Regorafenib (as monohydrate).
Each film-coated tablet contains 40 mg of regorafenib.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose, croscarmellose sodium, magnesium stearate, povidone, anhydrous colloidal silica. Film-coat: Iron oxide red, iron oxide yellow, lecithin (derived from soy), macrogol, partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide.
Pharmacotherapeutic Group: Antineoplastic agents, Protein kinase inhibitor. ATC Code: L01XE21.
Pharmacology: Pharmacodynamics: Mechanism of Action and Pharmacodynamic Effects: Regorafenib is an oral tumor deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), metastasis (VEGFR3, PDGFR, FGFR and tumor immunity (CSF1R). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumors, and thereby blocks tumor cell proliferation. In preclinical studies regorafenib has demonstrated potent antitumor activity in a broad spectrum of tumor models including colorectal, gastrointestinal stromal and hepatocellular tumor models which is likely mediated by its antiangiogenic and antiproliferative effects. In addition, regorafenib reduced the levels of tumor associated macrophages and has shown anti-metastatic effects in vivo. Major human metabolites (M-2 and M-5) exhibited similar efficacies compared to regorafenib in in vitro and in vivo models.
Pharmacokinetics: Absorption: Regorafenib reaches mean peak plasma levels of about 2.5 mg/L at about 3 to 4 hours after single oral dose of 160 mg regorafenib given as 4 tablets each containing 40 mg. The mean relative bioavailability of tablets compared to an oral solution is 69-83%.
The concentrations of regorafenib and its major pharmacologically active metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) were highest when given after a low-fat (light) breakfast as compared to either a high-fat breakfast or fasting condition. The exposure for regorafenib was increased by 48% when administered with high-fat breakfast and 36% when administered with a low fat breakfast, compared to fasting. The exposures of metabolic M-2 and M-5 are higher when regorafenib is given with low fat breakfast as compared to fasting condition and lower when given with a high fat meal as compared to fasting condition.
Distribution: Plasma concentration-time profiles for regorafenib as well as for the major circulating metabolites showed multiple peaks across the 24-hour dosing interval, which are attributed to enterohepatic circulation. In vitro protein binding of regonafenib to human plasma proteins is high (99.5%).
Metabolism/Biotransformation: Regorafenib is metabolized primarily in the liver by oxidative metabolism mediated by CYP3A4, as well as by glucuronidation mediated by UGT1A9. Two major and six minor metabolites of regorafenib have been identified in plasma. The main circulating metabolites of regorafenib in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), which are pharmacologically active and have similar concentrations as regorafenib at steady state.
In vitro protein binding of M-2 and M-5 is higher (99.8% and 99.95%, respectively) than that of regorafenib (99.5%).
Metabolites may be reduced or hydrolyzed in the gastrointestinal tract by microbial flora, allowing reabsorption of the unconjugated drug and metabolites (enterohepatic circulation).
Elimination: Following oral administration, mean elimination half-life for regorafenib and its metabolite M-2 in plasma ranges from 20 to 30 hours in different studies. The mean elimination half-life for the metabolite M-5 is approximately 60 hours (range from 40 to 100 hours).
Approximately 90% of the radioactive dose was recovered within 12 days after administration, with about 71% of the dose excreted in feces (47% as parent compound, 24% as metabolites), and about 19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides decreased below 10% under steady-state conditions. Parent compound found in feces could be derived from unabsorbed drug, intestinal degradation of glucuronides or reduction of metabolite M-2.
Toxicology: Preclinical Safety Data: Systemic Toxicity: After repeated dosing to mice, rats and dogs, adverse effects were observed in a number of organs, primarily in the kidneys, liver, digestive tract, heart, thyroid gland, lympho-/hematopoietic system, endocrine system, reproductive system and skin. These effects occurred at systemic exposures in the range of or below the anticipated human exposure (based on AUC comparison).
Alterations of teeth and bones were observed in young and growing rats and indicate a potential risk for children and adolescents.
