Sorafenib Methylphenidate Tablets Instructions

 
Trial 11849 is an international multicenter, randomized, placebo-controlled phase III clinical trial of sorafenib for advanced hepatocellular carcinoma conducted in Asia, including mainland China, Taiwan and Korea. Of all 149 patients who received at least one treatment with sorafenib, 121 patients (81.2%) experienced drug-related adverse events. With the exception of nausea and vomiting, the investigators determined that drug-related adverse events occurred significantly more frequently in patients in the sorafenib group than in the placebo group. The five most common drug-related adverse events in the sorafenib group were, in order, hand-foot skin reactions (44.3%), hair loss (24.2%), diarrhea (22.8%), rash (18.8%), and malaise (18.8%). The drug-related adverse events with an incidence of ≥5% observed in the study are listed in Table 7.
Table 7. Drug-related adverse events with an incidence of ≥5% during treatment in either group in trial 11849

 
As of March 19, 2007, a total of 95 serious adverse events occurred in the trial, 32 (42.7%) in the placebo group and 63 (42.3%) in the sorafenib group, with similar rates in both groups. Among them, there were 20 cases of treatment-related serious adverse events as judged by the investigator, 1 case (1.3%) in the placebo group and 19 cases (12.7%) in the sorafenib group. All of the serious adverse events associated with sorafenib were ≤ CTCAE grade 3 except for 2 cases of upper gastrointestinal bleeding (grade 4) and 1 case of pneumonia (grade 5). Table 8 shows the serious adverse events associated with sorafenib.
Table 8: Incidence of serious adverse events in at least 1% of patients during treatment in either treatment group in trial 11849

*Deaths not related to CTCAE terms
**Gastrointestinal bleeding
 
Adverse Reactions in the Differentiated Thyroid Cancer Study
The safety of 416 patients was evaluated in a double-blind clinical trial enrolling patients with radioiodine-refractory, locally recurrent or metastatic progressive differentiated thyroid cancer who were randomly assigned to receive sorafenib 0.4 g twice daily (n=207), or the corresponding placebo (n=209), until disease progression or intolerable toxicity occurred . The data described below reflect a median exposure time to sorafenib of 46 weeks (range 0.3 – 135). Fifty percent of patients treated with sorafenib were male and the median age of this population was 63 years.
Sixty-six percent of patients receiving sorafenib discontinued dosing due to adverse events, and 64% had a dose reduction. 14% of patients given sorafenib reported drug-related adverse reactions leading to discontinuation, compared with 1.4% of patients given placebo.
Table 9 shows the percentage of patients who experienced the following adverse reactions during the double-blind period of the differentiated thyroid cancer study: a higher incidence of adverse reactions in the sorafenib-treated group than in the placebo-treated group. 53% of patients receiving sorafenib reported CTCAE grade 3 adverse reactions compared with 23% of patients receiving placebo. 12% of patients receiving sorafenib reported CTCAE grade 4 adverse reactions compared with 23% of patients receiving placebo. Adverse reactions were reported by 12% of patients receiving sorafenib compared with 7% of patients receiving placebo.
TableTable strong>9: Incidence of adverse drug reactions reported in patients receiving sorafenib administration and more common than in patients receiving placebo administration [between-group difference ≥5% (all grades) ¹ or ≥2% (grades 3 and 4)]

Abnormal laboratory tests
See [Precautions] for a discussion of elevated thyrotropin (TSH) levels elsewhere in this insert. For the following laboratory test abnormalities, the relative elevations in patients with differentiated thyroid cancer treated with sorafenib compared with placebo-treated patients were similar to those observed in the renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia [see [Adverse Reactions]].
Elevated serum ALT and AST were seen in 59% and 54% of sorafenib-treated patients, respectively, compared with 24% and 15% of placebo-treated patients, respectively. High-grade (≥ grade 3) ALT and AST elevations were seen in 4% and 2% of sorafenib-treated patients, respectively, while these abnormalities were not seen in placebo-treated patients.
Hypocalcemia occurred more frequently and with greater severity in patients with differentiated thyroid cancer compared with patients with renal cell carcinoma (RCC) or hepatocellular carcinoma (HCC), particularly in patients with a history of hypoparathyroidism. The incidence of hypocalcemia was 36% in patients with differentiated thyroid cancer treated with sorafenib (10% ≥ grade 3) and 11% in placebo-treated patients (3% ≥ grade 3). In differentiated thyroid cancer studies, serum calcium levels should be monitored monthly.
 
