patients with mild
renal impairment (CrCl > 50 - -80 mL/min, N = 24) or moderate renal impairment
(CrCl 30 - 50 mL/min, N = 4), there was no relationship observed between
steady state sorafenib AUC and renal function at doses of 400 mg twice daily.
The pharmacokinetics of sorafenib has not been studied in patients with severe
renal impairment (CrCl < 30 mL/min) or patients undergoing dialysis.

Hepatic Impairment

Sorafenib is cleared primarily by the liver.

In patients with mild (Child-Pugh A, N = 14) or moderate (Child-Pugh B, N =
8) hepatic impairment, exposure values were within the range observed in
patients without hepatic impairment. The pharmacokinetics of sorafenib have
not been studied in patients with severe (Child-Pugh C) hepatic impairment
(see PRECAUTIONS).

Clinical Studies

The safety and efficacy of NEXAVAR in the treatment of advanced renal cell
carcinoma (RCC) were studied in the following 2 randomised controlled clinical
trials.

Study 11213, TARGET (Treatment Approaches in Renal cancer Global
Evaluation Trial)

The TARGET study was a Phase III multi-centre, randomised, double blind,
placebo-controlled trial in 903 patients with advanced renal cell carcinoma
who had received prior systemic therapy. Primary study end points included
overall survival and progression-free survival (PFS). Tumour response rate was
a secondary endpoint.

Patients were randomised to NEXAVAR 400 mg twice daily (N = 451) or to
placebo (N = 452). Baseline demographics and patient characteristics were well
balanced for both treatment groups. Approximately half of the patients had an
ECOG performance status of 0 and half of the patients were in the low MSKCC
(Memorial Sloan Kettering Cancer Centre) prognostic group.

Two planned interim analyses of survival were conducted. In the first
analysis based on 220 deaths, the estimated hazard ratio (risk of death with
NEXAVAR compared to placebo) was 0.72 (95% CI, 0.55-0.95; p= 0.018. The
threshold for statistical significance of the interim analysis was p <
0.0005). As of November 30, 2005, 367 deaths were reported, comprising 68% of
the protocol-specified 540 survival events, there was an estimated 30%
improvement in overall survival for patients receiving NEXAVAR compared to
placebo. A total of 216 placebo patients had crossed over to NEXAVAR
treatment. The median overall survival for the NEXAVAR and placebo group was
19.3 months and 15.9 months, respectively. The estimated hazard ratio (risk of
death with sorafenib compared to placebo) was 0.77 (95% CI: 0.63- 0.95;
p=0.015. The threshold for statistical significance of the interim analysis
was p < 0.0094).

Progression Free Survival (PFS) in the intent-to-treat population was
evaluated by blinded independent radiological review using RECIST criteria.
Figure 1 depicts Kaplan-Meier curves for PFS. The PFS analysis was a two-sided
Log-Rank test stratified by Motzer/MSKCC prognostic risk category¹
and country.

Figure 1: Kaplan-Meier Curves for Progression-Free Survival

NOTE: HR is from Cox regression model with the following covariates:
Motzer/MSKCC prognostic risk category¹ and country. P-value is from
two-sided Log-Rank test stratified by Motzer/MSKCC prognostic risk category¹
and country.

The PFS analysis included 769 patients randomised to NEXAVAR 400 mg twice
daily (N=384) or to placebo (N=385). The median progression free survival
(PFS) was double for patients randomised to NEXAVAR (167 days) compared to
patients randomised to placebo (84 days), (HR=0.44; 95% CI: 0.35-0.55;
p<0.000001).

A series of patient subsets were examined in exploratory univariate
analyses of PFS. These results are shown in Figure 2. The effect of NEXAVAR on
PFS was consistent across these subsets, including patients with no prior IL-2
or Interferon therapy (N = 137), for whom the median PFS was 172 days on
NEXAVAR compared to 85 days on placebo.

