Sorafenib

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Sorafenib: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Use in the elderly
14. Drug interactions
15. Analogs
16. Terms and conditions of storage
17. Terms of dispensing from pharmacies
18. Reviews
19. Price in pharmacies

Latin name: Sorafenib

ATX code: L01XE05

Active ingredient: sorafenib (Sorafenib)

Manufacturer: Pharmasintez-Nord JSC (Russia); Pharmasintez JSC (Russia)

Description and photo update: 2020-01-03

Sorafenib is a targeted anticancer drug, an inhibitor of cell proliferation and angiogenesis.

Release form and composition

The drug is produced in the form of film-coated tablets: round, biconvex, yellow shell and core (in blister packs of 7 pcs., In a cardboard box 4 or 8 packs; in blister packs of 10 pcs., In a cardboard box 3 or 6 packs; in polymer cans of 28, 30, 56, 60, 112, 120 or 240 pcs., in a cardboard box 1 can and instructions for the use of Sorafenib).

1 tablet contains:

active substance: sorafenib hemi-tosylate monohydrate - 245 mg, which is equivalent to 200 mg of sorafenib;
auxiliary components: croscarmellose sodium, microcrystalline cellulose, sodium lauryl sulfate, hypromellose E15, magnesium stearate;
film shell: macrogol 4000, hypromellose E15, titanium dioxide, dye iron oxide yellow.

Pharmacological properties

Pharmacodynamics

Sorafenib is a targeted antitumor drug, its clinical efficacy in suppressing tumor growth has been confirmed in the treatment of differentiated thyroid cancer, hepatocellular and renal cell carcinoma.

The active substance of the drug, sorafenib, being a multikinase inhibitor, in vitro helps to reduce the proliferation of tumor cells.

It was found that sorafenib inhibits both intracellular kinases (c-CRAF, BRAF, mutant BRAF kinase) and kinases located on the cell surface. The list of cell surface kinases includes VEGFR-1, VEGFR-2, VEGFR-3, KIT, FLT-3, RET and PDGFR-β. It is assumed that some of the listed kinases are involved in the signaling systems of the tumor cell, in the processes of angiogenesis and apoptosis.

Pharmacokinetics

After oral administration of sorafenib, its maximum concentration (C _max) in plasma is reached after approximately 3 hours. Simultaneous intake of food with a moderate fat content practically does not affect the bioavailability of sorafenib. But if the food contains a high concentration of lipids, then the bioavailability of the drug is reduced by about 29% in comparison with taking on an empty stomach. When the dose of the drug exceeds 400 mg 2 times a day, the average C _max and AUC (area under the concentration-time curve) increase disproportionately. The average relative bioavailability is 38–49%.

Plasma protein binding - 99.5%.

It takes 7 days to reach the equilibrium plasma concentration of sorafenib, the ratio of the maximum and minimum concentration is less than 2.

When repeated doses of sorafenib are taken for 7 days, there is an increase in its accumulation by 2.5-7 times compared to taking a single dose.

Sorafenib is metabolized mainly in the liver by oxidation with the participation of the CYP3A4 isoenzyme and glucuronidation, mediated by the UGT1A9 enzyme. Reabsorption of unconjugated drug is facilitated by bacterial glucuronidase, due to its activity, sorafenib conjugates can be cleaved in the gastrointestinal tract.

With the simultaneous use of neomycin, the average bioavailability of sorafenib decreases to 54%, after reaching an equilibrium state, sorafenib accounts for approximately 70-85%.

Of the identified 8 metabolites of sorafenib, 5 of which are found in plasma. The main plasma metabolite of sorafenib is pyridine N-oxide. In vitro, it is approximately 9-16% and has similar activity to sorafenib.

The half-life is approximately 25-48 hours.

After ingestion of a solution of sorafenib at a dose of 100 mg for 14 days, 96% of the dose taken is excreted from the body, of which 77% is excreted through the intestine, 19% is excreted through the kidneys in the form of glucuronides. In the feces, up to 51% of the taken dose of sorafenib is determined unchanged.

The patient's gender and age do not affect the pharmacokinetics of the drug.

The efficacy and safety of the anticancer drug Sorafenib in children has not been established.

