Nexavar, 200 mg 112 pcs.

Pharmacodynamics

The antitumor drug. Sorafenib is a multikinase inhibitor. Reduces proliferation of tumor cells in vitro.

Sorafenib has been shown to inhibit numerous intracellular kinases (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-β). Some of these kinases are believed to be involved in tumor cell signaling systems, angiogenesis and apoptosis. Sorafenib suppresses tumor growth in hepatic cell cancer and renal cell cancer and differentiated human thyroid cancer.

Pharmacokinetics

Intake

After oral administration, the average relative bioavailability is 38-49%. C_max of sorafenib in plasma is reached approximately 3 h after oral administration. When taken with a moderate-fat diet, the bioavailability of sorafenib is approximately equal to that of fasting food. When taken with a high-fat diet, the bioavailability is reduced by approximately 29% compared to fasting food.

When the drug is administered orally in doses greater than 400 mg 2 times/day, the mean C_max and AUC do not increase proportionally.

Distribution

The administration of repeated doses of sorafenib over 7 days resulted in a 2.5-7-fold increase in accumulation compared with a single dose.

The C_ss of sorafenib in plasma is reached within 7 days, the ratio of C_max to C_min is less than 2.

The pharmacokinetics of sorafenib in equilibrium at a dose of 400 mg 2 times/day when taken orally were studied in patients with thyroid cancer, hepatic cell cancer and renal cell cancer. The highest exposure was noted in patients with thyroid cancer, although the variability of exposure was high for all tumor types. The clinical significance of higher AUC in thyroid cancer patients has not been established.

Binding to plasma proteins is 99.5%.

Metabolism and excretion

The metabolism of sorafenib is primarily in the liver by oxidation mediated by the CYP3A4 isoenzyme and also by glucuronidation mediated by UGT1A9.

Sorafenib conjugates can be cleaved in the GI tract through the activity of bacterial glucuronidase, which allows the unconjugated active substance to be reabsorbed. Concomitant use of neomycin affects this process, reducing the average bioavailability of sorafenib to 54%.

Sorafenib is approximately 70-85% at equilibrium. Eight metabolites of sorafenib have been identified, five of which have been detected in plasma. The main plasma circulating metabolite of sorafenib, pyridine N-oxide, has in vitro activity similar to that of sorafenib and is approximately 9-16%.

After oral administration of sorafenib at a dose of 100 mg for 14 days, 96% of the administered dose is excreted, 77% is excreted through the intestine, 19% – in the urine in the form of glucuronides. Unchanged sorafenib, in the amount of 51% of the administered dose, is determined in the feces.

The T_1/2 of sorafenib is approximately 25-48 h.

Pharmacokinetics in Special Clinical Cases

A review of demographic data indicates that no adjustment of the drug dose according to age or sex is required.

There are no data on the pharmacokinetics of the drug in children.

The pharmacokinetics of sorafenib were studied after administration of the drug in a single dose of 400 mg in patients with normal renal function and in patients with mild (CK 50-80 ml/min), moderate (CK 30 to < 50 ml/min) and severe (CK < 30 ml/min) renal failure not requiring dialysis. No effect of impaired renal function on the pharmacokinetics of sorafenib has been found. For patients with mild, moderate and severe renal impairment not requiring hemodialysis, there is no need to reduce the dose.

Sorafenib is excreted primarily by the liver. In patients with hepatic cell cancer with mild (Child-Pugh grade A) or moderate (Child-Pugh grade B) renal impairment, the pharmacokinetic parameters of sorafenib were the same as in patients with normal hepatic function. The pharmacokinetics of sorafenib in patients without hepatic cell cancer with mild (Child-Pugh grade A) or moderate (Child-Pugh grade B) hepatic impairment were similar to sorafenib pharmacokinetics in healthy subjects. In patients with severe hepatic impairment (Child-Pugh class C), the pharmacokinetics of sorafenib have not been studied.

Indications

• Metastatic renal cell cancer;
• hepatic cell cancer;
• local or metastatic differentiated thyroid cancer resistant to radioactive iodine.

Active ingredient

Sorafenib

Composition

1 tablet contains:

Active ingredients:

sorafenib tosylate 274 mg, which corresponds to the content of sorafenib 200 mg.