Figure 2:Progression-Free Survival in Patient
Subgroups (Hazard Ratio and 95% Cl for NEXAVAR : Placebo)

Best overall tumour response was determined by investigator radiological
review according to RECIST criteria. In the NEXAVAR group 1 patient (0.2%) had
a complete response, 43 patients (9.5%) had a partial response, and 333
patients (73.8%) had stable disease. In the placebo group 0 patients (0%) had
a complete response, 8 patients (1.8%) had a partial response, and 239
patients (52.9%) had stable disease.

In Study 11213, there were 41 deaths within 30 days of study medicine: 18
in the placebo group and 23 in the sorafenib group. Only 4 of the deaths in
the sorafenib group occurred during treatment. The cause of death was reported
as progression of RCC in 12 placebo patients and 18 sorafenib patients. The
study was designed so that all patients were eligible for unblinding on
progressive disease (PD), and those on the sorafenib arm were eligible to
continue sorafenib treatment beyond documentation of PD per investigator
discretion. Four of 23 deaths in the sorafenib group occurred after documented
PD and continued open label sorafenib treatment. Furthermore, the mean
duration of therapy in Study 11213 was 135.8 days for the sorafenib group and
93.8 days for the placebo group.

NEXAVAR demonstrated no overall deterioration in kidney-cancer specific
symptoms (FKSI-10) or health-related quality of life compared to placebo.

Study 100391

Study 100391 was a Phase II discontinuation trial in patients with
metastatic malignancies including RCC. The primary endpoint was percentage of
randomised patients (N=65) remaining progression-free at 24 weeks.
Progression-free survival was significantly longer in the NEXAVAR group (163
days) than in the placebo group (41 days) (p=0.0001, HR= 0.29). The
progression-free rate was significantly higher in patients randomised to
NEXAVAR (50%) than in the placebo patients (18%) (p=0.0077).

Indications

NEXAVAR is indicated for the treatment of patients with advanced renal cell
carcinoma.

Contraindications

NEXAVAR is contraindicated in patients with known severe hypersensitivity
to sorafenib or any of the excipients in the tablet.

Precautions

Pregnancy and Lactation

Women should avoid becoming pregnant while on therapy. Women of
childbearing potential must be apprised of the potential hazard to the fetus,
which includes severe malformation (teratogenicity), failure to thrive and
fetal death (embryotoxicity). (See Use in Pregnancy).

NEXAVAR should not be used during pregnancy. Breastfeeding should be
discontinued during NEXAVAR therapy. (See Use in Lactation).

Effects on ability to drive and use machines

No studies on the effects of sorafenib on the ability to drive or use
machines have been performed. There is no evidence that sorafenib affects the
ability to drive or operate machinery.

Dermatological Toxicities

Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and rash
represent the most common adverse medicine reactions with NEXAVAR. Rash and
hand-foot skin reaction are usually CTC (National Cancer Institute Common
Toxicity Criteria) Grade 1 and 2 and generally appear during the first six
weeks of treatment with NEXAVAR. Management of dermatologic toxicities may
include topical therapies for symptomatic relief, temporary treatment
interruption and/or dose modification of NEXAVAR, or in severe or persistent
cases, permanent discontinuation of NEXAVAR (see ADVERSE EFFECTS).

Hypertension

An increased incidence of hypertension was observed in NEXAVAR-treated
patients. Hypertension was usually mild to moderate, occurred early in the
course of treatment, and was amenable to management with standard
antihypertensive therapy. Blood pressure should be monitored regularly and
treated, if required, in accordance with standard medical practice. In cases
of severe or persistent hypertension, or hypertensive crisis despite adequate
antihypertensive therapy, permanent discontinuation of NEXAVAR should be
considered (see ADVERSE EFFECTS).

Haemorrhage

An increase in the risk of bleeding may occur following NEXAVAR
administration. The incidence of severe bleeding events is uncommon. If any
bleeding event necessitates medical intervention, it is recommended that
permanent discontinuation of NEXAVAR should be considered (see ADVERSE
EFFECTS).

Warfarin

Infrequent bleeding events or elevations in the International Normalised
Ratio (INR) have been reported in some patients taking warfarin while on
NEXAVAR therapy. Patients taking warfarin concomitantly should be monitored
regularly for changes in prothrombin time, INR and for clinical bleeding
episodes (see ADVERSE EFFECTS).

