Stivarga Bayer treatment of colon and rectal cancer (28 tablets)
Dosage form Box of 28 tablets
Specifications Regorafenib
Ingredient
| Composition information | Content |
| Regorafenib | 40% |
Uses
Indications
Stivarga are appointed to treat colectrectal cancer (CRC) previous metastatic metastases, or not considered candidates to use chemotherapy regimen with fluoropyrimidine derivatives, VEGF resistance, and an EGFR resistant if patients have wild pulp.
Pharmacokology
Pharmacological properties:
Pharmacological group: anti -cancer agents, protein kinase inhibitors.
Code ATC: L01xe21
Mechanism of impact and pharmacological effects.
Regorafenib is an inactivated oral tumor, strong inhibition of many protein kinase, including kinase related to the new vascular birth in tumors (Vegfr1, -2, -3, tie2), cancer (Ret, RAF -1, Braf, BrafV600E) and tumor environment (PDGFR, FGFR). In preclinical studies, Regorafenib has been shown to have a strong anti -cancer activity on a large number of tumor models including duty tumors shown under anti -vascular and anti -proliferation effects. In addition, Regorafenib has shown the anti -metastatic effect in Vivo. Main metabolites in humans (M-2 and M-5) show the same effect compared to Regorafenib In Vitro and in Vivo models.
Clinically and effectively effective and effective
Please see more information about drugs in the instructions for the use of drugs attached.
pharmacokinetics
Regorafenib reaches an average plasma concentration of about 2.5 mg/l at about 3 to 4 hours after taking the only 160 Regorafenib dose in the form of 4 tablets containing 40 mg. Relatively average bioavailability of tablets compared to oral solution is 69-83%.
Regorafenib concentration and its active pharmacological metabolites M-2 (N-Oxide) and M-5 (N-Oxide and N-Desmethyl) are the highest after drinking low-fat breakfast compared to drinking high-fat breakfast or drinking when hungry. The level of exposure to Regorafenib increased by 48% when used with high -fat breakfast, and 36% when used with a low -fat breakfast, compared to vegetarians. The exposure level of M-2 and M-5 metabolites is higher when Regorafenib is used with low-fat breakfast compared to vegetarian, and lower when used with a fat-rich meal compared to vegetarian.
The concentration data - the plasma time of Regorafenib's plasma as well as the main metabolites shows that there are many nails during the 24 -hour dosage period, with the participation of the giver circulation. On Vitro, Regorafenib is attached to a high -ratio of plasma proteins (99.5%).
Regorafenib is metabolized mainly in the liver by oxidative metabolism through CYP3A4 intermediaries, as well as glucuronids via UGT1A9 intermediaries. The two main metabolites and six sub -metabolites of Regorafenib have been determined in plasma. The administrative metabolites of Regorafenib in human plasma are M-2 (N-site) and M-5 (N-Oxide and N-Desmethyl), have pharmacological activity and have similar concentrations as Regorafenib in stable state.
The protein cohesion on the in vitro of M-2 and M-5 is higher (in order of 99.8% and 99.95%) compared to Regorafenib.
Metabolic substances can be reduced or hydrolyzed in the gastrointestinal tract because the bacterial system only allows the reabsorption of drugs and non -conclusion metabolites (hepatic circulation).
After drinking, Regorafenib's average sale time and its M-2 metabolites in plasma fluctuate between 20 and 30 hours in different studies. The average selling time for M-5 metabolites is about 60 hours (from 40 to 100 hours).
About 90% of radioactive doses have been found within 12 days after taking the drug, with about 71% of the dose excreted in the feces (47% is the mother substance, 24% is metabolic), and about 19% the dose is excreted in urine in the form of glucuronid.
The excretion through the urine of glucuronides decreases below 10% under stable state conditions. The mother compound found in the feces can be derived from the absorption of the drug in the intestinal tract of Glucuronides or the M-2 metabolic, as well as the drug is not absorbed.