Associates:

Microcrystalline cellulose – 16 mg,

croscarmellose sodium – 36.4 mg,

Hypromellose 5 cP – 10.2 mg,

magnesium stearate – 2.55 mg,

sodium lauryl sulfate – 1.7 mg.

Shell composition:

Hypromellose 15 cP – 6 mg, macrogol 3350 – 2 mg, titanium dioxide – 1.73 mg, iron oxide red – 0.27 mg.

There are 28 tablets in the blister. In a carton pack of 4 blisters.

How to take, the dosage

The recommended daily dose of Nexavar is 800 mg (4 tablets of 200 mg). The daily dose is administered in 2 doses (2 tablets 2 times/day), either between meals or together with a low- or moderate-fat meal. Tablets are swallowed with a glass of water.

The treatment is continued as long as the clinical effectiveness of the drug is maintained or until unacceptable toxic effects occur.

The development of possible adverse drug reactions may require temporary discontinuation and/or reduction of the dose of Nexavar.

Dose reduction in patients with metastatic renal cell cancer and hepatic cell cancer

If necessary, the dose of Nexavar may be reduced to 400 mg once daily or to 400 mg every other day.

Table 1. Recommendations to reduce the dose of Nexavar in the development of cutaneous toxicity

Dose reduction in patients with differentiated thyroid cancer.

If reduction of the dose of Nexavar to 600 mg/day is necessary, the drug is given twice daily (2 tablets and 1 tablet 12 hours apart).

If necessary, the dose of Nexavar can be further reduced to 400 mg/day (1 tablet 2 times/day) or to 200 mg once daily. After reduction of the severity of adverse reactions, except hematological reactions, the dose of drug Nexavar can be increased.

Table 2. Recommended doses of Nexavar for patients with differentiated thyroid cancer who require dose reduction

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Table 3. Recommendations to reduce the dose of Nexavar in the development of cutaneous toxicity

* – If, within 28 days of therapy with Nexavar at the reduced dose, cutaneous toxicity does not exceed Grade 1, a one-dose increase in the dose of Nexavar over the reduced dose is possible.

Separate patient groups

The safety and effectiveness of Nexavar in children has not been established.

There is no need for dose adjustment depending on age (older than 65 years), sex or body weight.

In patients with liver dysfunction of classes A and B on the Child-Pugh scale, no dose adjustment is required. Treatment with Nexavar in patients with Child-Pugh class C liver dysfunction has not been studied.

Patients with mild, moderate or severe renal impairment (without hemodialysis) do not require dose reduction of Nexavar. The use of Nexavar in patients on hemodialysis has not been studied.

In patients at risk of renal dysfunction, the water-electrolyte balance should be monitored.

Interaction

CYP3A4 inducers: Drugs that induce CYP3A4 activity (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, dexamethasone and drugs containing Hypericum herb extract) may increase metabolism of sorafenib and thus reduce its concentration in the body. Long-term concomitant administration of sorafenib together with rifampicin resulted in reduction of AUC of sorafenib by 37% on average.

CYP3A4 inhibitors: Clinical pharmacokinetic interaction of sorafenib with CYP3A4 cytochrome inhibitors is unlikely.

CYP3A4 substrates: concomitant administration of sorafenib and warfarin has not resulted in changes in mean values of prothrombin time and MHO compared to placebo. However, regular MHO determination is recommended in all patients receiving combined therapy with warfarin and sorafenib.

Substrates of specific isoenzymes from cytochrome P450 group: simultaneous administration of midazolam, dextromethorphan and omeprazole, which are substrates of CYP3A4, CYP2D6 and CYP2C19 isoenzymes respectively, and 4 weeks of sorafenib did not lead to changes in exposure levels of listed drugs. These observations indicate that sorafenib neither inhibits nor induces cytochrome P450 isoenzymes. The concomitant use of sorafenib and paclitaxel resulted in an increase rather than a decrease in the exposure of 6-OH-paclitaxel, the active metabolite of paclitaxel, which is formed by CYP2C8. These data suggest that sorafenib in vivo may not be an inhibitor of CYP2C8.

The concomitant use of sorafenib and cyclophosphamide resulted in a slight decrease in exposure to cyclophosphamide, but there was no decrease in systemic exposure to 4-ON-cyclophosphamide, which is the active metabolite of cyclophosphamide that is formed primarily by CYP2B6. These data suggest that sorafenib in vivo may not be an inhibitor of CYP2B6.

