Sorafenat

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT SORAFENAT (SORAFENAT)

Composition:

Active substance: sorafenib;

One film-coated tablet contains 274 mg of sorafenib tosylate, equivalent to 200 mg of sorafenib;

Excipients: microcrystalline cellulose; sodium lauryl sulfate; croscarmellose sodium; carboxymethylcellulose calcium; hypromellose; magnesium stearate; Opadry Pink (02F540001): hypromellose, titanium dioxide (E 171), polyethylene glycol, iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: peach-colored, round, film-coated tablets, engraved with "200" on one side and "NAT" on the other.

Pharmacotherapeutic group. Antineoplastic agent, protein kinase inhibitor.

ATC code L01E X02.

Pharmacological properties.

Pharmacodynamics.

Sorafenib is a multikinase inhibitor and demonstrates anti-proliferative and anti-angiogenic properties in vitro and in vivo.

Mechanism of action and pharmacodynamic effects

Sorafenib is a multikinase inhibitor that reduces tumor cell proliferation in vitro. Sorafenib inhibits tumor growth in human tumor xenografts in immunocompromised mice by suppressing tumor angiogenesis. Sorafenib inhibits the activity of intracellular kinases present in tumor cells (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumor vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-β). RAF kinases are serine/threonine kinases, whereas c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β are receptor tyrosine kinases.

Clinical efficacy

The clinical safety and efficacy of sorafenib were evaluated in patients with hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and differentiated thyroid carcinoma (DTC).

Hepatocellular carcinoma

Study 3 (Study 100554) was an international, multicenter, randomized, double-blind, placebo-controlled Phase III trial involving 602 patients with hepatocellular carcinoma. Demographic data and disease characteristics were balanced between the sorafenib and placebo treatment groups according to the Eastern Cooperative Oncology Group (ECOG) performance status (status 0: 54% vs. 54%; status 1: 38% vs. 39%; status 2: 8% vs. 7%), TNM stage (Stage I: <1% vs. <1%; Stage II: 10.4% vs. 8.3%; Stage III: 37.8% vs. 43.6%; Stage IV: 50.8% vs. 46.9%), and BCLC (Barcelona Clinic Liver Cancer) stage (Stage B: 18.1% vs. 16.8%; Stage C: 81.6% vs. 83.2%; Stage D: <1% vs. 0%).

The study was terminated early after efficacy criteria were met during a pre-planned interim analysis of overall survival (OS). Results from this study demonstrated a statistically significant benefit of sorafenib over placebo in terms of OS (hazard ratio [HR] – 0.69; p = 0.00058; see Table 1). Limited data are available from this study for patients with Child-Pugh class B hepatic impairment; only one patient classified as Child-Pugh class C was enrolled in the study.

Table 1

Results of Study 3 (Study 100554) in hepatocellular carcinoma

Parameter of efficacy	Sorafenib (N = 299)	Placebo (N = 303)	p-value	HR (95 % CI)
Overall survival (OS) (months, median 95 % CI)	46.3 (40.9; 57.9)	34.4 (29.4; 39.4)	0.00058*	0.69 (0.55; 0.87)
Time to tumor progression (TTP) (months, median 95 % CI)**	24.0 (18.0; 30.0)	12.3 (11.7; 17.1)	0.000007	0.58 (0.45; 0.74)

CI – confidence interval.

HR – hazard ratio, sorafenib/placebo.

* Stratified log-rank test (for interim survival analysis, one-sided alpha boundary for early termination of the study alpha = 0.0077).

** Independent radiological assessment.

In the second (study 4), an international, multicenter, randomized, double-blind, placebo-controlled phase III trial involving 226 patients with progressive hepatocellular carcinoma (HCC), the clinical benefits of sorafenib were evaluated. This study, conducted in China, Korea, and Taiwan, confirmed the findings of study 3 regarding the positive benefit-risk profile of sorafenib (HR [CI]: 0.68; p = 0.01414).

In both studies (3 and 4), statistically significant benefit of sorafenib over placebo regarding overall survival (OS) was observed across pre-defined stratification factors (ECOG status, presence or absence of macroscopic vascular invasion and/or extrahepatic tumor spread). Subgroup analysis data suggest that patients with distant metastases at baseline derived less pronounced therapeutic benefit.

Renal cell carcinoma

The safety and efficacy of Sorafenat in the treatment of advanced renal cell carcinoma (RCC) were evaluated in two clinical trials.

Study 1 (study 11213) was a multicenter, randomized, double-blind, placebo-controlled phase III trial involving 903 patients. Only patients with RCC and low or intermediate risk according to MSKCC (Memorial Sloan-Kettering Cancer Center) classification were included in the study. Primary endpoints were overall survival (OS) and progression-free survival (PFS).

Approximately half of the patients had an ECOG performance status of 0, and half were in the low-risk group according to MSKCC classification. PFS was determined by blinded independent radiological assessment using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. PFS was assessed based on 342 events in 769 patients. The median PFS was 167 days for patients randomized to the sorafenib group compared to 84 days in the placebo group (HR = 0.44; 95% CI: 0.35–0.55; p < 0.000001). Age, predicted MSKCC risk category, ECOG status, and prior therapy did not influence the treatment effect.