Regorafenib system exposure in a stable state proportional to the dose increases to 60 mg and increasing less at a dose ratio greater than 60 mg. The accumulation of Regorafenib is in a stable state, resulting in an increase of about 2 times in plasma concentrations, suitable for the sale time and the number of drug use. In a stable state, Regorafenib achieved an average plasma peak concentration of about 3.9 mg/l (8.1 micromolar) after taking 160 mg of Regorafenib and the peak-ratio of the average plasma concentration is less than 2.
Both metabolites, M-2 and M-5, showing non-linear accumulation. Meanwhile, the plasma concentration of M-2 and M-5 after a single dose of Regorafenib is much lower than the plasma concentration of the mother compound, the concentration of plasma stable plasma of the M-2 and M-5 can be compared to the Regorafenib plasma plasma concentrations.
Additional information about the special patient population
Stivarga pharmacokinetics in patients with liver failure Child-Pugh A and B (mild to medium) similar to pharmacokinetics in patients with normal liver function. There is no data for patients with hepatic child-pgh c (severe). Regorafenib mainly eliminated through the liver, and exposed can increase in this patient population group.
There are clinical and pharmacokinetic data based on physiological model showing the exposure to the stable state of Regorafenib and its metabolites M-2 and M-5 are similar in patients with mild and medium renal function compared to patients with normal kidney function.
Regorafenib's pharmacokinetics have not been studied in patients with severe renal impairment or end -stage renal disease. However, physiological pharmacokinetic models do not predict any changes related to these patients.
Age does not affect the pharmacokinetics of Regorafenib in the study age (29 - 85 years).
The pharmacokinetics of Regorafenib is not affected by gender.
The exposure to Regorafenib in many different Asian population groups (China, Japan, South Korea) has the same exposure space for white skin patients.
Do not observe that it has the effect of extending QTC after taking Regorafenib 160mg in a stable state in a special QT study in male and female cancer patients.
Preceptic safety data
After the dose is repeated for rats, rats and dogs, harmful effects have been observed in some organs, mainly in the kidneys, liver, gastrointestinal tract, heart, hematoma system, lymphocytes, endocrine systems, reproductive systems and skin. These effects occur when exposed to the system within or lower than the exposure is predicted on humans (based on AUC comparison).
Change of teeth and bones was observed in young mice and mice growing and pointed out a potential risk for children and teenagers.
Regorafenib cancer -causing cancer studies have not been done.
There is no indication to test the ability to toxicity on the gene of Regorafenib in In vitro and in vivo standard tests in mice.
Specialized studies on reproduction have not been conducted. However, the potential of Regorafenib has adversely affected male and female reproduction has been considered based on the morphological changes in the testes, the ovaries and the uterus observed that after taking the drug with repeated doses in mice and dogs with the exposure level less than expected in humans (based on AUC comparison). Changes only partially recover.
A effect of Regorafenib on the development of the uterus has been shown on rabbits at a lesser exposure than the expected exposure level in humans (based on AUC comparison). Main findings include deformities in the urinary system, heart and large blood vessels, and bones.
Before taking Stivarga Bayer treatment of colon and rectal cancer (28 tablets)
Stivarga must be prescribed by a doctor with experience using chemotherapy for cancer treatment.
How to use
Stivarga should be taken at the same time every day. The pill must be swallowed with water after a snack.
Dosage
recommended dose is 160 mg of Regorafenib (4 Stivarga tablets, each containing 40 mg of Regorafenib), drink once a day for 3 weeks of treatment, then take 1 week leave to form a 4 -week cycle.
Should continue treatment when it is still beneficial or until an unacceptable toxicity occurs (see the "special and cautious warning").