Wound Healing Complications

No formal studies of the effect of NEXAVAR on wound healing have been
conducted. In patients undergoing major surgical procedures, temporary
interruption of NEXAVAR therapy is recommended for precautionary reasons.
There is limited clinical experience regarding the timing of reinitiation of
therapy following major surgical intervention. Therefore, the decision to
resume NEXAVAR therapy following a major surgical intervention should be based
on clinical judgment of adequate wound healing.

Cardiac Ischaemia and/or Infarction

In Study 11213, the incidence of treatment-emergent cardiac
ischaemia/infarction events was higher in the NEXAVAR group (2.9%) compared
with the placebo group (0.4%). Patients with unstable coronary artery disease
or recent myocardial infarction were excluded from this study. Temporary or
permanent discontinuation of NEXAVAR should be considered in patients who
develop cardiac ischaemia and/or infarction (see ADVERSE EFFECTS).

Gastrointestinal Perforation

Gastrointestinal perforation is an uncommon event and has been reported in
less than 1% of patients taking NEXAVAR. In some cases this was not associated
with apparent intra-abdominal tumour. NEXAVAR therapy should be discontinued.

Hepatic Impairment

No data is available on patients with Child Pugh C (severe) hepatic
impairment. Since sorafenib is mainly eliminated via the hepatic route,
exposure might be increased in patients with severe hepatic impairment (see
Pharmacokinetics).

Medicine-Medicine Interactions

UGT1A1 pathway

Caution is recommended when administering NEXAVAR together with compounds
that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g.
irinotecan) (see Interactions With Other Medicines).

Docetaxel

Concomitant use of docetaxel (75 or 100 mg/m²) with sorafenib
(200 or 400 mg twice daily), administered with a 3-day break in dosing around
administration of docetaxel, resulted in a 36-80% increase in docetaxel AUC.
Caution is recommended when NEXAVAR is co-administered with docetaxel (see
Interactions With Other Medicines).

Effects on Fertility

No specific studies with NEXAVAR have been conducted in animals to evaluate
the effect on fertility. An adverse effect on male and female fertility is
expected, however, based on histological changes in reproductive organs
observed in repeat-dose studies in animals. Sorafenib caused testicular
tubular degeneration and oligospermia in mice, rats, and dogs at daily doses
producing plasma exposures approximately 0.9-, 1.5- and 0.3-times respectively
that expected in patients (based on relative AUC for unbound sorafenib).
Retardation of prostatic and seminal vesicle development were also observed in
rats. In female mice and rats, arrested follicular development in the ovaries
was observed following treatment with sorafenib at doses producing exposure
levels 0.7-0.9 times that expected in patients.

Use in Pregnancy

Pregnancy category D

There are no adequate and well-controlled studies in pregnant women using
NEXAVAR. Sorafenib has been shown to be embryotoxic and teratogenic when
administered to rats and rabbits. Observed effects included decreases in
maternal and fetal body weights, an increased number of fetal resorptions and
an increased number of skeletal and visceral malformations. Adverse fetal
outcomes were observed at an oral dose of 1 mg/kg/day in rats (relative
exposure, 0.08) and 3 mg/kg/day in rabbits (relative exposure, 0.4). In rats,
sorafenib and/or its metabolites were demonstrated to cross the placenta.
NEXAVAR therapy in pregnant patients is anticipated to inhibit angiogenesis in
the fetus.

NEXAVAR should not be used during pregnancy. Women must be advised to avoid
becoming pregnant while on therapy. If NEXAVAR is used during pregnancy or if
the patient becomes pregnant while using NEXAVAR, the patient must be apprised
of the potential hazard to the fetus, which includes severe malformation
(teratogenicity), failure to thrive and fetal death (embryotoxicity). Adequate
contraception should be used during therapy and for at least 2 weeks after
completion of therapy.