An interim analysis (second interim analysis) of OS was conducted based on 367 deaths in 903 patients. The nominal alpha level for this analysis was 0.0094. Median survival was 19.3 months for patients randomized to the sorafenib group compared to 15.9 months for patients in the placebo group (HR = 0.77; 95% CI: 0.63–0.95; p = 0.015). At the time of this analysis, approximately 200 patients had crossed over from the placebo group to open-label sorafenib treatment.

Study 2 was conducted as a phase II trial assessing treatment withdrawal in patients with metastatic malignancies, including renal cell carcinoma. Patients with confirmed disease receiving sorafenib therapy were randomized to either placebo or continued sorafenib treatment. PFS in RCC was significantly longer in the sorafenib group (163 days) compared to the placebo group (41 days) (p = 0.0001; HR = 0.29).

Differentiated thyroid cancer

Study 5 (study 14295) was a multicenter, randomized, double-blind, placebo-controlled phase III trial involving 417 patients with locally advanced or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). The primary efficacy endpoint was PFS based on independent radiological assessment using RECIST (Response Evaluation Criteria in Solid Tumors). Secondary efficacy endpoints included OS, tumor response rate, and duration of tumor response. After disease progression, patients had the option to switch to open-label sorafenib.

All patients had actively progressive disease defined as progression within 14 months after enrollment and had radioactive iodine-refractory DTC. Refractoriness to radioactive iodine therapy was defined by the absence of iodine uptake on scanning, or cumulative radioactive iodine dose uptake ≥ 22.2 GBq, or progression after radioactive iodine therapy within 16 months after enrollment, or after each of two radioactive iodine treatments administered 16 months apart.

Baseline demographic and disease characteristics were comparable between the two treatment groups. Metastases were observed in the lungs in 86%, lymph nodes in 51%, and bones in 27%. The mean cumulative radioactive iodine therapy activity administered prior to enrollment was 14.8 GBq. In the study population, 56.8% of patients had papillary carcinoma, 25.4% had follicular carcinoma, and 9.6% had poorly differentiated carcinoma.

Median PFS was 10.8 months in the sorafenib group compared to 5.8 months in the placebo group (HR = 0.587; CI: 0.454, 0.758; p < 0.0001). The effect of sorafenib on PFS was independent of geographic region, patient age below or above 60 years, sex, histological subtype, and presence or absence of bone metastases.

According to the OS analysis performed 9 months after completion of data collection for the final PFS analysis, no statistically significant differences in overall survival were observed between the two treatment groups (HR = 0.884; 95% CI: 0.633, 1.236; p-value = 0.236). Median OS was not reached for the sorafenib group and was 36.5 months for the placebo group. 157 (75%) patients randomized to the control group crossed over to open-label sorafenib, while 61 patients (30%) in the sorafenib group initiated open-label treatment.

The mean duration of treatment during the double-blind period was 46 weeks (range 0.3–135) for patients receiving sorafenib and 28 weeks (range 1.7–132) for patients receiving placebo.

According to RECIST, no complete responses (CR) were observed. The overall response rate [CR + partial response (PR)] based on independent radiological assessment was higher in the sorafenib group (24 patients; 12.2%) compared to the placebo group (1 patient; 0.5%), one-sided p < 0.0001. The mean duration of response was 309 days (95% CI: 226; 505 days) in patients receiving sorafenib who achieved partial response.

A retrospective subgroup analysis of tumor size favored the therapeutic effect of sorafenib on PFS compared to placebo in patients with tumor size ≥1.5 cm [HR 0.54 (95% CI: 0.41–0.71)], whereas a numerically lower effect was observed in patients with tumor size <1.5 cm [HR 0.87 (95% CI: 0.40–1.89)].

A retrospective subgroup analysis of thyroid carcinoma symptoms at baseline indicated a favorable therapeutic effect of sorafenib on PFS compared to placebo in patients both with and without symptoms. The HR for PFS was 0.39 (95% CI: 0.21–0.72) in patients with symptoms at baseline and 0.60 (95% CI: 0.45–0.81) in patients without symptoms at baseline.

QT interval prolongation

During pharmacological studies under clinical use, QT/QTc measurements were recorded in 31 patients at baseline (prior to treatment) and after therapy. After one 28-day treatment cycle at maximum concentration (Cmax) of sorafenib, QTcB was prolonged by 4 ± 9 ms and QTcF by 9 ± 18 ms compared to placebo at baseline. No QTcB or QTcF > 500 ms was observed during ECG monitoring after treatment (see section "Special precautions").

Pediatric patients

The European Medicines Agency has deferred the obligation to submit the results of studies in all pediatric subpopulations with kidney cancer and renal cell carcinoma (except neuroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma, and renal rhabdoid tumor) and hepatocellular carcinoma and intrahepatic cholangiocarcinoma (except hepatoblastoma) and differentiated thyroid cancer (for information on use of the medicinal product in children, see section "Children").

Pharmacokinetics.

Absorption and bioavailability

After administration of sorafenib tablets, the mean relative bioavailability is 38–49% compared to an oral solution. Absolute bioavailability is unknown.

After oral administration, the Cmax of sorafenib in plasma is reached approximately 3 hours later. When administered with a high-fat meal, absorption was reduced by 30% compared to administration in the fasting state.

The mean Cmax and area under the concentration-time curve (AUC) increase less than proportionally at doses above 400 mg administered orally twice daily. In vitro, protein binding in plasma is 99.5%.