Genotoxicity and Carcinogenicity: Studies on the carcinogenic potential of regorafenib have not been performed.
There was no indication for a genotoxic potential of regorafenib tested in standard assays in vitro and in vivo in mice.
Reproductive and Developmental Toxicity: Specific studies on fertility have not been performed. However, a potential of regorafenib to adversely affect male and female reproduction has to be considered based on morphological changes in the testes, ovaries and the uterus observed after repeated dosing in rats and dogs at exposures below the anticipated human exposure (based on AUC comparison). The observed changes were only partially reversible.
An effect of regorafenib on intrauterine development was shown in rabbits at exposures below the anticipated human exposure (based on AUC comparison). Main findings consisted of malformations of the urinary system, the heart and major vessels and the skeleton.
Stivarga is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy.
Stivarga is indicated for the treatment of patients with gastrointestinal stromal tumors (GIST) who have been previously treated with 2 tyrosine kinase inhibitors.
Stivarga is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
Dosage Regimen: The recommended dose is 160 mg regorafenib (4 tablets Stivarga each containing regorafenib 40 mg), taken orally once daily for 3 weeks on therapy followed by 1 week off therapy to comprise a cycle of 4 weeks.
Stivarga should be taken at the same time each day. The tablets should be swallowed whole with water after a light meal.
If a dose of Stivarga is missed, then it should be taken on the same day as soon as the patient remembers. The patient should not take two doses on the same day to make up for a missed dose.
Treatment should continue as long as benefit is observed or unacceptable toxicity occurs (see Precautions).
Dose Modification: Dose interruptions and/or dose reductions may be required based on individual safety and tolerability. Dose modifications are to be applied in 40 mg (one tablet) steps. The lowest recommended daily dose is 80 mg. The maximum daily dose is 160 mg.
For recommended dose modifications and measures in case of hand-foot skin reaction (HFSR/palmar-plantar erythrodysesthesia syndrome). (See Table 1.)
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For recommended measures and dose modifications in case of worsening of liver function tests considered related to treatment with Stivarga (see Table 2 and Precautions.)
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Additional information on special populations: Patients with Hepatic Impairment:
Regorafenib is eliminated mainly via the hepatic route.
Additional information on special population: No clinically important differences in exposure were observed between patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function. No dose adjustment is required in patients with mild or moderate hepatic impairment.
Close monitoring of overall safety is recommended in these patients (see Precautions).
Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population.
Patients with Renal Impairment:
In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild renal impairment and patients with normal renal function. Limited pharmacokinetic data indicate no difference in exposure in patients with moderate renal impairment. No clinical data are available for patients with severe renal impairment.
In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. No dose adjustment is necessary based on ethnicity. A higher incidence of hand foot skin reaction (HFSR), severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga as compared with Caucasians. The Asian patients treated with Stivarga in clinical studies were primarily from East Asia (~90%).
Method of Administration:
For oral use.
The highest dose of Stivarga 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 specific antidote for Stivarga overdose. In the event of suspected overdose, Stivarga should be withheld immediately, with best supportive care initiated by a medical professional, and the patient should be observed until clinical stabilization.
There is no contraindication to the use of Stivarga.
Hepatic Effects: Abnormalities of liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin] have been frequently observed in patients treated with Stivarga. Severe liver function test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations (including fatal outcomes) have been reported in a small proportion of patients (see Adverse Reactions).
It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of treatment with Stivarga and monitor closely (at least every two weeks) during the first 2 months of treatment. Thereafter, periodic monitoring should be continued at least monthly and as clinically indicated.
Regorafenib is a uridine diphosphate glucuronosyl transferase UGT1A1 inhibitor (see Interactions). Mild, indirect (unconjugated, hyperbilirubinemia may occur in patients with Gilbert's syndrome.
For patients with observed worsening of liver function tests considered related to treatment with Stivarga (i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease progression), the dose modification and monitoring advice in Table 2 should be followed. (See Table 2 in Dosage & Administration.)
