Nexavar Information
Nexavar (Sorafenib tosylate) Dosage And Administration
The recommended daily dose of Nexavar (Sorafenib tosylate) is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.
Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of Nexavar (Sorafenib tosylate) . When dose reduction is necessary, the Nexavar (Sorafenib tosylate) dose may be reduced to 400 mg once daily. If additional dose reduction is required, Nexavar (Sorafenib tosylate) may be reduced to a single 400 mg dose every other day .
Suggested dose modifications for skin toxicity are outlined in Table 1.
No dose adjustment is required on the basis of patient age, gender, or body weight.
Nexavar (Sorafenib tosylate) Dosage Forms And Strengths
Tablets containing sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib.
Nexavar (Sorafenib tosylate) tablets are round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side.
Nexavar (Sorafenib tosylate) Warnings And Precautions
Nexavar (Sorafenib tosylate) can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid Nexavar (Sorafenib tosylate) in patients with congenital long QT syndrome. Monitor patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) .
Nexavar (Sorafenib tosylate) Adverse Reactions
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in sections 6.1 and 6.2 reflect exposure to Nexavar (Sorafenib tosylate) in 748 patients who participated in placebo controlled studies in hepatocellular carcinoma (N=297) or advanced renal cell carcinoma (N=451).
The most common adverse reactions (≥20%), which were considered to be related to Nexavar (Sorafenib tosylate) , in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.
Nexavar (Sorafenib tosylate) Use In Specific Populations
It is not known whether sorafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Nexavar (Sorafenib tosylate) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into the milk. The milk to plasma AUC ratio was approximately 5:1.
The safety and effectiveness of Nexavar (Sorafenib tosylate) in pediatric patients have not been studied.
Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥ 600 mg/m(approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m/day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less.
Nexavar (Sorafenib tosylate) Overdosage
There is no specific treatment for Nexavar (Sorafenib tosylate) overdose.
The highest dose of Nexavar (Sorafenib tosylate) studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.
In cases of suspected overdose, Nexavar (Sorafenib tosylate) should be withheld and supportive care instituted.
Nexavar (Sorafenib tosylate) Description
Nexavar (Sorafenib tosylate) , a kinase inhibitor, is the tosylate salt of sorafenib.
Sorafenib tosylate has the chemical name 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy) -methylpyridine-2-carboxamide 4-methylbenzenesulfonate and its structural formula is:
Sorafenib tosylate is a white to yellowish or brownish solid with a molecular formula of CHClFNO x CHOS and a molecular weight of 637.0 g/mole. Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400.
Each red, round Nexavar (Sorafenib tosylate) film-coated tablet contains sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib and the following inactive ingredients: croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.
Nexavar (Sorafenib tosylate) Clinical Pharmacology
Cardiac Electrophysiology
The effect of Nexavar (Sorafenib tosylate) 400 mg twice daily on the QTc interval was evaluated in a multi-center, open-label, non-randomized trial in 53 patients with advanced cancer. No large changes in the mean QTc intervals (that is, >20 ms) from baseline were detected in the trial. After one 28-day treatment cycle, the largest mean QTc interval change of 8.5 ms (upper bound of two-sided 90% confidence interval, 13.3 ms) was observed at 6 hours post-dose on day 1 of cycle 2
Nexavar (Sorafenib tosylate) Clinical Studies
The clinical safety and efficacy of Nexavar (Sorafenib tosylate) have been studied in patients with hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC).
The HCC Study
Demographics and baseline disease characteristics were similar between the Nexavar (Sorafenib tosylate) and placebo groups with regard to age, gender, race, performance status, etiology (including hepatitis B, hepatitis C and alcoholic liver disease), TNM stage (stage I:
(Class A: 95% vs. 98%; B: 5% vs. 2%). Only one patient with Child-Pugh class C was entered. Prior treatments included surgical resection procedures (19.1% vs. 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization; 38.8% vs. 40.6%), radiotherapy (4.3% vs. 5.0%) and systemic therapy (3.0% vs. 5.0%).
The trial was stopped for efficacy following a pre-specified second interim analysis for survival showing a statistically significant advantage for Nexavar (Sorafenib tosylate) over placebo for overall survival (HR: 0.69, p= 0.00058) (see and ). This advantage was consistent across all subsets analyzed.
Final analysis of time to tumor progression (TTP) based on data from an earlier time point (by independent radiologic review) also was significantly longer in the Nexavar (Sorafenib tosylate) arm (HR: 0.58, p=0.000007) (see ).
The safety and efficacy of Nexavar (Sorafenib tosylate) in the treatment of advanced renal cell carcinoma (RCC) were studied in the following two randomized controlled clinical trials.
RCC Study 1
prognostic risk category (low or intermediate) and country and randomized to Nexavar (Sorafenib tosylate) 400 mg twice daily
(N=384) or to placebo (N=385).
Table 5 summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and disease characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the Nexavar (Sorafenib tosylate) and placebo groups, respectively.
Progression-free survival, defined as the time from randomization to progression or death from any cause, whichever occurred earlier, was evaluated by blinded independent radiological review using RECIST criteria.
Figure 2 depicts Kaplan-Meier curves for PFS. The PFS analysis was based on a two-sided Log-Rank test stratified by MSKCC prognostic risk category and country.
NOTE: HR is from Cox regression model with the following covariates: MSKCC prognostic risk category and country. P-value is from two-sided Log-Rank test stratified by MSKCC prognostic risk category and country.
The median PFS for patients randomized to Nexavar (Sorafenib tosylate) was 167 days compared to 84 days for patients randomized to placebo. The estimated hazard ratio (risk of progression with Nexavar (Sorafenib tosylate) compared to placebo) was 0.44 (95% CI: 0.35, 0.55).
