Nexavar 200 mg film-coated tablets

REC 32757

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6.3    Shelf life

43 years 

10.         DATE OF REVISION OF THE TEXT

July 2023June 2024

REC 31438 (correlated with REC 18460) / REC 30494 / REC 31379 / REC 31108

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6.      Contents of the pack and other information

[...]

What Nexavar looks like and contents of the pack

Nexavar 200 mg faceted film-coated tablets are red and round with the Bayer cross on one side and “200” on the other side. They come in calendar packs of 112 tablets: four transparent blister packs of 28 tablets each.

[...]

This leaflet was last revised in 10/202207/2023.

REC 31438 (correlated with REC 18460) / REC 30494 / REC 31379 / REC 31108

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3.      PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Red, round, faceted biconvex film-coated tablets, debossed with Bayer cross on one side and "200" on the other side. 

[...]

10.         DATE OF REVISION OF THE TEXT

April 2022July 2023

REC30875

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6.           Contents of the pack and other information

[….]

Manufacturer

Bayer AG Kaiser-Wilhelm-Allee

51368 Leverkusen

Germany

Bayer HealthCare Manufacturing Srl.

Via delle Groane, 126

20024 Garbagnate Milanese

Italy

[….]

This leaflet was last revised in 04/202210/2022.

REC 30425

Implementation of PRAC recommendations on safety signals: EPITT 19733 (EMEA/PRAC/75387/2022) dated 07-MAR-2022

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2. What do you need to know before you take Nexavar

[….]

Take special care with Nexavar

[….]

• If you experience the following symptoms, contact your doctor immediately as this can be a life-threatening condition: nausea, shortness of breath, irregular heartbeat, muscular cramps, seizure, clouding of urine and tiredness. These may caused by a group of metabolic complications that can occur during treatment of cancer that are caused by the break-down products of dying cancer cells (Tumour lysis syndrome (TLS)) and can lead to changes in kidney function and acute renal failure (see also section 4: Possible side effects).

[….]

4. Possible side effects

[….]

Not known: frequency cannot be estimated from the available data

[….]

• nausea, shortness of breath, irregular heartbeat, muscular cramps, seizure, clouding of urine and tiredness (Tumour lysis syndrome (TLS)) (see section 2).

[….]

6. Content of the pack and other information

[….]

This leaflet booklet was last revised in 04/2022.

[….]

REC 30425

Implementation of PRAC recommendations on safety signals: EPITT 19733 (EMEA/PRAC/75387/2022) dated 07-MAR-2022

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Section 4.4 – Special Warnings and Precautions for Use

[….]

Tumour lysis syndrome (TLS)

Cases of TLS, some fatal, have been reported in postmarketing surveillance in patients treated with sorafenib. 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 and treated promptly as clinically indicated, and prophylactic hydration should be considered.

[….]

Section 4.8 – Undesirable Effects

[….]

Table 1

System Organ Class:  Metabolism and nutrition disorders:

Frequency ‘not known’: tumour lysis syndrome

[….]

Section 10 – Date of Revision of the Text

April 2022

BEC17137:

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4. Reporting of side effects

[….]

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL – Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie

6.  Contents of the pack and other information

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder

Ireland

Bayer Limited

Tel: +353 1 2999313 +353 1 216 3300

[….]

This booklet was last revised in 12/2021.

Type IA-0081_BEC19209

Reason for the update:

ATC Code Update - section 5.1 of the SmPC.

Editorial update: Correction of the Renewal Date – Section 9 of the SmPC.

These changes have no effect on the Essential Information.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XEX025

[…]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 July 2006

Date of latest renewal: 291 Junely 2011

[…]

10. DATE OF REVISION OF THE TEXT

March 2021

PRAC- Update sections 4.4 and 4.8 of the SmPC and sections 2 and 4 of the PL to implement the signal recommendations on Vascular Endothelial Growth Factor (VEGF) inhibitors for systemic administration - Artery dissections and aneurysms.

Under special warnings and precautions - added:

Hypoglycaemia

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

Information about excipients

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially "sodium free".

Section 4.8 Table of S/E added:

'Hypoglycaemia' under common - metabolism and nutrition disorders

4.8       Undesirable effects

...

