SORAFENIB ACCORD 200mg tablets medication leaflet

Sorafenib Accord 200 mg film-coated tablets

Each film-coated tablet contains 200 mg of sorafenib (as tosilate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Red, round, biconvex, bevel-edged, 12.0 mm in diameter, film-coated tablets debossed with 'H1' onone side and plain on the other side.

Hepatocellular carcinoma

Sorafenib Accord is indicated for the treatment of hepatocellular carcinoma (see section 5.1).

Sorafenib Accord is indicated for the treatment of patients with advanced renal cell carcinoma whohave failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for suchtherapy.

Differentiated thyroid carcinoma

Sorafenib Accord is indicated for the treatment of patients with progressive, locally advanced ormetastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactiveiodine.

Sorafenib Accord treatment should be supervised by a physician experienced in the use of anticancertherapies.

The recommended dose of Sorafenib Accord in adults is 400 mg sorafenib (two tablets of 200 mg)twice daily (equivalent to a total daily dose of 800 mg).

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

Posology adjustments

Management of suspected adverse drug reactions may require temporary interruption or dosereduction of sorafenib therapy.

When dose reduction is necessary during the treatment of hepatocellular carcinoma (HCC) andadvanced renal cell carcinoma (RCC), the Sorafenib Accord dose should be reduced to two tablets of200 mg sorafenib once daily (see section 4.4).

When dose reduction is necessary during the treatment of differentiated thyroid carcinoma (DTC), the

Sorafenib Accord dose should be reduced to 600 mg sorafenib daily in divided doses (two tablets of200 mg and one tablet of 200 mg twelve hours apart).

If additional dose reduction is necessary, Sorafenib Accord may be reduced to 400 mg sorafenib dailyin divided doses (two tablets of 200 mg twelve hours apart), and if necessary further reduced to onetablet of 200 mg once daily. After improvement of non-haematological adverse reactions, the dose of

Sorafenib Accord may be increased.

The safety and efficacy of Sorafenib Accord in children and adolescents aged <18 years have not yetbeen established. No data are available.

No dose adjustment is required in the elderly (patients above 65 years of age).

No dose adjustment is required in patients with mild, moderate or severe renal impairment. No dataare available in patients requiring dialysis (see section 5.2).

Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.

No dose adjustment is required in patients with Child Pugh A or B (mild to moderate) hepaticimpairment. No data are available on patients with Child Pugh C (severe) hepatic impairment (seesections 4.4 and 5.2).

Sorafenib Accord is for oral use.

It is recommended that sorafenib should be administered without food or with a low or moderate fatmeal. If the patient intends to have a high-fat meal, sorafenib tablets should be taken at least 1 hourbefore or 2 hours after the meal. The tablets should be swallowed with a glass of water.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Dermatological toxicities

Hand foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most commonadverse drug reactions with sorafenib. Rash and hand foot skin reaction are usually CTC (Common

Toxicity Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment withsorafenib. Management of dermatological toxicities may include topical therapies for symptomaticrelief, temporary treatment interruption and/or dose modification of sorafenib, or in severe orpersistent cases, permanent discontinuation of sorafenib (see section 4.8).

An increased incidence of arterial hypertension was observed in sorafenib-treated patients.

Hypertension was usually mild to moderate, occurred early in the course of treatment, and wasamenable to management with standard antihypertensive therapy. Blood pressure should be monitoredregularly and treated, if required, in accordance with standard medical practice. In cases of severe orpersistent hypertension, or hypertensive crisis despite institution of antihypertensive therapy,permanent discontinuation of sorafenib should be considered (see section 4.8).

The use of vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or withouthypertension may promote the formation of aneurysms and/or artery dissections. Before initiating

Sorafenib Accord, this risk should be carefully considered in patients with risk factors such ashypertension or history of aneurysm.

Decreases in blood glucose, in some cases clinically symptomatic and requiring hospitalization due toloss of consciousness, have been reported during sorafenib treatment. In case of symptomatichypoglycaemia, sorafenib should be temporarily interrupted. Blood glucose levels in diabetic patientsshould be checked regularly in order to assess if anti-diabetic medicinal product's dosage needs to beadjusted.

An increased risk of bleeding may occur following sorafenib administration. If any bleeding eventnecessitates medical intervention it is recommended that permanent discontinuation of sorafenibshould be considered (see section 4.8).

Cardiac ischaemia and/or infarction

In a randomised, placebo-controlled, double-blind study (study 1, see section 5.1) the incidence oftreatment-emergent cardiac ischaemia/infarction events was higher in the sorafenib group (4.9%)compared with the placebo group (0.4%). In study 3 (see section 5.1) the incidence of treatmentemergent cardiac ischaemia/infarction events was 2.7% in sorafenib patients compared with 1.3% inthe placebo group. Patients with unstable coronary artery disease or recent myocardial infarction wereexcluded from these studies. Temporary or permanent discontinuation of sorafenib should beconsidered in patients who develop cardiac ischaemia and/or infarction (see section 4.8).