Close monitoring of overall safety is recommended in patients with mild or moderate hepatic impairment (see Dosage & Administration). Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been in this population and exposure might be increased in these patients.
Infections: Stivarga has been associated with an increased incidence of infection events, some of which were fatal (see Adverse Reactions).
In cases of worsening infection events, interruption of Stivarga treatment should be considered.
Hemorrhage: Stivarga has been associated with an increased incidence of hemorrhagic events, some of which were fatal (see Adverse Reactions). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin) or other concomitant medicinal products that increase the risk of bleeding. In the event of severe bleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should be considered.
Gastrointestinal Perforation and Fistula: Gastrointestinal perforation and fistulae have been reported in patients treated with Stivarga (see Adverse Reactions). These events are also known to be common disease-related complications in patients with intra-abdominal malignancies. Discontinuation of Stivarga is recommended in patients developing gastrointestinal perforation or fistula. The safety of re-initiating Stivarga therapy following gastrointestinal perforation or fistula is not known.
Cardiac Ischemia and Infarction: Stivarga has been associated with an increased incidence of myocardial ischemia and infarction (see Adverse Reactions).
Patients with a history of ischemic heart disease should be monitored for clinical signs and symptoms of myocardial ischemia. In patients who develop cardiac ischemia and/or infarction, interruption of Stivarga is recommended until resolution. The decision to re-initiate treatment with Stivarga should be based on careful consideration of the potential benefits and risks of the individual patient. Stivarga should be permanently discontinued if there is no resolution.
No difference between Stivarga and placebo was observed in the incidence of clinically relevant cardiac arrhythmias or heart failure.
Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in association with Stivarga treatment (see Adverse Reactions).
Signs and symptoms of RPLS include seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated hypertension. A diagnosis of RPLS requires confirmation by brain imaging. In patients developing RPLS, discontinuation of Stivarga, along with control or hypertension and supportive medical management of other symptoms is recommended. The safety of re-initiating Stivarga therapy in patients previously experiencing RPLS is not known.
Arterial Hypertension: Stivarga has been associated with an increased incidence of arterial hypertension (see Adverse Reactions). Blood pressure should be controlled prior to initiation of treatment with Stivarga. It is recommended to monitor blood pressure and to treat hypertension in accordance with standard medical practice. In cases of severe or persistent hypertension despite adequate medical management, Stivarga should be temporarily interrupted and/or the dose reduced at the discretion of the treating physician (see Dosage & Administration). In case of hypertensive crisis, should be discontinued.
Wound Healing Complications: No formal studies of the effect of Stivarga on wound healing have been conducted. However, as medicinal products with anti-angiogenic properties may suppress or interfere with wound healing, temporary interruption of Stivarga is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of re-initiation of therapy following major surgical intervention. Therefore, the decision to resume treatment with Stivarga following major surgical intervention should be based on clinical judgment of adequate wound healing.
Dermatological Toxicity: Hand-foot skin reaction (HFSR/palmar-plantar erythrodysesthesia syndrome) and rash represent the most frequently observed dermatological adverse drug reactions with Stivarga (see Adverse Reactions). Measures for the prevention of HFSR include control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms. Management of HFSR may include the use of keratolytic creams (e.g. urea-, salicyclic acid- or alpha hydroxyl acid-based creams applied sparingly only on affected areas) and moisturizing creams (applied liberally) for symptomatic relief. Dose reduction and/or temporary interruption of Stivarga, or in severe or persistent cases, permanent discontinuation of Stivarga should be considered (see Dosage & Administration).
Biochemical and Metabolic Laboratory Test Abnormalities: Stivarga has been associated with an increased incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcemia, hyponatremia and hypokalemia) and metabolic abnormalities (including increases in thyroid stimulating hormone, lipase and amylase). The abnormalities are generally of mild to moderate severity, not associated with clinical manifestations, and do not usually require dose interruptions or reductions. It is recommended to monitor biochemical and metabolic parameters during Stivarga treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Dose interruption or reduction, or permanent discontinuation of Stivarga should be considered in case of persistent or recurrent significant abnormalities (see Dosage & Administration).