Patients with systemic condition (PS) are equal to 2 or higher from clinical research. There are very few data on patients with PS≥2.
dose adjustment
may need to stop and/ or reduce the dose based on safety and tolerance of each individual. The dose adjustment is applied to steps of 40 mg (one tablet). The lowest daily recommended dose is 80 mg. The maximum daily dose is 160 mg.
To recommend adjusting the dose and measures to apply in case of hand-foot-foot skin reaction (Hand Foot Skin Reaction- HFSR /- Hand-Foot syndrome /Syndrome of the palm-feet of the feet), see Table 1.
Table 1: Dosage adjustment and recommended measures for hand-foot syndrome (HFSR).
If not improved even though the dose has been reduced, the suspension of treatment is at least 7 days, until the toxicity is resolved to the level of 0-1.
Increasing a dose level is allowed by a doctor's decision.
When returning to treatment, the dose of 40 mg (one tablet).
Increasing a dose level is allowed by a doctor's decision.
appeared for the second time temporarily suspended treatment until the toxicity was resolved at 0-1.
When returning to treatment, the dose of 40 mg (one tablet).
Increasing a dose level is allowed by a doctor's decision.
The 4th appearance
When treated, the dose of 40 mg (1 tablet).
Increasing a dose level is allowed by a doctor's decision.
appears a second time Applying support measures immediately. Temporarily suspend treatment for at least 7 days until toxicity is resolved at 0-1. When treated, the dose of 40 mg (1 tablet).
Table 2: The recommended dose measures and methods in case of abnormalities in liver function tests related to drugs. continues to treat Stivarga. Weekly monitor liver function until the transaminase enzymes return to Weekly monitor liver function until the transaminase enzymes return to Start reusing: If the benefits are greater than the risk of toxicity on the liver, start treatment with Stivarga, reduce the dose of 40 mg (1 tablet) and monitor the weekly liver function for at least 4 weeks. Weekly monitor liver function until resolving or returning before treatment. Exceptions: Patients with Gilbert's syndrome have increased transaminases that need to be treated as recommended above for the signs of increasing ALT and/ or AST. Patients with liver failure There is no observation that there is an important clinical difference in exposure between patients with mild liver failure (Child-Pugh a) or patients with average liver failure (Child-Pugh B) compared to patients with normal liver function. No dose adjustment in patients with mild and medium liver failure. Careful safety surveillance recommendations in these patients (see more "special and cautious warnings when used" and "pharmacokinetic characteristics"). Stivarga is not recommended for use in patients with severe liver failure (Child-Pugh C) because Stivarga has not been studied in this population group. Patients with renal failure In clinical studies, there is no difference in exposure, safety or effectiveness between patients with mild renal impairment and patients with normal renal function. The limited pharmacokinetic data shows that there is no difference in the exposure in patients with medium renal failure. There is no need to adjust the dose in patients with mild or medium renal failure (see also the "pharmacokinetic characteristics"). There is no clinical data for patients with severe renal impairment. Old people In clinical studies, there is no significant difference in exposure. Safety or effectiveness is observed between old patients (age ≥ 65) and young patients. There is very little information in patients over 75 years old. Children Do not use Stivarga in pediatric patients in appointment of colorectal cancer. What to do when forgetting a dose? Patients should not take two doses in the same day to compensate for the forgotten dose.
Side Effects
Summary of safety information
StivARAGA's overall safety information is based on data from more than 1,200 patients treated in clinical trials including phase data III with a control of Placebo over 500 patients with metastatic colorectal cancer (CRC). The most common reaction of the most common (≥ 30%) in patients using StivARGA is weak/fatigue, foot-foot skin reaction, diarrhea, reducing appetite and reducing food, hypertension, loss of voice and infection.
The most serious reactions of in patients using Stivarga are severe liver damage, hemorrhage and puncture of the gastrointestinal tract.
Table of harmful reactions
Harmful reactions are reported in clinical studies in patients treated with Stivarga shown in Table 3. They are classified by organ systems. The most appropriate Meddra term is used to describe a certain reaction and its synonyms and related pathology.