While taking the drug at a dose of 400 mg 2 times a day, the pharmacokinetics of sorafenib in the equilibrium state was studied in patients with hepatocellular carcinoma, renal cell carcinoma and thyroid cancer. High variability of exposure was observed in all types of tumors.

With mild [creatinine clearance (CC) 50-80 ml / min], moderate (CC 30-50 ml / min) or severe (CC less than 30 ml / min) degrees of renal failure, if there is no need for hemodialysis, the pharmacokinetics of sorafenib is not changes, so there is no need to reduce the dose of the drug.

With mild to moderate hepatic impairment (class A and B according to the Child-Pugh classification) in patients with hepatocellular carcinoma or without it, the pharmacokinetic parameters of sorafenib are similar to those in patients with normal hepatic function.

In severe hepatic impairment (class C according to the Child-Pugh classification), there is no information on the pharmacokinetics of sorafenib.

Indications for use

hepatocellular carcinoma;
metastatic renal cell carcinoma;
locally advanced or metastatic differentiated thyroid cancer resistant to radioactive iodine.

Contraindications

Absolute:

period of pregnancy;
breast-feeding;
childhood;
hypersensitivity to the components of the drug.

Sorafenib should be prescribed with caution for the treatment of patients with skin abnormalities, increased bleeding or bleeding in history, arterial hypertension, unstable angina pectoris, myocardial infarction in history, ongoing prolongation of the QTc interval, congenital long QT interval syndrome, electokalemia imbalance (including hypocalcemia); with simultaneous treatment with high doses of anthracyclines, antiarrhythmic or other drugs that prolong the QT interval; in combination with docetaxel, irinotecan and other drugs, the metabolism of which is mainly associated with the participation of UGT1A1.

Sorafenib, instructions for use: method and dosage

Treatment with the drug should be carried out under the supervision of a physician with experience in the use of anticancer drugs.

Sorafenib tablets are taken orally, swallowed whole and washed down with 200 ml of water. The drug can be taken between meals and during meals with low or moderate fat content.

Recommended dosage: 400 mg (2 pcs.) 2 times a day. The doctor determines the duration of the course of treatment individually, the drug is stopped in the absence of clinical efficacy or the appearance of unacceptable toxic effects of sorafenib.

When adverse drug reactions occur, it is necessary to consider reducing the dose or temporarily discontinuing therapy.

With the development of skin toxicity in patients with hepatocellular carcinoma and metastatic renal cell carcinoma, it is recommended to titrate the dose downward, taking into account the degree and episode of skin toxicity:

I degree of toxicity (painless swelling, numbness, paresthesia, dysesthesia, the appearance of erythema or discomfort in the palms or feet that does not interfere with the patient's normal activity): for any episode, the use of the drug is continued simultaneously with local symptomatic therapy;
II degree of toxicity (swelling and erythema of the palms or feet, accompanied by a feeling of discomfort and / or pain, limiting the patient's normal activity): first episode - previous treatment should be accompanied by local symptomatic therapy. If there is no improvement in skin symptoms within 7 days or the appearance of a second or third episode, it is necessary to discontinue therapy until the relief of skin toxicity or a decrease in its severity to degree I toxicity. It is recommended to resume treatment by taking the drug at a dose of 400 mg 1 time per day or 400 mg 1 time per 2 days. The fourth episode - the use of sorafenib is stopped immediately;
III degree of toxicity (significant discomfort, blisters, ulceration, wet desquamation or severe pain in the palms / feet that prevent the patient from caring for himself or performing professional duties): first-second episode - therapy is suspended until skin toxicity is relieved or its level will not correspond to the I degree of toxicity. It is recommended to resume treatment by taking the drug at a dose of 400 mg 1 time per day or 400 mg 1 time per 2 days. Third episode - drug therapy should be discontinued immediately.

If it is necessary to reduce the dose for patients with differentiated thyroid cancer, the following recommendations are required:

1st dose reduction: 600 mg (400 mg and 200 mg every 12 hours);
2nd dose reduction: 400 mg (200 mg 2 times a day);
3rd dose reduction: 200 mg (200 mg once daily).

After a decrease in the severity of adverse reactions, with the exception of hematological, the dose of the drug may be increased.