Combination with other anticancer drugs: Sorafenib has no clinically significant effect on the pharmacokinetics of gemcitabine, cisplatin, oxaliplatin and cyclophosphamide.

Paclitaxel/carboplatin: Concomitant use of paclitaxel (225 mg/m²) and carboplatin (AUC=6) together with sorafenib (≤400 mg 2 times/day), with 3-day intervals of sorafenib administration before and after paclitaxel and carboplatin administration, had no significant effect on paclitaxel pharmacokinetics.

Concomitant use of paclitaxel (at 225 mg/m² 1 every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg 2 times/day without interruption of sorafenib) resulted in a 35% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in paclitaxel 6-ON derivative exposure. The pharmacokinetics of carboplatin remained unchanged.

These data indicate that there is no need to adjust the dosage when paclitaxel and carboplatin are used together with sorafenib at 3-day intervals when sorafenib is taken. The clinical significance of a small increase in exposure to sorafenib and paclitaxel when used concomitantly with sorafenib without interruption of its administration remains unknown.

Capecitabine: Concomitant use of capecitabine (at 750-1050 mg/m² days 1 through 14 every 21 days) and sorafenib (at 200 or 400 mg 2 times/day without interruption of administration) did not result in significant changes in sorafenib exposure. However, exposure to capecitabine increased by 15-50% and exposure to 5-fluorouracil (metabolite of capecitabine) increased by 0-52%. The clinical significance of this small to moderate increase in capecitabine and 5-fluorouracil exposure with concomitant administration of sorafenib remains unknown.

Doxorubicin/irinotecan: Simultaneous administration of sorafenib and doxorubicin results in a 21% increase in the AUC of doxorubicin. When concomitant administration of sorafenib and irinotecan, whose active metabolite SN-38 is further metabolized with participation of UGT1A1, there was 67-120% increase in AUCSN-38 and 26-42% increase in AUC of irinotecan. The clinical significance of these observations remains unknown.

Docetaxel: Concurrent use of docetaxel (75 or 100 mg/m² once every 21 days) and Nexavar (200 mg or 400 mg 2 times/day from day 2 to day 19 during a 21-day cycle) at 3-day intervals before and after administration of docetaxel is accompanied by increases in the AUC and C_max of docetaxel by 36-80% and 16-32%, respectively. Caution should be exercised when prescribing sorafenib and docetaxel concomitantly.

Neomycin: Concomitant use of neomycin, a non-systemic antibacterial drug used to eradicate gastrointestinal flora, affects the enterohepatic circulation of sorafenib, resulting in reduced sorafenib exposure. In healthy volunteers who received neomycin for 5 days, the mean bioavailability of sorafenib was reduced to 54%. The clinical significance of these data is not known. The effect of other antibiotics has not been studied, but will likely depend on the ability to reduce glucuronidase activity.

Special Instructions

The treatment with Nexavar should be done under the supervision of a specialist experienced in the use of antitumor drugs.

Peripheral blood counts (including leukocyte counts and platelets) should be monitored periodically during therapy with Nexavar.

The most common adverse reactions when taking Nexavar were skin reactions in the extremities (palm-topalar erythrodisesthesia) and rash. In most cases, they were 1st and 2nd degree of severity and occurred mainly during the first 6 weeks of treatment with Nexavar. For treatment of cutaneous toxic reactions, topical drugs with symptomatic effect may be used. If necessary, temporarily discontinue treatment and/or change the doses of Nexavar or, in severe or recurrent cases of skin reactions, discontinue treatment with Nexavar.

In patients treated with Nexavar, an increased incidence of arterial hypertension has been reported. Arterial hypertension was usually mild to moderate, was observed at the beginning of treatment, and was manageable with standard antihypertensive medications.

The BP should be monitored regularly during treatment with Nexavar and if necessary, its increase should be corrected with antihypertensive therapy. In cases of severe or persistent arterial hypertension or in case of hypertensive crises despite adequate antihypertensive therapy, discontinuation of treatment with Nexavar should be considered.

Nexavar may increase the risk of bleeding. Severe bleeding is rare. If any bleeding requiring medical intervention occurs, it is recommended that consideration be given to discontinuing treatment with Nexavar.

Given the potential risk of bleeding, patients with differentiated thyroid cancer should have local treatment of tumor infiltrates of the trachea, bronchi, and esophagus prior to administration of Nexavar.

When warfarin and Nexavar are coadministered, rare episodes of bleeding or increased MHO have been reported in some patients. When warfarin and Nexavar are coadministered, prothrombin time, MHO, and clinical signs of bleeding should be determined regularly.

In case of surgical interventions, temporary discontinuation of therapy with Nexavar is recommended as a precaution. There are very few clinical observations regarding resumption of Nexavar after surgical procedures. Therefore, the decision to resume Nexavar after surgery should be based on a clinical evaluation of the adequacy of wound healing.

In the event of ischemia and/or myocardial infarction, therapy with Nexavar should be temporarily or permanently discontinued.

The use of Nexavar has been found to prolong the QT/QTc interval, which may increase the risk of ventricular arrhythmias. Nexavar should be used with caution in the following patients with current prolongation of the QTc interval or with the risk of developing this condition: with congenital prolonged QT interval syndrome; receiving high total dose anthracycline therapy; taking certain antiarrhythmic agents or other drugs that lead to QT interval prolongation; and in patients with electrolyte disturbances, including hypokalemia, hypocalcemia or hypomagnesemia. Periodic ECG monitoring and measurement of electrolyte concentrations (magnesium, potassium, calcium) should be performed when using Nexavar in these patients.

Gastrointestinal perforation is infrequent and has been described in less than 1% of patients treated with Nexavar. In some cases, these events have not been associated with tumors in the abdomen. Treatment with Nexavar should be discontinued in cases of GI perforation.

There are no data on treatment with Nexavar in patients with severe hepatic impairment (Child-Pugh class C). Because sorafenib is excreted primarily by the liver, it may increase the potency of the drug in patients with severe hepatic impairment.

When using Nexavar in patients with differentiated thyroid cancer, it is recommended to monitor the blood calcium concentration. In clinical trials in patients with differentiated thyroid cancer, especially those with a history of hypoparathyroidism, more frequent and more severe manifestations of hypocalcemia were noted than in patients with renal cell and hepatic cell cancer.

A portion of patients with differentiated thyroid cancer treated with Nexavar in clinical trials had THT concentrations greater than 0.5 mU/l. When using Nexavar in these patients, the TTG concentration should be monitored.

With caution, Nexavar should be used with drugs that are metabolized/released primarily with UGT1A1 (e.g., irinotecan).

In two randomized placebo-controlled trials comparing the safety and efficacy of two-component platinum-based chemotherapy (carboplatin/paclitaxel and gemcitabine/cisplatin separately) in combination with or without sorafenib in patients with advanced non-small cell lung cancer (NSCLC) as first-line therapy, no improvement in overall survival was reported. The safety data were generally consistent with previously described results. However, in both studies in the group of patients with squamous cell lung cancer who received two-component chemotherapy based on platinum drugs in combination with sorafenib, a higher mortality was noted compared to the group of patients who received only two-component chemotherapy based on platinum drugs (paclitaxel/carboplatin: risk ratio 1.81, 95%, confidence interval 1.19-2.74; gemcitabine/cisplatin: risk ratio 1.22, 95%, confidence interval 0.82-1.80). No definitive cause for this phenomenon was identified.

Contraindications

• Pregnancy;
• lactation period (breast-feeding);
• childhood (efficacy and safety of use are not established);
• high sensitivity to sorafenib or any other component of the drug.

With caution: the drug should be prescribed in cases of skin disease, arterial hypertension, history of increased bleeding or bleeding, unstable angina pectoris, myocardial infarction, concomitantly with irinotecan and docetaxel.

Side effects

The following adverse events noted with Nexavar in clinical studies or based on post-marketing use are graded according to the following frequency of occurrence:

• very frequently (≥1/10);
• frequently (≥1/100 to < 1/10);
• infrequently (≥1/1000 to < 1/100);
• infrequently (≥1/10,000 to < 1/1,000).

Frequency unknown is indicated for adverse effects identified during post-marketing surveillance for which the frequency or causal relationship to the drug cannot be reliably estimated.

In each frequency group, adverse events are presented in decreasing order of importance.

Hematopoietic system: very common – lymphopenia; common – leukopenia, neutropenia, anemia, thrombocytopenia.

