Regorafenib - Dosages, Indication, Contraindications, and Adverse Effects

Overview

Regorafenib is utilized to treat cases of colon cancer or rectal cancer that has spread to additional parts of the body and for which they have obtained previous therapy with specific chemotherapy drugs. In addition, the drug is used to treat rare stomach cancer, bowel cancer, or esophagus cancer, known as gastrointestinal stromal tumors, that cannot be managed with surgical procedures or that have spread to different body parts and for which they have obtained previous therapy with specific drugs. Regorafenib has not been utilized to manage kids less than 18 years of age.

Indications and Usage

• Colorectal Cancer - It is indicated for the therapy of metastatic colorectal cancer patients who have been previously managed with Fluoropyrimidine, Oxaliplatin- and Irinotecan-based chemotherapy.

• Gastrointestinal Stromal Tumors - It is indicated for treating cases with locally advanced, metastatic type, or unresectable type gastrointestinal stromal tumors previously managed with Imatinib mesylate and Sunitinib malate.

• Hepatocellular Carcinoma - It is indicated for treating cases with hepatocellular carcinomas that have been previously managed with Sorafenib.

Dosage and Administration

Recommended Dose: The suggested dose is 160 mg of Regorafenib, four 40 mg tablets taken by oral route once every day for the initial 21 days per 28-day cycle. Resume therapy until the disease advances or until unacceptable toxicity. Take Regorafenib at the exact time daily. Swallow the tablet whole with water following a low-fat meal with less than 600 calories and less than 30 percent fat. Do not have two doses of Regorafenib on the exact day to make up for the missed dose from the last day.

Dose Modifications

If dose changes are needed, decrease the dose in 40 mg increments; the lower suggested daily dose of Regorafenib is 80 mg daily.

Interrupt Regorafenib for the following:

• Grade 2 hand-foot skin reaction that is recurrent or does not subside within seven days despite dose deduction interrupt treatment for around seven days for Grade 3 hand-foot skin reaction.

• Symptomatic grade 2 hypertension.

• Any type of grade 3 or 4 adverse reaction.

• Aggravating infection of any grade.

Decrease the dose of Regorafenib to 120 mg:

• For the initial grade 2 hand-foot skin reaction of any duration.

• Following the recovery of any time of Grade 3 or 4 adverse reactions besides infection

• For grade 3 aspartate aminotransferase, alanine aminotransferase (ALT) elevation only continues if the possible advantage outweighs the hazard of hepatotoxicity.

Reduce the Dose of Regorafenib to 80 mg: The dose can be reduced to prevent the recurrence of grade 2 hand-foot skin reaction at the 120 mg dose Following the recovery of any grade 3 or 4 adverse response at the 120 mg dosage.

Stop Regorafenib Completely for the Following:

• Aspartate aminotransferase or alanine aminotransferase is more than 20 times the upper limit of normal.

• Aspartate aminotransferase and alanine aminotransferase are more than three times the upper limit of normal, with concurrent bilirubin more than two times the upper limit of normal.

• The recurrence of aspartate aminotransferase or alanine aminotransferase is more than five times the upper limit of normal despite a dose deduction to 120 mg. Only restart any grade 4 adverse response if the possible advantage overpowers the hazards.

Dosage Forms and Strengths: Regorafenib is a 40 mg, light pink in color, oval-shaped, film-coated type tablet, debossed with BAYER on one of its sides and 40 on its other side.

Contraindications

There is no contraindication for Regorafenib.

Warnings and Precautions

• Hepatotoxicity - In clinical tests, extreme drug-induced liver injury with fatal results appeared in Regorafenib-treated cases. In most patients, liver dysfunction happened within the initial two months of treatment and was distinguished by a hepatocellular kind of injury. Get liver function tests before the beginning of Regorafenib and observe at least every two weeks at the time of the first two months of therapy. Temporarily stop and then decrease or permanently pause Regorafenib based on the severity and continuation of hepatotoxicity as displayed by raised liver function tests or hepatocellular necrosis.

• Infections - Regorafenib induced an improved risk of infections. Withhold Regorafenib for grade 3 or 4 infections or aggravating infections of any grade. Resume Regorafenib at the exact dosage after the resolution of infection.