QT interval prolongation

Sorafenib has been shown to prolong the QT/QTc interval (see section 5.1), which may lead to anincreased risk for ventricular arrhythmias. Use sorafenib with caution in patients who have, or maydevelop prolongation of QTc, such as patients with a congenital long QT syndrome, patients treatedwith a high cumulative dose of anthracycline therapy, patients taking certain anti-arrhythmicmedicines or other medicinal products that lead to QT prolongation, and those with electrolytedisturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia. When using sorafenib inthese patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium,potassium, calcium) should be considered.

Gastrointestinal perforation

Gastrointestinal perforation is an uncommon event and has been reported in less than 1% of patientstaking sorafenib. In some cases this was not associated with apparent intra-abdominal tumour.

Sorafenib therapy should be discontinued (see section 4.8).

Cases of TLS, some fatal, have been reported in postmarketing surveillance in patients treated withsorafenib. Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency,oliguria, dehydration, hypotension, and acidic urine. These patients should be monitored closely andtreated promptly as clinically indicated, and prophylactic hydration should be considered.

No data is available on patients with Child Pugh C (severe) hepatic impairment. Since sorafenib ismainly eliminated via the hepatic route exposure might be increased in patients with severe hepaticimpairment (see sections 4.2 and 5.2).

Warfarin co-administration

Infrequent bleeding events or elevations in the International Normalised Ratio (INR) have beenreported in some patients taking warfarin while on sorafenib therapy. Patients taking concomitantwarfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR orclinical bleeding episodes (see sections 4.5 and 4.8).

No formal studies of the effect of sorafenib on wound healing have been conducted. Temporaryinterruption of sorafenib therapy is recommended for precautionary reasons in patients undergoingmajor surgical procedures. There is limited clinical experience regarding the timing of reinitiation oftherapy following major surgical intervention. Therefore, the decision to resume sorafenib therapyfollowing a major surgical intervention should be based on clinical judgement of adequate woundhealing.

Cases of renal failure have been reported. Monitoring of renal function should be considered.

Caution is recommended when administering sorafenib with compounds that aremetabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways (seesection 4.5).

Caution is recommended when sorafenib is co-administered with docetaxel (see section 4.5).

Co-administration of neomycin or other antibiotics that cause major ecological disturbances of thegastrointestinal microflora may lead to a decrease in sorafenib bioavailability (see section 4.5). Therisk of reduced plasma concentrations of sorafenib should be considered before starting a treatmentcourse with antibiotics.

Higher mortality has been reported in patients with squamous cell carcinoma of the lung treated withsorafenib in combination with platinum-based chemotherapies. In two randomised trials investigatingpatients with non-small cell lung cancer in the subgroup of patients with squamous cell carcinomatreated with sorafenib as add-on to paclitaxel/carboplatin, the HR for overall survival was found to be1.81 (95% CI 1.19; 2.74) and as add-on to gemcitabine/cisplatin 1.22 (95% CI 0.82; 1.80). No singlecause of death dominated, but higher incidence of respiratory failure, hemorrhages and infectiousadverse reactions were observed in patients treated with sorafenib as add-on to platinum-basedchemotherapies.

Disease specific warnings

Differentiated thyroid cancer (DTC)

Before initiating treatment, physicians are recommended to carefully evaluate the prognosis in theindividual patient considering maximum lesion size (see section 5.1), symptoms related to the disease(see section 5.1) and progression rate.

Management of suspected adverse drug reactions may require temporary interruption or dosereduction of sorafenib therapy. In study 5 (see section 5.1), 37% of subjects had dose interruption and35% had dose reduction already in cycle 1 of sorafenib treatment.

Dose reductions were only partially successful in alleviating adverse reactions. Therefore repeatevaluations of benefit and risk is recommended taking anti-tumour activity and tolerability intoaccount.

Haemorrhage in DTC

Due to the potential risk of bleeding, tracheal, bronchial, and oesophageal infiltration should be treatedwith localized therapy prior to administering sorafenib in patients with DTC.

Hypocalcaemia in DTC

When using sorafenib in patients with DTC, close monitoring of blood calcium level is recommended.

In clinical trials, hypocalcaemia was more frequent and more severe in patients with DTC, especiallywith a history of hypoparathyroidism, compared to patients with renal cell or hepatocellularcarcinoma. Hypocalcaemia grade 3 and 4 occurred in 6.8% and 3.4% of sorafenib-treated patients with

DTC (see section 4.8). Severe hypocalcaemia should be corrected to prevent complications such as

QT-prolongation or torsade de pointes (see section QT prolongation).

