Regorafenib

Uses

Colorectal Cancer: Regorafenib is used 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.

Gastrointestinal Stromal Tumors: Regorafenib is used 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.

Hepatocellular Carcinoma: Regorafenib is used for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

Regorafenib is also used to associated treatment for these conditions: Hepatocellular Carcinoma, Metastatic Colorectal Cancer (MCRC), Metastatic Gastrointestinal Stromal Tumor, Locally advanced Gastrointestinal stromal tumor, Unresectable Gastrointestinal stromal tumor

How Regorafenib works

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.

Dosage

Regorafenib dosage

Recommended Dose: The recommended dose is 160 mg Regorafenib (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 Regorafenib 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. Do not take two doses of Regorafenib on the same day to make up for a missed dose from the previous day.

Dose Modifications: If dose modifications are required, reduce the dose in 40 mg (one tablet) increments; the lowest recommended daily dose of Regorafenib is 80 mg daily.

Interrupt Regorafenib for the following:

• Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] 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
• Worsening infection of any grade

Reduce the dose of Regorafenib to 120 mg:

• For the first occurrence of Grade 2 HFSR of any duration
• After recovery of any Grade 3 or 4 adverse reaction except infection
• 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 Regorafenib 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 or infection)

Discontinue Regorafenib 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

Advise patients to swallow the Regorafenib tablet whole with water at the same time each day following a low-fat meal. Inform patients that the low-fat meal should contain less than 600 calories and less than 30% fat

Advise patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes. Discard any remaining tablets 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle

Side Effects

Common side effects are Hepatotoxicity, Infections, Hemorrhage, Gastrointestinal Perforation or Fistula, Dermatological Toxicity, Hypertension, Cardiac Ischemia and Infarction, Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Toxicity

The most common adverse reactions (≥20%) are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, and infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea

Precaution

Severe hepatic impairment. Pregnancy and lactation.

Interaction

Effect Of Strong CYP3A4 Inducers On Regorafenib: Co-administration of a strong CYP3A4 inducer with Regorafenib decreased the plasma concentrations of regorafenib, increased the plasma concentrations of the active metabolite M-5, and resulted in no change in the plasma concentrations of the active metabolite M-2, and may lead to decreased efficacy. Avoid concomitant use of Regorafenib with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's Wort).

Effect Of Strong CYP3A4 Inhibitors On Regorafenib: Co-administration of a strong CYP3A4 inhibitor with Regorafenib increased the plasma concentrations of regorafenib and decreased the plasma concentrations of the active metabolites M-2 and M-5, and may lead to increased toxicity. Avoid concomitant use of Regorafenib with strong CYP3A4 inhibitors (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole).

Effect Of Regorafenib On Breast Cancer Resistance Protein (BCRP) Substrates: Co-administration of Regorafenib with a BCRP substrate increased the plasma concentrations of the BCRP substrate. Monitor patients closely for signs and symptoms of exposure related toxicity to the BCRP substrate (e.g. methotrexate, fluvastatin, atorvastatin). Consult the concomitant BCRP substrate product information when considering administration of such products together with Regorafenib.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels of regorafenib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of regorafenib.
• Take after a meal. Should be taken following a low-fat meal containing less than 600 calories and less than 30% fat.
• Take at the same time every day.

[Moderate] ADJUST DOSING INTERVAL: Depending on the amount of fat, food may enhance the oral bioavailability of both regorafenib and its active metabolites, M-2 and M-5.

In 24 healthy male subjects, administration of regorafenib with a high-fat meal (945 calories; 54.6 g fat) increased the mean systemic exposure (AUC) of regorafenib by 48% but decreased the mean AUC of M-2 and M-5 by 20% and 51%, respectively, compared to administration under the fasted state.

In contrast, administration with a low-fat meal (319 calories; 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively, compared to administration during fasting.

GENERALLY AVOID: Coadministration with grapefruit juice may alter the pharmacokinetics of regorafenib and its active metabolites.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

The interaction has not been studied specifically with grapefruit juice, but has been reported with the potent CYP450 3A4 inhibitor, ketoconazole.