With the development of skin toxicity in patients with differentiated thyroid cancer, it is recommended to lower the dose, taking into account the degree and episode of skin toxicity:

I degree of toxicity (numbness, painless swelling, paresthesia, dysesthesia, the appearance of erythema in the palms or feet, or a feeling of discomfort that does not interfere with the normal activity of the patient): for any episode, the drug continues to be used against the background of simultaneous local symptomatic therapy;
II degree of toxicity (edema and erythema of the palms or feet, accompanied by a feeling of discomfort and / or pain, limiting the patient's normal activity): the first episode - treatment is continued in a daily dose of 600 mg (400 mg and 200 mg with an interval of 12 hours), accompanying local symptomatic therapy. If there is no improvement in skin symptoms within 7 days or the appearance of a second or third episode, it is necessary to temporarily stop taking the pills. Treatment should be resumed after the relief of skin toxicity or a decrease in the level of its severity to grade I toxicity. It is recommended to resume treatment by taking the drug at a dose of 600 mg (400 mg and 200 mg with an interval of 12 hours). The fourth episode - the use of sorafenib is stopped immediately;
III degree of toxicity (significant discomfort, blisters, ulceration, wet desquamation or severe pain in the palms or feet that does not allow the patient to care for himself or perform professional duties): the first-second episode - the therapy is suspended until the skin toxicity is stopped or its level will not correspond to the I degree of toxicity. It is recommended to resume treatment after the first episode by taking the drug in a daily dose of 600 mg (400 mg and 200 mg with an interval of 12 hours), after the second episode - 400 mg (200 mg 2 times a day). The third episode - taking the pills should be stopped immediately.

If, against the background of taking the drug in a reduced dose for 28 days, there is no excess of the I degree of skin toxicity, then the dose may be increased by one dose level.

In the treatment of patients with impaired liver function (class A and B according to the Child-Pugh classification), renal failure, mild, moderate or severe (without hemodialysis) and over the age of 65 years, dose adjustment is not required.

The use of the drug in patients at risk of developing impaired renal function must be accompanied by monitoring of water and electrolyte balance.

Side effects

on the part of the hematopoietic system: very often - lymphopenia; often - anemia, thrombocytopenia, leukopenia, neutropenia;
from the cardiovascular system: very often - hemorrhage in the brain, bleeding from the gastrointestinal tract, bleeding from the respiratory tract and other types of bleeding (including with life-threatening consequences or death), hot flashes, increased blood pressure (blood pressure); often - chronic heart failure, myocardial ischemia and / or myocardial infarction (including with life-threatening consequences or death); infrequently - a hypertensive crisis (including with life-threatening consequences or death); rarely - lengthening of the QT interval;
from the respiratory system: often - dysphonia, rhinorrhea; infrequently - acute respiratory distress syndrome, pneumonia, pneumonitis, radiation pneumonitis, interstitial pneumonia, pulmonitis and other phenomena similar to interstitial lung diseases (including those with life-threatening consequences or death);
on the part of the skin and skin appendages: very often - skin rash, pruritus, dry skin, erythema, palmar-plantar erythrodysesthesia, alopecia; often - peeling of the skin, exfoliative dermatitis, hyperkeratosis, acne, folliculitis, keratoacanthoma or squamous cell skin cancer; infrequently - erythema multiforme, eczema; frequency not established - recurrent radiation dermatitis, leukocytoclastic vasculitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (including with life-threatening consequences or death);
from the digestive system: very often - nausea, vomiting, diarrhea, anorexia, constipation; often - stomatitis, dryness of the oral mucosa, glossodynia, dysphagia, dyspepsia, gastroesophageal reflux; infrequently - gastritis, pancreatitis, perforation of the gastrointestinal tract (including with life-threatening consequences or death), cholecystitis, cholangitis, jaundice, increased bilirubin concentration; rarely - medicinal hepatitis (including with consequences that are life-threatening or fatal);
from the nervous system: often - dysgeusia, peripheral sensory neuropathy; infrequently - syndrome of posterior reversible encephalopathy, including life-threatening cases up to death;
mental disorders: often - depression;
from the organ of hearing: often - ringing in the ears;
from the musculoskeletal system: very often - arthralgia; often - muscle spasms, myalgia; frequency not established - jaw necrosis, rhabdomyolysis;
from the genitourinary apparatus: often - proteinuria, renal failure; rarely - nephrotic syndrome;
from the reproductive system: often - erectile dysfunction; infrequently - gynecomastia;
from the endocrine system: often - hypothyroidism; infrequently - hyperthyroidism;
from the immune system: infrequently - skin reactions, urticaria and other hypersensitivity reactions, anaphylactic reactions; frequency not established - angioedema;
laboratory parameters: very often - increased activity of lipase and amylase, hypophosphatemia; often - a transient increase in the activity of ALT (alanine aminotransferase) and AST (aspartate aminotransferase), hyponatremia, hypokalemia, hypocalcemia; infrequently - transient increase in alkaline phosphatase activity, dehydration, deviation from the normal value of prothrombin and INR (international normalized ratio);
others: very often - increased body temperature, significant fatigue, headache, pain syndrome of various localization (including the oral cavity, abdomen, bones, tumor area), infections, weight loss; often - flu-like syndrome, inflammation of the mucous membranes, asthenia.

Overdose

Sorafenib overdose symptoms: severe diarrhea, skin allergic reactions, increased other side effects.

Since the drug does not have a specific antidote, symptomatic therapy is indicated.

special instructions

During the entire period of Sorafenib use, patients need to monitor peripheral blood parameters (including platelets and leukocyte counts) from time to time.

Most often, while taking the drug, unwanted skin toxic responses are observed in the form of a rash and reactions in the extremities (palmar-plantar erythrodysesthesia). In most cases, they occur during the first six weeks of therapy and, as a rule, have I – II severity.

The results of clinical studies indicate that patients with differentiated thyroid cancer are more likely than those with renal cell carcinoma or hepatocellular carcinoma to experience such adverse events as fever, diarrhea, alopecia, decreased body weight, hypocalcemia, keratoacanthoma or squamous cell carcinoma of the skin, palmar-plantar erythrodysesthesia.

It should be borne in mind that with differentiated thyroid cancer, especially in patients with a history of hypoparathyroidism, severe manifestations of hypocalcemia are more often observed. In this category of patients, it is recommended to monitor the concentration of calcium in the blood.

There is a risk of increased incidence of hypertension, which is usually mild to moderate and occurs early in treatment. Therefore, patients should be advised to regularly monitor blood pressure, for which to use standard antihypertensive drugs. If, against the background of adequate antihypertensive therapy, severe or persistent arterial hypertension appears or a hypertensive crisis develops, it is necessary to consider discontinuing the drug.

In the event of any bleeding that requires medical intervention, it is recommended to stop taking the drug. Due to the potential risk of bleeding in differentiated thyroid cancer, patients need topical treatment of tumor infiltrates of the esophagus, trachea, and bronchi before prescribing sorafenib.

It is recommended to temporarily stop taking the pills before conducting a planned surgical operation; it can be resumed after a clinical assessment of the adequacy of the wound healing process.

If ischemia and / or myocardial infarction occurs while taking Sorafenib, a decision should be made to temporarily or completely discontinue the drug. Due to the increased risk of ventricular arrhythmias due to prolongation of the QT interval, it is recommended to periodically conduct electrocardiography and control the concentration of electrolytes (potassium, magnesium, calcium) in patients with a current lengthening of the QTc interval or predisposed to its development.

If the gastrointestinal tract is perforated, the pills are immediately stopped.

Influence on the ability to drive vehicles and complex mechanisms

During the period of using Sorafenib when driving vehicles or complex mechanisms, patients are advised to be careful, given the profile of the side effects of the drug.

Application during pregnancy and lactation

The use of Sorafenib is contraindicated during pregnancy and breastfeeding.

Women taking the drug are required to avoid conception during treatment and for 2 weeks after stopping sorafenib.

Pediatric use

The safety and effectiveness of the use of an anticancer drug in children has not been established, therefore, its appointment to this category of patients is contraindicated.

With impaired renal function

When treating patients with mild, moderate or severe renal failure (without the need for hemodialysis), dose adjustment is not required.

The use of the drug in patients at risk of developing impaired renal function must be accompanied by monitoring of water and electrolyte balance.

For violations of liver function

When treating patients with impaired liver function (class A and B according to the Child-Pugh classification), dose adjustment is not required.

In patients with severe hepatic insufficiency (class C according to the Child-Pugh classification), the effect of the drug may be increased.

Use in the elderly

No dose adjustment is required for patients over the age of 65.