TSH suppression in DTC

In study 5 (see section 5.1), increases in TSH levels above 0.5mU/L were observed in sorafenib treatedpatients. When using sorafenib in DTC patients, close monitoring of TSH level is recommended.

High risk patients, according to MSKCC (Memorial Sloan Kettering Cancer Center) prognostic group,were not included in the phase III clinical study in renal cell carcinoma (see study 1 in section 5.1),and benefit-risk in these patients has not been evaluated.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose that is to say essentially“sodium free”.

Inducers of metabolic enzymes

Administration of rifampicin for 5 days before administration of a single dose of sorafenib resulted inan average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity and/orglucuronidation (e.g. Hypericum perforatum also known as St. John’s wort, phenytoin, carbamazepine,phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and thus decreasesorafenib concentrations.

Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy malevolunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. These data suggest thatclinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.

CYP2B6, CYP2C8 and CYP2C9 substrates

Sorafenib inhibited CYP2B6, CYP2C8 and CYP2C9 in vitro with similar potency. However, inclinical pharmacokinetic studies, concomitant administration of sorafenib 400 mg twice daily withcyclophosphamide, a CYP2B6 substrate, or paclitaxel, a CYP2C8 substrate, did not result in aclinically meaningful inhibition. These data suggest that sorafenib at the recommended dose of 400 mgtwice daily may not be an in vivo inhibitor of CYP2B6 or CYP2C8.

Additionally, concomitant treatment with sorafenib and warfarin, a CYP2C9 substrate, did not resultin changes in mean PT-INR compared to placebo. Thus, also the risk for a clinically relevant in vivoinhibition of CYP2C9 by sorafenib may be expected to be low. However, patients taking warfarin orphenprocoumon should have their INR checked regularly (see section 4.4).

CYP3A4, CYP2D6 and CYP2C19 substrates

Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which aresubstrates for cytochromes CYP3A4, CYP2D6 and CYP2C19 respectively, did not alter the exposureof these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome

P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates ofthese enzymes are unlikely.

UGT1A1 and UGT1A9 substrates

In vitro, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9. The clinical relevance of thisfinding is unknown (see below and section 4.4).

In vitro studies of CYP enzyme induction

CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes withsorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4.

P-gp-substrates

In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P-gp). Increasedplasma concentrations of P-gp substrates such as digoxin cannot be excluded with concomitanttreatment with sorafenib.

Combination with other anti-neoplastic agents

In clinical studies sorafenib has been administered with a variety of other anti-neoplastic agents attheir commonly used dosing regimens including gemcitabine, cisplatin, oxaliplatin, paclitaxel,carboplatin, capecitabine, doxorubicin, irinotecan, docetaxel and cyclophosphamide. Sorafenib had noclinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin orcyclophosphamide.

Paclitaxel/carboplatin

Administration of paclitaxel (225 mg/m2) and carboplatin (AUC=6) with sorafenib (≤400 mg twicedaily), administered with a 3-day break in sorafenib dosing (two days prior to and on the day ofpaclitaxel/carboplatin administration), resulted in no significant effect on the pharmacokinetics ofpaclitaxel.

Co-administration of paclitaxel (225 mg/m2, once every 3 weeks) and carboplatin (AUC=6) withsorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47% increase insorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxelexposure. The pharmacokinetics of carboplatin were unaffected.

These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administeredwith sorafenib with a 3-day break in sorafenib dosing (two days prior to and on the day ofpaclitaxel/carboplatin administration). The clinical significance of the increases in sorafenib andpaclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.

Capecitabine

Co-administration of capecitabine (750-1050 mg/m2 twice daily, Days 1-14 every 21 days) andsorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in nosignificant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52%increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabineand 5-FU exposure when co-administered with sorafenib is unknown.

Doxorubicin/Irinotecan

Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. Whenadministered with irinotecan, whose active metabolite SN-38 is further metabolised by the UGT1A1pathway, there was a 67-120% increase in the AUC of SN-38 and a 26-42% increase in the AUC ofirinotecan. The clinical significance of these findings is unknown (see section 4.4).

Docetaxel

Docetaxel (75 or 100 mg/m2administered 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 a3-day break in dosing around administration of docetaxel) resulted in a 36-80% increase in docetaxel

AUC and a 16-32% increase in docetaxel Cmax. Caution is recommended when sorafenib isco-administered with docetaxel (see section 4.4).

Combination with other agents

Neomycin

Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinalflora, interferes with the enterohepatic recycling of sorafenib (see section 5.2, Metabolism and

Elimination), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-dayregimen of neomycin the average exposure to sorafenib decreased by 54%. Effects of other antibioticshave not been studied, but will likely depend on their ability to interfere with microorganisms withglucuronidase activity.

Women of childbearing potential must use effective contraception during treatment.