[Contraindicated]
Sorafenib is contraindicated in patients with severe hypersensitivity to sorafenib or any of the inactive components of the product.
The combination regimen of sorafenib with paclitaxel and carboplatin is contraindicated in squamous cell lung cancer (see [Precautions]).
 
[Precautions]
Sorafenib must be taken under the supervision of a physician experienced in its use.
There is a lack of data from randomized controlled clinical studies comparing sorafenib with interventional therapy such as TACE in patients with advanced hepatocellular carcinoma, so it is not clear how advantageous sorafenib is relative to interventional therapy or whether it is beneficial to use sorafenib in patients after prior interventional therapy. It is recommended that physicians choose the appropriate treatment based on the patient’s specific circumstances.
Pregnancy: Women of childbearing potential should be advised to use contraception during treatment. Women patients of childbearing age should be informed of the possible risks of the drug to the fetus, including severe malformations (teratogenicity), developmental disorders and fetal death (embryotoxicity). Sorafenib should be avoided during pregnancy. It should be used in pregnant women only if the therapeutic benefit outweighs the possible harm to the fetus.
Based on the mechanism of inhibition of multiple kinases by sorafenib and the multiple adverse effects seen in animal studies when sorafenib was exposed at significantly lower than clinical doses, it is presumed that sorafenib can be harmful to the fetus when administered to pregnant women.
Lactating women should discontinue breastfeeding during treatment with sorafenib.
Skin toxicity: Hand and foot skin reactions and rash are the most common adverse reactions to sorafenib administration. Rash and hand-foot skin reactions are usually NCICTCAE grade 1 to 2 and tend to occur within 6 weeks of starting sorafenib. Management of skin toxicity reactions includes topical administration to reduce symptoms, temporary discontinuation or/and dose adjustment of sorafenib. Permanent discontinuation of sorafenib is required for patients with severe skin toxicity or persistent reactions.
Hypertension: There is an increased incidence of hypertension in patients taking sorafenib. Hypertension is mostly mild to moderate, mostly in the early stages after initiation of the drug, and can be controlled with conventional antihypertensive medications. Blood pressure should be monitored regularly and treated according to standard treatment protocols if needed. Permanent discontinuation of sorafenib needs to be considered in patients with severe or persistent hypertension or hypertensive crisis despite the application of antihypertensive drugs.
Bleeding: There may be an increased chance of bleeding after treatment with sorafenib. Severe bleeding is uncommon. Once bleeding requires treatment, it is recommended that permanent discontinuation of sorafenib be considered (see [Adverse Reactions]). Due to the potential risk of bleeding, tracheal, bronchial, and esophageal infiltrates should be treated locally in patients with differentiated thyroid cancer prior to treatment with sorafenib.
Warfarin: Some patients treated with concomitant sorafenib and warfarin experienced occasional bleeding or elevated INR. Patients on combined warfarin should be monitored regularly for changes in prothrombin time, INR values, and noted for clinical signs of bleeding.
Wound healing complications: No formal studies have been conducted on the effects of sorafenib administration on wound healing. Withholding sorafenib is recommended in patients requiring major surgery, and there is limited clinical experience with when to reapply sorafenib in post-surgical patients, so clinical considerations should be made before deciding to reapply the patient to ensure wound healing.
Myocardial ischemia and/or myocardial infarction: In trial 11213, the incidence of treatment-related myocardial ischemia/myocardial infarction was higher in the sorafenib group (4.9%) than in the placebo group (0.4%). In trial 100554, the incidence of treatment-related myocardial ischemia/myocardial infarction was 2.7% in the sorafenib group and 1.3% in the placebo group. Patients with unstable coronary artery disease and patients with recent myocardial infarction were not enrolled in either trial. Temporary or permanent discontinuation of treatment with sorafenib should be considered in patients who develop myocardial ischemia and/or myocardial infarction.
QT interval prolongation: Sorafenib prolongs the QT/QTc interval and can cause an increased risk of ventricular arrhythmias. In a clinical pharmacology study, baseline (pre-treatment) and post-treatment QT/QTc measurements were performed in 31 patients. After a 28-day treatment cycle, QTcB was prolonged by 4±19msec and QTcF was prolonged by 9±18msec at the moment of highest in vivo concentration of sorafenib compared to baseline with placebo treatment. in electrocardiogram (ECG) monitoring performed after treatment, no patient showed QTcB or QTcF greater than 500msec. therefore, it is important for patients with or likely to Sorafenib should be used with caution in patients who have or may develop QTc interval prolongation (e.g., patients with congenital QT prolongation syndrome, patients treated with high cumulative doses of anthracycline antibiotics, patients taking antiarrhythmic drugs or other drugs that cause QT prolongation, patients with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia). Regular monitoring of ECG and electrolytes (magnesium, potassium, calcium) during the treatment period should be considered when sorafenib is used in patients mentioned above.
Gastrointestinal perforation: Gastrointestinal perforation is relatively uncommon. Gastrointestinal perforation has been reported in less than 1% of patients taking sorafenib. In some cases, gastrointestinal perforation has not been associated with intra-abdominal tumors. Treatment with this product should be discontinued (see [Adverse Reactions]).
Hepatic impairment: There is no information on studies of sorafenib in patients with severe hepatic impairment (Child-Pugh Class C). Because sorafenib is primarily eliminated by the liver, its exposure is elevated in patients with severely impaired liver function.
Hypocalcemia: Close monitoring of blood calcium levels is recommended when treating patients with differentiated thyroid cancer with sorafenib. In clinical trials, hypocalcemia was more frequent and more severe in patients with differentiated thyroid cancer relative to patients with renal or hepatocellular carcinoma, particularly in patients with a history of hypoparathyroidism (see [Adverse Reactions]).
Thyrotropin (TSH) suppression in differentiated thyroid cancer: In clinical trials in differentiated thyroid cancer, increases in TSH levels greater than 0.5 mU/L have been observed in patients treated with sorafenib. Close monitoring of TSH levels is recommended when treating patients with differentiated thyroid cancer with sorafenib.
Sorafenib in combination with paclitaxel and carboplatin in squamous cell lung cancer resulted in increased mortality: Results of subgroup analysis of two randomized controlled clinical trials conducted in chemotherapy-naïve patients with IIIB-IV non-small cell lung cancer showed that patients with squamous cell cancer experienced higher mortality in the combination administration group relative to the chemotherapy alone group (relative risk ratio compared to paclitaxel/carboplatin group: HR=1.81, 95% CI 1.19-2.74; relative risk ratio compared with the gemcitabine/cisplatin group: HR 1.22, 95% CI 0.82-1.80). The combination regimen of sorafenib with paclitaxel and carboplatin is contraindicated in squamous cell lung cancer. Sorafenib is not recommended in combination with gemcitabine and cisplatin in squamous cell lung cancer. The safety and efficacy of sorafenib in non-small cell lung cancer has not been established.
Drug-Drug Interactions.
UGT1A1 pathway: Caution is advised when combining sorafenib with drugs that are metabolized/cleared via the UGT1A1 pathway (e.g., irinotecan) (see [Drug-Drug Interactions]).
Docetaxel: Results of previous studies have shown that docetaxel (75 mg/m² or 100 mg/m²) in combination with sorafenib (0.2 g or 0.4 g administered twice daily) (sorafenib was discontinued for three days before and after docetaxel dosing) resulted in a 36%-80% increase in the AUC of docetaxel. Caution is advised when this product is used in combination with docetaxel (see [Drug Interactions]).
Neomycin: May lead to decreased bioavailability of sorafenib when used in combination with neomycin (see [Drug Interactions]).
Effects on Driving and Machine Operation: There are no studies on the effects of sorafenib on driving and machine operation. There is no evidence that sorafenib affects the ability to drive and operate machines.
 