Adverse reactions reported in multiple clinical trials or through post-marketing use are listed below in table 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 (³1/10,000 to <1/1,000), not known (cannot be estimated from the available data available).

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

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

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

° Cases have been reported in the post marketing setting.

10.        DATE OF REVISION OF THE TEXT

November 2014

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via IMB HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.imb.ie www.hpra.ie; e-mail: imbpharmacovigilance@imb.ie medsafety@hpra.ie.

4.1       Therapeutic indications

Differentiated thyroid carcinoma

Nexavar is indicated for the treatment of patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.

4.2     Posology and method of administration

Nexavar treatment should be supervised by a physician experienced in the use of anticancer therapies.

Posology

The recommended dose of Nexavar 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 dose reduction of Nexavarsorafenib therapy.

When dose reduction is necessary during the treatment of hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC), the Nexavar dose should be reduced to two tablets of 200 mg sorafenib once daily (see section 4.4).

When dose reduction is necessary during the treatment of differentiated thyroid carcinoma (DTC), the Nexavar dose should be reduced to 600 mg sorafenib daily in divided doses (two tablets of 200 mg and one tablet of 200 mg twelve hours apart).

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

4.4     Special warnings and precautions for use

Dermatological toxicities

Hand- foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most common adverse drug reactions with Nexavarsorafenib. 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 with Nexavarsorafenib. Management of dermatological toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of Nexavarsorafenib, or in severe or persistent cases, permanent discontinuation of Nexavarsorafenib (see section 4.8).

Hypertension

An increased incidence of arterial hypertension was observed in Nexavarsorafenib-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 institution of antihypertensive therapy, permanent discontinuation of Nexavarsorafenib should be considered (see section 4.8).

Haemorrhage

An increased risk of bleeding may occur following Nexavarsorafenib administration. If any bleeding event necessitates medical intervention it is recommended that permanent discontinuation of Nexavarsorafenib should 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 of treatment-emergent cardiac ischaemia/infarction events was higher in the Nexavarsorafenib group (4.9 %) compared with the placebo group (0.4 %). In study 3 (see section 5.1) the incidence of treatment-emergent cardiac ischaemia/infarction events was 2.7 % in Nexavarsorafenib patients compared with 1.3 % in the placebo group. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from these studies. Temporary or permanent discontinuation of Nexavarsorafenib should be considered in patients who develop cardiac ischaemia and/or infarction (see section 4.8).

QT interval prolongation

NexavarSorafenib has been shown to prolong the QT/QTc interval (see section 5.1), which may lead to an increased risk for ventricular arrhythmias. Use sorafenib with caution in patients who have, or may develop prolongation of QTc, such as patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking certain anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia. When using Nexavarsorafenib in these 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 patients taking sorafenib. In some cases this was not associated with apparent intra-abdominal tumour. Sorafenib therapy should be discontinued (see section 4.8).

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 sections 4.2 and 5.2).

Warfarin co-administration

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

Wound healing complications

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

Elderly population

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

Renal cell carcinoma

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.

Drug-drug interactions

Caution is recommended when administering Nexavarsorafenib with compounds that are metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways (see section 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 the gastrointestinal microflora may lead to a decrease in sorafenib bioavailability (see section 4.5). The risk of reduced plasma concentrations of sorafenib should be considered before starting a treatment course with antibiotics.

Higher mortality has been reported in patients with squamous cell carcinoma of the lung treated with sorafenib in combination with platinum-based chemotherapies. In two randomised trials investigating patients with Non-Small Cell Lung Cancer in the subgroup of patients with squamous cell carcinoma treated with sorafenib as add-on to paclitaxel/carboplatin, the HR for overall survival was found to be 1.81 (95% CI 1.19; 2.74) and as add-on to gemcitabine/cisplatin 1.22 (95% CI 0.82; 1.80). No single cause of death dominated, but higher incidence of respiratory failure, hemorrhages and infectious adverse events were observed in patients treated with sorafenib as add-on to platinum-based chemotherapies.

Disease specific warnings

Differentiated thyroid cancer (DTC)

Before initiating treatment, physicians are recommended to carefully evaluate the prognosis in the individual 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 dose reduction of sorafenib therapy. In study 5 (see section 5.1), 37% of subjects had dose interruption and 35% had dose reduction already in cycle 1 of sorafenib treatment.

