Consumer medicine information

Nexavar

Sorafenib

BRAND INFORMATION

Brand name

Nexavar

Active ingredient

Sorafenib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nexavar.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Nexavar.

This leaflet does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Nexavar against the benefits they expect it will have for you.

Nexavar is a prescription medicine. It should only be used under medical supervision.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT NEXAVAR IS USED FOR

Nexavar is used to treat advanced liver cancer (hepatocellular carcinoma), advanced kidney cancer (renal cell carcinoma), or thyroid cancer (differentiated thyroid carcinoma).

Nexavar is a multi-kinase inhibitor. It works by slowing down the rate of growth of cancer cells and cutting off the blood supply that keeps cancer cells growing.

Nexavar should be prescribed and managed only by healthcare professionals specialising in treating your type of cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU TAKE NEXAVAR

When you must not take it

Do not take Nexavar if you have an allergy to:

  • sorafenib tosilate, the active ingredient in Nexavar
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine after the expiry date printed on the pack and blister. The expiry date is printed on the carton and on each blister after “EXP” (e.g. 11 18 refers to November 2018). The expiry date refers to the last day of that month. If it has expired return it to your pharmacist for disposal.

Do not take this medicine if the packaging is torn or shows signs of tampering. If the packaging is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or breast-feeding. Women should avoid becoming pregnant while undergoing treatment with Nexavar.

You should speak to your doctor right away if you think that you are pregnant because Nexavar may harm the foetus. Both men and women should use effective birth control measures.

Nexavar is not recommended for use while breast-feeding because it could harm the baby.

Do not give Nexavar to children or growing adolescents.

Tell your doctor if you:

  • Experience skin problems.
    Nexavar can cause rashes and skin reactions, especially on hands and feet. These can usually be treated by your doctor. If not, your Nexavar treatment may be interrupted or stopped altogether.
  • Have high blood pressure. Nexavar can raise blood pressure, and your doctor will usually monitor your blood pressure and may give you medicine to treat your high blood pressure.
  • Have any bleeding problems, or are taking warfarin. Treatment with Nexavar may lead to a higher risk of bleeding. If you are taking warfarin, which thins the blood to prevent blood clots, there may be a greater risk of bleeding.
  • Are going to have surgery, or you have had an operation recently. Nexavar might affect the way your wounds heal. You will usually be taken off Nexavar if you are having an operation. Your doctor will decide when to start with Nexavar again.
  • Suffer from chest pain (angina) or have suffered a heart attack (myocardial infarction) recently. Your doctor may decide to interrupt treatment or stop it altogether.
  • Have an abnormality of your heart trace known as prolonged QT interval. Nexavar may affect your heart rhythm.
  • Have severe hepatic impairment (liver failure). You may experience more severe side effects when taking this medicine.
  • Are taking irinotecan (Camptosar), capecitabine (Xeloda) or docetaxel (Taxotere), which are other drugs used in the treatment of cancer, or other related drugs. You may experience more side effects when taking combination therapy.
  • If you have thyroid cancer, your doctor will monitor blood calcium and thyroid hormone levels.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Nexavar. You may need extra treatment, or your doctor may decide to change your dose of Nexavar, or stop treatment altogether.

Taking other medicines

Whilst being treated with Nexavar, you must seek your doctor's advice before taking any other medication, whether provided on a prescription or bought from a pharmacy, supermarket or health food shop including any over-the-counter drugs, vitamins, or herbal medicines.

Some medication may be affected by Nexavar or vice versa. These medicines are:

  • Rifampicin and neomycin, which are antibiotics
  • St John’s Wort, a herbal treatment for depression
  • Phenytoin, carbamazepine or phenobarbital, treatments for epilepsy and other conditions
  • Dexamethasone, a corticosteroid used for various conditions.
  • Warfarin, an anticoagulant used to prevent blood clots
  • Doxorubicin, capecitabine, paclitaxel, carboplatin, irinotecan or docetaxel which are other cancer treatments.

You may need to use different amounts of your medicine or a different medicine. Your doctor will be able to advise you. Your doctor and pharmacist will have a complete list of medicines to be careful of and to avoid while taking Nexavar.

HOW TO TAKE NEXAVAR

Always take Nexavar exactly as your doctor has told you to.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions printed on the pharmacy label, ask your doctor or pharmacist for help.

How much to take

The usual dose of Nexavar is two 200 mg tablets twice a day. This is equivalent to 800 mg total daily dose.

Your doctor may put you on a lower dose or stop Nexavar treatment if you get severe side effects – in particular high blood pressure, bleeding or skin reactions.

If you are worried, talk to your doctor or pharmacist.

How to take it

Swallow the tablets whole with a full glass of water.

Take Nexavar either without food or with a low fat or moderate fat meal. Do not take this medicine with high fat meals, as this may make your Nexavar less effective.