• Hemorrhage - Regorafenib caused an improved incidence of hemorrhage. Permanently discontinue Regorafenib in cases with extreme or life-threatening hemorrhage. Check INR (international normalized ratio) levels more frequently in cases receiving Warfarin.

• Gastrointestinal Perforation or Fistula - Stop Regorafenib permanently when patients develop gastrointestinal perforation or fistula.

• Dermatologic Toxicity - Withhold Regorafenib, decrease the dose, or stop Regorafenib permanently based on the severity and continuation of dermatologic toxicity.

• Hypertension - Do not start Regorafenib unless blood pressure is satisfactorily managed. Monitor blood pressure every week for the initial six weeks of therapy and then every cycle, or more often, as clinically demonstrated. Temporarily or permanently withhold Regorafenib for extreme or uncontrolled hypertension.

• Cardiac Ischemia and Infarction - Continue Regorafenib only after the resolution of acute cardiac ischemic circumstances if the possible advantages outweigh the hazards of additional cardiac ischemia.

• Reversible Posterior Leukoencephalopathy Syndrome - Complete an assessment for reversible posterior leukoencephalopathy syndrome, in any case, delivering with seizures, extreme headache, visual disruptions, confusion, or changed mental function. Quit Regorafenib in cases that develop reversible posterior leukoencephalopathy syndrome.

• Wound Healing Complications - Stop Regorafenib in cases with wound dehiscence.

• Embryo-Fetal Toxicity - Advise females of reproductive potential to utilize adequate contraception at the time of therapy with Regorafenib and for two months following the final dose. Notify males with female partners of the possibility of utilizing adequate contraception during therapy with Regorafenib and for two months following the final dose.

For Patients

What Is Metastatic Cancer of the Colon and Rectum?

Metastasis indicates that cancer has extended beyond the rectum to further body parts. This is usually directed as progressive rectal cancer. The therapy options will rely on several elements involving the extent of the cancer. Colorectal cancer typically metastases to the liver.

What Special Precautions Should Be Followed While Taking Regorafenib?

Before Taking Regorafenib

Tell the doctor and pharmacist if the patient is allergic to Regorafenib, medications, or ingredients in Regorafenib tablets. Ask the pharmacist for a list of the ingredients.

• Inform the doctor what other prescription and nonprescription medicines, vitamins, and nutritional supplements are planned to take. Be sure to note any of the following: anticoagulants (blood thinning medications) such as Warfarin, certain antifungal medicines such as Itraconazole, and certain medicines for seizures such as Carbamazepine. The doctor may require altering the medicines' doses or observing for side effects.

• Inform the doctor if any herbal products are taken, particularly St. John's wort. The patient should not take St. John's wort while taking Regorafenib.

• Inform the doctor of any wound that has not healed or if the patient has had bleeding problems, increased blood pressure, chest ache, or heart, kidney, or liver disorders. Also, inform the doctor if the patient recently had any surgery.

• Inform the doctor in case of pregnancy or intend to become pregnant. In the case of a female patient, the patient should not become pregnant while taking Regorafenib and for up to two months following her final dose. Discuss with the doctor about birth control approaches. In the case of a male patient, the patient and his female partner should utilize birth control during their therapy and resume using birth control for two months following their final dose. Call the doctor in case of pregnancy while taking Regorafenib. Regorafenib may induce harm to the fetus.

• Inform the doctor in case of breastfeeding. The patient should not breastfeed at the time of therapy with Regorafenib and for up to two weeks after the final dose.

• If the patient has any dental surgery, inform the doctor or dentist regarding the intake of Regorafenib. The doctor will inform the patient to quit taking Regorafenib at least two weeks before surgery. The doctor will advise the patient when it is safe for him to initiate retaking Regorafenib after his surgery.

What Should Special Dietary Instructions Be Followed While Taking Regorafenib?

Do not consume grapefruit or have grapefruit juice when taking this medicine. Unless the doctor informs the patient otherwise, resume the regular diet.

What Should a Patient Do in Case of Missed Dose?

In case of a missed dose of Regorafenib, take the forgotten dose immediately when recalling it on that day. Do not have two doses on the exact day to make up for a forgotten one.