The harmful reaction of the drug is grouped by frequency. The frequency groups are determined by the following conventions: Very common: ≥ 1/10; Common: ≥ 1/100 to
In each frequency group, unwanted effects are presented in the order of severity.
Table 3: The harmful reactions are reported in clinical trials on patients treated with Stivarga
Agency systems
(Meddra)
Healed, malignant and nonspecific tumors (including cysts and polyps).
Anemia.
Lower blood phosphate.
Lower blood calcium.
Lower blood sodium.
Lower blood.
hyperuricemia.
Myocardial infarction.
myocardial ischemia.
Hypertension.
stomatitis.
vomiting.
Nausea.
Disorders of taste.
dry mouth.
Stomach - esophagus.
Gastritis.
Perforated gastrointestinal tract*.
Digestive tract leaks.
Legs-Hand **.
Redders.
Hair loss.
dry skin.
Skin peeling.
Nail disorders.
Diverse roses.
Stevens-Johnson syndrome.
Poisoned epidermal necrosis.
Pain. Fever. Mucinitis. Increase lipase. abnormal INR. ** Palmar-Plantar erythrodysthesia syndrome in Meddra terminology # According to Drug -Indieu Liver Injury -Dili) of the International Dili Expert group. Describe some harmful reactions bleeding In two phase III tests with pot control, the general ratio of bleeding/ bleeding is 19.3% in patients treated with Stivarga. Most cases of bleeding events in patients treated with Stivarga have mild to medium levels (levels 1 and 2: 16.9%), most notably nosebleeds (7.6%). Deathly fatal events in patients treated with StivARGA are rarely seen (0.6%), and occurs in the respiratory, digestive and sexual tract. Infections In two phase tests III with a control of Placebo, patients treated with Stivarga more infected than patients with placebo (all levels: 31.0% compared to 14.4%). Most infections in patients treated with StivARGA are mild to moderate (levels and 2: 22.9%), and including urinary tract infections (6.8%) as well as fungal infections in the mucosa and systemic fungal infections (2.4%). There is no difference in fatal consequences related to infections between treatment groups (0.6% in Stivarga group compared to 0.6%, in the Placebo group). Hand -palm -skin reaction - Foot In the III phase test with a control of Placebo on CRC patients with metastatic CRC, the overall frequency of the skin-to-hand skin reaction is 45.2% in patients treated with Stivarga compared to 7.1% in patients using Placebo. Most cases of hand -foot reactions in patients treated with Stivarga appear in the first and mild to medium treatment cycle (level 1 and 2: 28.6%, CRC). The ratio of skin-to-hand skin reactions level 3 is 16.6% (CRC). Hypertension In the phase III test with a control of Placebo in CRC patients with metastatic CRC, the general ratio of hypertension is 30.4% in patients treated with Stivarga compared to 7.9% in patients using Placebo. Most cases of hypertension in patients treated with Stivarga appear in the first treatment cycle and have mild to moderate levels (levels 1 and 2: 22.8%). The rate of hypertension level 3 is 7.6% (CRC). Testing abnormalities Emergency testing abnormalities are observed in phase III tests with controls that are presented in Table 4 (see more "special and cautious warning"). Side effects that can occur during the use of the drug should be reported to the doctor.
Warnings
Before using the drug you need to read the instructions carefully and refer to the information below.
Contraindicated
Patients with hypersensitivity to active ingredients and any excipients ingredients in the formula.
Be cautious when using
The effects on the liver
The liver functional tests (alanine aminotransferase -Alt, Aspartate Aminotransferase -ast and Bilirubin) are often observed in patients treated with Stivarga. Serious abnormalities in liver function tests (level 3 to 4) and liver dysfunction with clinical manifestations (including death) have been reported on a small percentage of patients (see the "unwanted effect").
Recommendations to perform liver function tests (ALT, AST and Bilirubin) before starting StivARGA treatment and closely monitoring (at least 2 weeks/ time) within the first 2 months of treatment. After that, it is advisable to continue monitoring at least monthly and when clinical indications.
Regorafenib is an uridine diphosphate glucuronosyl transferase UGT1A1 (see interaction with other drugs and other forms of interactions "). Increased (indirect (non -conjugate) bilirubin can occur in patients with Gilbert syndrome.
For patients with deteriorating liver function tests may be due to Stivarga treatment (for example, when there is no other clear cause, such as the post -liver biliary obstruction or the progression of the disease), it is necessary to comply with the adjustment of the dose and supervision advice in Table 2 (see the "dose and use" section - the dose adjustment section ").
Need to closely monitor general safety in patients with mild or medium liver failure (see the "dose and usage" section - the "Hepatoostatic patient" and "pharmacokinetic characteristics"). Stivarga is not recommended to use in patients with severe liver failure (Child-Pugh c) because Stivarga has not been studied in this population group and exposure may be increased in these patients.
Patients with mutant tumors Kras
In patients with Kras mutant tumors, the time of life is not progressing (PFS) has been recorded significantly improved and the effectiveness of the whole survival (OS) has been recorded as lower in terms of quantity (see the "pharmacological properties"). Because toxicity related to treatment is significant, doctors should carefully assess the benefits and risks when prescribing Regorafenib in patients with mutant tumors Kras.
bleeding
Stivarga is associated with increased frequency of bleeding events, sometimes fatal. (See the "unwanted effect" section). The number of blood cells and blood coagulation parameters should be monitored in patients with risk factors for bleeding, and on patients treated with anticoagulants (such as warfarin) or using other and other treatment products that increase the risk of bleeding. In cases of bleeding that requires emergency medical intervention, it is advisable to consider stopping Stivarga.
ischemia and myocardial infarction
Stivarga is associated with an increase in the frequency of new ischemic heart disease and myocardial infarction (see the "unwanted effect"). Patients with unstable angina or newly triggered angina (within 3 months starting to treat Stivarga), recent myocardial infarction (within 6 months of Stivarga treatment) and patients with NYHA II heart failure or higher from clinical research.
Patients with a history of ischemia should be monitored with clinical signs and clinical symptoms of ischemic heart disease. In patients with ischemic heart disease and/ or progressive myocardial infarction is recommended to use Stivarga interrupt until the disease is resolved. The decision to re -treat Stivarga must be based on careful consideration of the potential benefits and risks of each patient. Stivarga should be terminated if there is no solution.
Reversible posterior leukentphalopathy syndrome
Reversible posterior leukencephalopathy syndrome (RPLS) has been reported related to Stivarga treatment (see the "unwanted effect"). The signs and symptoms of the RPLS include convulsions, headaches, mental disorders, visual disorders or cortex blindness, with or without hypertension. Diagnosis determines the RPLS needs to take brain photography. In patients with RPLS, stop using Stivarga, along with hypertension control and treatment support for other symptoms. It is unclear the safety of the start of reusing Stivarga therapy in patients who had previously undergone RPLS.
puncture and gastrointestinal leaks
Perforation and gastrointestinal leaks have been reported in patients treated with Stivarga (see the "unwanted effect" section). These incidents are also known as common complications related to diseases in patients with malignant tumors in the abdomen. Stivarga should be stopped in patients with perforation or gastrointestinal leaks. It is not known about the safety of starting to reuse Stivarga after puncturing or leaking the digestive tract.
arterial hypertension
Stivarga is associated with increasing the frequency of arterial hypertension (see the "unwanted effect" section). Blood pressure control is required before starting treatment with Stivarga. Recommended monitoring of blood pressure and treating hypertension according to standard treatment guidelines. In case of severe or prolonged hypertension whether it is fully treated, Stivarga and// or reduced dose as decisions of the treating doctor (see the "Dosage and usage" section - the "dose adjustment" section). In the case of drama hypertension, Stivarga should be stopped.
complications on wound healing
There is no official research conducted on the effects of Stivarga on wound healing. However, due to anti -vascular treatment products that can inhibit or affect wound healing, temporarily recommend stopping Stivarga due to caution in patients with large surgery. Clinical experience in the beginning of the time of treatment after large surgical intervention is limited. Therefore, the decision to continue treating Stivarga after a major surgical intervention needs to be based on the clinical assessment of the healing situation of the wound.
Skin toxicity
Hand -Palmar -Plantar ErythrodySesthesia Syndrome) and rash are the most common skin reactions on the skin of Stivarga (see the "unwanted effect" section). HFSR prevention measures include the treatment of bottles and the use of shoe cushions and gloves to prevent pressure on the soles of the feet and palms. HFSR treatment may include the use of horned creams (such as urea, salicylic acid, or alpha hydroxyl acid- applied just enough on affected areas) and moisturizers (widely applied) to reduce symptoms. Dosage reduction and/ or temporary suspension Stivarga, or in severe or prolonged cases, need to consider long -term stopping Stivarga (see the "Dosage and usage" section - the "dose adjustment" section).
abnormalities in biochemical and metabolism
Stivarga is associated with an increase in electrolyte abnormalities (including hypoglycemia, blood calcium, hypoglyc sodium and hypokalemia) and metabolic abnormalities (including hormonal hormones that stimulate thyroid, lipase and amylase). The general abnormalities are from light to moderate not related to clinical manifestations, and often do not need to suspend drugs or reduce the dose. It is recommended to monitor biochemical and metabolic parameters during Stivarga treatment and apply alternative treatments in accordance with clinical practical guidelines if necessary. Temporarily suspend or reduce the dose or permanently stop Stivarga should be considered in case of significant abnormalities that last long or relapse (see the "Dosage and usage" section - the "dose correction" section).
The effect of the drug on driving and operating machinery
There is no study of Stivarga's effects on driving or using machinery.
If the patient has symptoms that affect the ability to concentrate and react when treating with Stivarga, they must not drive or operate machinery until the effects are reduced.
Use drugs for women during pregnancy and lactation
contraceptive contraception
Pregnant women must be notified that Regorafenib may harm the fetus.
Women who are likely to be pregnant and men should ensure effective contraceptive use during treatment and last up to 8 weeks after treatment.
Pregnant women
There is no data on the use of Regorafenib in pregnant women.
Based on the mechanism of action, Regorafenib is suspected of causing damage to the fetus during pregnancy.
Animal studies have shown toxicity on reproduction (see data "Pre -clinical safety data").
Do not use Stivarga during pregnancy, unless it is clear and after careful consideration of the maternal benefits and the risk of the fetus.
breastfeeding
It is not known whether Regorafenib/ metabolites will be excreted in breast milk.
In mice, Regorafenib/ metabolites are excreted through milk.
Cannot rule out the risk of breastfeeding, Regorafenib can harm children's growth and development (see data "Pre -clinical safety data" data). Must stop breastfeeding during treatment with Stivarga.
fertility
There is no data on Stivarga's effect on human fertility. Animal research results show that Regorafenib may reduce the fertility of male and female animals (see the data "Pre -clinical safety data" data).
Drug interaction
CYP3A4 inhibitors/Touch Inhibitors
In vitro figures indicate that Regorafenib is metabolized by cytochrome CYP3A4 and Uridine Diphosphate Glucuronosyltransferase UGT1A9.
Use ketoconazole (400 mg for 18 days) A powerful CYP3A4 inhibitor, with a single dose of Regorafenib (160 mg on 5) leading to an average increase in the Regorafenib exposure (AUC), about 33%, and reduce the exposure of active metabolites, M-2 (N-OXIT) and M-5 (N-Oxide and N-Desmethyl) 90%. It is necessary to avoid using strong intensive inhibitors CYP3A4 (eg clarithromycin, grapefruit juice, iTraconazole, ketoconazole, posaconazole, telithromycin and voriconazole) because of their influence on the exposure to the stable state of Regorafenib and its transformations (M-2 and M-5) Rescue.
Use Rifampin (600 mg for 9 days), a powerful CYP3A4 induction, with a single dose of Regorafenib (160 mg on the 7th day), leading to a reduction of the AUC of Regorafenib on average about 50%, an increase of 3 to 4 times of the average exposure of M-5 activity metabolites, and does not change the exposure of M-2 activity. Other strong active touch substances CYP3A4 (such as Phenytoin, Carbamazepine, Phenobarbital) can also increase Regorafenib metabolism. Due to the decrease in the plasma concentration of Regorafenib can lead to effective reduction, avoiding the use of strong CYP3A4 induction substances, or should consider choosing an alternative drug when used simultaneously, without or very little capable of CYP3A4 touch.
UGT1A1 and UGT1A9
In vitro figures show that Regorafenib as well as its active metabolites M-2 inhibit intermediate glucuronids by Uidine Transferases Glucuronosyl diphosphate UGT1A1 and UGT1A9, while M-5 inhibits UGT1A1 in concentration in the body in a stable state.
Use Regorafenib for a 5-day-long break before using Irinotecan increases about 44% of the average AUC of SN-38, a substrate of UGT1A1 and is a metabolic substance with activity of Irinotecan. Also observed that there is an average increase in exposure of AUC with Irinotecan. This shows that the simultaneous use of Regorafenib may increase the system exposure to substrates of UGT1A1 and UGT1A9.
BCRP substrate (Breast Cancer Resistance Protein: Breast Cancer Protein) and P-Glycoprotein
In vitro data shows that Regorafenib is a -bcrp and p -Glycoprotein inhibitor. Simultaneous treatment of Regorafenib may increase the plasma concentration of the substrate of BCRP, such as methotrexate, or substrates of p-glycoprotein, such as digoxin.
Selective substrates of CYP subgroups
In vitro data shows that Regorafenib is a competitive inhibitor of cytochrome CYP2C8, CYP2C9, CYP2B6 in the concentration of Vivo in a stable state (plasma nail concentration is 8.1 micromolar). The potential inhibitors in vitro for CYP3A4 and CYP2C19 is less obvious.
A substrate clinical research has been conducted to evaluate the effectiveness of 14 days of using Regorafenib with a dose of 160 mg on the pharmacokinetics of the substrate of CYP2C8 (Rosiglitazone), CYP2C9 (S-Warfarin), CYP2C19 (Omeprazole) and CYP3A4 (Midazolam). Pharmacokinetic data shows that Regorafenib can be used simultaneously with CYP2C8, CYP2C9, CYP3A4, and CYP2C19 substrates without clinical drug interactions (see more "special and cautious warnings").
antibiotics
Analysis of concentration - time shows that Regorafenib and its metabolites can undergo a giving -giver (see the "pharmacokinetic properties" section). The simultaneous use of antibiotics that affects the gastrointestinal tract nerves can hinder the liver circulation of Regorafenib and can lead to reduction of Regorafenib's exposure. The clinical significance of these potential interactions is unknown, but may reduce the effectiveness of Regorafenib.
Bile acid -mounted drugs
Regorafenib, M-2 and M-5 are capable of undergoing intestinal circulation (see section 5.2). Bile acid -mounted drugs such as cholestyramine and cholesterol can interact with Regorafenib by forming insoluble complexes that can affect absorption (or reabsorption), thus leading to the ability to reduce exposure. The clinical significance of these potential interactions is unknown, but it can lead to the reduction of Regorafenib's effectiveness.
Storage
not more than 30 ° C.
Stored in the original packaging to avoid moisture.
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