When to take it

Take your Nexavar tablets at the same time each day. Taking it at the same time each day (usually morning and evening) will have the best effect. It will also help you remember when to take it.

If you forget to take it

If you miss a dose of Nexavar, do not take the missed dose and do not double the next one. Instead, continue your regular dosing schedule and check with your doctor.

How long to take it

Your doctor will continue to treat you with Nexavar as long as you are receiving benefit from therapy. Your doctor might interrupt your Nexavar therapy and/or change the number of tablets you take every day depending on how you are tolerating it.

If you take too much (overdose)

There is no information on symptoms of Nexavar overdose.

Immediately telephone your doctor or the Poisons Information Centre (Australia: 13 11 26 or New Zealand: 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Nexavar. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING NEXAVAR

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Nexavar.

Take Nexavar exactly as told by your doctor.

Tell all doctors, dentists and pharmacists who are treating you that you are taking Nexavar.

Tell your doctor if you are taking medicine to thin your blood such as warfarin.

Tell your doctor if you need to have a surgical or dental procedure.

It is not known whether Nexavar will affect your ability to drive or to operate machinery, but if you feel light-headed stop the activity and consult your doctor.

Things you must not do

Do not take Nexavar to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Nexavar.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. In serious cases, you may need medical attention.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • Diarrhoea
  • Feeling and/or being sick (nausea and/or vomiting)
  • Feeling weak or tired
  • Fever, flu-like illness
  • Constipation
  • Dry mouth, difficulty swallowing, hoarseness
  • Indigestion
  • Loss of appetite, weight loss
  • Ringing in the ear (tinnitus)
  • Pain (including mouth pain, abdominal pain, headache, bone pain, joint pain and muscle pain)
  • Hair thinning or patchy hair loss
  • Flushing
  • Redness, pain, swelling or blistering on the palms or soles of your feet (called hand foot skin reaction)
  • Disturbed sensations in fingers and toes, including tingling or numbness
  • Muscle cramps, weakness and/or spasms in your legs and arms or heart palpitations which can be from low levels of calcium or potassium in your blood
  • Frothy urine, swelling in abdomen, face, feet or hands which can be from abnormally high levels of protein in urine
  • Inflamed, dry or scaly skin that sheds
  • Acne
  • Itching or rash
  • Bleeding (haemorrhage)
  • Depression
  • Erection problems (impotence)
  • High blood pressure, or increases in blood pressure. You may not experience any specific symptoms but your doctor will check you regularly for this side effect and may start or change your blood pressure treatment.
  • Passing little or no urine, drowsiness, nausea, vomiting, breathlessness. These symptoms may be associated with a decrease in the function of your kidneys.
  • Infections
  • Heartburn
  • Skin cancer
  • Distortion of the sense of taste
  • Runny nose

These are the more common side effects, other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Tell your doctor immediately, or go to accident and emergency at your nearest hospital if you notice any of the following:

  • Chest pain which may spread to the neck and shoulders, changes in the way your heart beats (for example, if you notice it beating faster), abnormal heart rhythm
  • Severe headache, confusion, seizures, visual loss
  • Vomiting blood or material that looks like coffee grounds, bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea
  • Shortness of breath, difficulty breathing, swelling of the feet or legs due to fluid build-up
  • Severe abdominal pain intensified by movement, nausea, vomiting, fever and/or chills
  • sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, mouth, tongue, throat or other parts of the body, shortness of breath, wheezing or trouble breathing, difficulty in swallowing
  • severe blisters and bleeding in the lips, eyes, mouth, nose and genitals (a rare skin condition known as Stevens-Johnson syndrome)
  • sun-burn like rash that may occur on skin that has been previously exposed to radiotherapy and can be severe (a condition known as radiation recall dermatitis)
  • nausea, vomiting, loss of appetite, feeling generally unwell, fever, itching, yellowing of the skin and eyes, light coloured bowel motions, dark coloured urine (these symptoms may be associated with liver disease)
  • inflammation of small blood vessels (a condition known as leukocytoclastic vasculitis)
  • temporary paralysis or weakness of muscles (a condition known as rhabdomyolysis)
  • swelling of face, legs, abdomen and body from damage of the kidney causing them to leak large amounts of protein (a condition known as nephrotic syndrome)

These may be more serious side effects of Nexavar. You may need urgent medical attention. Serious side effects are rare and uncommon.

AFTER TAKING NEXAVAR

Storage

Keep your tablets in their blister pack until it is time to take them. If you take the tablets out of the box or blister pack they may not keep well.

Store the tablets in a cool dry place where the temperature stays below 25°C.

Do not store Nexavar or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. Heat and damp can destroy some medicines.

Keep all medicines out of reach of children. A locked cupboard at least one-and-a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Return any unused medicine to your pharmacist.