What Are the Side Effects of Regorafenib?

Regorafenib may induce side effects. Inform the doctor if any of these manifestations are severe or do not go away:

• Weakness.

• Loss of appetite.

• Diarrhea.

• Pain, inflammation, and redness of the mouth or throat lining.

• Weight loss.

• Hoarseness of voice.

Specific side effects can be severe. Contact the doctor instantly or get emergency medical therapy:

• Chest ache and shortness of breath.

• Uncommon vaginal discharge or irritation.

• Burning or ache at the time of urination.

• Dizziness.

• Fever, sore throat, chills, cough, and different symptoms of infection.

• Abdomen swelling.

• High fever and chills.

• Intense diarrhea.

• Intense headache.

• Seizure and confusion.

• Alterations in vision.

• Dry mouth, muscle twitches, or reduced urination.

• Ache, blisters, bleeding, or inflammation on the palms of the hands or soles of the feet.

• Rashes.

• Vomiting blood and vomitus look like coffee grounds.

• Pink urine or brown urine.

• Red stool or black stools.

• Coughing up blood or clots.

• Abnormally heavy menstrual bleeding.

• Unusual bleeding.

• Frequent nosebleeds.

Regorafenib may induce additional side effects. Contact the doctor in case of any unusual issues while taking this medicine.

How Can Regorafenib Be Stored?

• Store Regorafenib tablets at room temperature between 68° F to 77° F (20° C to 25° C).

• Keep Regorafenib in the bottle that it arrives in.

• Do not put Regorafenib tablets in every day or weekly pill containers.

• The Regorafenib bottle includes a desiccant to assist in keeping the medicine dry.

• Keep the desiccant in the container.

• Keep the container of Regorafenib tightly closed.

• Safely discard any new Regorafenib tablets after 28 days of opening the container. Keep Regorafenib and all medications out of the reach of children.

For Doctors

What Are the Adverse Reactions of Regorafenib?

• Hepatic toxicity.

• Bleeding.

• Dermatological toxicity.

• Hypertension.

• Cardiac ischemia and myocardial infarction.

• Reversible posterior leukoencephalopathy syndrome (RPLS).

• Gastrointestinal perforation or fistula.

Drug Interactions

• Effect of Strong CYP3A4 Inducers on Regorafenib - Co-administration of a strong CYP3A4 inducer with a single 160 mg of Regorafenib reduced the mean exposure of the drug and raised the mean exposure of the metabolite M-5 and thus induced no difference n the mean exposure of the metabolite M-2. Bypass using strong CYP3A4 inducers with Regorafenib.

• Effect of Strong CYP3A4 Inhibitors on Regorafenib - Co-administration of a strong CYP3A4 inhibitor with 160 mg of Regorafenib improved the mean exposure of Regorafenib and reduced the mean exposure of the metabolites M-2 and M-5.

Use in Specific Populations:

Pregnancy

Regorafenib can induce fetal harm when taken by a pregnant woman depending on the mechanism of action. There are no sufficient and well-controlled investigations with Regorafenib in pregnant women. If this medicine is utilized during pregnancy or if the female becomes pregnant while having this medicine, the patient must be notified of the potential threat to a fetus.

Nursing Mothers

Due to numerous medications secreted in human milk and the possibility of adverse severe responses in nursing infants from Regorafenib, a conclusive study should be done on whether to stop nursing or quit the medication, considering the significance of the medication to the mother.

Pediatric Use

The safety and effectiveness of Regorafenib in pediatric cases less than 18 years of age have not been confirmed.

Hepatic Impairment

No dose adjustment is suggested in mild or moderate hepatic impairment cases. Closely observe cases with hepatic impairment for adverse responses.

Renal Impairment

No dose adjustment is suggested for cases with mild renal impairment. Regorafenib has not been investigated in cases with extreme renal impairment or an end-stage renal disorder.

Females and Males of Reproductive Potential

Utilize adequate contraception at the time of therapy and up to two months after completion of treatment.