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

Haemorrhage in DTC

Due to the potential risk of bleeding, tracheal, bronchial, and oesophageal infiltration should be treated with 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, especially with a history of hypoparathyroidism, compared to patients with renal cell or hepatocellular carcinoma. 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 treated patients. When using sorafenib in DTC patients, close monitoring of TSH level is recommended.

Renal cell carcinoma

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.

4.5     Interaction with other medicinal products and other forms of interaction

…

Combination with other anti-neoplastic agents

In clinical studies Nexavarsorafenib has been administered with a variety of other anti-neoplastic agents at their commonly used dosing regimens including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, irinotecan, docetaxel and cyclophosphamide. Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin or cyclophosphamide.

…

Doxorubicin/Irinotecan

Concomitant treatment with Nexavarsorafenib 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 section 4.4).

4.6     Fertility, pregnancy and lactation

Pregnancy

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

Women of childbearing potential must use effective contraception during treatment.

4.7     Effects on ability to drive and use machines

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

4.8     Undesirable effects

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

The most common adverse reactions were diarrhoea, fatigue, alopecia, infection, rash, alopecia and hand- foot skin syndrome reaction (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 in Ttable 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 (³1/10,000 to <1/1,000), not known (cannot be estimated from the data available).

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

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

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

Further information on selected adverse drug reactions

Congestive heart failure:

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 with congestive heart failure were reported in 1.7% of patients treated with sorafenib and 0.7% receiving placebo. In study 100554 (HCC), 0.99% of those treated with sorafenib and 1.1% receiving placebo were 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 skin occurred at a substantially higher frequency in patients with differentiated thyroid compared to patients 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 elevations occurred in 11 % and 9 % of patients in the Nexavarsorafenib 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 amylase elevations were reported in 1 % and 2 % of patients in the Nexavarsorafenib group in study 1 and study 3, respectively, compared to 3 % of patients in each placebo group. Clinical pancreatitis was reported in 2 of 451 Nexavarsorafenib treated patients (CTCAE Grade 4) in study 1, 1 of 297 Nexavarsorafenib treated patients in study 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 Nexavarsorafenib treated 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 Nexavarsorafenib treated patients and 3 % of patients in the placebo group, in study 3 in 11 % of Nexavarsorafenib treated patients and 2 % of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia (< 1 mg/dl) reported in either Nexavarsorafenib or placebo patients in study 1, and 1 case in the placebo group in study 3. The aetiology of hypophosphataemia associated with Nexavarsorafenib is not known.

CTCAE Grade 3 or 4 laboratory abnormalities occurring in ≥ 5 % of Nexavarsorafenib treated patients included lymphopenia and neutropenia.

Hypocalcaemia was reported in 12% and 26.5% of sorafenib treated patients compared to 7.5% and 14.8% of placebo patients in study 1 and study 3, respectively. Most reports of hypocalcaemia were low grade (CTCAE Grade 1 and 2). CTCAE grade 3 hypocalcaemia (6.0 – 7.0 mg /dL) occurred in 1.1% 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 patients and 0.5% and 0% of patients in the placebo group in study 1 and 3, respectively. The aetiology of hypocalcaemia associated with sorafenib is not known.

In studies 1 and 3 decreased potassium was observed in 5.4% and 9.5% of Nexavarsorafenib-treated patients compared to 0.7% and 5.9% of placebo patients, respectively. Most reports of hypokalaemia were low grade (CTCAE Grade 1). In these studies CTCAE Grade 3 hypokalaemia occurred in 1.1% and 0.4% of Nexavarsorafenib treated patients and 0.2% and 0.7% of patients in the placebo group. There were no reports 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 placebo patients. Most reports of hypocalcaemia were low grade. CTCAE grade 3 hypocalcaemia occurred in 6.8% of sorafenib treated patients and 1.9% of patients in the placebo group, and CTCAE grade 4 hypocalcaemia occurred in 3.4% of sorafenib treated patients and 1.0% of patients in the placebo group.

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

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via IMB Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie.

4.9     Overdose

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

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

…

Clinical efficacy

The clinical safety and efficacy of sorafenibNexavar have been studied in patients with hepatocellular carcinoma (HCC), and in patients with advanced renal cell carcinoma (RCC) and in patients with differentiated 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 baseline disease characteristics were comparable between the sorafenibNexavar 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 efficacy boundary. This OS analysis showed a statistically significant advantage for sorafenibNexavar over placebo for OS (HR: 0.69, p = 0.00058, see Ttable 23).

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

Table 23: Efficacy Rresults from study 3 (study 100554) in hepatocellular carcinoma

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

*statistically significant as the p-value was below the prespecified O’Brien Fleming stopping boundary of 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 sorafenibNexavar in 226 patients with advanced hepatocellular carcinoma. This study, conducted in China, Korea and Taiwan confirmed the findings of Study 3 with respect to the favourable benefit-risk profile of sorafenibNexavar (HR (OS): 0.68, p = 0.01414).

In the pre-specified stratification factors (ECOG status, presence or absence of macroscopic vascular invasion and/or extrahepatic tumour spread) of both Study 3 and 4, the hazard ratioHR consistently favoured sorafenibNexavar over placebo. Exploratory subgroup analyses suggested that patients with distant metastases at baseline derived a less pronounced treatment effect.

Renal cell carcinoma

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

Study 1 (study 11213) was a Phase III, multi-centre, randomised, double blind, placebo-controlled study 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 were overall survival and progression-free survival (PFS).

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

PFS was evaluated by blinded independent radiological review using RECIST criteria. The PFS analysis was conducted at 342 events in 769 patients. The median PFS was 167 days for patients randomised to sorafenibNexavar 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 treatment effect size.

An interim analysis (second interim analysis) for overall survival was conducted at 367 deaths in 903 patients. The nominal alpha value for this analysis was 0.0094. The median survival was 19.3 months for patients randomised to sorafenibNexavar 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 sorafenibNexavar were randomised to placebo or continued sorafenibNexavar therapy. Progression-free survival in patients with RCC was significantly longer in the sorafenibNexavar 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 radioactive iodine. Progression-free survival (PFS) as evaluated by a blinded independent radiological review using RECIST criteria was the primary endpoint of the study. Secondary endpoints included overall survival (OS), tumour response rate and duration of response. Following progression, patients were allowed to receive open label sorafenib.

Patients were included in the study if they experienced progression within 14 months of enrollment and had DTC refractory to radioactive iodine (RAI). DTC refractory to RAI was defined as having a lesion without iodine uptake on a RAI scan, or receiving cumulative RAI ≥ 22.2  GBq, or experiencing a progression after a RAI treatment within 16 months of enrollment or after two RAI treatments within 16 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. The median 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 poorly differentiated carcinoma (9.6%).

Median PFS time was 10.8 months in the sorafenib group compared to 5.8 months in the placebo group (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 below 60 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 analysis there 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 the sorafenib arm and was 36.5 months in the placebo arm. One hundred fifty seven (75%) patients randomised 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 patients receiving 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 (24 patients, 12.2%) than in the placebo group (1 patient, 0.5%), one-sided p<0.0001. The median duration of 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 of sorafenib 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 size of 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 effect for PFS in favour of sorafenib over placebo for both symptomatic and asymptomatic patients. The HR of progression free survival was 0.39 (95% CI: 0.21 - 0.72) for patients with symptoms at baseline and 0.60 (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 maximum concentration of sorafenib, QTcB was prolonged by 4 ±19 msec and QTcF by 9 ±18 msec, as compared to placebo treatment at baseline. No subject showed a QTcB or QTcF >500 msec during the post-treatment ECG monitoring (see section 4.4).

Paediatric population

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

5.2     Pharmacokinetic properties

Absorption and distribution

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

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

Multiple dosing of sorafenibNexavar for 7 days resulted in a 2.5- 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.

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 for all tumour types. The reason for the increased concentration in DTC patients is unknown.

Biotransformation and elimination

The elimination half-life of sorafenib is approximately 25 - 48 hours. Sorafenib is metabolised primarily in the liver and undergoes oxidative metabolism, mediated by CYP 3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinal tract by bacterial glucuronidase activity, allowing reabsorption of unconjugated drug active substance. Co-administration of neomycin has been shown to interfere with this process, decreasing the mean bioavailability 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. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This metabolite 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, indicating that biliary excretion of unchanged drug active substance might contribute to the elimination of sorafenib.

