Nexavar 200 mg film-coated tablets

  • Name:

    Nexavar 200 mg film-coated tablets

  • Company:
    info
  • Active Ingredients:

    Sorafenib tosilate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 08/11/19

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Summary of Product Characteristics last updated on medicines.ie: 8/11/2019

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Bayer Limited

Bayer Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 8 November 2019

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Free text change information supplied by the pharmaceutical company

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.

Updated on 8 November 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 4 - possible side effects

Updated on 17 July 2018

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects

Free text change information supplied by the pharmaceutical company

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

 

 

Updated on 16 July 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - excipient warnings
  • Change to section 4 - possible side effects
  • Change to MA holder contact details

Updated on 30 November 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 30 November 2017 PIL

Reasons for updating

  • Change to section 4 - how to report a side effect
  • Change to MA holder contact details

Updated on 21 September 2017 PIL

Reasons for updating

  • Change to MA holder contact details

Updated on 21 September 2017 PIL

Reasons for updating

  • Change to section 4 - how to report a side effect

Updated on 3 August 2017

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 3 August 2017 SPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

In section 7, the marketing authorisation holder has been changed from 'Bayer Pharma AG, 13342 Berlin, Germany' to 'Bayer AG, 51368 Leverkusen, Germany'.

Updated on 31 July 2017 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 3 December 2014 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 3 December 2014 SPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

System organ class

Very common

Common

Uncommon

Rare

Not known

Infections and infestations

infection

folliculitis

 

 

 

Blood and lymphatic system disorders

lymphopenia

leucopenia

neutropenia

anaemia

thrombocytopenia

 

 

 

Immune system disorders

 

 

hypersensitivity reactions (including skin reactions and urticaria)

anaphylactic reaction

angioedema

 

Endocrine disorders

 

hypothyroidism

hyperthyroidism

 

 

Metabolism and nutrition disorders

anorexia

hypo-phosphataemia

hypocalcaemia

hypokalaemia

hyponatraemia

dehydration

 

 

Psychiatric disorders

 

depression

 

 

 

Nervous system disorders

 

peripheral sensory neuropathy

dysgeusia

 

reversible posterior leukoencephalo-pathy*

 

 

encephalopathy°

Ear and labyrinth disorders

 

tinnitus

 

 

 

Cardiac disorders

 

congestive heart failure*

myocardial ischaemia and infarction*

 

QT prolongation

 

Vascular disorders

haemorrhage (inc. gastrointestinal*, respiratory tract* and cerebral haemorrhage*)

hypertension

flushing

hypertensive crisis*

 

 

Respiratory, thoracic and mediastinal disorders

 

rhinorrhoea

dysphonia

interstitial lung disease-like events* (pneumonitis, radiation pneumonitis, acute respiratory distress, etc. )

 

 

Gastro-intestinal disorders

diarrhoea

nausea

vomiting

constipation

stomatitis (including dry mouth and glossodynia)

dyspepsia

dysphagia

gastro oesophageal reflux disease

pancreatitis

gastritis

gastrointestinal perforations*

 

 

Hepatobiliary disorders

 

 

increase in bilirubin and jaundice, cholecystitis, cholangitis

drug induced hepatitis*

 

Skin and subcutaneous tissue disorders

dry skin

rash

alopecia

hand foot skin reaction**

erythema

pruritus

keratoacanthoma/ squamous cell cancer of the skin

dermatitis exfoliative

acne

skin desquamation

hyperkeratosis

eczema

erythema multiforme

radiation recall dermatitis

Stevens-Johnson syndrome

leucocytoclastic vasculitis

toxic epidermal necrolysis*

 

Musculo-skeletal and connective tissue disorders

arthralgia

myalgia

muscle spasms

 

rhabdomyolysis

 

Renal and urinary disorders

 

renal failure

proteinuria

 

nephrotic syndrome

 

Reproductive system and breast disorders

 

erectile dysfunction

gynaecomastia

 

 

General disorders and administration site conditions

fatigue

pain (including mouth, abdominal, bone, tumour pain and headache)

fever

asthenia

influenza like illness

mucosal inflammation

 

 

 

Investigations

weight decreased

increased amylase

increased lipase

transient increase in transaminases

transient increase in blood alkaline phosphatase

INR abnormal, prothrombin level abnormal

 

 

* 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

 

 

Updated on 16 July 2014 PIL

Reasons for updating

  • Addition of information on reporting a side effect.

Updated on 16 July 2014 SPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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.

Updated on 10 June 2014 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to date of revision
  • Change to MA holder contact details
  • Changes to therapeutic indications
  • Addition of information on reporting a side effect.

Updated on 10 June 2014 SPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

 

System organ class

Very common

Common

Uncommon

Rare

Infections and infestations

infection

folliculitis

folliculitis

infection

 

Blood and lymphatic system disorders

lymphopenia

leucopenia

neutropenia

anaemia

thrombocytopenia

 

 

Immune system disorders

 

 

hypersensitivity reactions (including skin reactions and urticaria)

anaphylactic reaction

angioedema anaphylactic reaction

Endocrine disorders

 

hypothyroidism

hypothyroidism

hyperthyroidism

 

Metabolism and nutrition disorders

anorexia

hypo-phosphataemia

anorexia

hypocalcaemia

hypokalaemia

hyponatraemia

hyponatraemia

dehydration

 

Psychiatric disorders

 

depression

 

 

Nervous system disorders

 

peripheral sensory neuropathy

dysgeusia

reversible posterior leukoencephalo-pathy*

 

Ear and labyrinth disorders

 

tinnitus

 

 

Cardiac disorders

 

congestive heart failure*

myocardial ischaemia and infarction*

 

QT prolongation

Vascular disorders

haemorrhage (inc. gastrointestinal*, respiratory tract* and cerebral haemorrhage*)

hypertension

flushing

hypertensive crisis*

 

Respiratory, thoracic and mediastinal disorders

 

rhinorrhoea

dysphoniahoarseness

rhinorrhoea

interstitial lung disease-like events* (pneumonitis, radiation pneumonitis, acute respiratory distress, etc. )

 

Gastro-intestinal disorders

diarrhoea

nausea

vomiting

constipation

constipation

stomatitis (including dry mouth and glossodynia)

dyspepsia

dysphagia

gastro oesophageal reflux disease

gastro oesophageal reflux disease

pancreatitis

gastritis

gastrointestinal perforations*

 

Hepatobiliary disorders

 

 

increase in bilirubin and jaundice, cholecystitis, cholangitis

drug induced hepatitis*

Skin and subcutaneous tissue disorders

dry skin

rash

alopecia

hand foot syndromeskin reaction**

erythema

pruritus

dry skin

keratoacanthoma/ squamous cell cancer of the skin

dermatitis exfoliative

acne

skin desquamation

hyperkeratosis

eczema

erythema multiforme keratoacanthoma/ squamous cell cancer of the skin

radiation recall dermatitis

Stevens-Johnson syndrome

leucocytoclastic vasculitis

toxic epidermal necrolysis*

Musculo-skeletal and connective tissue disorders

arthralgia

arthralgia

myalgia

muscle spasms

 

rhabdomyolysis

Renal and urinary disorders

 

renal failure

proteinuria

 

nephrotic syndrome

Reproductive system and breast disorders

 

erectile dysfunction

gynaecomastia

 

General disorders and administration site conditions

fatigue

pain (including mouth, abdominal, bone, tumour pain and headache)

fever

asthenia

fever

influenza like illness

mucosal inflammation

 

 

Investigations

weight decreased

increased amylase

increased lipase

weight decreased transient increase in transaminases

transient increase in blood alkaline phosphatase,

INR abnormal, prothrombin level abnormal

 

* 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

 

Laboratory parameter,
(in % of samples investigated)

Sorafenib N=207

Placebo N=209

All Grades*

Grade 3*

Grade 4*

All Grades*

Grade 3*

Grade 4*

Blood and lymphatic system disorders

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

Metabolism and nutrition disorders

Hypokalemia

17.9

1.9

0

2.4

0

0

Hypophosphatemia**

19.3

12.6

0

2.4

1.4

0

Hepatobiliary disorders

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

Investigations

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 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

 

Efficacy Parameter

SorafenibNexavar

(N=299)

Placebo

(N=303)

P-value

HR

(95% CI)

Overall Survival (OS) [median, weeks (95% CI)]

46.3

(40.9, 57.9)

34.4

(29.4, 39.4)

0.00058*

 

0.69

(0.55, 0.87)

Time to Progression (TTP) [median, weeks (95% CI)]**

24.0

(18.0, 30.0)

12.3

(11.7, 17.1)

0.000007

0.58

(0.45, 0.74)

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 Cmax 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

 

Updated on 27 March 2013 SPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

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Section 4.4 Special Warnings and Precautions for use

Elderly population

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

 

Updated on 21 March 2013 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 13 July 2012 SPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.3 - Contraindications
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 6.6 - Special precautions for disposal and other handling
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  • Change to section 10 - Date of revision of the text

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Section 2:
"For a full list of excipients. . ." was changed to "for the full list of excipients. . ."