A series of patient subsets were examined in exploratory univariate analyses of PFS. The subsets included age above or below 65 years ECOG PS 0 or 1, MSKCC prognostic risk category, whether the prior therapy was for progressive metastatic disease or for an earlier disease setting, and time from diagnosis of less than or greater than 1.5 years. The effect of Nexavar (Sorafenib tosylate) on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (N=137; 65 patients receiving Nexavar (Sorafenib tosylate) and 72 placebo), for whom the median PFS was 172 days on Nexavar (Sorafenib tosylate) compared to 85 days on placebo.
Tumor response was determined by independent radiologic review according to RECIST criteria. Overall, of 672 patients who were evaluable for response, 7 (2%) Nexavar (Sorafenib tosylate) patients and 0 (0%) placebo patients had a confirmed partial response. Thus the gain in PFS in Nexavar (Sorafenib tosylate) -treated patients primarily reflects the stable disease population.
At the time of a planned interim survival analysis, based on 220 deaths, overall survival was longer for Nexavar (Sorafenib tosylate) than placebo with a hazard ratio (Nexavar (Sorafenib tosylate) over placebo) of 0.72. This analysis did not meet the prespecified criteria for statistical significance. Additional analyses are planned as the survival data mature.
RCC Study 2
Two hundred and two patients with advanced RCC were enrolled into RCC Study 2, including patients who had received no prior therapy and patients with tumor histology other than clear cell carcinoma. After the initial 12 weeks of Nexavar (Sorafenib tosylate) , 79 patients with RCC continued on open-label Nexavar (Sorafenib tosylate) , and 65 patients were randomized to Nexavar (Sorafenib tosylate) or placebo. After an additional 12 weeks, at week 24, for the 65 randomized patients, the progression-free rate was significantly higher in patients randomized to Nexavar (Sorafenib tosylate) (16/32, 50%) than in patients randomized to placebo (6/33, 18%) (p=0.0077). Progression-free survival was significantly longer in the Nexavar (Sorafenib tosylate) group (163 days) than in the placebo group (41 days) (p=0.0001, HR=0.29).
Nexavar (Sorafenib tosylate) How Supplied/storage And Handling
Nexavar (Sorafenib tosylate) tablets are supplied as round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side, each containing sorafenib tosylate equivalent to 200 mg of sorafenib.
Bottles of 120 tablets NDC 50419-488-58
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) (see USP controlled room temperature). Store in a dry place.
Nexavar (Sorafenib tosylate) Patient Counseling Information
See FDA-approved Patient Labeling
Inform patients that Nexavar (Sorafenib tosylate) can increase the risk of bleeding and that they should promptly report any episodes of bleeding.
Advise patients that cases of gastrointestinal perforation have been reported in patients taking Nexavar (Sorafenib tosylate)
Advise patients of the possible occurrence of hand-foot skin reaction and rash during Nexavar (Sorafenib tosylate) treatment and appropriate countermeasures.
Inform patients that hypertension can develop during Nexavar (Sorafenib tosylate) treatment, especially during the first six weeks of therapy, and that blood pressure should be monitored regularly during treatment
Instruct patients that if a dose of Nexavar (Sorafenib tosylate) is missed, to take the next dose at the regularly scheduled time, and not double the dose. Instruct patients to contact their healthcare provider immediately if they take too much Nexavar (Sorafenib tosylate) .
FDA-approved Patient Labeling
Patient Information:
Nexavar (Sorafenib tosylate) (NEX-A-VAR)
(sorafenib) tablets, oral
Read the Patient Information before you start taking Nexavar (Sorafenib tosylate) and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.
What is Nexavar (Sorafenib tosylate) ?
Nexavar (Sorafenib tosylate) is an anticancer medicine used to treat a certain type of liver or kidney cancer called:
Nexavar (Sorafenib tosylate) has not been studied in children.
Who should not take Nexavar (Sorafenib tosylate) ?
Do not take Nexavar (Sorafenib tosylate) if you:
What should I tell my doctor before starting Nexavar (Sorafenib tosylate) ?
Before you take Nexavar (Sorafenib tosylate) , tell your doctor if you:
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.
Especially tell your doctor if you are taking the following medicines:
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. Do not take other medicines with Nexavar (Sorafenib tosylate) until you have talked with your doctor.
How do I take Nexavar (Sorafenib tosylate) ?
What are the possible side effects of Nexavar (Sorafenib tosylate) ?
Nexavar (Sorafenib tosylate) may cause serious side effects, including:
The most common side effects of Nexavar (Sorafenib tosylate) may include:
Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Nexavar (Sorafenib tosylate) . Ask your doctor or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Nexavar (Sorafenib tosylate) ?
General information about Nexavar (Sorafenib tosylate)
Medicines are sometimes prescribed for purposes other than those listed in the patient information leaflet. Do not use Nexavar (Sorafenib tosylate) for a condition for which it is not prescribed. Do not give Nexavar (Sorafenib tosylate) to other people even if they have the same symptoms you have. It may harm them.
This patient information leaflet summarizes the most important information about Nexavar (Sorafenib tosylate) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Nexavar (Sorafenib tosylate) that is written for healthcare professionals. For more information, go to , or call 1-866-Nexavar (Sorafenib tosylate) (1-866-639-2827).
What are the ingredients in Nexavar (Sorafenib tosylate) ?
Active Ingredient:
Inactive Ingredients
This Patient Information has been approved by the U.S. Food and Drug Administration.
Manufactured for:
Manufactured in Germany
Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080
Distributed and marketed by: Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470
Marketed by:
© 2011 Bayer HealthCare Pharmaceuticals Inc. Printed in U.S.A.
Nexavar (Sorafenib tosylate)