Disease-Specific Precautions: Hepatocellular Carcinoma (HCC): In the pivotal placebo-controlled phase III study, patients received prior therapy with sorafenib.
There is insufficient data on patients who discontinued sorafenib therapy due to sorafenib-related toxicity or only tolerated a low dose (< 400 mg daily) of sorafenib. The tolerability of Stivarga in these patients has not been established.
Effects on Ability to Drive or Use Machinery: No studies on the effects of Stivarga on the ability to drive and use machines have been performed.
Impairment of Fertility: There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Contraception: Women of childbearing potential must be informed that regorafenib may cause fetal harm. Women of childbearing potential and men should ensure effective contraception during treatment and up to 8 weeks after completion of therapy.
Use in Pregnancy: There are no data on the use of regorafenib in pregnant women.
Based on its mechanism of action, regorafenib is suspected to cause fetal harm when administered during pregnancy.
Animal studies have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Stivarga should not be used during pregnancy unless clearly necessary and after careful consideration of the benefits for the mother and the risk to the fetus.
Use in Lactation: It is unknown whether regorafenib or its metabolites are excreted in human milk.
In rats, regorafenib or its metabolites are excreted in milk.
A risk to the breast-fed child cannot be excluded. Regorafenib could harm infant growth and development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Breast-feeding must be discontinued during treatment with Stivarga.
Summary of the Safety Profile:
The overall safety profile of Stivarga is based on data from more than 4,800 treated patients in clinical trials including placebo-controlled phase III data for 636 patients with metastatic colorectal cancer (CRC) and 132 patients with gastrointestinal stromal tumors (GIST) and 374 patients with hepatocellular carcinoma (HCC).
The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are pain, hand-foot skin reaction, asthenia/fatigue, diarrhea, decreased appetite and food intake, hypertension and infection.
The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, hemorrhage, gastrointestinal perforation and infection.
The adverse drug reactions reported in clinical trials in patients treated with Stivarga are shown in Table 3. They are classified according to System Organ Class. The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1,000).
Within each frequency group, undesirable effects are presented in order of decreasing seriousness.
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Description of Selected Adverse Reactions: Hemorrhage:
In the placebo-controlled phase III trials, the overall incidence of hemorrhage/bleeding events was 18.2% in patients treated with Stivarga. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 15.2%), most notably epistaxis (6.1%). Fatal outcome in patients treated with Stivarga was uncommon (0.7%), and involved the respiratory, gastrointestinal and genitourinary events.
In the placebo-controlled phase III trials, infections were more often observed in patients treated with Stivarga as compared to patients receiving placebo (all grades: 31.6% vs 17.2%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 23.0%), and included urinary tract infections (5.7%) nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) as well as pneumonia (2.6%). Fatal outcomes associated with infection were more often observed in patients treated with Stivarga (1.0%) as compared to patients receiving placebo (0.3%) and were mainly respiratory events.
Hand-Foot Skin Reaction:
In the placebo-controlled phase III trials, hand-foot skin reaction (HFSR) were more often observed in patients treated with Stivarga as compared to patients receiving placebo (all grades: 51.4% vs. 6.5% CRC, 66.7% vs. 15.2% GIST and 51.6% vs. 7.3% HCC). Most cases of HFSR in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 34.3% CRC, 44.7% GIST and 39.3% HCC). The incidence of Grade 3 HFSR was 17.1% (CRC), 22.0% (GIST) and 12.3% (HCC). A higher incidence of HFSR was observed in Stivarga-treated Asian patients (all grades: 74.8% CRC, 88.2% GIST and 67.1% HCC and Grade 3: 20.5% CRC, 23.5% GIST and 13.5% HCC) (see Dosage & Administration).