[Use in Pregnant and Lactating Women]
Pregnancy
There are no adequate, rigorous controlled studies of sorafenib in women during pregnancy. Animal studies have demonstrated reproductive toxicity including teratogenicity of the drug. Sorafenib and its metabolites cross the placental barrier in rats, and sorafenib is presumed to inhibit fetal angiogenesis.
Women of childbearing potential should be advised to use contraception during treatment. Women patients of childbearing age should be informed of the possible hazards of the drug to the fetus, including severe malformations (teratogenicity), developmental disorders and fetal death (embryotoxicity).
Avoid sorafenib application during pregnancy. It should be used in pregnant women only if the therapeutic benefit outweighs the possible harms to the fetus (see [Precautions]).
Women of childbearing potential
Animal studies have shown sorafenib to be teratogenic and embryotoxic. Adequate contraception should be used during treatment and for at least 2 weeks after treatment ends.
Lactation
It is not known whether sorafenib is secreted into human breast milk. Animal studies have shown that sorafenib and/or its metabolites can be secreted into breast milk. Because many drugs are secreted through breast milk and because the effects of sorafenib on infants have not been studied, women should stop breastfeeding during treatment with this drug.
Fertility
Results from animal studies have shown that sorafenib can impair fertility in both men and women.
[Pediatric Use]
There is no information on the safety and efficacy of sorafenib in pediatric patients.

[Geriatric Use]
No dose adjustment based on patient’s age (65 years or older), sex, or weight is required.
 
[Drug Interactions]
CYP3A4 inducers: The continued combination of rifampin and sorafenib resulted in a mean 37% reduction in the AUC of sorafenib. Other CYP3A4 inducers (e.g., onychomycin or onychomycin, commonly known as St. John’s wort; phenytoin; carbamazepine; phenobarbital and dexamethasone) may accelerate the metabolism of sorafenib and therefore reduce the drug concentration of sorafenib.
CYP3A4 inhibitors: ketoconazole is a strong inhibitor of CYP3A4. The mean AUC of sorafenib was not altered in healthy male volunteers who received ketoconazole (1 time/day) for 7 consecutive days along with a single oral sorafenib dose of 50 mg daily. Therefore, it is unlikely that CYP3A4 inhibitors interact with sorafenib in terms of clinical pharmacokinetics.
CYP2C9 substrate: Warfarin is a substrate of CYP2C9 and the effect of sorafenib on warfarin was assessed by comparing patients taking sorafenib with placebo. Mean PT-INR values were not altered in patients on sorafenib in combination with warfarin compared to the placebo group. However, patients should be monitored regularly for INR values when combined with warfarin (see [Precautions]).
CYP isoenzyme-selective substrates: Midazolam, dextromethorphan and omeprazole are substrates for cytochrome CYP3A4, CYP2D6 and CYP2C19, respectively. The combination of sorafenib with these three drugs for 4 weeks did not alter their exposure. This suggests that for these cytochrome P450 isozymes, sorafenib is neither an inhibitor nor an inducer. In a clinical trial, coadministration of this product with paclitaxel resulted in increased, but not decreased, in vivo exposure to 6-hydroxypaclitaxel, the active metabolite of paclitaxel metabolized by CYP2C8. These data suggest that this product may not be an in vivo inhibitor of CYP2C8. In another clinical study, coadministration of this product with cyclophosphamide resulted in a small decrease in cyclophosphamide exposure, but not in systemic exposure to 4-OH cyclophosphamide (the active metabolite of cyclophosphamide initially metabolized by CYP2B6), and these data suggest that this product may not be an in vivo inhibitor of CYP2B6.
Combination with other antineoplastic agents: In clinical trials, sorafenib was combined with other conventional doses of antineoplastic agents, including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, adriamycin, docetaxel, irinotecan, and cyclophosphamide. Sorafenib does not have clinically relevant effects on the drug metabolism of gemcitabine, cisplatin, carboplatin, oxaliplatin or cyclophosphamide.
Paclitaxel/carboplatin: Paclitaxel (225 mg/m²) and carboplatin (AUC=6) do not significantly affect the pharmacokinetics of paclitaxel when administered (≤0.4 g twice daily) concomitantly with this product (before and after paclitaxel/carboplatin administration, with 3 days of discontinuation of this product). Paclitaxel (225 mg/m² once every 3 weeks) and carboplatin (AUC=6) in combination with this product (0.4 g twice daily without interruption of this product administration) resulted in a 47% increase in in vivo exposure to sorafenib, a 29% increase in in vivo exposure to paclitaxel, and a 50% increase in in vivo exposure to 6-hydroxypaclitaxel. However, there was no effect on the pharmacokinetics of carboplatin. These data suggest that no dose adjustment is required when paclitaxel and carboplatin are used concomitantly with this product (before and after paclitaxel/carboplatin, with 3 days of discontinuation of this product); whereas the clinical significance of the increased in vivo exposure of this product and paclitaxel in combination and without discontinuation of this product is not known.
Capecitabine: Capecitabine (750 mg/m²-1050 mg/m², administered twice daily in 21-day cycles on days 1-14) in combination with this drug (0.2 g or 0.4 g administered twice daily without interruption) did not result in significant changes in the in vivo exposure of this product, but increased in vivo exposure of capecitabine by 15%-50% and 5-FU by 0%-52%. The clinical significance of the mild to moderate increases in in vivo exposure to capecitabine and 5-FU is not known.
Adriamycin/irinotecan: The combination of sorafenib and adriamycin caused a 21% increase in the AUC value of adriamycin in patients. Since the active metabolite of irinotecan, SN-38, is further metabolized via the UGT1A1 enzyme pathway, the combination of sorafenib and irinotecan resulted in a 67%-120% increase in the AUC value of SN-38, along with a 26%-42% increase in the AUC value of irinotecan. The clinical significance associated with this is not known. (See [Caution]).
Docetaxel: Docetaxel (75 mg/m² or 100 mg/m² every 21 days) when given in combination with sorafenib (0.2 g or 0.4 g administered twice daily from day 2 to day 19 during a 21-day treatment cycle) (sorafenib was discontinued for three days before and after docetaxel dosing) resulted in an increase in docetaxel AUC values increased by 36%-80% and Cmax increased by 16%-32%. Caution is advised when this product is used in combination with docetaxel. (See [Precautions]).
In combination with other antibiotics.
Neomycin: Neomycin, a non-systemically absorbed antibiotic used to eradicate the GI tract flora, causes a decrease in sorafenib exposure by affecting the hepatic-intestinal circulation of sorafenib (see Pharmacokinetics, Metabolism and Clearance). In healthy volunteers, the mean bioavailability of sorafenib decreased by 54% after 5 days of neomycin treatment. The clinical significance of this decrease is unclear. The effects of other antibiotics have not been studied, and the antibiotic-decreased sorafenib exposure effect is likely related to its impairment of glucuronide glucosidase activity.
In combination with proton pump inhibitors.
Omeprazole: Combination with omeprazole does not affect the pharmacokinetics of sorafenib and does not require adjustment of the drug dose of sorafenib.
 
[Drug overdose]
There is no specific treatment for sorafenib overdose.
The maximum dose of sorafenib is 0.8 g twice daily. The major adverse reactions observed at this dose are diarrhea and skin toxicities.
If an overdose is suspected, the drug should be discontinued and the patient treated with appropriate supportive therapy.
 
[Pharmacology and Toxicology]
Pharmacological effects
Sorafenib is a multi-kinase inhibitor
In vitro tests have shown that it inhibits tumor cell proliferation and anti-angiogenic effects. Sorafenib inhibits tumor cell target sites CRAF, BRAF, V600EBRAF, c-Kit, FLT-3 and tumor vascular target sites CRAF, VEGFR-2, VEGFR-3, PDGFR-β. RAF kinases are serine/threonine kinases, while c-Kit, FLT-3, VEGFR-2, VEGFR-3. PDGFR-β are tyrosine kinases, and these kinases act on tumor cell signaling pathways, angiogenesis and apoptosis.
In vivo assays have shown inhibition of tumor growth and angiogenesis in various human cancer transplantation nude mouse models, such as human hepatocellular carcinoma and renal cell carcinoma.
Toxicological studies
The preclinical safety of sorafenib was evaluated in mice, rats, dogs and rabbits.
Repeated dose toxicity tests showed mild to moderate alterations (degeneration and regeneration) in different organs.
Effects on bone and teeth were observed after multiple doses in juvenile and developing dogs, including irregular thickening of the femoral epiphyseal plate at doses of sorafenib up to 600 mg/m2 body surface area (equivalent to 1.2 times the clinically recommended dose of 500 mg/m2 body surface area), reduction of bone marrow cells near this growth plate (0.2 g/m2/day) and alterations in dental composition (600 mg/m2/day). No similar conditions were found in adult dogs.
Mutagenicity: In vitro chromosomal aberration tests were performed with mammalian cells (Chinese hamster ovaries) and sorafenib was genotoxic upon metabolic activation. The in vitro cytogenetic test (Ames test) for an intermediate in the manufacturing process was positive and the limit was controlled to less than 0.15% in the drug. the Ames test and the in vivo micronucleus test in mice showed that sorafenib was not genotoxic (0.34% of this intermediate in the tested drug).
Carcinogenicity: No carcinogenicity test was performed for sorafenib.
Reproductive toxicity: No specific animal fertility tests were performed. Repeated dosing toxicity tests observed alterations in the reproductive organs of animals, so that drug impairment of male and female fertility could be expected. Typical alterations include degeneration and blockage of the testis, paratestis, prostate and seminal vesicles in rats. These effects are more pronounced when daily doses of sorafenib reach 150 mg/m2 body surface area (equivalent to 0.3 times the clinically recommended dose at 500 mg/m2 body surface area). At doses up to 30 mg/m2/day, central necrosis of the corpus luteum and arrest of follicular development were observed in the ovaries of female rats. In test dogs, degeneration of the spermatogenic ducts was observed at doses up to 600 mg/m2/day, and a decrease in seminal fluid was observed at doses up to 1200 mg/m2/day.
Embryotoxicity, teratogenicity, including maternal and fetal weight loss, increased chance of miscarriage, and increased appearance and visceral malformations were observed in rats and rabbits with sorafenib application. Adverse effects on the fetus were observed in rats and rabbits at oral doses of 6 mg/m2/day and 36 mg/m2/day, respectively.
 
[Pharmacokinetics]
The mean relative bioavailability of sorafenib tablets was 38%-49% when compared to oral solution.
The clearance half-life of sorafenib is approximately 25-48 hours. Repeated dosing for 7 days achieves 2.5-7 times the accumulation compared to single dose administration.
After 7 days of administration, sorafenib blood concentrations reach steady state with a mean peak-to-valley ratio of less than 2.
Absorption distribution
The highest blood concentration is reached approximately 3 hours after oral administration of sorafenib. The bioavailability was similar between the moderate fat diet and the fasted state. The bioavailability of sorafenib was reduced by 29% with a high-fat diet compared to the fasted state.
When oral doses exceeded 0.4 g twice daily, the mean Cmax and AUC did not increase linearly.
In vitro, sorafenib was 99.5% bound to human plasma proteins.
Metabolism and clearance
Sorafenib is metabolized primarily in the liver via CYP3A4-mediated oxidation, in addition to glucuronidation mediated by UGT1A9. Sorafenib conjugates are catabolized by glucuronidase from GI bacteria, which allows the unconjugated component of sorafenib to be reabsorbed. Neomycin interferes with this process when combined with sorafenib, resulting in a 54% decrease in the average bioavailability of sorafenib.
At steady-state blood concentrations, sorafenib accounts for approximately 70-85% of all blood analytes in plasma. Sorafenib has eight known metabolites, five of which were detected in plasma. The major circulating metabolite of sorafenib in plasma is pyridine-N-oxide. In vitro tests have shown that this substance has similar potency to sorafenib, and it contains approximately 9%-16% of the blood analytes in steady-state plasma.
Following oral administration of 100 mg of sorafenib (solution), 96% of the drug was eliminated within 14 days, of which 77% was excreted in the feces and 19% in the urine as a glycosylated metabolite. Fifty-one percent of the prodrug was excreted in the feces, and no prodrug was found in the urine.
Enzyme inhibition tests
Human hepatic microsomal assays showed that sorafenib competitively inhibited CYP2C19, CYP2D6, and CYP3A4. When midazolam, dextromethorphan, and omeprazole (substrates of cytochromes CYP3A4, CYP2D6, and CYP2C19, respectively) were clinically coadministered, followed by 4 weeks of administration of this drug did not alter the in vivo exposure to these drugs. This suggests that this product is neither an inhibitor nor an inducer of these cytochrome P450 isozymes.
In vitro data suggest that sorafenib inhibits glycosidic acid metabolism via the UGT1A1 and UGT1A9 pathways. When this product is clinically co-administered with irinotecan (whose active metabolite SN-38 can be further metabolized via the UGT1A1 pathway), it leads to a 67%-120% increase in the AUC of SN-38. When these drugs are combined with sorafenib, they may increase the exposure concentration of metabolic substrates of UGT1A1 and UGT1A9.
In vitro assays showed that sorafenib inhibited CYP2B6 and CYP2C8 with Ki values of 6 and 1-2 µM, respectively. The coadministration of this product with paclitaxel resulted in increased, rather than decreased, in vivo exposure to 6-hydroxypaclitaxel, the active metabolite of paclitaxel metabolized by CYP2C8. These data suggest that this product may not be an in vivo inhibitor of CYP2C8.
Human liver microsomal assays demonstrated competitive inhibition of CYP2C9 by sorafenib with Ki values of 7-8 µM. The potential effect of sorafenib on CYP2C9 substrates was evaluated by combining warfarin in patients (sorafenib and placebo groups), and the mean change in PT-INR relative to baseline was not higher in patients in the sorafenib group than in the placebo group. This result suggests that sorafenib is not an in vivo inhibitor of CYP2C9. The coadministration of this product with cyclophosphamide resulted in a small reduction in cyclophosphamide exposure, but not in systemic exposure to 4-OH cyclophosphamide (the active metabolite of cyclophosphamide initially metabolized by CYP2B6), data that suggest that this product may not be an in vivo inhibitor of CYP2B6.
CYP3A4 Inhibitors
Ketoconazole, a strong inhibitor of CYP3A4, was administered to healthy male volunteers at 0.4 g once daily for 7 days along with a single oral dose of sorafenib at 50 mg daily, and mean blood concentrations of sorafenib were not altered. Therefore, sorafenib is unlikely to have clinical pharmacokinetic interactions with CYP3A4 inhibitors.
CYP enzyme inducers