PRODUCT DESCRIPTION

What it looks like

Nexavar is packed in blister packs of 60 tablets. They are red, round film-coated tablets marked with “200” on one side and the "BAYER" cross on the other side.

Ingredients

Active ingredient:

  • Nexavar - 200 mg sorafenib as sorafenib tosilate

Inactive ingredients:

  • croscarmellose sodium
  • microcrystalline cellulose
  • hypromellose
  • sodium lauryl sulphate
  • magnesium stearate
  • macrogol
  • titanium dioxide
  • iron oxide red

Supplier

Made in Germany for:

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble, NSW 2073

Bayer New Zealand Limited
3 Argus Place, Hillcrest
North Shore, Auckland 0627

Australian Registration Number

Nexavar 200 mg - AUST R 123158

Date of Preparation

22 October 2019

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered trademark of Bayer Group, Germany

© Bayer Australia Ltd
All rights reserved.

Published by MIMS December 2019

BRAND INFORMATION

Brand name

Nexavar

Active ingredient

Sorafenib

Schedule

S4

 

1 Name of Medicine

Nexavar (sorafenib tosilate).

6.7 Physicochemical Properties

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

Chemical structure.


CAS number.

28844-1-73-01 (sorafenib) and 475207-59-1 (sorafenib tosilate).

Chemical name.

4-(4-{3-[4-chloro-3- (trifluoromethyl)phenyl]- ureido}phenoxy)- N2-methylpyridine-2- carboxamide 4-methylbenzenesulfonate.

Empirical formula.

C21H16ClF3N4O3 x C7H8O3S.

2 Qualitative and Quantitative Composition

Nexavar 200 mg tablets.

Each tablet contains 274 mg sorafenib tosilate, equivalent to 200 mg of sorafenib.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nexavar 200 mg tablets.

Film-coated, red, round, biconvex marked with a Bayer cross on one side and "200" on the other.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Sorafenib is a multikinase inhibitor that targets various receptor tyrosine kinases and RAF kinases (serine/ threonine kinases) associated with tumour growth. Sorafenib inhibits the activity of targets present in tumour cells (Raf-1 [CRAF], BRAF, V600E BRAF, KIT and FLT-3) and in the tumour vasculature (Raf-1 [CRAF], VEGFR-2, VEGFR-3 and PDGFR-β). Sorafenib has been shown to inhibit tumour cell proliferation in vitro and to inhibit the growth of mouse renal cell carcinoma (RENCA) allografts, human renal cell carcinoma (A498) xenografts, human hepatocellular carcinoma (PLC/PRF/5) xenographs, as well as a broad range of other human tumour xenografts, in nude mice. Inhibition of tumour growth was accompanied by a reduction in tumour angiogenesis.

Clinical trials.

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

Hepatocellular carcinoma.

Study 100554 was a phase III, international, multicentre, randomised, double blind, placebo controlled trial in 602 patients with hepatocellular carcinoma. Overall survival (OS) was a primary endpoint of this study, time to progression (TTP) a secondary endpoint.
Demographics and baseline disease characteristics were comparable between the Nexavar and placebo groups with regard to age, gender, ethnicity, performance status, aetiology (including hepatitis B, hepatitis C and alcoholic liver disease), TNM (tumour node metastasis) 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%), absence of both macroscopic vascular invasion and extrahepatic tumour spread (30.1% vs. 30.0%), and BCLC (Barcelona Clinic Liver Cancer) stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: < 1% vs. 0%). Liver function Child-Pugh status was comparable between the Nexavar and placebo groups (A: 95% vs. 98%; B: 5% vs. 2%). Only one patient with Child-Pugh C liver dysfunction was treated in the study. Prior treatment included surgical resection procedures (19.1% vs. 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolisation; 38.8% vs. 40.6%), radiotherapy (4.3% vs. 5.0%) and systemic therapy (3.0% vs. 5.0%).
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 Nexavar over placebo for OS (HR: 0.69; p = 0.00058, see Table 7 and Figure 1). This advantage was consistent across all subsets analysed. In the prespecified stratification factors [ECOG (Eastern Cooperative Oncology Group) status, presence or absence of macroscopic vascular invasion and/or extrahepatic tumour spread and region] the hazard ratio consistently favoured Nexavar over placebo. The TTP (by independent radiological review) was significantly longer in the Nexavar arm (HR: 0.58; p = 0.000007, see Table 7).

Renal cell carcinoma.

