1.1 Colorectal Cancer

Stivarga® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy.

1.2 Gastrointestinal Stromal Tumors

Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

2.1 Recommended Dose

The recommended dose is 160 mg Stivarga (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.

Take Stivarga at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat [see Clinical Pharmacology (12.3)]. Do not take two doses of Stivarga on the same day to make up for a missed dose from the previous day.

2.2 Dose Modifications

Interrupt Stivarga for the following:

•

Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR

•

Symptomatic Grade 2 hypertension

•

Any Grade 3 or 4 adverse reaction.

Reduce the dose of Stivarga to 120 mg:

•

For the first occurrence of Grade 2 HFSR of any duration

•

After recovery of any Grade 3 or 4 adverse reaction

•

For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity

Reduce the dose of Stivarga to 80 mg:

•

For re-occurrence of Grade 2 HFSR at the 120 mg dose

•

After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity)

Discontinue Stivarga permanently for the following:

•

Failure to tolerate 80 mg dose

•

Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)

•

Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN

•

Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg

•

For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

5.1 Hepatotoxicity

Severe drug-induced liver injury with fatal outcome occurred in Stivarga-treated patients in clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury.

In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm [see Adverse Reactions (6.1)].

Obtain liver function tests (ALT, AST, and bilirubin) before initiation of Stivarga and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.

Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

5.2 Hemorrhage

Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivarga-treated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 and involved the respiratory, gastrointestinal, or genitourinary tracts.

Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].

5.3 Dermatologic Toxicity

Stivarga increased the incidence of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification.

The overall incidence of HFSR was higher in Stivarga-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2) than in the placebo-treated patients. Most cases of HFSR in Stivarga-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens-Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Stivarga-treated patients [see Adverse Reactions (6.1)]. In both studies, a higher incidence of HFSR was observed in Asian patients treated with Stivarga (all grades: 78.4% in Study 1 and 88.2% in Study 2 and Grade 3: 28.4% in Study 1 and 23.5% in Study 2) [see Use in Specific Populations (8.8)].

Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients across all clinical trials.

Withhold Stivarga, reduce the dose, or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief.

5.4 Hypertension

Stivarga caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.25% of 1200 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2).

Do not initiate Stivarga unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and Administration (2.2)].

5.5 Cardiac Ischemia and Infarction

Stivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%) [see Adverse Reactions (6.1)]. Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia.

5.6 Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Stivarga-treated patients across all clinical trials. Perform an eva luation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion or altered mental function. Discontinue Stivarga in patients who develop RPLS.

5.7 Gastrointestinal Perforation or Fistula

Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Stivarga across all clinical trials; this included four fatal events. In Study 2, 2.1% (4/188) of Stivarga-treated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula.

5.8 Wound Healing Complications

No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, discontinue treatment with regorafenib at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Discontinue regorafenib in patients with wound dehiscence.

5.9 Embryo-Fetal Toxicity

Based on animal studies and its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no available data on Stivarga use in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with Stivarga and for 2 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Stivarga and for 2 months after the final dose [see Use in Specific Populations (8.1), (8.3)].

6.1 Clinical Trials Experience

Colorectal Cancer

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for patients receiving Stivarga. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation occurred in 8.2% of Stivarga-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Stivarga.

Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1).

Laboratory abnormalities observed in Study 1 are shown in Table 2.

Table 2: Laboratory test abnormalities reported in Study 1

Laboratory Parameter	Stivarga (N=500 *)			Placebo (N=253 *)
	Grade †			Grade †
	All %	3 %	4 %	All %	3 %	4 %
* % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). † Common Terminology Criteria for Adverse Events (CTCAE), v3.0. ‡ International normalized ratio: No Grade 4 denoted in CTCAE, v3.0.
Blood and lymphatic system disorders
Anemia	79	5	1	66	3	0
Thrombocytopenia	41	2	<1	17	<1	0
Neutropenia	3
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