Repeated administration of sorafenib over 7 days compared to single-dose administration results in accumulation by 2.5–7 times. Steady-state concentrations of sorafenib in plasma are achieved within 7 days of administration, with a Cmax to trough concentration ratio of less than 2.

Steady-state concentrations of sorafenib after administration of Sorafenat 400 mg twice daily were evaluated in patients with DTC, RCC, and HCC. The mean steady-state concentration in patients with DTC was 1.8 times higher than in patients with HCC and 2.3 times higher than in patients with RCC. The reason for the increased sorafenib concentration in patients with DTC is unknown.

Metabolism and elimination

The elimination half-life of sorafenib is approximately 25–48 hours. Sorafenib is primarily metabolized by oxidative metabolism in the liver involving CYP3A4 and glucuronidation involving UGT1A9. Sorafenib conjugates may be cleaved in the gastrointestinal tract by microorganisms with glucuronidase activity, promoting reabsorption of the unconjugated active substance. Concomitant administration with neomycin indicated an interaction within this process and reduced the mean bioavailability of sorafenib by 54%.

At steady state, approximately 70–85% of circulating sorafenib derivatives in plasma are unchanged sorafenib. Eight metabolites of sorafenib have been identified, five of which were detected in plasma. The main metabolite in plasma, the N-oxide of pyridine, showed in vitro activity comparable to sorafenib. At steady state, this metabolite accounts for approximately 9–16% of all circulating metabolites.

After oral administration of a 100 mg sorafenib solution, 96% of the dose was excreted within 14 days, with 77% excreted in feces and 19% in urine as glucuronidated metabolites. Unmodified sorafenib, accounting for 51% of the dose, was found in feces but not in urine, indicating that biliary excretion of unchanged active substance may contribute to sorafenib elimination.

Pharmacokinetics in special populations

Demographic data analysis indicates no need for dose adjustment based on age (up to 65 years) or sex of patients.

Pediatric patients

Pharmacokinetic studies of sorafenib in pediatric patients have not been conducted.

Race

There is no clinically significant difference in pharmacokinetics between Caucasian and Mongoloid populations.

Renal impairment

In four phase I studies, steady-state exposure to sorafenib was similar in patients with mild or moderate renal impairment and in patients with normal renal function. In a clinical pharmacology study (single 400 mg dose of sorafenib), no correlation was observed between sorafenib disposition and renal function in patients with normal renal function, mild, moderate, or severe renal impairment. Data are lacking for patients requiring dialysis.

Patients with hepatic impairment

In patients with HCC and Child-Pugh class A or B (mild or moderate) hepatic impairment, exposure values were comparable and within the ranges observed in patients without hepatic impairment. The pharmacokinetics (PK) of sorafenib in patients without HCC but with Child-Pugh class A or B hepatic impairment were similar to those in healthy volunteers. Data are lacking for patients with Child-Pugh class C (severe) hepatic impairment. Sorafenib is predominantly eliminated by the liver; therefore, exposure may increase in this patient population.

Preclinical safety data

Positive results for clastogenicity were obtained in an in vitro mammalian cell test system (Chinese Hamster Ovaries) with metabolic activation. Sorafenib did not show mutagenic effects in the Ames test or in an in vivo test system (Mouse Micronucleus Assay). An intermediate product of sorafenib synthesis, present in the active substance in minor quantities (< 0.15%), showed a positive result in an in vitro bacterial mutagenicity test (Ames test).

Carcinogenicity studies of sorafenib have not been conducted.

Specific preclinical studies on the effect of sorafenib on fertility have not been performed. However, adverse effects on male and female fertility can be expected, as results from repeated-dose animal studies showed changes in male and female reproductive organs at exposures below the expected clinical exposure (based on AUC values). Typical findings in rats included signs of degeneration and retardation of testes, epididymides, prostate, and seminal vesicles. In female rats, central necrosis of corpus luteum and impaired follicular development in ovaries were observed. In dogs, testicular degeneration and oligospermia were observed.

Clinical characteristics.

Indications.

Hepatocellular carcinoma (HCC)

Sorafenat is indicated for the treatment of patients with hepatocellular carcinoma.

Renal cell carcinoma (RCC)

Sorafenat is indicated for the treatment of patients with advanced renal cell carcinoma who have previously been treated with interferon-alpha or interleukin-2, or who are unsuitable for such therapy.

Differentiated thyroid cancer (DTC)

Sorafenat is indicated for the treatment of patients with locally advanced or metastatic, progressive, differentiated thyroid cancer (papillary/follicular/Hürthle cell) refractory to radioactive iodine treatment.

Contraindications.

Hypersensitivity to sorafenib or to any of the excipients of the medicinal product.

The medicinal product is contraindicated when used concomitantly with carboplatin and paclitaxel in patients with squamous cell lung cancer (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Enzyme inducers

Administration of rifampicin for 5 days prior to a single dose of sorafenib resulted in a mean reduction of 37% in sorafenib AUC. Other inducers of cytochrome CYP3A4 and/or glucuronidation (e.g. St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase sorafenib metabolism and consequently reduce sorafenib concentrations.

Cytochrome CYP3A4 inhibitors

Ketoconazole, a potent CYP3A4 inhibitor administered once daily for 7 days to healthy volunteers, did not alter the mean AUC after a single 50 mg dose of sorafenib. These data suggest that clinically significant interactions between sorafenib and CYP3A4 inhibitors are unlikely.

CYP2B6, CYP2C8 and CYP2C9 substrates

Sorafenib inhibits CYP2B6, CYP2C8 and CYP2C9 in vitro with comparable potency. However, in clinical pharmacokinetic studies, co-administration of sorafenib 400 mg twice daily with cyclophosphamide, a CYP2B6 substrate, or paclitaxel, a CYP2C8 substrate, did not show clinically significant inhibition. These data indicate that sorafenib, when administered at the recommended dose of 400 mg twice daily, is not an in vivo inhibitor of CYP2B6 or CYP2C8.

Additionally, co-administration of sorafenib with warfarin (a CYP2C9 substrate) did not result in changes in mean prothrombin time/international normalized ratio (INR) compared to placebo. Therefore, the risk of clinically significant in vivo inhibition of CYP2C9 substrates by sorafenib is expected to be low. However, regular monitoring of INR is recommended for all patients receiving concomitant therapy with warfarin or phenprocoumon (see section "Special precautions").

CYP3A4, CYP2D6 and CYP2C19 substrates

Co-administration of sorafenib with midazolam, dextromethorphan, or omeprazole, substrates of cytochrome CYP3A4, CYP2D6, and CYP2C19, respectively, did not affect exposure to these drugs. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. Therefore, clinically significant interactions between sorafenib and substrates of these enzymes are unlikely.

UGT1A1 and UGT1A9 substrates

In vitro, sorafenib inhibits glucuronidation by affecting substrates of UGT1A1 and UGT1A9. The clinical relevance of these data is currently unknown (see section "Special precautions").

In vitro enzyme induction studies

Activity of CYP1A2 and CYP3A4 was not altered following treatment of cultured human hepatocytes with sorafenib; sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4.

P-glycoprotein substrates

In vitro, sorafenib inhibits the P-glycoprotein transporter. Increased plasma concentrations of P-glycoprotein substrates such as digoxin cannot be excluded during concomitant administration with sorafenib.

Combination with other antineoplastic agents

In clinical trials, sorafenib was administered in combination with various antineoplastic agents, including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, irinotecan, docetaxel, and cyclophosphamide, using standard dosing regimens. Sorafenib has no clinically significant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin, or cyclophosphamide.

Paclitaxel/carboplatin

• Administration of paclitaxel (225 mg/m²) and carboplatin (AUC = 6) with sorafenib (≤ 400 mg twice daily) and a three-day break in sorafenib dosing (two days before and on the day of paclitaxel/carboplatin administration) had no significant effect on paclitaxel pharmacokinetics.
• Concomitant administration of paclitaxel (225 mg/m² once every three weeks) and carboplatin (AUC = 6) with sorafenib (≤ 400 mg twice daily without interruption in sorafenib dosing) resulted in a 47% increase in sorafenib exposure, a 29% increase in paclitaxel exposure, and a 50% increase in 6-OH paclitaxel exposure. No effect on carboplatin pharmacokinetics was observed.

These data indicate that no dose adjustment of paclitaxel and carboplatin is required when administered concomitantly with sorafenib with a three-day break in sorafenib dosing (two days before and on the day of paclitaxel/carboplatin administration). The clinical significance of increased sorafenib and paclitaxel exposure with continuous sorafenib dosing is unknown.

Capecitabine

Concomitant administration of capecitabine (750–1050 mg/m² twice daily on days 1–14 every 21 days) and sorafenib (200 mg or 400 mg twice daily, continuous long-term administration) did not result in significant changes in sorafenib exposure, but was associated with:

15–50% increase in capecitabine exposure and 0–52% increase in 5-FU exposure. The clinical significance of this minor/moderate increase in capecitabine and 5-FU exposure with concomitant administration of sorafenib remains unknown.

Doxorubicin/irinotecan

Concomitant administration of sorafenib and doxorubicin resulted in a 21% increase in doxorubicin AUC. When sorafenib was administered concomitantly with irinotecan, whose active metabolite SN-38 is further metabolized via UGT1A1, increases in SN-38 AUC of 67–120% and in irinotecan AUC of 26–42% were observed. The clinical significance of these observations has not been fully established (see section "Special precautions").

Docetaxel

Concomitant administration of docetaxel (75 mg/m² or 100 mg/m² once every 21 days) with sorafenib (200 mg or 400 mg twice daily for 19 days of a 21-day treatment cycle, starting on day 2), with a three-day break during docetaxel administration, resulted in a 36–80% increase in docetaxel AUC and a 16–32% increase in Cmax. Caution is recommended when administering sorafenib concomitantly with docetaxel (see section "Special precautions").

Effect of sorafenib on other medicinal products

Neomycin. Concomitant administration of neomycin, a non-systemic antimicrobial agent used for eradication of gastrointestinal flora, affects the enterohepatic circulation of sorafenib (see section "Pharmacological properties") and leads to reduced sorafenib exposure. In healthy volunteers receiving neomycin for 5 days, mean sorafenib exposure was reduced by 54%. The effect of other antibiotics on sorafenib pharmacokinetics has not been studied, but is likely to depend on their ability to interact with microorganisms possessing glucuronidase activity.

Medicinal products that increase gastric pH

Sorafenib water solubility is pH-dependent: the higher the pH, the lower the solubility. However, the proton pump inhibitor omeprazole, administered at a dose of 40 mg once daily for 5 days, did not cause clinically significant changes in the exposure of a single dose of sorafenib. Dose adjustment of Sorafenat is not required.

Special precautions for use

Skin toxic reactions

The most common adverse reactions observed during sorafenib administration were skin reactions at extremities (hand-foot skin reaction) and rash. In most cases, these were of grade I or II severity according to the Common Terminology Criteria for Adverse Events (CTCAE) and occurred primarily within the first six weeks of sorafenib treatment. Local symptomatic therapy may be used to manage skin toxic reactions. If necessary, temporarily interrupt treatment and/or adjust the dose of sorafenib; in cases of severe or persistent skin reactions, sorafenib therapy should be discontinued (see section "Adverse reactions").

Arterial hypertension

An increased incidence of arterial hypertension has been observed in patients receiving sorafenib. Hypertension was usually mild to moderate in severity, occurred early during the treatment course, and was manageable with standard antihypertensive therapy. Blood pressure should be monitored periodically, and antihypertensive treatment should be initiated if blood pressure increases. In cases of severe or persistent hypertension or hypertensive crisis despite adequate antihypertensive therapy, temporary or permanent discontinuation of sorafenib should be considered (see section "Adverse reactions").

Aneurysms and arterial dissection

The use of VEGF inhibitors in patients with or without arterial hypertension may lead to the development of aneurysms and/or arterial dissection. This risk should be carefully considered before initiating treatment with Sorafenat in patients with risk factors such as arterial hypertension or history of aneurysm.

Hypoglycemia

Decreased blood glucose levels have been observed in patients receiving sorafenib therapy, in some cases with clinical symptoms and requiring hospitalization due to loss of consciousness. In case of symptomatic hypoglycemia, temporary discontinuation of sorafenib therapy should be considered. In patients with diabetes mellitus, blood glucose levels should be monitored regularly to assess the need for adjustment of antidiabetic medications.

Bleeding

An increased incidence of arterial bleeding has been observed in patients receiving sorafenib. In case of any bleeding event requiring medical intervention, temporary discontinuation of sorafenib therapy should be considered (see section "Adverse reactions").

Myocardial ischemia and/or infarction

In a randomized, double-blind, placebo-controlled trial (Study 1), the incidence of treatment-related myocardial ischemia/infarction was higher in the sorafenib group (4.9%) compared to the placebo group (0.4%). In Study 3, myocardial ischemia/infarction occurred in 2.7% of patients in the sorafenib group compared to 1.3% in the placebo group. Patients with acute coronary syndrome or recent myocardial infarction were excluded from these trials. In case of myocardial ischemia and/or infarction, temporary or permanent discontinuation of sorafenib therapy should be considered (see section "Adverse reactions").

QT interval prolongation

Sorafenib may cause QT/QTc interval prolongation (see section "Pharmacological properties"), which may increase the risk of ventricular arrhythmias. Sorafenib should be used with caution in patients with prolonged QT interval or those at risk of developing it, such as patients with congenital long QT syndrome, those receiving high cumulative doses of anthracyclines, those taking certain antiarrhythmic drugs or other medicinal products known to prolong the QT interval, and patients with electrolyte imbalances such as hypokalemia, hypocalcemia, or hypomagnesemia. Periodic monitoring of plasma electrolyte levels (magnesium, potassium, calcium) is recommended in patients receiving sorafenib.

Gastrointestinal perforation

Gastrointestinal perforation has been reported as an uncommon adverse event in less than 1% of patients receiving sorafenib. In some cases, perforation occurred without evidence of intra-abdominal tumor. Sorafenib therapy should be discontinued if gastrointestinal perforation occurs (see section "Adverse reactions").

Tumor lysis syndrome (TLS)

Cases of TLS, some of which were fatal, have been reported during post-marketing surveillance in patients receiving sorafenib. Risk factors for TLS include high tumor burden, pre-existing chronic renal failure, oliguria, dehydration, arterial hypotension, and acidic urine pH. Patients with these risk factors should be closely monitored and promptly treated as clinically indicated; prophylactic hydration should also be considered.

Patients with hepatic impairment

Data are lacking in patients with Child-Pugh class C (severe) hepatic impairment. Exposure may be increased in patients with severe hepatic impairment, as sorafenib is primarily eliminated by the liver (see sections "Pharmacological properties" and "Dosage and administration").

Concomitant use with warfarin

In some patients receiving concomitant warfarin and sorafenib, rare episodes of bleeding or increased INR have been reported. When warfarin is used concomitantly with sorafenib, prothrombin time and INR should be monitored regularly, and clinical signs of bleeding should be observed (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Wound healing complications

No specific studies have been conducted on the effect of sorafenib on wound healing. In case of major surgical procedures, temporary discontinuation of sorafenib therapy is recommended. Clinical experience regarding resumption of sorafenib after surgery is limited. Therefore, the decision to resume treatment after major surgery should be based on clinical assessment of the postoperative recovery.

Elderly patients

Cases of renal failure have been reported. Renal function should be monitored.

Drug interactions

Sorafenib should be used with caution in combination with compounds primarily metabolized or eliminated via UGT1A1 (e.g., irinotecan) or UGT1A9 (see section "Interaction with other medicinal products and other forms of interaction").

Sorafenib should be used with caution in combination with docetaxel (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of neomycin or other antibiotics causing significant disruption of gastrointestinal microbiota may lead to reduced bioavailability of sorafenib (see section "Interaction with other medicinal products and other forms of interaction"). The risk of reduced sorafenib concentration should be considered before initiating antibiotic therapy.

Increased mortality has been observed in patients with squamous cell lung cancer receiving sorafenib in combination with platinum-based chemotherapy. In two randomized trials in non-small cell lung cancer, in the subgroup of patients with squamous cell lung cancer, overall survival was 1.81 (95% CI 1.19; 2.74) when sorafenib was added to carboplatin/paclitaxel and 1.22 (95% CI 0.82; 1.80) when added to gemcitabine/cisplatin. No single cause of death predominated, but increased rates of respiratory failure, bleeding, and infection-related adverse events were observed in patients receiving sorafenib with platinum-based chemotherapy.

Warnings for specific diseases

Differentiated thyroid cancer (DTC)

Physicians are advised to carefully evaluate the prognosis for each patient, considering the maximum tumor size (see section "Pharmacological properties"), disease-related symptoms (see section "Pharmacological properties"), and rate of progression before initiating therapy. Evaluation of suspected adverse reactions may require temporary interruption or dose reduction of sorafenib. In a clinical trial (see section "Pharmacological properties"), 37% of patients discontinued treatment and 35% required dose reduction during the first cycle of sorafenib therapy. Dose reduction was partially effective in alleviating adverse reactions. Therefore, repeated benefit-risk assessment of sorafenib is recommended, taking into account antitumor activity and tolerability.

Bleeding in DTC

Patients with DTC should undergo localized treatment of tracheal, bronchial, and esophageal infiltration prior to starting sorafenib therapy due to the potential risk of bleeding.

Hypocalcemia in DTC

Careful monitoring of serum calcium levels is recommended in patients with DTC receiving sorafenib. Hypocalcemia was most frequently observed and most severe in patients with DTC, especially in those with a history of hypoparathyroidism, compared to patients with renal cell carcinoma or hepatocellular carcinoma. Grade III and IV hypocalcemia was observed in 6.8% and 3.4% of DTC patients receiving sorafenib, respectively (see section "Adverse reactions"). Severe hypocalcemia should be corrected to prevent complications such as QT interval prolongation or torsade de pointes (see subsection "QT interval prolongation").

Thyroid-stimulating hormone (TSH) suppression in DTC

In a clinical trial, baseline TSH levels in patients receiving sorafenib were below 0.5 mIU/L. Monitoring of TSH levels is recommended in patients with DTC receiving sorafenib therapy.

Renal cell carcinoma

Patients with poor prognosis according to the Memorial Sloan Kettering Cancer Center prognostic group were not included in the phase III clinical trial of renal cell carcinoma (Study 1 in section "Pharmacological properties"), and the benefit-risk ratio of sorafenib in this patient group has not been evaluated.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per milliliter, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the use of sorafenib in pregnant women. Animal studies have shown reproductive toxicity, including teratogenic effects (see section "Pharmacological properties"). In rat studies, sorafenib and its metabolites crossed the placenta; sorafenib is expected to have harmful effects on the fetus.

Sorafenib should not be used during pregnancy except in cases of clear necessity and after careful assessment of the benefit-risk balance for the mother and risk to the fetus.

Women of childbearing potential should be informed of the need to use effective contraception during sorafenib therapy.

Lactation. It is unknown whether sorafenib is excreted in human breast milk. In animal studies, sorafenib and/or its metabolites were excreted in milk. Since sorafenib may have adverse effects on the growth and development of infants (see section "Pharmacological properties"), discontinuation of breastfeeding should be considered during sorafenib therapy.

Fertility. Animal studies indicate that sorafenib may impair fertility in both women and men (see section "Pharmacological properties").

Contraception

Women. The use of Sorafenat may cause harm to the fetus if used during pregnancy. Women of childbearing potential should be informed of the need to use effective contraception during treatment with the medicinal product and for 6 months after the last dose of Sorafenat.

Men. Based on genotoxicity data and reproductive studies in animals, men whose partners are women of childbearing potential or pregnant should be informed of the need to use effective contraception during treatment with Sorafenat and for 3 months after the last dose of the medicinal product.

Ability to drive and use machines.

No studies have been conducted on the effect of sorafenib on the ability to drive or operate machinery. There have been no reports of sorafenib affecting reaction time during driving or operating machinery.

Method of Administration and Dosage

Treatment should be conducted under the supervision of a physician experienced in anticancer therapy.

Dosage

The recommended daily dose of sorafenib for adults is 400 mg (2 tablets of 200 mg) twice daily (equivalent to a total daily dose of 800 mg).

Treatment should continue as long as clinical benefit is observed or until severe toxic reactions occur.

Dosage Adjustment

Evaluation of suspected adverse reactions may require temporary interruption of therapy or dose reduction of sorafenib.

If dose reduction is necessary during therapy for HCC or RCC, the dose of Sorafenat may be reduced to 2 tablets of 200 mg sorafenib once daily (see section "Special Instructions").

If dose reduction is required during therapy for DTC, the dose of Sorafenat may be reduced to 600 mg sorafenib per day administered in divided doses (2 tablets of 200 mg and 1 tablet of 200 mg, with a 12-hour interval between doses).

If further dose reduction is needed, the dose of Sorafenat may be decreased to 400 mg sorafenib per day administered in divided doses (2 tablets of 200 mg with a 12-hour interval between doses). If necessary, the dose may be further reduced to 1 tablet of 200 mg per day. After improvement of non-hematological adverse reactions, the dose of Sorafenat may be increased.

Elderly Patients

No dose adjustment is required for elderly patients (aged 65 years and older).

Renal Impairment

No dose adjustment is required for patients with mild, moderate, or severe renal impairment. Data are lacking for patients requiring dialysis (see section "Pharmacological Properties").

Monitoring of fluid and electrolyte balance is recommended in patients with renal dysfunction.

Hepatic Impairment

No dose adjustment is required for patients with Child-Pugh class A or B (mild or moderate) hepatic impairment. Data are lacking for patients with Child-Pugh class C (severe) hepatic impairment (see sections "Pharmacological Properties" and "Special Instructions").

Method of Administration

For oral use.

Sorafenib should be taken without food or with a low- to medium-fat meal. If a patient intends to consume a high-fat meal, the sorafenib tablet should be taken at least 1 hour before or 2 hours after the meal. The tablet should be swallowed with a glass of water.

Children

Safety and efficacy of Sorafenat in children have not been established. Data are lacking.

Overdose.

There is no specific antidote for sorafenib overdose.

The highest clinically studied dose of sorafenib was 800 mg twice daily. Adverse reactions observed at this dose were primarily diarrhea and skin reactions. In case of suspected overdose, administration of sorafenib should be discontinued and symptomatic treatment should be initiated as necessary.

Adverse reactions

The most important serious adverse reactions were myocardial infarction/ischemia, gastrointestinal tract perforations, drug-induced hepatitis, hemorrhages, and arterial hypertension/hypertensive crisis.

The most frequently observed adverse reactions were diarrhea, fatigue, infections, alopecia, palmar-plantar syndrome (corresponding to palmar-plantar erythrodysesthesia according to MedDRA classification), and rash.

Adverse reactions observed during multicenter clinical studies or in the post-marketing period are listed in Table 2 by system organ class (according to MedDRA classification) and frequency. Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and frequency not known (cannot be estimated from available data).

Within each category, adverse reactions are listed in order of decreasing severity.

Table 2

Adverse reactions observed during multicenter clinical studies or in the post-marketing period

Body systems	Very common	Common	Uncommon	Rare	Frequency unknown
Infections and infestations	infections	folliculitis
Blood and lymphatic system disorders	lymphopenia	leukopenia, neutropenia, anemia, thrombocytopenia
Immune system disorders			hypersensitivity reactions (including skin reactions and urticaria, anaphylactic reactions)	angioneurotic edema
Endocrine disorders		hypothyroidism	hyperthyroidism
Nutrition and metabolism disorders	anorexia, hypophosphatemia	hypocalcemia, hypokalemia, hyponatremia, hypoglycemia	dehydration		tumor lysis syndrome
Psychiatric disorders		depression
Nervous system disorders		peripheral sensory neuropathy, dysgeusia	reversible leukoencephalopathy*		encephalopathy°
Ear and labyrinth disorders		tinnitus
Cardiac disorders		congestive heart failure*, myocardial ischemia and infarction*		QT interval prolongation
Vascular disorders	bleeding (including gastrointestinal*, respiratory tract* and intracranial hemorrhage), arterial hypertension	flushing	hypertensive crisis*		aneurysms and arterial dissection
Respiratory, thoracic and mediastinal disorders		rhinorrhea, dysphonia	conditions resembling interstitial lung disease* (pneumonitis, radiation pneumonitis, acute respiratory distress)
Gastrointestinal disorders	diarrhea, nausea, vomiting, constipation	stomatitis (including dry mouth and glossalgia), dyspepsia, dysphagia, gastroesophageal reflux disease	pancreatitis, gastritis, gastrointestinal perforation*
Hepatobiliary disorders			increased bilirubin levels and jaundice, cholecystitis, cholangitis	drug-induced hepatitis*
Skin and subcutaneous tissue disorders	dry skin, rash, alopecia, palmar-plantar erythrodysesthesia**, erythema, pruritus	keratoacanthoma/squamous cell carcinoma of the skin, exfoliative dermatitis, acne, skin desquamation, hyperkeratosis	eczema, erythema multiforme	reappearance of radiation burns, dermatitis, Stevens-Johnson syndrome, leukocytoclastic vasculitis, toxic epidermal necrolysis*
Musculoskeletal and connective tissue disorders	arthralgia	myalgia, muscle spasms		rhabdomyolysis
Renal and urinary disorders		renal failure, proteinuria		nephrotic syndrome
Reproductive system and breast disorders		erectile dysfunction	gynecomastia
General disorders and administration site conditions	fatigue, pain (including oral pain, abdominal pain, bone pain, tumor pain, and headache), fever	asthenia, influenza-like illness, mucosal inflammation
Investigations	weight loss, increased amylase levels, increased lipase levels	transient increase in transaminase levels	transient increase in alkaline phosphatase levels in blood, abnormal PT/INR values, abnormal prothrombin levels

* Adverse reactions may have life-threatening or fatal consequences. Such events were observed infrequently or less frequently than infrequent.

** Hand-foot skin reaction corresponds to hand-foot erythrodysesthesia syndrome according to MedDRA classification.

° Observed in the post-marketing period.

Description of selected adverse reactions

Congestive heart failure

Congestive heart failure was reported as an adverse reaction in 1.9% of patients receiving sorafenib (N = 2276) in clinical trials. In study 11213 (RCC), adverse reactions indicating congestive heart failure occurred in 1.7% of patients receiving sorafenib and in 0.7% of patients receiving placebo. In study 100554 (HCC), such adverse reactions occurred in 0.99% of patients receiving sorafenib and in 1.1% of patients receiving placebo.