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

The TARGET study was a phase III multicentre, randomised, double blind, placebo controlled trial in 903 patients with advanced renal cell carcinoma who had received prior systemic therapy. Primary study endpoints included overall survival and progression free survival (PFS). Tumour response rate was a secondary endpoint.
Patients were randomised to Nexavar 400 mg twice daily (N = 451) or to placebo (N = 452). Baseline demographics and patient characteristics were well balanced for both treatment groups. Approximately half of the patients had an ECOG performance status of 0 and half of the patients were in the low MSKCC (Memorial Sloan Kettering Cancer Centre) prognostic group.
Two planned interim analyses of survival were conducted. In the first analysis based on 220 deaths, there was an estimated 39% improvement in overall survival for patients receiving Nexavar vs. placebo. The estimated hazard ratio (risk of death with Nexavar compared to placebo) was 0.72 (95% CI: 0.55 to 0.95; p = 0.018. The threshold for statistical significance of the interim analysis was p < 0.0005). As of 30 November 2005, 367 deaths were reported, comprising 68% of the protocol specified 540 survival events, there was an estimated 30% improvement in overall survival for patients receiving Nexavar compared to placebo. A total of 216 placebo patients had crossed over to Nexavar treatment. The median overall survival for the Nexavar and placebo group was 19.3 months and 15.9 months, respectively. The estimated hazard ratio (risk of death with sorafenib compared to placebo) was 0.77 (95% CI: 0.63-0.95; p = 0.015. The threshold for statistical significance of the interim analysis was p < 0.0094).
Progression free survival in the intent to treat population was evaluated by blinded independent radiological review using RECIST criteria. Figure 2 depicts Kaplan-Meier curves for PFS. The PFS analysis was a two sided log rank test stratified by Motzer/MSKCC prognostic risk category1 and country.
1Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;223:454-63.
The PFS analysis included 769 patients randomised to Nexavar 400 mg twice daily (N = 384) or to placebo (N = 385). The median PFS was double for patients randomised to Nexavar (167 days) compared to patients randomised to placebo (84 days), representing a 56% reduction in risk of progression for patients receiving Nexavar compared to placebo (HR = 0.44; 95% CI: 0.35-0.55; p < 0.000001).
A series of patient subsets were examined in exploratory univariate analyses of PFS. These results are shown in Figure 3. The effect of Nexavar on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (N = 137), for whom the median PFS was 172 days on Nexavar compared to 85 days on placebo.
Best overall tumour response was determined by investigator radiological review according to RECIST criteria. In the Nexavar group 1 patient (0.2%) had a complete response, 43 patients (9.5%) had a partial response and 333 patients (73.8%) had stable disease. In the placebo group 0 patients (0%) had a complete response, 8 patients (1.8%) had a partial response and 239 patients (52.9%) had stable disease.
Overall, 293 patients in the Nexavar group and 281 patients in the placebo group had at least one post-baseline radiographic tumour evaluation available for independent review; tumour shrinkage was reported in 74% of patients receiving Nexavar compared to 20% of patients in the placebo group (see Figure 4).
Nexavar demonstrated no overall deterioration in kidney cancer specific symptoms (FKSI-10) or health related quality of life compared to placebo.

Study 100391.

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

Differentiated thyroid carcinoma.

Study 14295, a phase III, international, multicentre, randomised, double blind, placebo controlled trial included 417 patients with locally advanced or metastatic differentiated thyroid carcinoma refractory to radioactive iodine.
Progression free survival (PFS) was the primary endpoint of the study. Secondary endpoints included overall survival (OS), tumor response rate and duration of response. Following progression, patients were allowed to receive open label Nexavar. Concomitant radioactive iodine treatment was not permitted.
Patients were included in the study if they experienced progression within 14 months of enrollment and had differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI). DTC refractory to RAI was defined as having a lesion without iodine uptake on a radioactive iodine (RAI) scan, or receiving cumulative RAI ≥ 600 mCi, or experiencing 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. Almost all patients had thyroidectomy (99.5%) and had a median delivered cumulative radioactive activity of approximately 400 mCi. The majority of patients had papillary carcinoma (56.8%), followed by follicular (25.4%) and poorly differentiated carcinoma (9.6%).
The full analysis set included 207 patients randomised to Nexavar 400 mg twice daily and 210 patients randomised to placebo. PFS was evaluated by blinded independent radiological review using RECIST criteria.
Median PFS was 329 days (10.8 months) in the Nexavar group compared to 175 days (5.8 months) in the placebo group. (HR): 0.587; 95% confidence interval (CI): 0.454-0.758; one sided p < 0.0001). (See Table 8 and Figure 5).
The effect of Nexavar on PFS was consistent across all subsets including geographic region, age above or below 60 years, gender, histological subtype, tumor burden and presence or absence of bone metastasis.
There was no statistical difference in overall survival between the treatment groups (the HR was 0.802; 95% CI: 0.539-1.194; one sided p-value of 0.138, see Table 8). The median OS was not reached for either arm. One hundred fifty (71.4%) patients randomised to placebo and 55 (26.6%) patients randomised to Nexavar received open label Nexavar.
The median duration of therapy in the double blind period was 46 weeks (range 0.3-135) for patients receiving Nexavar and 28 weeks (range 1.7-132) for patients receiving placebo.
No complete response (CR) according to RECIST were observed. The overall response rate (CR + partial response (PR) per independent radiological assessment was higher in the Nexavar 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 Nexavar treated patients who experienced a PR.