There are no data on the use of sorafenib in pregnant women. Studies in animals have shownreproductive toxicity including malformations (see section 5.3). In rats, sorafenib and its metaboliteswere demonstrated to cross the placenta and sorafenib is anticipated to cause harmful effects on thefoetus. Sorafenib should not be used during pregnancy unless clearly necessary, after carefulconsideration of the needs of the mother and the risk to the foetus.

It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or itsmetabolites were excreted in milk. Because sorafenib could harm infant growth and development (seesection 5.3), women must not breast-feed during sorafenib treatment.

Results from animal studies further indicate that sorafenib can impair male and female fertility (seesection 5.3).

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

The most important serious adverse reactions were myocardial infarction/ischaemia, gastrointestinalperforation, drug induced hepatitis, haemorrhage, and hypertension/hypertensive crisis.

The most common adverse reactions were diarrhoea, fatigue, alopecia, infection, hand foot skinreaction (corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA) and rash.

Adverse reactions reported in multiple clinical trials or through post-marketing use are listed below intable 1, by system organ class (in MedDRA) and frequency. Frequencies are defined as: very common(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to<1/1,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: All adverse reactions reported in patients in multiple clinical trials or through post-marketing use

System Very common Common Uncommon Rare Not knownorgan class

Infections infection folliculitisandinfestations

Blood and lymphopenia leucopenialymphatic neutropeniasystem anaemiadisorders thrombocytopenia

Immune hypersensitivity angioedemasystem reactionsdisorders (including skinreactions andurticaria)anaphylacticreaction

Endocrine hypothyroidism hyperthyroidismdisorders

Metabolism anorexia hypocalcaemia dehydration tumour lysisand nutrition hypo- hypokalaemia syndromedisorders phosphataemia hyponatraemiahypoglycaemia

Psychiatric depressiondisorders

Nervous peripheral sensory reversible encephalo-system neuropathy posterior pathy°disorders dysgeusia leukoencephalo-pathy*

System Very common Common Uncommon Rare Not knownorgan class

Ear and tinnituslabyrinthdisorders

Cardiac congestive heart QTdisorders failure* prolongationmyocardialischaemia andinfarction*

Vascular haemorrhage flushing Hypertensive aneurysmsdisorders (inc. crisis* and arterygastrointestinal*, dissectionsrespiratory tract*and cerebralhaemorrhage*)hypertension

Respiratory, rhinorrhoea interstitial lungthoracic and dysphonia disease-likemediastinal events*disorders (pneumonitis,radiationpneumonitis,acute respiratorydistress, etc )

Gastro- diarrhoea stomatitis pancreatitisintestinal nausea (including dry gastritisdisorders vomiting mouth and gastrointestinalconstipation glossodynia) perforations*dyspepsiadysphagiagastro oesophagealreflux disease

Hepatobiliary increase in drug induceddisorders bilirubin and hepatitis*jaundice,cholecystitis,cholangitis

Skin and dry skin keratoacanthoma/ eczema radiationsubcutaneous rash squamous cell erythema recalltissue alopecia cancer of the skin multiforme dermatitisdisorders hand foot skin dermatitis Stevens-reaction** exfoliative Johnsonerythema acne syndromepruritus skin desquamation leucocytoclahyperkeratosis sticvasculitistoxicepidermalnecrolysis*

Musculoskele arthralgia myalgia rhabdomyoltal and muscle spasms ysisconnectivetissuedisorders

Renal and renal failure nephroticurinary proteinuria syndromedisorders

Reproductive erectile dysfunction gynaecomastiasystem andbreastdisorders

System Very common Common Uncommon Rare Not knownorgan class

General fatigue astheniadisorders and pain (including influenza likeadministratio mouth, illnessn site abdominal, mucosalconditions bone, tumour inflammationpain andheadache)fever

Investigations weight transient increase transient increasedecreased in transaminases in blood alkalineincreased phosphataseamylase INR abnormal,increased lipase prothrombin levelabnormal

* The adverse reactions may have a life-threatening or fatal outcome. Such events are either uncommon orless frequent than uncommon.

** Hand foot skin reaction corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA.

° Cases have been reported in the post marketing setting.

In company sponsored clinical trials congestive heart failure was reported as an adverse event in 1.9%of patients treated with sorafenib (N=2276). In study 11213 (RCC) adverse events consistent withcongestive heart failure were reported in 1.7% of patients treated with sorafenib and 0.7% receivingplacebo. In study 100554 (HCC), 0.99% of those treated with sorafenib and 1.1% receiving placebowere reported with these events.

Additional information on special populations

In clinical trials, certain adverse drug reactions such as hand foot skin reaction, diarrhoea, alopecia,weight decrease, hypertension, hypocalcaemia, and keratoacanthoma/squamous cell carcinoma of skinoccurred at a substantially higher frequency in patients with differentiated thyroid compared topatients in the renal cell or hepatocellular carcinoma studies.