In the placebo-controlled phase III trials, the overall incidence of hypertension was higher in patients treated with Stivarga as compared to patients receiving placebo (29.6% vs. 7.5% CRC, 60.6% vs. 25.8% GIST and 31.0% vs. 6.2% HCC). Most cases of hypertension in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 20.9 % CRC, 31.8% GIST and 15.8% HCC). The incidence of Grade 3 hypertension was 8.7% (CRC), 28.0% (GIST) and 15.2% (HCC). One case of Grade 4 hypertension was reported in the GIST trial.
Severe Liver Injury:
In most cases of severe liver injury, liver dysfunction had an onset within the first 2 months of therapy, and was characterized by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase. In clinical trials, a higher incidence of severe liver injury with fatal outcome was observed in Japanese patients (~1.5%) treated with Stivarga compared with non-Japanese patients (<0.1%).
Laboratory Test Abnormalities:
Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are shown in Tables 4, 5 and 7 (see Precautions).
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Compared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian patients enrolled, a higher incidence of liver enzyme increases was observed in Stivarga treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (>90%) East Asian patients enrolled.
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Inhibitors/inducers of CYP3A4: In vitro data indicate that regorafenib is metabolized by cytochrome CYP3A4 and uridine diphosphate glucuronosyl transferase UGT1A9.
Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single dose of regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of regorafenib of approximately 33% and a decrease in mean exposure of the active metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), of approximately 90%. It is recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole) as their influence on the steady-state exposure of regorafenib and its metabolites (M-2 and M-5) has not been studied.
Administration of rifampin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose of regorafenib (160 mg on day 7) resulted in a reduction in mean exposure (AUC) of regorafenib of approximately 50%, a 3- to 4-fold increase in mean exposure of the active metabolite M-5, and no change in exposure of active metabolite M-2. Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital) may also increase metabolism of regorafenib. Since a reduction in plasma regorafenib concentrations may result in a decreased efficacy, strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.
UGT1A1 and UGT1A9 Substrates:In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibits glucuronidation mediated by uridine diphosphate glucuronosyl transferases UGT1A1 and UGT1A9, whereas M-5 only inhibits UGT1A1 at concentrations which are achieved in vivo at steady state.
Administration of regorafenib with a 5-day break prior to administration of irinotecan resulted in an increase of approximately 44% in mean exposure (AUC) to SN-38, a substrate of UGT1A1 and an active metabolite of irinotecan. An increase in mean exposure to irinotecan of approximately 28% was also observed. This indicates that co-administration of regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates. The clinical significance of these findings is unknown.
Breast Cancer Resistance Protein (BCRP) and P-glycoprotein Substrates: In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibits glucuronidation mediated by uridine diphosphate glucuronosyl transferases UGT1A1 and UGT1A9, whereas M-5 only inhibits UGT1A1 at concentrations which are achieved in vivo at steady state.
Administration of regorafenib with a 5-day break prior to administration of irinotecan resulted in an increase of approximately 44% in mean exposure (AUC) of SN-38, a substrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan of approximately 28% was also observed. This indicates that co-administration of regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates.
CYP Isoform-Selective Substrates: In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8, CYP2C9, CYP2B6 at concentrations which are achieved in vivo at steady state (peak plasma concentration of 8.1 micromolar). The in vitro inhibitory potency towards CYP3A4 and CYP2C19 was less pronounced.
A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mg regorafenib on the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone), CYP2C9 (S-warfarin), CYP2C19 (omeprazole) and CYP3A4 (midazolam).
Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of CYP2C8, CYP2C9, CYP3A4 and CYP2C19 without a clinically meaningful drug interaction (see Precautions).
Instructions for Use/Handling: Press down the closure according to instructions on the cap while turning to the left. Keep the bottle tightly closed after first opening. The desiccant capsule must not be consumed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Keep the dessicant in the bottle.
Shelf-Life: 3 years, do not store above 30°C.
Keep the bottle tightly closed after first opening. Once the bottle is opened the medicinal product has shown to be stable for 7 weeks even without the desiccant. Thereafter, the medicinal product is to be discarded.
L01XE21 - regorafenib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.