…

5.3     Preclinical safety data

Environmental Risk assessment studies have shown that sorafenib tosylate has the potential to be persistent, bioaccumulative and toxic to the environment. Environmental Risk Assessment information is available in the EPAR of this medicine (see section 6.6).

6.       PHARMACEUTICAL PARTICULARS

6.6     Special precautions for disposal

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

10.       DATE OF REVISION OF THE TEXT

May 2014

Removal of the following sentence:
'The experience with the use of Nexavar in elderly patients is limited'

Section 4.8 Undesirable effects - Table 1

- Addition of 'hypokalaemia' and 'proteinuria' as common adverse reactions

- Addition of 'nephrotic syndrome' as a rare adverse reaction

- rhinorrhoea interstitial lung disease-like events* (may have a life-threatening or fatal outcome. Such events are either uncommon or less frequent than uncommon.

Section 4.8 Undesirable effects - Laboratory test abnormalities

- Addition of the following text:
'In studies 1 and 3 decreased potassium was observed in 5.4% and 9.5% of Nexavar-treated patients compared to 0.7% and 5.9% of placebo patients, respectively. Most reports of hypokalaemia were low grade (CTCAE Grade 1). In these studies CTCAE Grade 3 hypokalaemia occurred in 1.1% and 0.4% of Nexavar treated patients and 0.2% and 0.7% of patients in the placebo group. There were no reports of hypokalaemia CTCAE grade 4.'

Section 10 Date of revision of the text
February 2013

The following two adverse events (displayed in red text) have been added to Table 1 of

section 4.8 (Undesirable effects):  

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

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

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

The date of revision of the text (section 10) has been updated to “24^th October 2011”

4.4    Special warnings and precautions for use

The following paragraph has been deleted from section 4.4:

“A randomized controlled trial comparing safety and efficacy of carboplatin and paclitaxel plus or minus sorafenib in chemonaive patients with Stage IIIB-IV Non-Small Cell Lung Cancer (NSCLC) was stopped early, when the independent Data Monitoring Committee concluded that the study would not meet its primary endpoint of improved overall survival. Safety events were generally consistent with those previously reported. However, higher mortality was observed in the subset of patients with squamous cell carcinoma of the lung treated with sorafenib and carboplatin and paclitaxel versus those treated with carboplatin and paclitaxel alone (HR 1.81, 95% CI 1.19-2.74). No definitive cause was identified for this finding.”

The following paragraph has been added to section 4.4:

“Higher mortality has been reported in patients with squamous cell carcinoma of the lung treated with sorafenib in combination with platinum-based chemotherapies. In two randomised trials investigating patients with Non-Small Cell Lung Cancer in the subgroup of patients with squamous cell carcinoma treated with sorafenib as add-on to paclitaxel/carboplatin, the HR for overall survival was found to be 1.81 (95% CI 1.19; 2.74) and as add-on to gemcitabine/cisplatin 1.22 (95% CI 0.82; 1.80). No single cause of death dominated, but higher incidence of respiratory failure, hemorrhages and infectious adverse events were observed in patients treated with sorafenib as add-on to platinum-based chemotherapies.”


The date of revision of the text (section 10) has been updated to "1st August 2011"

Deleted text: red text with Strikethrough

New text: Green text

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

2.1          General description

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

2.2          Qualitative and quantitative composition

For a full list of excipients, see section 6.1.

3.         PHARMACEUTICAL form

Film-coated tablet (tablet)…

4.2       Posology and method of administration

In section 4.2, the following sentences have been moved from subsection “Posology” and moved to subsection “Method of administration”:

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

4.6       Fertility, pregnancy and lactation

“Pregnancy

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

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

Women of childbearing potential must use effective contraception during treatment.

Lactation

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

Fertility

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

4.8       Undesirable effects

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

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

Table 1: Adverse reactions reported in at least 5 % of patients in any treatment group – study 11213 in renal cell carcinoma (see study 1 in section 5.1).

Table 2: Adverse reactions reported in at least 5 % of patients in any treatment group – study 100554 in hepatocellular carcinoma (see study 3 in section 5.1).

Adverse reactions reported in multiple clinical trials or through post-marketing use are listed below in Table 3 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 (³1/10,000, to <1/1,000), not known (cannot be estimated from the data available).

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

Table 3 1: All adverse reactions reported in patients in multiple clinical trials or through post-marketing use