Laboratory test abnormalities in HCC (study 3) and RCC (study 1) patients

Increased lipase and amylase were very commonly reported. CTCAE Grade 3 or 4 lipase elevationsoccurred in 11% and 9% of patients in the sorafenib group in study 1 (RCC) and study 3 (HCC),respectively, compared to 7% and 9% of patients in the placebo group. CTCAE Grade 3 or 4 amylaseelevations were reported in 1% and 2% of patients in the sorafenib group in study 1 and study 3,respectively, compared to 3% of patients in each placebo group. Clinical pancreatitis was reported in2 of 451 sorafenib treated patients (CTCAE Grade 4) in study 1, 1 of 297 sorafenib treated patients instudy 3 (CTCAE Grade 2), and 1 of 451 patients (CTCAE Grade 2) in the placebo group in study 1.

Hypophosphataemia was a very common laboratory finding, observed in 45% and 35% of sorafenibtreated patients compared to 12% and 11% of placebo patients in study 1 and study 3, respectively.

CTCAE Grade 3 hypophosphataemia (1-2 mg/dl) in study 1 occurred in 13% of sorafenib treatedpatients and 3% of patients in the placebo group, in study 3 in 11% of sorafenib treated patients and2% 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 in study 1, and 1 case in the placebo groupin study 3. The aetiology of hypophosphataemia associated with sorafenib is not known.

CTCAE Grade 3 or 4 laboratory abnormalities occurring in ≥5% of sorafenib treated patients includedlymphopenia and neutropenia.

Hypocalcaemia was reported in 12% and 26.5% of sorafenib treated patients compared to 7.5% and14.8% of placebo patients in study 1 and study 3, respectively. Most reports of hypocalcaemia werelow grade (CTCAE Grade 1 and 2). CTCAE grade 3 hypocalcaemia (6.0-7.0 mg /dL) occurred in1.1% and 1.8% of sorafenib treated patients and 0.2% and 1.1% of patients in the placebo group, and

CTCAE grade 4 hypocalcaemia (<6.0 mg/dL) occurred in 1.1% and 0.4% of sorafenib treated patientsand 0.5% and 0% of patients in the placebo group in study 1 and 3, respectively. The aetiology ofhypocalcaemia associated with sorafenib is not known.

In studies 1 and 3 decreased potassium was observed in 5.4% and 9.5% of sorafenib-treated patientscompared to 0.7% and 5.9% of placebo patients, respectively. Most reports of hypokalaemia were lowgrade (CTCAE Grade 1). In these studies CTCAE Grade 3 hypokalaemia occurred in 1.1% and 0.4%of sorafenib treated patients and 0.2% and 0.7% of patients in the placebo group. There were noreports of hypokalaemia CTCAE grade 4.

Laboratory test abnormalities in DTC patients (study 5)

Hypocalcaemia was reported in 35.7% of sorafenib treated patients compared to 11.0% of placebopatients. Most reports of hypocalcaemia were low grade. CTCAE grade 3 hypocalcaemia occurred in6.8% of sorafenib treated patients and 1.9% of patients in the placebo group, and CTCAE grade 4hypocalcaemia occurred in 3.4% of sorafenib treated patients and 1.0% of patients in the placebogroup.

Other clinically relevant laboratory abnormalities observed in the study 5 are shown in table 2.

Table 2: Treatment-emergent laboratory test abnormalities reported in DTC patient (study 5)double blind period

Laboratory parameter, Sorafenib N=207 Placebo N=209(in % of samples All Grade Grade All Grade Gradeinvestigated) Grades* 3* 4* Grades* 3* 4*

Anemia 30.9 0.5 0 23.4 0.5 0

Thrombocytopenia 18.4 0 0 9.6 0 0

Neutropenia 19.8 0.5 0.5 12 0 0

Lymphopenia 42 9.7 0.5 25.8 5.3 0

Hypokalemia 17.9 1.9 0 2.4 0 0

Hypophosphatemia** 19.3 12.6 0 2.4 1.4 0

Bilirubin increased 8.7 0 0 4.8 0 0

ALT increased 58.9 3.4 1.0 24.4 0 0

AST increased 53.6 1.0 1.0 14.8 0 0

Amylase increased 12.6 2.4 1.4 6.2 0 1.0

Lipase increased 11.1 2.4 0 2.9 0.5 0

* Common Terminology Criteria for Adverse Events (CTCAE), version 3.0

** The aetiology of hypophosphatemia associated with sorafenib is not known.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for sorafenib overdose. The highest dose of sorafenib studied clinicallyis 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhoea anddermatological events. In the event of suspected overdose sorafenib should be withheld and supportivecare instituted where necessary.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EX02

Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and anti-angiogenicproperties in vitro and in vivo.