Section 4.3:
"listed in section 6.1" added at the end of the sentence.

Section 4.5:
In the subsection "Combination with other neoplastic agents", "carboplatin" was added to the last sentence.

Section 4.8:
In the System organ class(SOC) "Metabolism and nutrition disorders", "hypocalcaemia" was added to the "Common" column.
In the SOC "Skin and subcutaneous tissue disorders", "toxic epidermal necrolysis" was added to the "Rare" column.

The paragraph "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 etiology of hypocalcaemia associated with sorafenib is not known." was added at the end of the section.

Section 6.6:
the words "and other handling" were removed from the heading.

"No special requirements" was removed from the section.

"any unused product or waste material. . . ." was updated to "any unused medicinal product or waste material. . ."

Section 9:
"Date of last renewal" was changed to "Date of latest renewal"

Section 10:
Date of revision of the text updated to "27th June 2012"

Updated on 6 July 2012 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to instructions about overdose
  • Change to storage instructions
  • Change to side-effects
  • Change to drug interactions
  • Change to date of revision
  • Correction of spelling/typing errors

Updated on 12 April 2012 PIL

Reasons for updating

  • Change to date of revision
  • Addition of manufacturer

Updated on 1 December 2011 SPC

Reasons for updating

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  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

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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

 

System organ class

Very common

Common

Uncommon

Rare

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)

angioedema anaphylactic reaction

Endocrine disorders

 

 

hypothyroidism

hyperthyroidism

 

Metabolism and nutrition disorders

hypo-phosphataemia

anorexia

hyponatraemia

dehydration

 

Psychiatric disorders

 

depression

 

 

Nervous system disorders

 

peripheral sensory neuropathy

reversible posterior leukoencephalo-pathy*

 

Ear and labyrinth disorders

 

tinnitus

 

 

Cardiac disorders

 

congestive heart failure*

myocardial ischaemia and infarction*

 

QT prolongation

Vascular disorders

haemorrhage (inc. gastrointestinal*, respiratory tract* and cerebral haemorrhage*)

hypertension

 

hypertensive crisis*

 

Respiratory, thoracic and mediastinal disorders

 

hoarseness

rhinorrhoea

interstitial lung disease-like events (pneumonitis, radiation pneumonitis, acute respiratory distress, etc.)

 

Gastro-intestinal disorders

diarrhoea

nausea

vomiting

constipation

stomatitis (including dry mouth and glossodynia)

dyspepsia

dysphagia

gastro oesophageal reflux disease

pancreatitis

gastritis

gastrointestinal perforations*

 

Hepatobiliary disorders

 

 

increase in bilirubin and jaundice

cholecystitis

cholangitis

drug induced hepatitis*

Skin and subcutaneous tissue disorders

rash

alopecia

hand foot syndrome**

erythema

pruritus

dry skin

dermatitis exfoliative

acne

skin desquamation

eczema

erythema multiforme keratoacanthoma/ squamous cell cancer of the skin

radiation recall dermatitis

Stevens-Johnson syndrome

leucocytoclastic vasculitis

Musculo-skeletal and connective tissue disorders

 

arthralgia

myalgia

 

rhabdomyolysis

Renal and urinary disorders

 

renal failure

 

 

Reproductive system and breast disorders

 

erectile dysfunction

gynaecomastia

 

General disorders and administration site conditions

fatigue

pain (including mouth, abdominal, bone, tumour pain and headache)

asthenia

fever

influenza like illness

 

 

Investigations

increased amylase increased lipase

weight decreased transient increase in transaminases

transient increase in blood alkaline phosphatase,

INR abnormal, prothrombin level abnormal

 

* 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 “24th October 2011”

Updated on 29 November 2011 PIL

Reasons for updating

  • Change to side-effects
  • Change to further information section
  • Change to date of revision

Updated on 13 September 2011 SPC

Reasons for updating

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The name of the Marketing Authorisaiton Holder in section 7 has been changed from "Bayer Schering Pharma AG" to "Bayer Pharma AG".

Updated on 7 September 2011 PIL

Reasons for updating

  • Change to further information section
  • Change to date of revision
  • Change to name of manufacturer

Updated on 6 September 2011 SPC

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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"

Updated on 12 August 2011 SPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container
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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).

 

 

Nexavar N=451

Placebo N=451

System organ class

Preferred term

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%