In 18 healthy male study subjects, administration of a single 160 mg dose of regorafenib on day 5 of treatment with ketoconazole (400 mg daily for 18 days) resulted in a 33% increase in mean regorafenib systemic exposure (AUC) compared to administration of regorafenib alone.

Additionally, there was a 93% decrease each in the mean AUC of the M-2 and M-5 metabolites.

Both have been shown to have similar in vitro pharmacological activity and steady-state concentrations as regorafenib, thus the net clinical effect of these pharmacokinetic changes is unknown.

MANAGEMENT: To ensure optimal oral absorption, regorafenib should be administered with a low-fat breakfast that contains less than 30% fat.

Examples of a low-fat breakfast include: 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, plus 8 ounces of skim milk (319 calories; 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories; 2 g fat).

Patients should be advised to avoid consuming grapefruit or grapefruit juice during treatment with regorafenib.

Regorafenib Drug Interaction

Major: aspirin, heparinModerate: citalopram, duloxetineUnknown: paclitaxel protein-bound, charcoal, doxorubicin, RHO Immunoglobulin , multivitamin with minerals, bevacizumab, drospirenone / ethinyl estradiol / levomefolate calcium, calcium / vitamin d, multivitamin, multivitamin, ubiquinone, acetaminophen, vitamin a topical, bioflavonoids, sotalol, cholecalciferol

Regorafenib Disease Interaction

Moderate: lung toxicity

Volume of Distribution

Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval.

Elimination Route

Cmax = 2.5 μg/mL; Tmax = 4 hours; AUC = 70.4 μgh/mL; Cmax, steady-state = 3.9 μg/mL; AUC, steady-state = 58.3 μgh/mL; The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.

Half Life

Regorafenib, 160 mg oral dose = 28 hours (14 - 58 hours); M2 metabolite, 160 mg oral dose = 25 hours (14-32 hours); M5 metabolite, 160 mg oral dose = 51 hours (32-72 hours);

Elimination Route

Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.

Pregnancy & Breastfeeding use

Pregnancy: Based on animal studies and its mechanism of action, Regorafenib can cause fetal harm when administered to a pregnant woman. There are no available data on Regorafenib use in pregnant women. Administration of 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 hazard to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively.

Lactation: There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production. In rats, regorafenib and its metabolites are excreted in milk. Because of the potential for serious adverse reactions in breastfed infants from Regorafenib, do not breastfeed during treatment with Regorafenib and for 2 weeks after the final dose.

Contraindication

None

Special Warning

Pediatric Use: The safety and efficacy of Regorafenib in pediatric patients less than 18 years of age have not been established.

Geriatric Use: Of the 1142 Regorafenib-treated patients enrolled in randomized, placebo-controlled trials, 40% were 65 years of age and over, while 10% were 75 and over. No overall differences in efficacy were observed between these patients and younger patients. There was an increased incidence of Grade 3 hypertension (18% versus 9%) in the placebo-controlled trials among Regorafenib-treated patients 65 years of age and older as compared to younger patients. In addition, one Grade 4 hypertension event has been reported in the 65 years and older age group and none in the younger age group.

Hepatic Impairment: No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions. Regorafenib is not recommended for use in patients with severe hepatic impairment as Regorafenib has not been studied in this population.

Renal Impairment: No dose adjustment is recommended for patients with renal impairment. The pharmacokinetics of regorafenib have not been studied in patients who are on dialysis and there is no recommended dose for this patient population

Acute Overdose

The highest dose of Regorafenib studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no known antidote for Regorafenib overdose. In the event of suspected overdose, interrupt Regorafenib, institute supportive care, and observe until clinical stabilization.

Storage Condition

Store Regorafenib at 25°C; excursions are permitted from 15 to 30°C. Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening. Discard any unused tablets 7 weeks after opening the bottle. Dispose of unused tablets in accordance with local requirements.

Innovators Monograph

You find simplified version here Regorafenib