Additional information on specific patient groups

In clinical trials, certain adverse reactions such as hand-foot skin reaction, diarrhea, alopecia, weight loss, arterial hypertension, hypocalcemia, and keratoacanthoma/squamous cell carcinoma of the skin occurred more frequently in patients with differentiated thyroid cancer compared to patients with renal cell carcinoma or hepatocellular carcinoma.

Laboratory test abnormalities in HCC patients (study 3) and RCC patients (study 1)

Elevated lipase and amylase levels were very commonly observed. Grade III and IV increases in amylase levels according to CTCAE were observed in 11% and 9% of patients in the sorafenib group in study 1 (RCC) and study 3 (HCC), compared to 7% and 9% in the placebo group, respectively. Grade III and IV increases in lipase levels according to CTCAE were observed in 1% and 2% of patients in the sorafenib group in study 1 and study 3, compared to 3% in the placebo group. Pancreatitis was reported in 2 of 451 patients receiving sorafenib (Grade IV according to CTCAE) in study 1, in 1 of 279 patients receiving sorafenib in study 3 (Grade II according to CTCAE), and in 1 of 451 patients in the placebo group in study 1 (Grade II according to CTCAE).

Hypophosphatemia was a very common disorder, observed in 45% and 35% of patients treated with sorafenib, compared to 12% and 11% of patients receiving placebo in study 1 and study 3, respectively. Grade III hypophosphatemia according to CTCAE (1–2 mg/dL) occurred in 13% of patients in the sorafenib group and 3% in the placebo group in study 1, and in 11% of patients in the sorafenib group and 2% in the placebo group in study 3. No cases of Grade IV hypophosphatemia according to CTCAE (< 1 mg/dL) were recorded in either the sorafenib or placebo group in study 1. In study 3, one case was recorded in the placebo group. The mechanism of sorafenib-associated hypophosphatemia is unknown.

Lymphopenia and neutropenia of Grade III or IV according to CTCAE occurred in ≥ 5% of patients in the sorafenib group.

Hypokalemia was observed in 12% and 26.5% of patients in the sorafenib group, compared to 7.5% and 14.8% of patients receiving placebo in study 1 and study 3, respectively. In most cases, hypokalemia was mild (Grade I and II according to CTCAE). Grade III hypokalemia (6.0–7.0 mg/dL) occurred in 1.1% and 1.8% of patients in the sorafenib group and in 0.2% and 1.1% of patients in the placebo group. Grade IV hypokalemia (< 6.0 mg/dL) occurred in 1.1% and 0.4% of patients in the sorafenib group and in 0.5% and 0% of patients in the placebo group in study 1 and study 3, respectively. The mechanism of sorafenib-associated hypokalemia is unknown.

In study 1 and study 3, decreased potassium levels were observed in 5.4% and 9.5% of patients in the sorafenib group and in 0.7% and 5.9% of patients in the placebo group. In most cases, hypokalemia was mild (Grade I according to CTCAE). Grade III hypokalemia was reported in 1.1% and 0.4% of patients in the sorafenib group and in 0.2% and 0.7% of patients in the placebo group in these studies. No reports of Grade IV hypokalemia were recorded.

Laboratory test abnormalities in patients with DTC (study 5)

Hypokalemia was observed in 35.7% of patients in the sorafenib group compared to 11.0% of patients receiving placebo. In most cases, hypokalemia was mild. Grade III hypokalemia occurred in 6.8% of patients in the sorafenib group and in 1.9% of patients receiving placebo. Grade IV hypokalemia occurred in 3.4% of patients in the sorafenib group and in 1.0% of patients in the placebo group. Other clinically significant laboratory abnormalities observed in study 5 are presented in Table 3.

Table 3

Laboratory test abnormalities in patients with DTC (study 5)

Laboratory test results	Sorafenib (N = 207)			Placebo (N = 209)
	All grades %	Grade III* %	Grade IV* %	All grades %	Grade III* %	Grade IV* %
Blood and lymphatic system disorders
Anaemia	30.9	0.5	0	23.4	0.5	0
Thrombocytopenia	18.4	0	0	9.6	0	0
Neutropenia	19.8	0.5	0.5	12	0	0
Lymphopenia	42	9.7	0.5	25.8	5.3	0
Metabolism and nutrition disorders
Hypokalemia	17.9	1.9	0	2.4	0	0
Hypophosphatemia**	19.3	12.6	0	2.4	1.4	0
Hepatobiliary disorders
Increased bilirubin levels	8.7	0	0	4.8	0	0
Elevated ALT levels	58.9	3.4	1.0	24.4	0	0
Elevated AST levels	53.6	1.0	1.0	14.8	0	0
Investigations
Elevated amylase levels	12.6	2.4	1.4	6.2	0	1.0
Elevated lipase levels	11.1	2.4	0	2.9	0.5	0

*Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.

** The mechanism of sorafenib-associated hypophosphatemia is unknown.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging.

120 tablets in a bottle, 1 bottle in a cardboard box; or 10 tablets in a blister, 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Natco Pharma Limited.

Manufacturer's address and location of its business activities.

Pharma Division, Kothur, Rangareddy, Telangana 509228, India.