The activity of CYP1A2 and CYP3A4 was not altered after treatment of cultured human hepatocytes with sorafenib. This suggests that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4. Clinical concomitant administration of sorafenib and rifampicin resulted in a mean decrease in sorafenib AUC values of 37%. Other CYP3A4 enzyme activation inducers (e.g., through-leaf Hypericum, commonly known as St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase the metabolism of sorafenib and so decrease sorafenib concentrations.
Combinations with other antineoplastic agents
In clinical trials, sorafenib has been used in combination with other conventional doses of antitumor agents, including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, adriamycin, docetaxel, irinotecan, and cyclophosphamide. Sorafenib does not have a clinically relevant effect on the drug metabolism of gemcitabine, cisplatin, carboplatin, oxaliplatin or cyclophosphamide.
Paclitaxel (225 mg/m2) and carboplatin (AUC=6) do not significantly affect the pharmacokinetics of paclitaxel when administered concomitantly (≤0.4 g twice daily) (before and after paclitaxel/carboplatin administration with 3 days of discontinuation of this product). Paclitaxel (225 mg/m2 once every 3 weeks) and carboplatin (AUC=6) in combination with this product (0.4 g twice daily without interruption of this product administration) resulted in a 47% increase in in vivo exposure to sorafenib, a 29% increase in in vivo exposure to paclitaxel, and a 50% increase in in vivo exposure to 6-hydroxypaclitaxel. There was no effect on the pharmacokinetics of carboplatin. These data suggest that no dose adjustment is required when paclitaxel and carboplatin are used concomitantly with this product (before and after paclitaxel/carboplatin, with 3 days of discontinuation of this product); whereas the clinical significance of the increased in vivo exposure of this product and paclitaxel when combined “and” this product is not discontinued is not known.
Capecitabine (750 mg/m2-1050 mg/m2 administered twice daily in 21-day cycles on days 1-14) in combination with paclitaxel (0.2 or 0.4 g administered twice daily without interruption) did not result in significant changes in in vivo exposure to paclitaxel, but capecitabine in vivo exposure had 15%-50% increase and 0%-52% increase in 5-FU exposure in vivo. The clinical significance of the mild to moderate increases in in vivo exposure of capecitabine and 5-FU is not known.
The combination of sorafenib and adriamycin caused a 21% increase in the AUC of adriamycin in patients. The combination of sorafenib and irinotecan resulted in a 67%-120% increase in the AUC of SN-38 and a 26%-42% increase in the AUC value of irinotecan due to further metabolism of the active metabolite of irinotecan via the UGT1A1 enzyme pathway. The clinical significance associated with this is not known.
Docetaxel (75 mg/m2 or 100 mg/m2 every 21 days) in combination with sorafenib (0.2 g or 0.4 g administered twice daily from day 2 to day 19 of a 21-day treatment cycle) (sorafenib was discontinued for three days while doxorubicin was administered) resulted in a 36%-80% increase in the AUC of doxorubicin and a 16%- 32%. Caution is advised when combining this product with doxorubicinol.
Combination with other antibiotics
Neomycin, a non-systemically absorbed antibiotic used to eradicate the GI tract flora, causes a decrease in sorafenib exposure by affecting the hepatic-intestinal circulation of sorafenib (see Pharmacokinetics, Metabolism and Clearance). The clinical significance of the 54% decrease in mean bioavailability of sorafenib after 5 days of neomycin treatment in healthy volunteers is not known. The effect of other antibiotics has not been studied, and the antibiotic-decreased sorafenib exposure effect is likely related to its impairment of glucuronide glucosidase activity.
In combination with proton pump inhibitors
Omeprazole
Combination with omeprazole does not affect the pharmacokinetics of sorafenib and does not require adjustment of the drug dose of sorafenib.
Pharmacokinetics in Special Populations
Elderly (65+ years), gender
Demographic data data indicate no need for dose adjustment based on the patient’s age or gender.
Pediatric Patients
No pharmacokinetic data are available for pediatric patients.
Patients with hepatic impairment
Sorafenib is primarily cleared by the liver.
Drug exposure in patients with mild (Child-PughA) or moderate (Child-PughB) hepatocellular carcinoma with hepatic impairment is consistent with the range of exposure in patients without hepatic impairment. Exposures were located within the range of variation for patients without liver impairment. Drug metabolism of sorafenib in non-hepatocellular carcinoma patients with Child-PughA and Child-PughB was similar to that of healthy volunteers. Pharmacokinetic studies with sorafenib in patients with severe liver impairment (Child-PughC) have not been performed.
Patients with renal impairment
In a clinical pharmacology study, sorafenib (single dose 0.4 g) was evaluated in patients with normal renal function, patients with mild renal impairment (CrCL 50-80 ml/min), patients with moderate renal impairment (CrCL 30-50 ml/min), and patients with severe renal impairment (CrCL<30 ml/min) not requiring dialysis (n=8/group). ) was evaluated for pharmacokinetics. The pharmacokinetics of sorafenib was not affected by hyperalgesia. No dose adjustment was required for patients with mild, moderate or severe renal impairment not requiring dialysis.
Race
Pharmacokinetic analysis of trial 11559 showed a slow absorption phase, a long elimination phase, and a relatively flat drug-time curve for sorafenib. There were significant individual differences in the pharmacokinetic parameters of sorafenib and its metabolites. In this study, the Cmax and AUC (0-12 h) of sorafenib in the Taiwanese and mainland populations were similar to the values in the Japanese population, and there was a large overlap in the range of data measured between these groups.
The pharmacokinetic analysis of trial 11849 (24 cases) was similar to the results of several previous studies, with steady-state plasma concentrations achieved at 7 days of dosing and relatively stable over the treatment period. The drug metabolism data were consistent with the Japanese study (trial 10875), with sorafenib Cmax,ss and AUCss at 3-4 mg/L and 30-mgh/L, respectively. The relative amounts of each metabolite were also consistent with the Japanese and Caucasian results. The pharmacokinetics of sorafenib in Chinese patients were similar to those of other study populations.
Trial 12162 was a pharmacokinetic study in healthy volunteers with the primary objective of comparing sorafenib exposure in Caucasian and Asian populations. It was administered to healthy, age-equivalent subjects under controlled conditions in a fasted state and without concomitant co-administration that could lead to pharmacokinetic disturbances. Japanese and Chinese subjects representing Asian ethnic groups were enrolled in the trial. A total of 40 Japanese, 38 Chinese and 40 Caucasian subjects were enrolled in the study. The study data showed that sorafenib exposure (AUC) was 30% lower in Asian subjects than in Caucasian subjects. Compared to Caucasian subjects, the geometric mean plasma AUC of sorafenib was 25% lower in Japanese subjects and 35% lower in Chinese subjects. The difference observed between Japanese subjects and Caucasian subjects in this study (25%) was lower than the previously reported value (45%). There was no significant difference between the mean Cmax of Japanese subjects and Caucasian subjects, and the mean Cmax of Chinese subjects was 16% lower than that of Caucasian subjects.
The pharmacokinetic differences observed during the single-dose pharmacokinetic inter-ethnic comparison and the steady-state pharmacokinetic inter-ethnic comparison were consistent with the population pharmacokinetic assessment. Population pharmacokinetic models for sorafenib were developed using data from seven single-agent phase I clinical studies conducted in cancer patients and supporting data derived from healthy subjects. In the primary analysis dataset, Caucasian subjects constituted the majority (64.7%, n=191), followed by 21.4% (Japanese) in Asians. The results of the population pharmacokinetic analysis (which focused specifically on ethnic differences) showed that exposure was 28.9% lower in Japanese patients than in Caucasian patients. However, the drug-time curves simulated for Asians and Caucasians based on the final model overlapped, suggesting that the pharmacokinetic differences between the two ethnic groups may not be clinically significant.
Due to the high degree of individual differences in pharmacokinetics between patients and the high overlap in AUC and Cmax values between Asians and Caucasians, the small apparent differences regarding systemic exposure to sorafenib may not be clinically significant given the similar efficacy and safety data for Asian and Caucasian patients with renal cell carcinoma.
 
[Storage].
Store sealed below 25°C.
 
[Packaging]
Polyamide/aluminum/polyvinyl chloride cold press molding solid pharmaceutical composite hard tablets, pharmaceutical aluminum foil
10 tablets/plate×3 plates/box, 10 tablets/plate×4 plates/box, 10 tablets/plate×6 plates/box.
 
[Expiration date]
36 months
 
[Execution Standard]
[Approval Number]
[Drug Listing Licensee] Name: Chongqing Yuyou Pharmaceutical Co.
Registered address: Chongqing Yubei District, Renhe Town, No. 100 Starlight Avenue
 
[Manufacturer]
Company name: Chongqing Yuyou Pharmaceutical Co.
Address: No. 100, Xingguang Avenue, Renhe Town, Yubei District, Chongqing
Postal code: 401121
Telephone number: (023) 67518018
Fax number: (023) 67527018
Web address: www.yaopharma.com