Drug interactions

With simultaneous use with Sorafenib:

rifampicin, phenytoin, drugs with St. John's wort extract, carbamazepine, phenobarbital, dexamethasone: a combination with each of these or other drugs that induce CYP3A4 activity may increase the metabolism of sorafenib and reduce its concentration in the body. Against the background of prolonged therapy with rifampicin, the AUC of sorafenib decreases on average by 37%;
drugs that inhibit the activity of cytochrome CYP3A4: pharmacokinetic interaction is unlikely when sorafenib is combined with inhibitors of cytochrome CYP3A4;
warfarin: although the combination with warfarin does not lead to a change in the average values of prothrombin time and INR, nevertheless, it is necessary to regularly determine the INR, prothrombin time and identify clinical signs of bleeding;
midazolam, dextromethorphan, omeprazole: the level of exposure of the listed drugs does not change, based on this, it can be assumed that sorafenib does not affect substrates of specific isoenzymes from the cytochrome P450 group, including CYP3A4, CYP2D6 and CYP2C19;
paclitaxel: due to an increase rather than a decrease in exposure to the active metabolite of paclitaxel (6-OH-paclitaxel), formed under the influence of the isoenzyme CYP2C8, it is highly likely that sorafenib is not an inhibitor of CYP2C8 in vivo;
cyclophosphamide: there is a slight decrease in the exposure of cyclophosphamide, but the systemic exposure of its active metabolite (4-OH-cyclophosphamide), which is formed mainly by the isoenzyme CYP2B6, remains unchanged, this may indicate that in vivo sorafenib does not inhibit CYP2B6;
other anticancer drugs (for example, gemcitabine, cisplatin, carboplatin, oxaliplatin, cyclophosphamide): the combination with these drugs does not have a clinically significant effect on the pharmacokinetics of sorafenib, so there is no need for dose adjustment;
capecitabine at a dose of 750-1050 mg per 1 m2 ^of body surface 2 times a day for the first 2 weeks of a 3-week course: combined use with sorafenib at a dose of 200 or 400 mg 2 times a day (without interruption), does not cause significant changes in the exposure of the latter, but the AUC of capecitabine and its metabolite (fluorouracil) increases by 15–50% and 0–52%, respectively, the clinical significance of this small or moderate increase remains unknown;
docetaxel: Caution should be exercised with the combination of sorafenib (at a dose of 200 mg or 400 mg 2 times a day from 2 to 19 days for a 3-week cycle) with an interval of 3 days before and after prescribing a single dose of docetaxel at a dose of 75 or 100 mg per 1 m ² of body surface with an interval of 3 weeks, due to the fact that against the background of this combination there is an increase in AUC (36-80%) and C _max (16-32%) of docetaxel;
neomycin: combination therapy with an antibacterial agent for the eradication of the gastrointestinal flora helps to reduce the exposure and average bioavailability of sorafenib.

Analogs

Sorafenib's analogs are Sorafenib-native, Soranib, Nexavar.

Terms and conditions of storage

Keep out of the reach of children.

Store at temperatures up to 25 ° C in a dark place.

The shelf life is 3 years.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Sorafenib

The drug passed state registration less than two years ago, therefore, reviews of Sorafenib from patients are extremely rare, and they are not very informative.

In the studies of specialists in the study of disseminated renal cell carcinoma (RCC), it is noted that until recently, only cytokines were used for its therapy, the effectiveness of which was only 15%. At the same time, serious side effects developed. In recent years, the situation has changed, fundamentally new targeted substances have appeared, purposefully blocking certain links of tumor pathogenesis. The first of these to be approved by the Food and Drug Administration (FDA) for the treatment of metastatic kidney cancer was sorafenib, a Bayer drug under the brand name Nexavar.

In a multistage preparation process for the registration of sorafenib, including in a multicenter, randomized, placebo-controlled, double-blind study, with the participation of 903 patients with advanced RCC, the efficacy, safety and tolerability of this drug were finally confirmed.

Price for Sorafenib in pharmacies

The price of Sorafenib, film-coated tablets, 200 mg, can be: 28 pcs. in the package - from 25 928 rubles., 56 pcs. in the package - from 51 856 rubles., 112 pcs. in the package - from 103 712 rubles.

Anna Kozlova Medical journalist About the author

Education: Rostov State Medical University, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!