Use in Lactation

It is not known whether NEXAVAR is excreted in human milk. In lactating
rats, sorafenib and/or its metabolites were readily excreted in milk (milk:
plasma AUC ratio of approximately 5:1). Because of the potential for excretion
in human milk and the likelihood that infants will be particularly sensitive
to the toxic effects of sorafenib, women must be advised to discontinue
breastfeeding during NEXAVAR treatment.

Paediatric Use

The safety and effectiveness of NEXAVAR in paediatric patients has not been
established.

Effects on bone and teeth were observed after repeated dosing to young and
growing dogs. The changes consisted of irregular thickening of the femoral
growth plate at a dose of 30 mg/kg/day (relative exposure 0.5 based on
relative AUC for unbound drug), hypocellularity of the bone marrow at 10
mg/kg/day (relative exposure, 0.25) and alteration of dentin composition at 30
mg/kg/day (relative exposure, 0.3). Similar effects were observed in mice and
rats. A study in adult dogs revealed no effects on teeth and minimal effects
on bone marrow.

Carcinogenicity

Carciogenicity studies have not been performed with sorafenib.

Genotoxicity

Sorafenib has been tested for genotoxicity in a series of in vitro
(bacterial mutation and mammalian chromosomal aberration) and in vivo
(mouse micronucleus test) assays. Sorafenib did not cause genetic damage in
the bacterial reverse mutation and mouse micronucleus tests. Weak
clastogenicity was displayed by sorafenib in the in vitro mammalian
chromosomal aberration assay (using Chinese Hamster lung cells) in the
presence of metabolic activation but only at cytotoxic concentrations. An
impurity in the final medicine (<0.15%), picolinamide phenylether (PAPE), was
mutagenic in the bacterial reverse mutation assay.

Interactions With Other Medicines

Sorafenib is metabolized primarily in the liver undergoing oxidative
metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9.
Studies with human liver microsomes demonstrated that sorafenib is a
competitive inhibitor of CYP2B6, CYP2C8, and CYP2C9. Sorafenib may increase
the blood level of medicines that are substrates of these enzymes.

Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways.
Systemic exposure to substrates of UGT1A1 and UGT1A9 may be increased when
co-administered with sorafenib.

CYP3A4 inducers:

Continuous concomitant administration of sorafenib and rifampicin resulted
in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4
activity (e.g. Hypericum perforatum also known as St. John's Wort,
phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase
metabolism of NEXAVAR and thus decrease NEXAVAR concentrations.

CYP3A4 Inhibitors

Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7
days to healthy male volunteers did not alter the mean AUC of a single 50 mg
dose of NEXAVAR. Therefore, clinical pharmacokinetic interactions of NEXAVAR
with CYP3A4 inhibitors are unlikely.

CYP2C9 Substrates

In vitro studies with human liver microsomes demonstrated that
sorafenib is a competitive inhibitor of CYP2C9 with a Ki value of 7-8 µM. The
possible effect of sorafenib on warfarin, a CYP2C9 substrate, was assessed
in vivo in NEXAVAR-treated patients compared to placebo treated patients.
The concomitant treatment with NEXAVAR and warfarin did not result in changes
in mean PT-INR compared to placebo suggesting that NEXAVAR may not be an in
vivo inhibitor of CYP2C9. However, patients taking warfarin should have
their INR checked regularly.

CYP Isoform-selective Substrates

Concomitant administration of midazolam, dextromethorphan and omeprazole,
which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively,
following 4 weeks of NEXAVAR administration did not alter the exposure of
these agents. This indicates that NEXAVAR is neither an inhibitor nor an
inducer of these cytochrome P450 isoenzymes.

Combination with other Anti-neoplastic Agents

In clinical studies, NEXAVAR has been administered together with a variety
of other anti-neoplastic agents at their commonly used dosing regimens,
including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. NEXAVAR had
no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant
treatment with NEXAVAR resulted in a 21% increase in the AUC of doxorubicin.
When administered with irinotecan, whose active metabolite SN-38 is further
metabolised by the UGT1A1 pathway, there was a 67 - 120% increase in the AUC
of SN-38 and a 26 - 42% increase in the AUC of irinotecan. The clinical
significance of these findings is unknown (see PRECAUTIONS).

Docetaxel (75 or 100 mg/m² administered once every 21 days) when
co-administered with sorafenib (200 mg twice daily or 400 mg twice daily
administered on Days 2 through 19 of a 21-day cycle) with a 3-day break in
dosing around administration of docetaxel, resulted in a 36-80% increase in
docetaxel AUC and a 16-32% increase in docetaxel C_max. Caution is
recommended when NEXAVAR is co-administered with docetaxel. (see
PRECAUTIONS).

Effect on Laboratory Tests

Elevated lipase and amylase levels were very commonly reported. In the
TARGET Study CTC AE grade 3 or 4 lipase elevations occurred in 10% of patients
in the NEXAVAR group compared to 5% of patients in the placebo group. CTC AE
grade 3 or 4 amylase elevations were reported in 1% of patients in the NEXAVAR
group compared to 3% of patients in the placebo group. Clinical pancreatitis
was reported in 2 of 384 NEXAVAR treated patients (CTC AE grade 4) and 1 of
384 patients (CTC AE grade 2) in the placebo group.

Hypophosphataemia was a common laboratory finding, observed in 45% of
sorafenib treated patients compared to 11% of placebo patients. CTCAE grade 3
hypophosphataemia (1-2 mg/dl) occurred in 13% on sorafenib treated patients
and 3% of patients in the placebo group. There were no cases of CTCAE grade 4
hypophosphataemia (< 1 mg/dl) reported in either sorafenib or placebo
patients. The aetiology of hypophosphataemia associated with sorafenib is not
known.

Adverse Effects

The overall safety profile of NEXAVAR is based on 1286 cancer patients, who
received NEXAVAR as single agent.

Table 1 includes all medicine-related adverse events that are reported in
at least 5% of patients in the TARGET Study (see CLINICAL TRIALS). The
most common medicine-related adverse events reported with NEXAVAR were
diarrhoea, rash, alopecia and hand-foot skin reaction.

Table 1. Medicine-Related Adverse Events Reported in at Least 5% of
Patients in Any Treatment Group - TARGET Study (listed according to CTCAE v3)

Medicine-related Adverse Event NCI-CTC AE v3 Category/Term	NEXAVAR N = 451			Placebo N = 451
	All Grades %	Grade 3 %	Grade 4 %	All Grades %	Grade 3 %	Grade 4 %
Metabolism and Nutrition Disorders
Anorexia	9	<1	0	5	<1	0
Nervous System Disorders
Headache	6	0	0	3	0	0
Vascular Disorders
Hypertension	12	2	<1	1	<1	0
Flushing	6	0	0	2	0	0
Gastrointestinal Disorders
Diarrhoea	38	2	0	9	<1	0
Nausea	16	<1	0	12	<1	0
Vomiting	10	<1	0	6	<1	0
Constipation	6	0	0	3	0	0
Skin and Subcutaneous Tissue Disorders
Rash	28	<1	0	9	<1	0
Alopecia	25	<1	0	3	0	0
Hand foot syndrome	19	4	0	3	0	0
Pruritis	17	<1	0	4	0	0
Erythema	15	0	0	4	0	0
Dry skin	11	0	0	2	0	0
Skin exfoliation	7	<1	0	2	0	0
Musculoskeletal, Connective Tissue and Bone Disorders
Pain in extremity	6	<1	0	2	0	0
Arthralgia	6	<1	0	3	0	0
General Disorders and Administrative Site Conditions
Fatigue	15	2	0	12	<1	0
Asthenia	9	<1	0	4	<1	0

Medicine related adverse reactions reported in multiple clinical trials are
listed below in Table 2, by system organ class (in MedDRA) and frequency.
Frequencies are defined as: very common (≥ 10%), common (≥ 1% to < 10%),
uncommon (≥ 0.1% to < 1%).

Table 2: All Adverse Medicine Reactions reported in patients in multiple
clinical trials in MedDRA Coding

System Organ Class	Very Common ≥ 10%	Common ≥ 1% to < 10%	Uncommon ≥ 0.1% to < 1%
Infections and Infestations			folliculitis infection
Blood and Lymphatic System Disorders	lymphopenia	leucopenia neutropenia anaemia thrombocytopenia
Immune system Disorders			hypersensitivity reactions (including skin reactions and urticaria)
Endocrine Disorders			Hypothyroidism
Metabolism and Nutrition Disorders	hypophosphataemia	anorexia	hyponatraemia dehydration
Psychiatric Disorders		depression
Nervous System Disorders		peripheral sensory neuropathy	reversible posterior leukoencepalopathy*
Ear and Labyrinth Disorders		tinnitus
Cardiac Disorders			myocardial ischaemia and infarction* congestive heart failure*
Vascular Disorders	Haemorrhage (inc. gastrointestinal* & respiratory tract* and cerebral haemorrhage*) hypertension		hypertensive crisis
Respiratory, Thoracic and Mediastinal Disorders		hoarseness	Rhinorrhoea
Gastrointestinal Disorders	diarrhoea nausea vomiting	Constipation stomatitis (including dry mouth and glossodynia) dyspepsia dysphagia	gastro oesophageal reflux disease pancreatitis gastritis gastrointestinal perforations*
Hepato-biliary Disorders			increase in bilirubin and jaundice
Skin and Subcutaneous Tissue Disorders	rash alopecia handfoot syndrome** pruritis erythema	dry skin dermatitis exfoliative acne skin desquamation	eczema erythema multiforme minor keratoacanthomas/ squamous cell cancer of the skin
Musculoskeletal, Connective Tissue and Bone Disorders		arthralgia myalgia
Reproductive System and Breast Disorders		erectile dysfunction	Gynaecomastia
General Disorders and Administration Site Conditions	fatigue pain (including mouth, abdominal, bone pain, headache and tumour pain)	asthenia influenza like illness fever
Investigations	increased amylase increased lipase	weight decreased transient increase in transaminases	transient increase in blood alkaline phosphatase INR abnormal, prothrombin level abnormal

* events may have a life-threatening or fatal outcome. Such events are rare

** palmar plantar erythrodysaethesia syndrome in MedDRA

Dosage And Administration

Use in Adults

The recommended daily dose of NEXAVAR is 400 mg (2 x 200 mg tablets) taken
twice a day, either without food or together with a moderate fat meal.

Treatment should be continued until the patient is no longer clinically
benefiting from therapy or until unacceptable toxicity occurs.

Management of suspected adverse medicine reactions may require temporary
interruption and/or dose reduction of NEXAVAR therapy. When dose reduction is
necessary, the NEXAVAR dose should be reduced to two tablets of 200 mg once
daily (see PRECAUTIONS).

Elderly (above 65 years), Gender and Body Weight

No dose adjustment is required on the basis of patient age (above 65
years), gender, or body weight.

Use in Patients with Renal Impairment

No dose adjustment is required in patients with mild to moderate renal
impairment. NEXAVAR has not been studied in patients with severe renal
impairment or patients undergoing dialysis (see PHARMACOLOGY-Pharmacokinetics-Renal
Impairment).

Use in Patients with Hepatic Impairment

No dose adjustment is required in patients with Child-Pugh A and B hepatic
impairment. NEXAVAR has not been studied in patients with Child-Pugh C hepatic
impairment (see PHARMACOLOGY-Pharmacokinetics-Hepatic Impairment).

Use in Children

The safety and effectiveness of NEXAVAR in paediatric patients has not been
established.

Overdosage

There is no specific treatment for NEXAVAR overdose.

The highest dose of NEXAVAR studied clinically is 800 mg twice daily. The
adverse reactions observed at this dose were primarily diarrhoea and
dermatologic events.

In the event of suspected overdose, NEXAVAR should be withheld and
supportive care instituted.

Presentation And Storage Conditions

NEXAVAR tablets contain 200 mg of sorafenib (274 mg sorafenib tosylate).
The tablets are film coated red round, biconvex marked with a Bayer cross on
one side and "200" on the other and supplied in packs of 60 and 112 tablets
(the 112 tablet pack is not marketed).

Shelf life is 3 years when stored below 25°C.

Medicine Classification

Prescription Medicine