Regorafenib - Stivarga (Sept 2012) -Chemotherapeutic Agent
Drug Name:Regorafenib - Stivarga (Sept 2012) -Chemotherapeutic Agent
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
1. Effect of Strong CYP3A4 Inducers on Regorafenib
Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose
of Stivarga decreased the mean exposure of regorafenib, increased the mean
exposure of the active metabolite M-5, and resulted in no change in the mean
exposure of the active metabolite M-2.
Avoid concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenytoin,
carbamazepine, phenobarbital, and St. John’s Wort)
2. Effect of Strong CYP3A4 Inhibitors on Regorafenib
Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg
dose of Stivarga increased the mean exposure of regorafenib and decreased
the mean exposure of the active metabolites M-2 and M-5.
Avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin,
grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin,
and voriconazole)
Indication:
STIVARGA (re gorafenib) tablets, oral
Initial U.S. Approval: 2012
WARNING: HEPATOTOXICITY
See full prescribing information for complete boxed warning.
Severe and sometimes fatal hepatotoxicity has been observed in clinical
trials. Monitor hepatic function prior to and during treatment. Interrupt
and then reduce or discontinue Stivarga for hepatotoxicity as manifested
by elevated liver function tests or hepatocellular necrosis, depending upon
severity and persistence.
Drug Name- Stivarga
Active Ingredient - Regorafenib
To treat patients with corectal cancer that has progressed after treatment
and spread to other parts of the body (metastatic)
Indication-
Patients with corectal cancer that has progressed after treatment and
spread to other parts of the body(metastatic)
Approved by FDA on 27-9--2012 (Ref- FDA approved List- 2012)
New Drugs Approved by (DCI) Drug Controller GENERAL - India For Marketing
(Ref- IDMA Publication)
Name of Drug Indication Date of Approval
Regorafenib Film coated tablets 01-07-2014
40mg
For the treatment of Patients with Metastatic Colorectal Cancer(CRC)
who have been previously treated with Fluoropyrimidine,Oyliplatin
and Irinotecan-Base Chemotherapy, Anati-vegf therapy and if KRAS
wild type, An Anti-EGFR therapy
Regorafenib film coated tablet 40mg
Indication-
For treatment of patients with metastatic colorectal cancer (CRC) who have
been previously treated with fluropyrimidine , oxaliplatin and irinotecan base
chemotherapy, ananti VEGF therapy, and if KRAS wild type, an anti EGFR therapy
Approved by FDA on 01-07--2014 (Ref- FDA approved List- 2014)
Adverse Reaction:
The most common adverse reactions (.30%) are asthenia/fatigue, decreased
appetite and food intake, hand-foot skin reaction (HFSR) [palmar-plantar
erythrodysesthesia (PPE)], diarrhea, mucositis, weight loss, infection,
hypertension, and dysphonia.
Contra-Indications:
CONTRINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Hemorrhage:
Permanently discontinue Stivarga for severe or life-threatening hemorrhage.
Dermatological toxicity:
Interrupt and then reduce or discontinue Stivarga depending on severity
and persistence of dermatologic toxicity.
Hypertension:
Temporarily or permanently discontinue Stivarga for severe or uncontrolled
hypertension.
Cardiac ischemia and infarction:
Withhold Stivarga for new or acute cardiac ischemia/infarction and resume
only after resolution of acute ischemic events.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
Discontinue Stivarga.
Gastrointestinal perforation or fistulae:
Discontinue Stivarga.
Wound healing complications:
Stop Stivarga before surgery. Discontinue in patients with wound dehiscence.
Embryofetal toxicity:
Can cause fetal harm. Advise women of potential risk to a fetus.
Dosages/ Overdosage Etc:
Indication-
For treatment of patients with metastatic colorectal cancer (CRC) who have
been previously treated with fluropyrimidine , oxaliplatin and irinotecan base
chemotherapy, ananti VEGF therapy, and if KRAS wild type, an anti EGFR therapy
INDICATIONS AND USAGE
Stivarga is a kinase inhibitor 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 KRAS wild type, an anti-EGFR therapy.
DOSAGE AND ADMINISTRATION
Recommended Dose: 160 mg orally, once daily for the first 21 days of each
28-day cycle.
Take Stivarga with food (a low-fat breakfast).
DOSAGE FORMS AND STRENGTHS
40 mg film-coated tablets
Patient Information:
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information).
Inform your patients of the following:
1. Stivarga may cause severe or life-threatening liver damage. Inform patients that they
will need to undergo monitoring for liver damage and to immediately report any
signs or symptoms of severe liver damage to their health care provider.
2. Stivarga can cause severe bleeding. Advise patients to contact their health care
provider for any episode of bleeding.
3. Stivarga can cause hand-foot skin reactions or rash elsewhere. Advise patients
to contact their health care provider if they experience skin changes associated
with redness, pain, blisters, bleeding, or swelling.
4. Stivarga can cause or exacerbate existing hypertension. Advise patients
they will need to undergo blood pressure monitoring and to contact their health
care provider if blood pressure is elevated or if symptoms from hypertension
occur including severe headache, lightheadedness, or neurologic symptoms.
5. Stivarga increased the risk for myocardial ischemia and infarction.
Advise patients to seek immediate emergency help if they experience
chest pain, shortness of breath, or feel dizzy or like passing out.
6. Contact a healthcare provider immediately if they experience severe pains
in their abdomen, persistent swelling of the abdomen, high fever, chills,
nausea, vomiting, severe diarrhea (frequent or loose bowel movements),
or dehydration.
7. Stivarga may complicate wound healing. Advise patients to inform their health
care provider if they plan to undergo a surgical procedure or had recent surgery.
8. Inform patients that regorafenib can cause fetal harm. Advise women of
reproductive potential and men of the need for effective contraception during
Stivarga treatment and for up to 2 months after completion of treatment.
Instruct women of reproductive potential to immediately contact her health
care provider if pregnancy is suspected or confirmed during or within
2 months of completing treatment with Stivarga.
9. Advise nursing mothers that it is not known whether regorafenib is
present in breast milk and discuss whether to discontinue nursing
or to discontinue regorafenib.
10. Inform patients to take any missed dose on the same day, as soon a
they remember, and that they must not take two doses on the same day
to make up for a dose missed on the previous day.
11. Inform patients to store medicine in the original container.
Do not place medication in daily or weekly pill boxes.
Any remaining tablets should be discarded 28 days after opening the bottle.
Tightly close bottle after each opening and keep the desiccant in the bottle.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
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.
2. Pharmacokinetics
Absorption
Following a single 160 mg dose of Stivarga in patients with advanced solid tumors,
regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 ìg/mL
at a median time of 4 hours and a geometric mean area under the plasma
concentration vs. time curve (AUC) of 70.4 ìg*h/mL.
The AUC of regorafenib at steady-state increases less than dose proportionally
at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric
mean Cmax of 3.9 ìg/mL and a geometric mean AUC of 58.3 ìg*h/mL.
The coefficient of variation of AUC and Cmax is between 35% and 44%.
The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Pregnancy Category D
Risk Summary
Based on its mechanism of action, Stivarga can cause fetal harm when administered
to a pregnant woman. There are no adequate and well-controlled studies
with Stivarga in pregnant women.
If this drug is used during pregnancy or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to a fetus.
2. Nursing Mothers
It is unknown whether regorafenib or its metabolites are excreted in human milk.
In rats, regorafenib and its metabolites are excreted in milk.
Because many drugs are excreted in human milk and because of the potential
for serious adverse reactions in nursing infants from Stivarga, a decision
should be made whether to discontinue nursing or discontinue the drug,
taking into account the importance of the drug to the mother.
3. Pediatric Use
The safety and efficacy of Stivarga in pediatric patients less than18 years of age
have not been established.
4. Geriatric Use
Of the total number of subjects in clinical studies of Stivarga, 39% were 65 and over
while 8% were 75 and over. No overall differences in safety or efficacy were
observed between these patients and younger patients.
