SORAFENIB EL KENDI

Sorafenib is a bi-aryl urea and an oral multikinase inhibitor.

It targets cell surface tyrosine kinase receptors and downstream intracellular kinases that are implicated in tumour cell proliferation and tumour angiogenesis.

First approved by the FDA and European Commission in for the treatment of hepatocellular carcinoma, sorafenib is also indicated to treat renal carcinoma and differentiated thyroid carcinoma.

Sorafenib is indicated for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. 5, 6 In the US, it is also indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma that is refractory to radioactive iodine treatment.

Sorafenib decreases tumour cell proliferation in vitro.

It attenuated tumour growth of human tumour xenografts in immunocompromised mice, reduced tumour angiogenesis, and increased tumour apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. 1, 5 Some studies suggest that sorafenib induces apoptosis in several tumour cell lines, although this effect is inconsistent across cell lines.

Antiviral effects of sorafenib have been documented, as it was shown to inhibit hepatitis C viral replication in vitro.

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The administration of multiple doses for seven days resulted in a 2.5.

• to 7-fold accumulation compared to a single dose.

Steady-state concentrations were achieved within seven days, with a peak-to-trough ratio of mean concentrations of less than 2.

Mean C max and

AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily.

T max is approximately three hours.

The mean relative bioavailability was 38–49% following the administration of oral sorafenib tablets.

Sorafenib is widely distributed to tissues, indicating that it is lipophilic.

Sorafenib undergoes oxidative metabolism by

CYP3A4 in the liver, as well as glucuronidation by UGT1A9 in the liver and kidneys. 1, 5 At steady-state, sorafenib accounts for 70-85% of the circulating analytes in plasma.

About eight metabolites of sorafenib have been identified, of which five were detected in plasma.

The main circulating metabolite was the pyridine N-oxide form, which comprises approximately 9–16% of the total circulating dose at steady-state: the pharmacological activity of this metabolite was comparable to the parent drug.

Hover over products below to view reaction partners Sorafenib Sorafenib N-oxide Sorafenib beta-D-Glucuronide.

Following oral administration of a 100 mg dose of sorafenib, about 96% of the dose was recovered within 14 days, with 77% of the dose being excreted in feces and 19% of the dose being excreted in urine as glucuronidated metabolites.

Unchanged sorafenib accounted for 51% of the dose excreted in feces.

The mean elimination half-life of sorafenib was approximately 25-48 hours.

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The oral lowest published toxic dose (Toxic Dose Low, TDLo) is 2.84 mg/kg/21D (intermittent).

The oral

LD of sorafenib tosylate in rats is >2000 mg/kg.

The adverse reactions observed at 800 mg sorafenib twice daily (twice the recommended 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.

The prescribing information recommends the discontinuation of sorafenib treatment and initiation of supportive care in cases of suspected overdose.

Sorafenib tablets are contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of sorafenib tablets.

Sorafenib tablets in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer.

Sorafenib tablets in combination with carboplatin and paclitaxel are contraindicated in patients with squamous cell lung cancer.

• The recommended dosage is 400 mg orally twice daily without food. 2.1 Recommended Dosage The recommended dosage of sorafenib tablets is 400 mg orallytwice daily without food (at least 1 hourbefore or 2 hours after a meal) until the patient is no longer clinically benfiting from therapy or untilunacceptable toxicity. 2.2 Dose Modifications for Adverse Reactions Recommended Dosage Modifications The recommended dosage modifications for adverse reactions are provided in Tables 1, 2, and 3.

Table 1: Recommended Dose Reductions forAdverse Reactions Dose Reduction Hepatocellular Carcinoma Differentiated Thyroid Carcinoma First Dose Reduction 400 mg orally once daily 400 mg orally in the morning and 200 mg orally in the evening about 12 hours apart OR 200 mg orally in the morning and 400 mg orally in the evening about 12 hours apart Second Dose Reduction 200 mg orally once daily OR 400 every other day 200 mg orally twice daily Third Dose Reduction None 200 mg orally once daily Table 2: Recommended Dosage Modifications of Sorafenib Tablets for Adverse Reactions Adverse Reaction Severity 1 Sorafenib T ablets Dosage M odification Cardiovascular Events Cardiac Ischemia and/or Infarction Grade and above Permanently discontinue.

Grade 3 Interrupt2 until Grade 1 or less, resume at reduced dose by 1 dose level.3 Grade 4 Permanently discontinue.

Hemorrhage Grade and above requiring medical intervention Permanently discontinue.

Grade 2 (symptomatic/persistent) OR Grade 2 symptomatic increase by greater than 20 mm Hg (diastolic) or greater than 140/90 mm Hg if previously within normal limits OR Grade 3 Interrupt until symptoms resolve and diastolic blood pressure less than 90 mm Hg, then resume at reduced dose by 1 dose level.3 If needed, reduce another dose level.3 Grade 4 Permanently discontinue.

G astrointestinal Perforation Any grade

Permanently discontinue.

Greater than 500 milliseconds OR Increase from baseline of 60 milliseconds or greater Interrupt and correct electrolyte abnormalities (magnesium, potassium, calcium).

Use medical judgement before restarting.

Grade 3 ALT or higher in the absence of another cause4 OR AST/ALT greater than 3 × upper limit normal (ULN) with bilirubin greater than 2 × ULN in the absence of another cause4 Permanently discontinue.

Non-hematological toxicities

Grade 2 Continue treatment at reduced dose by 1 dose level.

Grade 3 1st occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 1 dose level.

No improvement within 7 days OR 2nd or 3rd occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels. 4th occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels for HCC or 3 dose levels for DTC.

Grade 4 Permanently discontinue.

Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0).

If no recovery after 30 day interruption, discontinue treatment unless the patient is deriving clinical benefit.

If more than 2 dose reductions are required, permanently discontinue treatment.

In addition, any grade increased alkaline phosphatase in the absence of known bone pathology and Grade 2 or worse increased bilirubin; any of the following: INR of 1.5 or greater, ascites and/or encephalopathy in the absence of underlying cirrhosis or other organ failure considered to be due to drug-induced liver injury.

Table 3: Recommended Dosage Modifications for Dermatologic Toxicities Dermatologic Toxicity Grade Occurrence Sorafenib T ablets Dosage Modification Hepatocellular Differentiated Thyroid Carcinoma Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities 1st occurrence Continue sorafenib tablets and consider topical therapy for symptomatic relief.

If no improvement within 7 days, see below.

Decrease sorafenib tablets to 600 mg daily If no improvement within 7 days, see below.

No improvement within 7 days at reduced dose OR 2nd and 3rd occurrence Interrupt sorafenib tablets until resolved or improved to Grade to 1.

Interrupt sorafenib tablets until completely resolved or improved to Grade 1.

When resuming treatment, decrease dose by 1 dose level.

When resuming treatment, decrease dose by 1 dose level for 2nd occurrence and 2 dose levels for 3rd occurrence. 4th occurrence Discontinue sorafenib tablets treatment.

Grade 3:Moist desquamation, ulceration, blistering, or severe pain of the hands or feet, resulting in inability to work or perform activities of daily living 1st occurrence Interrupt sorafenib tablets until resolved or improved to Grade to 1.

When resuming treatment, decrease dose by 1 dose level. 2nd occurrence Interrupt sorafenib tablets until resolved or improved to Grade to 1.

When resuming treatment, decrease dose by 2 dose levels. 3rd occurrence Discontinue sorafenib tablets treatment.

Following improvement of

Grade 2 or 3 dermatologic toxicity to Grade 0 or for at least 28 days on a reduced dose of sorafenib tablets, the dose of sorafenib tablets may be increased 1 dose level from the reduced dose.

Approximately 50% of patients requiring a dose reduction for dermatologic toxicity are expected to meet these criteria for resumption of the higher dose and roughly 50% of patients resuming the previous dose are expected to tolerate the higher dose (that is, maintain the higher dose level without recurrent Grade 2 or higher dermatologic toxicity).

Tablets, USP are supplied as round, pink, film-coated tablets, debossed with “YB” on one side and “201” on the other side.

Bottles of 120 tablets NDC 51990-201-12 Bottles of 60 tablets NDC 51990-201-06 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Store in a dry place.