5.2 Pharmacokinetic Properties

After administration of Nexavar tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. Absolute bioavailability has not been determined.
The elimination half-life of sorafenib is approximately 25-48 hours. Multiple dosing of Nexavar for 7 days results in a 3 to 7-fold accumulation compared to single dose administration.
Steady-state plasma sorafenib concentrations are achieved within 7 days, with a peak to trough ratio of mean concentrations of less than 2.
The steady-state pharmacokinetics of sorafenib administered at 400 mg twice a day were evaluated in thyroid carcinoma, renal cell carcinoma and hepatocellular carcinoma. The highest mean exposure was observed in thyroid carcinoma patients (approximately twice that observed in patients with RCC and HCC), though variability was high for all tumor types. The clinical relevance of the increased exposure in thyroid carcinoma patients is unknown.

Absorption and distribution.

Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate fat meal, bioavailability is similar to that in the fasted state. With a high fat meal, sorafenib bioavailability is reduced by 29% compared to administration in the fasted state.
Mean Cmax and AUC increase less than proportionally beyond doses of 400 mg administered orally twice daily.
In vitro binding of sorafenib to human plasma proteins is 99.5%.

Metabolism and elimination.

Sorafenib is metabolised primarily in the liver undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the GI tract by bacterial glucuronidase activity, allowing reabsorption of unconjugated drug. Coadministration of neomycin interferes 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 and comprises approximately 9-16% of circulating analytes at steady state.
Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in faeces and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in faeces but not in urine.

Renal impairment.

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

Hepatic impairment.

Sorafenib is cleared primarily by the liver.
In HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, exposure values were within the range observed in patients without hepatic impairment. In non-HCC patients the pharmacokinetics (PK) of sorafenib in Child-Pugh A and Child-Pugh B patients were similar to the PK in healthy volunteers. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

QT interval prolongation.

In a clinical pharmacology study, QT/QTc measurements were recorded in 31 patients at baseline (pretreatment) and post-treatment. After one 28 day treatment cycle, at the time of maximum concentration of sorafenib, QTcB was prolonged by 4 ± 19 ms and QTcF by 9 ± 18 ms, as compared to placebo treatment at baseline. No subject showed a QTcB or QTcF > 500 ms during the post-treatment ECG monitoring. (See Section 4.4 Special Warnings and Precautions for Use.)

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

Carcinogenicity studies have not been performed with sorafenib.

4 Clinical Particulars

4.1 Therapeutic Indications

Hepatocellular carcinoma.

Nexavar is indicated for the treatment of patients with advanced hepatocellular carcinoma.

Renal cell carcinoma.

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

Differentiated thyroid carcinoma.

Nexavar is indicated for the treatment of patients with locally advanced or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Pregnancy and lactation.

Women should avoid becoming pregnant while on therapy. Women of childbearing potential must be apprised of the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity). (See Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy.)
Nexavar should not be used during pregnancy. Breastfeeding should be discontinued during Nexavar therapy. (See Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.)

Dermatological toxicities.

Hand foot skin reaction (palmar plantar erythrodysaesthesia) and rash represent the most common adverse drug reactions with Nexavar. Rash and hand foot skin reaction are usually CTC (National Cancer Institute Common Toxicity Criteria) grade 1 and 2 and generally appear during the first six weeks of treatment with Nexavar. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of Nexavar, or in severe or persistent cases, permanent discontinuation of Nexavar (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hypertension.

An increased incidence of hypertension was observed in Nexavar treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was amenable to management with standard antihypertensive therapy. Blood pressure should be monitored regularly and treated, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension, or hypertensive crisis despite adequate antihypertensive therapy, permanent discontinuation of Nexavar should be considered (see Section 4.8 Adverse Effects (Undesirable Effects)).

Haemorrhage.

An increase in the risk of bleeding may occur following Nexavar administration. The incidence of severe bleeding events is uncommon. If any bleeding event necessitates medical intervention, it is recommended that permanent discontinuation of Nexavar should be considered (see Section 4.8 Adverse Effects (Undesirable Effects)). Due to the potential risk of bleeding, tracheal, bronchial, and oesophageal infiltration should be treated with localised therapy prior to administering Nexavar in patients with differentiated thyroid carcinoma.

Warfarin.

Infrequent bleeding events or elevations in the international normalised ratio (INR) have been reported in some patients taking warfarin while on Nexavar therapy. Patients taking warfarin concomitantly should be monitored regularly for changes in prothrombin time, INR and for clinical bleeding episodes (see Section 4.8 Adverse Effects (Undesirable Effects)).