The cardiovascular system: very common – bleeding (including gastrointestinal bleeding*, respiratory tract bleeding* and cerebral hemorrhage*), increased BP; common – chronic heart failure*, myocardial ischemia and/or myocardial infarction*, hot flashes; infrequent – hypertensive crisis*; rare – QT interval prolongation*.

Respiratory system: frequently – rhinorrhea, dysphonia; infrequently – rhinorrhea, phenomena similar to interstitial lung disease* (including pneumonitis, radiation pneumonitis, acute respiratory distress syndrome, interstitial pneumonia, pulmonitis, pneumonia).

Skin and skin appendages: very common – dry skin, skin rash, alopecia, palpebral erythrodysesthesia, erythema, skin itching; common – keratoacanthoma/plosocellular skin cancer, exfoliative dermatitis, acne, skin flaking, hyperkeratosis, folliculitis; infrequent – eczema, erythema multiforme; frequency unknown – relapsing radiation dermatitis, Stevens-Johnson syndrome, leukocytoclastic vasculitis, toxic epidermal necrolysis*.

Digestive system disorders: Very common – diarrhea, nausea, vomiting, constipation, anorexia; common – stomatitis, dry oral mucosa, glossodynia, dyspepsia, dysphagia, gastroesophageal reflux; infrequent – gastritis, pancreatitis, GIT perforation*, increased bilirubin concentration (including jaundice), cholecystitis, cholangitis; rare – drug hepatitis*.

Nervous system disorders: frequent – peripheral sensory neuropathy, dysgeusia; infrequent – posterior reversible encephalopathy syndrome*.

Psychiatric disorders: often – depression.

Hearing organ: often – tinnitus.

Muscular system: very common – arthralgia; common – myalgia, muscle cramps; frequency unknown – rhabdomyolysis, necrosis of the jaw.

Relinary system: often – renal failure, proteinuria; rarely – nephrotic syndrome.

Reproductive function: often – erectile dysfunction; infrequent – gynecomastia.

Endocrine system: often – hypothyroidism; infrequent – hyperthyroidism.

The immune system: infrequent – anaphylactic reactions, hypersensitivity reactions (including skin reactions and urticaria); frequency unknown – angioedema.

Laboratory indices: very frequently – hypophosphatemia, increased lipase and amylase activity; frequently – transient increase of transaminases activity (ALT, AST), hypocalcemia, hypokalemia, hyponatremia; infrequent – dehydration, hyponatremia, transient increase of ALP activity, deviation of MHO and prothrombin values from normal.

Others: very frequently – fatigue, pain syndrome of different localization (including oral pain, abdominal pain, pain in the tumor area, headache), weight loss, infections, increased body temperature; frequently – asthenia, flu-like syndrome, inflammation of mucous membranes.

* – Adverse reactions can have life-threatening consequences or death. These events occurred either infrequently or less frequently than infrequently.

In clinical trials, patients with differentiated thyroid cancer were markedly more likely to have palpebral erythrodysesthesia, diarrhea, alopecia, weight loss, body temperature increase, hypocalcemia, and keratoacanthoma/ploid cell skin cancer than were patients with renal cell cancer and hepatic cell cancer.

Overdose

In case of overdose, there may be increased adverse events, especially diarrhea and skin reactions.

Treatment: symptomatic therapy is carried out. An antidote to sorafenib is not known.

Pregnancy use

There have been no studies on the use of sorafenib in pregnant women.

Pregnancy during treatment with sorafenib should be avoided. During and for at least 2 weeks after therapy with sorafenib, reliable contraceptive methods should be used.

Women of reproductive age should be informed about the potential danger of sorafenib to the fetus, which includes teratogenicity, fetal survival problems and embryotoxicity.

It is not known whether sorafenib is excreted with breast milk. Because many medications are excreted with breast milk and the effects of sorafenib on young children have not been studied, women should stop breastfeeding during treatment with sorafenib.

The reproductive toxicity of sorafenib, including the ability of this substance to cause malformations, has been shown in experimental animal studies. In experiments on rats it has been shown that sorafenib and its metabolites penetrate the placental barrier. It is assumed that sorafenib inhibits fetal angiogenesis. In animals, excretion with milk of sorafenib and/or its metabolites has been observed.