Overdosage

The highest amount examined clinically is 220 mg daily. The most repeatedly seen adverse drug reactions at this dose were dermatological circumstances, dysphonia, loose motion, inflammation in the mucosa, dry mouth, reduced appetite, hypertension, and exhaustion. There is no clear antidote for Regorafenib overdose. In case of a doubted overdose, interrupt Regorafenib, institute supporting care, and monitor until clinical stabilization.

Clinical Pharmacology

Mechanism of Action

Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases in normal cellular functions and pathologic methods like oncogenesis, tumor angiogenesis, and maintaining the tumor microenvironment.

Pharmacokinetics

• Absorption - After a single 160 mg dose of Regorafenib in cases with advanced solid tumors, the drug attains a geometric mean peak plasma level (Cmax) of 2.5 µg per mL at a median duration of four hours and a geometric mean area under the plasma concentration vs. The AUC (area under the curve) of Regorafenib at regular-state boosts reduced than dose proportionally at doses more than 60 mg.

• Distribution - Regorafenib experiences enterohepatic circulation with multiple plasma concentration elevations across the 24-hour dosing interval. Regorafenib is increasingly bound to human plasma proteins.

• Metabolism - CYP3A4 and UGT1A9 metabolize Regorafenib. The primary circulating metabolites of Regorafenib estimated at steady-state in plasma are M-2 and M-5, both having identical in vitro pharmacological function and steady-state concentrations as Regorafenib. M-2 and M-5 are highly protein bound.

• Elimination - After a 160 mg dose of Regorafenib given orally, the geometric mean elimination half-lives for Regorafenib and the M-2 metabolite in plasma are 28 hours and 25 hours, respectively. M-5 has a longer mean removal half-life of 51 hours.

How is Regorafenib Supplied or Stored?

Regorafenib tablets are provided in three bottles, each containing 28 tablets, for a total of 84 tablets in a package.

Storage and Handling - Store Regorafenib at 25°C. However, excursions are allowed from 15 to 30°C. Store tablets in the actual bottle and do not release the desiccant. Keep the container tightly sealed following the first opening. Dump any new tablets 28 days following opening the bottle. Dispose of unused tablets in accordance with local needs.

Patient Counseling Information

Inform Patients of the Following:

• Regorafenib may induce severe liver damage or life-threatening liver damage.

• Notify patients that they will need to monitor for liver impairment and instantly inform their doctor of any symptoms of intense liver damage.

• Regorafenib can induce severe bleeding.

• Instruct patients to reach their doctor for any episode of bleeding.

• Regorafenib can induce hand-foot skin reactions or rash elsewhere.

• Instruct patients to reach their healthcare provider if they undergo skin transformations connected with redness, pain, blisters, bleeding, or swelling.

• Regorafenib can induce or aggravate existing hypertension.

• Instruct patients that they will require blood pressure monitoring and to reach their doctor if blood pressure is boosted or if manifestations from hypertension occur, including intense headache, lightheadedness, or neurologic manifestation.

• Regorafenib raised the hazard of myocardial ischemia and myocardial infarction.

• Instruct patients to pursue prompt emergency help if they undergo chest ache, shortness of breath, sense light-headedness, or pass out.

• Reach a healthcare provider instantly if they undergo intense abdomen aches, continuous abdomen swelling, increased fever, nausea, vomiting, extreme diarrhea, or dehydration. Regorafenib may intensify wound healing.

• Instruct patients to notify their doctor if they intend to undergo a surgical approach or have had current surgery.

• Advise patients that Regorafenib can induce fetal damage.

• Inform women of reproductive possibilities and men of the need for adequate contraception during Regorafenib therapy and up to two months following the completion of therapy.

• Advise women of reproductive possibility to reach their health care provider in case of pregnancy instantly is suspected or verified during two months or within two months of completing therapy with Regorafenib.

• Instruct nursing mothers whether Regorafenib is present in breast milk is not understood and discuss whether to quit nursing or Regorafenib.

• Notify patients to have any skipped dose on the exact day as shortly as they recall and that they must not have two doses on the exact day to make up for a dosage missed on the previous day. Notify patients to keep the drug in the original container.

• Do not keep the drug in daily pill boxes or weekly pill boxes.

• Any remaining tablets must be removed 28 days after the bottle's opening.

• Tightly seal the bottle after each opening and maintain the desiccant in the bottle.