Wound healing complications.

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

Additional information on sorafenib combinations in 1st line NSCLC.

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.

Cardiac ischaemia and/or infarction.

In study 11213, the incidence of treatment emergent cardiac ischaemia/ infarction events was higher in the Nexavar group (4.9%) compared with the placebo group (0.4%). In study 100554, the incidence of treatment emergent cardiac ischaemia/ infarction events was 2.7% in sorafenib 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 Nexavar should be considered in patients who develop cardiac ischaemia and/or infarction (see Section 4.8 Adverse Effects (Undesirable Effects)).

QT interval prolongation.

Nexavar has been shown to prolong the QT/QTc interval (see Section 5 Pharmacological Properties), which may lead to an increased risk for ventricular arrhythmias. Use Nexavar 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 antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcaemia, or hypomagnesemia. When using Nexavar 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 Nexavar. In some cases this was not associated with apparent intra-abdominal tumour. Nexavar therapy should be discontinued.

Use in 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 Section 5.2 Pharmacokinetic Properties).

Hypocalcaemia.

When using Nexavar in patients with differentiated thyroid carcinoma, close monitoring of blood calcium level is recommended. In clinical trials, hypocalcaemia was more frequent and more severe in patients with differentiated thyroid carcinoma, especially with a history of hypoparathyroidism, compared to patients with renal cell or hepatocellular carcinoma. (See Section 4.8 Adverse Effects (Undesirable Effects)).

TSH suppression in differentiated thyroid carcinoma (DTC).

In the DTC clinical trials, increases in TSH levels above 0.5 mU/L were observed in Nexavar treated patients. When using Nexavar in differentiated thyroid carcinoma patients, close monitoring of TSH level and appropriate adjustment of thyroxine dosing is recommended.

Use in elderly.

No data available.

Paediatric use.

The safety and effectiveness of Nexavar in paediatric patients has not been established.
Effects on bone and teeth were observed after repeated dosing to young and growing dogs. The changes consisted of irregular thickening of the femoral growth plate at a dose of 30 mg/kg/day (relative exposure 0.5 based on relative AUC for unbound drug), hypocellularity of the bone marrow at 10 mg/kg/day (relative exposure, 0.25) and alteration of dentin composition at 30 mg/kg/day (relative exposure, 0.3). Similar effects were observed in mice and rats. A study in adult dogs revealed no effects on teeth and minimal effects on bone marrow.

Effects on laboratory tests.

Laboratory test abnormalities in RCC patients (study 11213).

Elevated lipase and amylase levels were very commonly reported. In the TARGET study CTC AE grade 3 or 4 lipase elevations occurred in 10% of patients in the Nexavar group compared to 5% of patients in the placebo group. CTC AE grade 3 or 4 amylase elevations were reported in 1% of patients in the Nexavar group compared to 3% of patients in the placebo group. Clinical pancreatitis was reported in 2 of 384 Nexavar treated patients (CTC AE grade 4) and 1 of 384 patients (CTC AE grade 2) in the placebo group.
Hypophosphataemia was a common laboratory finding, observed in 45% of sorafenib treated patients compared to 11% of placebo patients. CTCAE grade 3 hypophosphataemia (10-20 mg/L) occurred in 13% on sorafenib treated patients and 3% of patients in the placebo group. There were no cases of CTCAE grade 4 hypophosphataemia (< 10 mg/L) reported in either sorafenib or placebo patients. The aetiology of hypophosphataemia associated with sorafenib is not known.

Laboratory abnormalities in HCC patients (study 100554).

Elevated lipase was observed in 40% of patients treated with Nexavar compared to 37% of patients in the placebo group. CTCAE grade 3 or 4 lipase elevations occurred in 9% of patients in each group. Elevated amylase was observed in 34% of patients treated with Nexavar compared to 29% of patients in the placebo group. CTCAE grade 3 or 4 amylase elevations were reported in 2% of patients in each group. Many of the lipase and amylase elevations were transient, and in the majority of cases Nexavar treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 Nexavar treated patients (CTCAE grade 2).
Hypophosphataemia was a common laboratory finding, observed in 35% of sorafenib treated patients compared to 11% of placebo patients; CTCAE grade 3 hypophosphataemia (10-20 mg/L) occurred in 11% of sorafenib treated patients and 2% of patients in the placebo group; there was 1 case of CTCAE grade 4 hypophosphataemia (< 10 mg/L) reported in the placebo group. The aetiology of hypophosphataemia associated with sorafenib is not known.

Laboratory test abnormalities in thyroid carcinoma patients (study 14295).