Mechanism of action and pharmacodynamic effects

Sorafenib is a multikinase inhibitor that decreases tumour cell proliferation in vitro. Sorafenib inhibitstumour growth of a broad spectrum of human tumour xenografts in athymic mice accompanied by areduction of tumour angiogenesis. Sorafenib inhibits the activity of targets present in the tumour cell(CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumour vasculature (CRAF, VEGFR-2,

VEGFR-3, and PDGFR-ß). RAF kinases are serine/threonine kinases, whereas c-KIT, FLT-3,

VEGFR-2, VEGFR-3, and PDGFR-ß are receptor tyrosine kinases.

The clinical safety and efficacy of sorafenib have been studied in patients with hepatocellularcarcinoma (HCC), in patients with advanced renal cell carcinoma (RCC) and in patients withdifferentiated thyroid carcinoma (DTC)..

Hepatocellular carcinoma

Study 3 (study 100554) was a Phase III, international, multi-centre, randomised, double blind,placebo-controlled study in 602 patients with hepatocellular carcinoma. Demographics and baselinedisease characteristics were comparable between the sorafenib and the placebo group with regard to

ECOG status (status 0: 54% vs. 54%; status 1: 38% vs. 39%; status 2: 8% vs. 7%), TNM stage (stage

I: <1% vs. <1%; stage II:10.4% vs. 8.3%; stage III: 37.8% vs. 43.6%; stage IV: 50.8% vs. 46.9%), and

BCLC stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs. 0%).

The study was stopped after a planned interim analysis of OS had crossed the prespecified efficacyboundary. This OS analysis showed a statistically significant advantage for sorafenib over placebo for

OS (HR: 0.69, p=0.00058, see table 3).

There are limited data from this study in patients with Child Pugh B liver impairment and only onepatient with Child Pugh C had been included.

Table 3: Efficacy results from study 3 (study 100554) in hepatocellular carcinoma

Efficacy Parameter Sorafenib Placebo P-value HR(N=299) (N=303) (95% CI)

Overall Survival (OS) 46.3 34.4 0.00058* 0.69[median, weeks (95% (40.9, 57.9) (29.4, 39.4) (0.55, 0.87)

CI)]

Time to Progression 24.0 12.3 0.000007 0.58(TTP) [median, weeks (18.0, 30.0) (11.7, 17.1) (0.45, 0.74)(95% CI)]**

CI=Confidence interval, HR=Hazard ratio (sorafenib over placebo)

* statistically significant as the p-value was below the prespecified O’Brien Fleming stopping boundaryof 0.0077

** independent radiological review

A second Phase III, international, multi-centre, randomised, double blind, placebo-controlled study(Study 4, 11849) evaluated the clinical benefit of sorafenib in 226 patients with advancedhepatocellular carcinoma. This study, conducted in China, Korea and Taiwan confirmed the findingsof Study 3 with respect to the favourable benefit-risk profile of sorafenib (HR (OS): 0.68, p=0.01414).

In the pre-specified stratification factors (ECOG status, presence or absence of macroscopic vascularinvasion and/or extrahepatic tumour spread) of both Study 3 and 4, the HR consistently favouredsorafenib over placebo. Exploratory subgroup analyses suggested that patients with distant metastasesat baseline derived a less pronounced treatment effect.

The safety and efficacy of sorafenib in the treatment of advanced renal cell carcinoma (RCC) wereinvestigated in two clinical studies:

Study 1 (study 11213) was a Phase III, multi-centre, randomised, double blind, placebo-controlledstudy in 903 patients. Only patients with clear cell renal carcinoma and low and intermediate risk

MSKCC (Memorial Sloan Kettering Cancer Center) were included. The primary endpoints wereoverall survival and progression-free survival (PFS).

Approximately half of the patients had an ECOG performance status of 0, and half of the patients werein the low risk MSKCC prognostic group.

PFS was evaluated by blinded independent radiological review using RECIST criteria. The PFSanalysis was conducted at 342 events in 769 patients. The median PFS was 167 days for patientsrandomised to sorafenib compared to 84 days for placebo patients (HR=0.44; 95% CI: 0.35-0.55; p<0.000001). Age, MSKCC prognostic group, ECOG PS and prior therapy did not affect the treatmenteffect size.

An interim analysis (second interim analysis) for overall survival was conducted at 367 deaths in903 patients. The nominal alpha value for this analysis was 0.0094. The median survival was19.3 months for patients randomised to sorafenib compared to 15.9 months for placebo patients(HR=0.77; 95% CI: 0.63-0.95; p=0.015). At the time of this analysis, about 200 patients had crossed-over to sorafenib from the placebo group.

Study 2 was a Phase II, discontinuation study in patients with metastatic malignancies, including RCC.

Patients with stable disease on therapy with sorafenib were randomised to placebo or continuedsorafenib therapy. Progression-free survival in patients with RCC was significantly longer in thesorafenib group (163 days) than in the placebo group (41 days) (p=0.0001, HR=0.29).

Differentiated thyroid carcinoma (DTC)

Study 5 (study 14295) was a Phase III, international, multi-centre, randomised, double blind, placebo-controlled trial in 417 patients with locally advanced or metastatic DTC refractory to radioactiveiodine. Progression-free survival (PFS) as evaluated by a blinded independent radiological reviewusing RECIST criteria was the primary endpoint of the study. Secondary endpoints included overallsurvival (OS), tumour response rate and duration of response. Following progression, patients wereallowed to receive open label sorafenib.

Patients were included in the study if they experienced progression within 14 months of enrollmentand had DTC refractory to radioactive iodine (RAI). DTC refractory to RAI was defined as having alesion without iodine uptake on a RAI scan, or receiving cumulative RAI ≥ 22.2 GBq, or experiencinga progression after a RAI treatment within 16 months of enrollment or after two RAI treatments within16 months of each other.

Baseline demographics and patient characteristics were well balanced for both treatment groups.

Metastases were present in the lungs in 86%, lymph node in 51% and bone in 27% of the patients. Themedian delivered cumulative radioactive iodine activity before enrollment was approximately 14.8

GBq. Majority of patients had papillary carcinoma (56.8%), followed by follicular (25.4%) and poorlydifferentiated carcinoma (9.6%).

Median PFS time was 10.8 months in the sorafenib group compared to 5.8 months in the placebogroup (HR=0.587; 95% Confidence Interval (CI): 0.454, 0.758; one-sided p <0.0001).

The effect of sorafenib on PFS was consistent independent of geographic region, age above or below60 years, gender, histological subtype, and presence or absence of bone metastasis.

In an overall survival analysis conducted 9 months after the data cut-off for the final PFS analysisthere was no statically significant difference in overall survival between the treatment groups(HR=0.884; 95% CI: 0.633, 1.236, one-sided p value of 0.236). The median OS was not reached in thesorafenib arm and was 36.5 months in the placebo arm. One hundred fifty seven (75%) patientsrandomised to placebo and 61 (30%) patients randomised to sorafenib received open-label sorafenib.

The median duration of therapy in the double-blind period was 46 weeks (range 0.3-135) for patientsreceiving sorafenib and 28 weeks (range 1.7-132) for patients receiving placebo.

No complete response (CR) according to RECIST was observed. The overall response rate (CR +partial response (PR) per independent radiological assessment was higher in the sorafenib group (24patients, 12.2%) than in the placebo group (1 patient, 0.5%), one-sided p<0.0001. The median durationof response was 309 days (95% CI: 226-505 days) in sorafenib treated patients who experienced a PR.

A post-hoc subgroup analysis by maximum tumour size showed a treatment effect for PFS in favour ofsorafenib over placebo for patients with maximum tumour size of 1.5 cm or larger (HR 0.54 (95% CI:

0.41 - 0.71)) whereas a numerically lower effect was reported in patients with a maximum tumour sizeof less than 1.5 cm (HR 0.87 (95% CI: 0.40 - 1.89).

A post-hoc subgroup analysis by thyroid carcinoma symptoms at baseline showed a treatment effectfor PFS in favour of sorafenib over placebo for both symptomatic and asymptomatic patients. The HRof progression free survival was 0.39 (95% CI: 0.21 - 0.72) for patients with symptoms at baseline and0.60 (95% CI: 0.45 - 0.81) for patients without symptoms at baseline.

QT interval prolongation

In a clinical pharmacology study, QT/QTc measurements were recorded in 31 patients at baseline (pre-treatment) and post-treatment. After one 28-day treatment cycle, at the time of maximumconcentration of sorafenib, QTcB was prolonged by 4±19 msec and QTcF by 9±18 msec, as comparedto placebo treatment at baseline. No subject showed a QTcB or QTcF >500 msec during the post-treatment ECG monitoring (see section 4.4).

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing sorafenib in all subsets of the paediatric population, in kidneyand renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma,mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) and liver andintrahepatic bile duct carcinoma (excluding hepatoblastoma) and differentiated thyroid carcinoma (seesection 4.2 for information on paediatric use).

After administration of sorafenib tablets the mean relative bioavailability is 38-49% when compared toan oral solution. The absolute bioavailability is not known. Following oral administration sorafenibreaches peak plasma concentrations in approximately 3 hours. When given with a high-fat mealsorafenib absorption was reduced by 30% compared to administration in the fasted state.

Mean Cmax and AUC increased less than proportionally beyond doses of 400 mg administered twicedaily. In vitro binding of sorafenib to human plasma proteins is 99.5%.

Multiple dosing of sorafenib for 7 days resulted in a 2.5- to 7-fold accumulation compared to singledose administration. Steady state plasma sorafenib concentrations are achieved within 7 days, with apeak to trough ratio of mean concentrations of less than 2.

The steady-state concentrations of sorafenib administered at 400 mg twice daily were evaluated in

DTC, RCC and HCC patients. The highest mean concentration was observed in DTC patients(approximately twice that observed in patients with RCC and HCC), though variability was high forall tumour types. The reason for the increased concentration in DTC patients is unknown.

The elimination half-life of sorafenib is approximately 25-48 hours. Sorafenib is metabolizedprimarily in the liver and undergoes oxidative metabolism, mediated by CYP 3A4, as well asglucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinaltract by bacterial glucuronidase activity, allowing reabsorption of unconjugated active substance. Co-administration of neomycin has been shown to interfere with this process, decreasing the meanbioavailability of sorafenib by 54%.

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. Themain circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potencysimilar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes atsteady state.

Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of thedose was recovered within 14 days, with 77% of the dose excreted in faeces, and 19% of the doseexcreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose,was found in faeces but not in urine, indicating that biliary excretion of unchanged active substancemight contribute to the elimination of sorafenib.

Analyses of demographic data suggest that there is no relationship between pharmacokinetics and age(up to 65 years), gender or body weight.

No studies have been conducted to investigate the pharmacokinetics of sorafenib in paediatric patients.

There are no clinically relevant differences in pharmacokinetics between Caucasian and Asiansubjects.

In four Phase I clinical trials, steady state exposure to sorafenib was similar in patients with mild ormoderate renal impairment compared to the exposures in patients with normal renal function. In aclinical pharmacology study (single dose of 400 mg sorafenib), no relationship was observed betweensorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severerenal impairment. No data is available in patients requiring dialysis.

In hepatocellular carcinoma (HCC) patients with Child-Pugh A or B (mild to moderate) hepaticimpairment, exposure values were comparable and within the range observed in patients withouthepatic impairment. The pharmacokinetics (PK) of sorafenib in Child-Pugh A and B non-HCCpatients were similar to the PK in healthy volunteers. There are no data for patients with Child-Pugh C(severe) hepatic impairment. Sorafenib is mainly eliminated via the liver, and exposure might beincreased in this patient population.

The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits.

Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs atexposures below the anticipated clinical exposure (based on AUC comparisons).

After repeated dosing to young and growing dogs effects on bone and teeth were observed atexposures below the clinical exposure. Changes consisted in irregular thickening of the femoralgrowth plate, hypocellularity of the bone marrow next to the altered growth plate and alterations of thedentin composition. Similar effects were not induced in adult dogs.

The standard program of genotoxicity studies was conducted and positive results were obtained as anincrease in structural chromosomal aberrations in an in vitro mammalian cell assay (Chinese hamsterovary) for clastogenicity in the presence of metabolic activation was seen. Sorafenib was notgenotoxic in the Ames test or in the in vivo mouse micronucleus assay. One intermediate in themanufacturing process, which is also present in the final active substance (<0.15%), was positive formutagenesis in an in vitro bacterial cell assay (Ames test). Furthermore, the sorafenib batch tested inthe standard genotoxicity battery included 0.34% PAPE.

Carcinogenicity studies have not been conducted with sorafenib.

No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility.

An adverse effect on male and female fertility can however be expected because repeat-dose studies inanimals have shown changes in male and female reproductive organs at exposures below theanticipated clinical exposure (based on AUC). Typical changes consisted of signs of degeneration andretardation in testes, epididymides, prostate, and seminal vesicles of rats. Female rats showed centralnecrosis of the corpora lutea and arrested follicular development in the ovaries. Dogs showed tubulardegeneration in the testes and oligospermia.

Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits atexposures below the clinical exposure. Observed effects included decreases in maternal and foetalbody weights, an increased number of foetal resorptions and an increased number of external andvisceral malformations.

Environmental Risk assessment studies have shown that sorafenib tosilate has the potential to bepersistent, bioaccumulative and toxic to the environment. Environmental Risk Assessment informationis available in the EPAR of this medicine (see section 6.6).

Croscarmellose sodium

Cellulose, microcrystalline

Hypromellose

Sodium laurilsulfate

Magnesium stearate

Hypromellose (E464)

Macrogol (E1521)

Titanium dioxide (E171)

Ferric oxide red (E172)

Not applicable.

2 years.

This medicinal product does not require any special storage condition.

Aluminium-Aluminium perforated unit dose blisters in pack size of 112x1 film-coated tablets in acarton.

This medicinal product could have potential risk for the environment. Any unused medicinal productor waste material should be disposed of in accordance with local requirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est, 6a Planta08039 Barcelona

Spain

EU/1/22/1696/001

Date of first authorisation: 09 November 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: http://www.ema.europa.eu.