Hypocalcaemia was reported in 35.7% of sorafenib treated patients compared to 11.0% of the patients in the placebo group. 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Sorafenib is metabolised primarily in the liver undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2B6, CYP2C8 and CYP2C9 (Ki = 1-8 micromolar).
Caution is recommended when administering Nexavar together with compounds that are metabolised/ eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan). In vitro data show that sorafenib inhibits glucuronidation by the UGT1A1 (Ki = 1 micromolar) and UGT1A9 (Ki = 2 micromolar) pathways. Concomitant clinical administration of sorafenib with irinotecan, whose active metabolite SN-38 is further metabolised by the UGT1A1 pathway, resulted in a 67-120% increase in the AUC of SN-38. Systemic exposure to substrates of UGT1A1 and UGT1A9 may be increased when coadministered with sorafenib.

CYP inducers.

CYP1A2, 2A6, 2B6, 2C9, 2C19 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of these enzymes. Continuous concomitant clinical administration of sorafenib and rifampicin resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity (e.g. Hypericum perforatum also known as St. John's wort, phenytoin, carbamazepine, phenobarbital and dexamethasone) may also increase metabolism of Nexavar and thus decrease Nexavar concentrations.

CYP3A4 inhibitors.

Ketoconazole (400 mg), a potent inhibitor of CYP3A4 and P-glycoprotein, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of Nexavar. Therefore, clinical pharmacokinetic interactions of Nexavar with CYP3A4 inhibitors are unlikely.

CYP2C9 substrates.

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

CYP isoform selective substrates.

Concomitant clinical administration of midazolam, dextromethorphan and omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, following four weeks of Nexavar administration did not alter the exposure of these agents. This indicates that Nexavar is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes.
Sorafenib inhibits CYP2C8 and CYP2B6 in vitro with Ki values of 1-2 and 6 micromolar, respectively. Concomitant clinical administration of sorafenib with paclitaxel resulted in an increase, instead of a decrease, in the exposure of 6-OH paclitaxel, the active metabolite of paclitaxel that is formed by CYP2C8. These data suggest that sorafenib may not be an in vivo inhibitor of CYP2C8. Concomitant clinical administration of sorafenib with cyclophosphamide resulted in a small decrease in cyclophosphamide exposure, but no decrease in the systemic exposure of 4-OH cyclophosphamide, the active metabolite of cyclophosphamide that is formed primarily by CYP2B6. These data suggest that sorafenib may not be an in vivo inhibitor of CYP2B6.

P-glycoprotein substrates.

Sorafenib inhibited P-glycoprotein in vitro. Sorafenib could increase the concentrations of concomitantly administered drugs that are P-glycoprotein substrates.

Combination with other antineoplastic agents.

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

Paclitaxel/ carboplatin.

Administration of paclitaxel (225 mg/m2) and carboplatin (AUC = 6) with sorafenib (≤ 400 mg twice daily), administered with a 3 day break in sorafenib dosing around administration of paclitaxel/ carboplatin, resulted in no significant effect on the pharmacokinetics of paclitaxel.
Coadministration of paclitaxel (225 mg/m2, once every 3 weeks) and carboplatin (AUC = 6) with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected.
These data indicate no need for dose adjustments when paclitaxel and carboplatin are coadministered with sorafenib with a 3 day break in sorafenib dosing. The clinical significance of the increases in sorafenib and paclitaxel exposure, upon coadministration of sorafenib without a break in dosing, is unknown.

Capecitabine.

Coadministration of capecitabine (750-1050 mg/m2 twice daily, days 1-14 every 21 days) and sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52% increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine and 5-FU exposure when coadministered with sorafenib is unknown.

Cyclophosphamide.

Concomitant administration with Nexavar resulted in a 37% increase in the AUC of 4-OH cyclophosphamide, the active metabolite of cyclophosphamide. The clinical significance of this finding is unknown.

Doxorubicin/ irinotecan.

Concomitant treatment with Nexavar resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolised by the UGT1A1 pathway, there was a 67 to 120% increase in the AUC of SN-38 and a 26 to 42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown (see Section 4.4 Special Warnings and Precautions for Use).

Docetaxel.

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

Combination with other agents.

Neomycin.

Coadministration of neomycin, a nonsystemic antimicrobial agent used to eradicate GI flora, interferes with the enterohepatic recycling of sorafenib (see Section 5.2 Pharmacokinetic Properties, Metabolism and elimination), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5 day regimen of neomycin the average bioavailability of sorafenib decreased by 54%. The clinical significance of these findings is unknown. Effects of other antibiotics have not been studied, but will likely depend on their ability to decrease glucuronidase activity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No specific studies with Nexavar have been conducted in animals to evaluate the effect on fertility. An adverse effect on male and female fertility is expected, however, based on histological changes in reproductive organs observed in repeat dose studies in animals. Sorafenib caused testicular tubular degeneration and oligospermia in mice, rats and dogs at daily doses producing plasma exposures approximately 0.9, 1.5 and 0.3 times, respectively, that expected in patients (based on relative AUC for unbound sorafenib). Retardation of prostatic and seminal vesicle development were also observed in rats. In female mice and rats, arrested follicular development in the ovaries was observed following treatment with sorafenib at doses producing exposure levels 0.7-0.9 times that expected in patients.
(Category D)
There are no adequate and well controlled studies in pregnant women using Nexavar. Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits. Observed effects included decreases in maternal and fetal bodyweights, an increased number of fetal resorptions and an increased number of skeletal and visceral malformations. Adverse fetal outcomes were observed at an oral dose of 1 mg/kg/day in rats (relative exposure, 0.08) and 3 mg/kg/day in rabbits (relative exposure, 0.4). In rats, sorafenib and/or its metabolites were demonstrated to cross the placenta. Nexavar therapy in pregnant patients is anticipated to inhibit angiogenesis in the fetus.
Nexavar should not be used during pregnancy. Women must be advised to avoid becoming pregnant while on therapy. If Nexavar is used during pregnancy or if the patient becomes pregnant while using Nexavar, the patient must be apprised of the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity). Adequate contraception should be used during therapy and for at least two weeks after completion of therapy.
It is not known whether Nexavar is excreted in human milk. In lactating rats, sorafenib and/or its metabolites were readily excreted in milk (milk:plasma AUC ratio of approximately 5:1). Because of the potential for excretion in human milk and the likelihood that infants will be particularly sensitive to the toxic effects of sorafenib, women must be advised to discontinue breastfeeding during Nexavar treatment.

4.8 Adverse Effects (Undesirable Effects)

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

Hepatocellular carcinoma.

See Table 3.

Renal cell carcinoma.

The overall safety profile of Nexavar is based on 1,286 cancer patients, who received Nexavar as single agent. See Table 4.

Differentiated thyroid carcinoma.

Adverse reactions in differentiated thyroid carcinoma study 14295: double blind period.

Table 5 shows the percentage of differentiated thyroid carcinoma patients experiencing adverse reactions (TEAE - treatment emergent adverse events) that were reported in at least 5% of patients and at a higher rate in the Nexavar treated subjects than the placebo arm in double blind phase. Grade 3 adverse reactions were reported in 53% of patients receiving Nexavar compared to 23% of patients receiving placebo. Grade 4 adverse reactions were reported in 12% of patients receiving Nexavar compared to 7% of patients receiving placebo.

Multiple clinical trials.

Adverse reactions reported in multiple clinical trials are listed in Table 6, by system organ class (in MedDRA) and frequency. Frequencies are defined as: very common (≥ 10%), common (≥ 1% to < 10%), uncommon (≥ 0.1% to < 1%), rare (≥ 0.01% to < 0.1%). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Postmarketing experience.

The following adverse drug reactions have been identified during postapproval use of Nexavar. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders.

Radiation recall dermatitis, Stevens-Johnson syndrome, leukocytoclastic vasculitis, toxic epidermal necrolysis.

Immune system disorders.

Angioedema.

Musculoskeletal, connective tissue and bone disorders.

Rhabdomyolysis.

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 those 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 consistent with congestive heart failure.

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 cancer compared to patients in the renal cell or hepatocellular carcinoma studies.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting- problems (Australia).

4.2 Dose and Method of Administration

Use in adults.

Recommended dose.

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

Duration of treatment.

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

Dose titration, dose adjustment, special monitoring advice.

Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of Nexavar 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 once daily (see Section 4.4 Special Warnings and Precautions for Use).
When dose reduction is necessary during the treatment of differentiated thyroid carcinoma, the Nexavar dose should be reduced to 600 mg 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 one tablet of 200 mg twice daily, followed by one tablet of 200 mg once daily. After improvement of nonhaematological adverse reactions, the dose of Nexavar may be increased. See Tables 1 and 2.

Additional information on special populations.

Patients with hepatic impairment.

No dose adjustment is required in patients with Child-Pugh A or B hepatic impairment. Nexavar has not been studied in patients with Child-Pugh C hepatic impairment (see Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

Patients with renal impairment.

No dose adjustment is required in patients with mild to moderate renal impairment. Nexavar has not been studied in patients with severe renal impairment or patients undergoing dialysis (see Section 5.2 Pharmacokinetic Properties, Renal impairment).
Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.

Elderly (above 65 years), gender and body weight.

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

Paediatric use.

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

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

There is no specific treatment for Nexavar overdose.
The highest dose of Nexavar studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhoea and dermatologic events.
In the event of suspected overdose, Nexavar should be withheld and supportive care instituted.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

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

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Supplied in (Al/Al) blister pack in 120, 112, and 60 tablets. (120 and 112 tablet pack sizes are not marketed in Australia).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes