Capecitabine-Vista tablets 500 mg, 120 pcs.

Pharmacological properties of the drug Capecitabine

Antitumor agent, antimetabolite. It is a prodrug that turns into a cytotoxic compound - fluorouracil. The formation of fluorouracil occurs in tumor tissue under the influence of the tumor angiogenic factor - thymidine phosphorylase, as a result of which the systemic effect of fluorouracil on healthy tissues of the body is minimal. Consistent enzymatic metabolism into fluorouracil creates high concentrations of the latter in tumor cells (thymidine phosphorylase activity in the primary tumor is 4 times higher than in healthy tissue). Absorption is high (food reduces absorption). Metabolized in the liver by carboxylesterase to the metabolite 5-deoxy-5-fluorocytidine (5-DFCT), which is then transformed into 5-deoxy-5-fluorouridine (5-DFUR) by cytidine deaminase in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite fluorouracil occurs in the tumor under the influence of thymidine phosphorylase. The content of fluorouracil and its active phosphorylated derivative in the tumor significantly exceeds the levels in healthy tissues, which ensures the relative selectivity of the cytotoxic effect. For capecitabine, 5-DFCT, 5-DFUR and fluorouracil, the binding to plasma proteins is 54, 10 and 62 and 10%, respectively, AUC - 7.4 mg/h/ml, 5.21 mg/h/ml, 21.7 mg/h/ml, for fluorouracil - 1.63 mg/h/ml. Maximum concentrations in blood plasma are determined 2 hours after administration. Then the concentrations decrease exponentially, the half-life is 0.7–1.14 hours. α-Fluoro-β-alanine, a breakdown product of fluorouracil, reaches its maximum concentration in the blood plasma after 3 hours and has a half-life of 3–4 hours. Excreted mainly by the kidneys (84% of the dose), including 57% in the form of α-fluoro-β-alanine. In patients with renal failure, when creatinine clearance decreases by 50%, the concentration of α-fluoro-β-alanine increases by 45%.

Capecitabine

The following categories are used to describe the frequency of adverse reactions: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and <1/1000), very rarely (<1/10000, including isolated cases). The following adverse reactions are listed in order of clinical significance.

The most common and/or clinically significant adverse reactions during capecitabine therapy were gastrointestinal disorders (especially diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome, fatigue, drowsiness, anorexia, cardiotoxicity. , increasing renal failure in patients with a history of impaired renal function, thrombosis/embolism.

Monotherapy with capecitabine

Infectious and parasitic diseases: often - herpes virus infection, nasopharyngitis, lower respiratory tract infection; uncommon - sepsis, urinary tract infection, cellulitis, tonsillitis, pharyngitis, candidiasis of the oral mucosa, influenza, gastroenteritis, fungal infections, infections, tooth abscess.

Benign, malignant and unspecified neoplasms: uncommon - lipoma.

Disorders of the blood and lymphatic system: often - neutropenia; uncommon - febrile neutropenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increase in international normalized ratio (INR), prolongation of prothrombin time.

Immune system disorders: uncommon - increased sensitivity.

Metabolic and nutritional disorders: very often - anorexia; often - dehydration, weight loss, loss of appetite; uncommon - diabetes mellitus, hypokalemia, indigestion, hypertriglyceridemia.

Mental disorders: uncommon - panic attacks, depressed mood, decreased libido.

Nervous system disorders: often - headache, dizziness (except vertigo), lethargy, paresthesia, dysgeusia (taste perversion); Uncommon: aphasia, memory impairment, fainting, imbalance, loss of sensitivity, peripheral neuropathy.

Visual disturbances: often - increased lacrimation, conjunctivitis; infrequently - decreased visual acuity, diplopia.

Hearing and labyrinthine disorders: uncommon - vertigo, ear pain.

Cardiac disorders: uncommon - angina, including unstable, arrhythmia, sinus tachycardia, palpitations.

Vascular disorders: often - thrombophlebitis; uncommon - deep vein thrombosis, increased blood pressure, petechiae, decreased blood pressure, hot flashes, coldness of the distal extremities.

Disorders of the respiratory system, chest and mediastinal organs: often - nosebleeds, rhinorrhea; uncommon - pneumothorax, hemoptysis, bronchial asthma, shortness of breath on exertion.

Gastrointestinal disorders: very often - diarrhea, vomiting, nausea, stomatitis (including ulcerative), abdominal pain; often - constipation, epigastric pain, dyspepsia; uncommon - intestinal obstruction, ascites, enteritis, dysphagia, lower abdominal pain, abdominal discomfort, gastroesophageal reflux disease, blood in the stool.

Disorders of the liver and biliary tract: often - changes in liver function tests; infrequently - jaundice.

Skin and subcutaneous tissue disorders: very common - hand-foot syndrome (paresthesia, edema, flushing, skin peeling, blistering; post-marketing experience has shown that persistent or severe hand-foot syndrome (grade 2 or higher) may subsequently lead to loss of fingerprints), dermatitis; often - skin hyperpigmentation, macular rash, rash, skin pigmentation disorder, alopecia, erythema, dry skin; Uncommon: blisters, skin ulcers, urticaria, palmar erythema, facial edema, purpura. Skin cracks at least thought to be related to capecitabine therapy were reported in less than 2% of patients in 7 completed clinical studies (N=949).

Musculoskeletal and connective tissue disorders: often - pain in the limbs, back pain; Uncommon: joint swelling, bone pain, facial pain, stiffness, muscle weakness.

Renal and urinary tract disorders: uncommon - hydronephrosis, urinary incontinence, hematuria, nocturia, increased plasma creatinine.

Disorders of the genital organs and breast: infrequently - vaginal bleeding.

General disorders and disorders at the injection site: very often - fatigue, drowsiness; often - peripheral edema, malaise, chest pain, fever, weakness, asthenia; infrequently - swelling, chills, flu-like syndrome, trembling, increased body temperature.

Impact on the results of laboratory and instrumental studies: often - hyperbilirubinemia.

The following adverse reactions are toxicities known to occur with fluoropyrimidine therapy; At least an indirect association between the development of such reactions and the use of capecitabine was reported in less than 5% of patients participating in 7 completed clinical studies (N=949):

disorders of the gastrointestinal tract: dry mouth, flatulence, adverse reactions associated with inflammation/ulceration of the mucous membranes, such as esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding;

disorders of the cardiovascular system: edema of the lower extremities, cardialgia, including angina pectoris, cardiomyopathy, myocardial ischemia, myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including atrial fibrillation, ventricular extrasystoles;

Nervous system disorders: taste disturbance, insomnia, confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, impaired balance and coordination); mental disorders: depression;

infectious and parasitic diseases: infectious complications associated with myelosuppression, immunosuppression and/or mucositis, such as local and fatal systemic infections (bacterial, viral or fungal etiology) and sepsis;

disorders of the blood and lymphatic system: anemia, myelosuppression/pancytopenia;

disorders of the skin and subcutaneous tissues: itching, focal peeling of the skin, hyperpigmentation of the skin, changes in the nails, photosensitivity reactions, radiation dermatitis;

visual disturbances: eye irritation;

disorders of the respiratory system, chest and mediastinal organs: shortness of breath, cough;

musculoskeletal and connective tissue disorders: arthralgia, myalgia, back pain;

general disorders and disorders at the injection site: chest pain (non-cardiac etiology), pain in the extremities.

Use of capecitabine in combination therapy

The safety profile did not differ between indications and combinations, but the adverse reactions listed with monotherapy may occur with greater frequency when capecitabine is used in combination therapy.

The following are undesirable reactions that were observed in addition to those with monotherapy:

infectious and parasitic diseases: often - candidiasis of the oral mucosa, herpes zoster, urinary tract infections, upper respiratory tract infections, rhinitis, influenza, infection, oral herpes;

disorders of the blood and lymphatic system: very often - neutropenia (including grade 3-4 neutropenia associated with an increase in body temperature above 38 ° C), anemia, thrombocytopenia, leukopenia, febrile neutropenia; often - myelosuppression;

Immune system disorders: often - hypersensitivity;

metabolic and nutritional disorders: very often - weight loss, loss of appetite; often - hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia;

mental disorders: often - sleep disorders, anxiety;

Nervous system disorders: very often - paresthesia, dysgeusia, headache, peripheral neuropathy, peripheral sensory neuropathy, dysesthesia; often - neurotoxicity, tremor, neuralgia, hypoesthesia;

visual disturbances: very often - lacrimation; often - visual disturbances, dryness, pain in the eyes, blurred vision;

disorders of the organ of hearing and labyrinthine disorders: often - ringing in the ears, hearing loss;

cardiac disorders: often - atrial fibrillation;

vascular disorders: very often - thrombosis/embolism, increased blood pressure (BP), edema of the lower extremities; often - hyperemia, decreased blood pressure, hypertensive crisis, hot flashes, phlebitis;

disorders of the respiratory system, thoracic and mediastinal organs: very often - pharyngeal dysesthesia, sore throat; often - nosebleeds, dysphonia, rhinorrhea, hiccups, pain in the pharynx and larynx;

disorders of the gastrointestinal tract: very often - constipation, dyspepsia; often - bleeding from the upper gastrointestinal tract, oral ulcers, gastritis, bloating, gastroesophageal reflux disease, oral pain, dysphagia, rectal bleeding, lower abdominal pain, dysesthesia, paresthesia and hypoesthesia in the mouth, abdominal discomfort;

disorders of the liver and biliary tract: often - impaired liver function;

disorders of the skin and subcutaneous tissues: very often - alopecia, changes in nails; often - hyperhidrosis, erythematous rash, urticaria, night sweats;

disorders of the musculoskeletal and connective tissue: very often - myalgia, arthralgia, pain in the extremities; often - jaw pain, muscle spasms, trismus, muscle weakness;

disorders of the kidneys and urinary tract: often - hematuria, proteinuria, decreased creatinine clearance, dysuria;

general disorders and disorders at the injection site: very often - weakness, lethargy, increased sensitivity to high and low temperatures; often - fever, pain, inflammation of the mucous membrane, chills, chest pain, flu-like syndrome, bruising.

Cases of liver failure and cholestatic hepatitis have been reported in clinical studies and post-marketing. A cause-and-effect relationship with capecitabine has not been established.

When treating capecitabine in combination with other chemotherapy drugs, cases of hypersensitivity reactions (2%) and myocardial ischemia/infarction (3%) were frequently reported (but in less than 5% of patients).

Below is information on individual adverse reactions.

Diarrhea

Diarrhea was observed in 50% of patients during capecitabine therapy. A meta-analysis of 14 clinical trials involving more than 4,700 patients treated with capecitabine identified covariates that were statistically associated with an increased risk of developing diarrhea: increasing the initial dose of capecitabine (in grams), lengthening the study period of therapy (in weeks), increasing age ( every 10 years) and female iol. Covariates statistically associated with a reduced risk of diarrhea: increasing the cumulative dose of capecitabine (0.1 x kg), increasing the relative dose intensity in the first 6 weeks of therapy (see section "Special Instructions").

Cardiotoxicity

As a result of an analysis of the safety profile of seven clinical studies involving 949 patients receiving capecitabine as monotherapy, the following adverse reactions were identified (incidence less than 0.1%): cardiomyopathy, heart failure, sudden cardiac arrest and ventricular premature beats (see section "Special instructions").

Encephalopathy

Encephalopathy has also been associated with capecitabine monotherapy (incidence less than 0.1%).

Adverse reactions in special clinical groups

Elderly patients

In a safety profile analysis, patients aged ≥ 60 years who received capecitabine in combination with docetaxel and as monotherapy found an increase in the number of serious adverse reactions and grade 3 and 4 treatment-related adverse reactions compared with patients aged < 60 years. Patients aged ≥ 60 years who received capecitabine in combination with docetaxel also dropped out of the study earlier due to adverse reactions compared with patients aged < 60 years. A meta-analysis of 14 clinical studies involving more than 4,700 patients receiving capecitabine found that as the patient's age increased (every 10 years), the risk of developing hand-foot syndrome and diarrhea increased, while the risk of developing neutropenia, on the contrary, increased , decreased (see section “Method of administration and dosage”).

Floor

A meta-analysis of 14 clinical trials involving more than 4,700 patients treated with capecitabine found that female patients had a higher risk of developing hand-foot syndrome and diarrhea, while the risk of developing neutropenia was reduced.

Patients with renal failure (see also sections “Dosage and Administration”, “Special Instructions”)

In a safety profile analysis of patients with renal impairment receiving capecitabine monotherapy (colorectal cancer), an increased incidence of grade 3 and 4 toxicities was found compared with patients with normal renal function (36% (n = 268) of patients with normal renal function compared with 41% (n = 257) of patients with mild renal failure and 54% (n = 59) of patients with moderate renal failure) (see section "Pharmacological properties"). Among patients with moderate renal impairment, capecitabine dose reduction was most common (44%) compared with patients with normal renal function (33%) and patients with mild renal impairment (32%). There was also an increase in the number of patients who dropped out of the study early (21% of patients who dropped out during the first two cycles) compared with patients with normal renal function (5%) and patients with mild renal impairment (8%).

Changes in laboratory parameters

Decreased neutrophil count, decreased granulocyte count, decreased lymphocyte count, decreased platelet count, decreased hemoglobin, hyperbilirubinemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, hypercreatininemia, hyperglycemia, hypo-/hypercalcemia, hyponatremia, hypokalemia.

Post-registration surveillance

During post-marketing use of capecitabine, the following adverse reactions were detected:

Use of the drug Capecitabine

Orally 30 minutes after meals at a daily dose of 2.5 g/m2/day (in 2 doses) for 2 weeks, followed by a break for 1 week. Calculation of the total daily dose depending on the body surface: less than 1.24 m2 - 3 g, 1.25-1.36 m2 - 3.3 g, 1.37-1.51 m2 - 3.6 g, 1.52 –1.64 m2 – 4 g, 1.65–1.76 m2 – 4.3 g, 1.77–1.91 m2 – 4.6 g, 1.92–2.04 m2 – 5 g, 2 .05–2.17 m2 - 5.3 g, more than 2.18 m2 - 5.6 g. Manifestations of toxicity during the treatment period can be eliminated by symptomatic therapy and/or dose reduction. Changing the dose depending on the degree of toxicity (Canadian classification of cytotoxicity): Grade I - do not change the dose; Grade II - at the first appearance of signs of toxicity, it is necessary to discontinue therapy until they disappear or decrease to grade I. Treatment is resumed at 100% of the recommended dose; at the second appearance of signs of toxicity - from 75%, at the third appearance - from 50%; at the fourth appearance of signs of toxicity, the drug is discontinued; Grade III - at the first appearance of signs of toxicity, it is necessary to stop therapy until they disappear or decrease to grade I. Treatment is resumed with 75% of the recommended dose; at the second appearance of signs of toxicity - from 50%; at the third appearance of signs of toxicity, the drug is discontinued; IV degree - the drug is discontinued.

Side effects of the drug Capecitabine

From the gastrointestinal tract: diarrhea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, dry mouth, flatulence, anorexia, oral candidiasis, hyperbilirubinemia. From the nervous system: increased fatigue, weakness, paresthesia, sleep disturbance (including drowsiness, insomnia), asthenic syndrome, headache, dizziness. From the skin: palmar-plantar syndrome (numbness, paresthesia, tingling, swelling and hyperemia, peeling, blistering), dermatitis, erythematous rash, dry skin, itching, focal peeling, hyperpigmentation and skin cracks. From the senses: disturbance of taste, increased lacrimation. Metabolism: dehydration, weight loss. From the respiratory system: shortness of breath, cough. From the musculoskeletal system: myalgia, pain in the limbs, lower back. From the hematopoietic organs: anemia, neutropenia, lymphocytopenia, granulocytopenia, thrombocytopenia. From the cardiovascular system : manifestation of cardiotoxic effects (most likely in patients with coronary artery disease). Other: increased body temperature, swelling of the lower extremities, alopecia, inflammation of the mucous membranes.

Capecitabine-Vista tablets 500 mg, 120 pcs.

Security Profile Summary

The overall safety profile is based on data from more than 3000 patients treated with capecitabine alone or in combination with various chemotherapy regimens for various indications. The safety profile of capecitabine monotherapy in metastatic breast cancer, metastatic colorectal cancer and colon cancer in the adjuvant setting is comparable.

Frequent and/or clinically significant treatment-related adverse reactions included gastrointestinal reactions (diarrhea, nausea, vomiting, abdominal pain, stomatitis), hand-foot syndrome (palm-plantar erythrodysesthesia), weakness, asthenia, anorexia, cardiotoxicity, progression of renal dysfunction in patients with renal failure, thrombosis/embolism.

Adverse reactions considered possibly, possibly, or remotely related to CAPEVISTA, in the opinion of the investigator, were reported in clinical studies of capecitabine monotherapy and in clinical studies of capecitabine in combination with various chemotherapy regimens for various indications.

The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1 /10000 to <1/1000), very rare (<1/10000). In each frequency group, adverse reactions are presented in order of decreasing severity of manifestations.

Monotherapy with capecitabine

The following are adverse reactions associated with capecitabine monotherapy based on a pooled analysis of safety data from three pivotal studies involving 1900 patients (M66001, SO14695 and SO14796). Adverse reactions are included in the appropriate frequency group according to the overall frequency in the pooled analysis.

Infections and infestations: often - herpes (viral infection), nasopharyngitis, lower respiratory tract infections; infrequently - sepsis, urinary tract infections, cellulitis (inflammation of loose tissue), tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, infection, abscess of teeth.

Benign, malignant and unspecified neoplasms: uncommon - lipoma.

From the blood and lymphatic system: often - anemia, neutropenia; uncommon - febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased international normalized ratio (INR) / increased prothrombin time.

From the immune system: rarely - hypersensitivity reactions.

From the side of metabolism, metabolism: very often - anorexia; often - dehydration, weight loss; infrequently - diabetes mellitus, hypokalemia, appetite disturbances, malnutrition, hypertriglyceridemia.

Mental disorders: often - insomnia, depression, infrequently - confusion, acute anxiety with a panic reaction, depressed mood, decreased libido.

From the nervous system: often - headache, lethargy, dizziness, paresthesia, perversion of taste; uncommon - aphasia, memory impairment, ataxia, fainting, balance disorders, sensory disorders, peripheral neuropathy; very rarely - toxic leukoencephalopathy.

On the part of the organ of vision: often - lacrimation, conjunctivitis, irritation of the organs of vision; infrequently - decreased visual acuity, diplopia; rarely - lacrimal duct stenosis, corneal dysfunction, keratitis, punctate keratitis.

From the organs of hearing and labyrinth of the ear: infrequently - dizziness, ear pain.

Cardiac disorders: uncommon - unstable angina, angina pectoris, myocardial ischemia/infarction, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations; rarely - ventricular fibrillation, prolongation of the QT interval, torsade de pointes, ventricular tachycardia, bradycardia, vasospasm.

From the side of blood vessels: frequent - thrombophlebitis; uncommon - deep vein thrombosis, arterial hypertension, petechiae, arterial hypotension, hot flashes, peripheral sensation of cold.

From the respiratory system, chest and mediastinal organs: often - shortness of breath, nosebleeds, cough, rhinorrhea; uncommon - pulmonary embolism, pneumothorax, hemoptysis, asthma, dyspnea on exertion.

From the gastrointestinal tract: very often - diarrhea, nausea, vomiting, stomatitis, abdominal pain often - gastrointestinal bleeding, constipation, pain in the upper abdomen, dyspepsia, flatulence, dry mouth uncommon - intestinal obstruction, ascites, enteritis, gastritis, dysphagia, pain in the lower abdomen, esophagitis, abdominal discomfort, gastroesophageal reflux disease, colitis, blood in the stool.

From the digestive system: often - hyperbilirubinemia, deviation of the level of functional liver tests; infrequently - jaundice; rarely - liver failure and cholestatic hepatitis.

Skin and subcutaneous tissue disorders: very common - palmoplantar erythrodysesthesia syndrome (based on post-marketing experience, persistent or severe palmoplantar erythrodysesthesia syndrome may ultimately lead to loss of fingerprints (see section "Peculiarities of Application"); frequent - rash, alopecia, erythema, dry skin, itching, hyperpigmentation of the skin, macular rash, peeling of the skin, dermatitis, pigmentation disorders, nail disorders; uncommon - formation of blisters and ulcers on the skin, rash, urticaria, photosensitivity, erythema of the palms, swelling of the face , purpura, radiation reversal syndrome, rarely - cutaneous lupus erythematosus, very rarely - skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the musculoskeletal system and connective tissue: often - pain in the limbs, back pain, arthralgia; infrequently - joint swelling, bone pain, facial pain, rigidity of the musculoskeletal system, muscle weakness.

From the kidneys and urinary system: infrequently - hydronephrosis, urinary incontinence, hematuria, nocturia, increased blood creatinine levels.

From the reproductive system and mammary glands: infrequently - vaginal bleeding.

General disorders: very often - weakness, asthenia often - hyperthermia, peripheral edema, malaise, chest pain; uncommon - edema, fever, flu-like symptoms, chills, increased body temperature.

In this context, “common adverse reactions” under “capecitabine monotherapy” refers to severe adverse reactions and/or life-threatening (grade 3-4) or medically significant adverse reactions.

Combination therapy

The following are adverse reactions reported with capecitabine in combination with various chemotherapy regimens for various indications based on safety data from more than 3000 patients, in addition to those already reported with monotherapy and/or observed with high frequency in any of the main clinical trials .

Some adverse reactions are often observed with chemotherapy (for example, peripheral sensory neuropathy with docetaxel or oxaliplatin, hypersensitivity reactions with bevacizumab). However, an increase in these adverse reactions when using the drug KAPEVISTA cannot be ruled out.

Infections and infestations: often - herpes zoster, urinary tract infections, oral candidiasis, upper respiratory tract infections, rhinitis, influenza, infections *, oral herpes.

From the blood and lymphatic system: very often - neutropenia *, leukopenia * neutropenic fever *, thrombocytopenia *, anemia *; often - bone marrow depression, febrile neutropenia *.

From the immune system: often - hypersensitivity reactions.

From the side of metabolism, metabolism: very often - loss of appetite often - hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia.

Mental disorders: often - sleep disorders, anxiety.

From the nervous system: very often - paresthesia and dysesthesia, peripheral neuropathy, peripheral sensory neuropathy, taste perversion, headache often - neurotoxicity, tremor, neuralgia, hypersensitivity reactions, hypoesthesia.

On the part of the organ of vision: very often - tearfulness; often - blurred vision, dry eyes, eye pain, blurred vision, blurred vision.

From the organs of hearing and the labyrinth of the ear: often - ringing in the ears, hearing loss.

Cardiac disorders: often - atrial fibrillation, myocardial ischemia / infarction.

From the side of blood vessels: very often - edema of the lower extremities, arterial hypertension, thrombosis / embolism *; often - hot flashes, arterial hypotension, hypertensive crisis, hyperemia, phlebitis.

From the respiratory system, chest and mediastinal organs: very often - sore throat, pharyngeal dysesthesia often - hiccups, pharyngolaryngeal pain, dysphonia.

From the gastrointestinal tract: very often - constipation, dyspepsia often - bleeding from the upper gastrointestinal tract, ulcers of the oral mucosa, gastritis, bloating, gastroesophageal reflux disease, pain in the mouth, dysphagia, rectal bleeding, pain in the lower abdomen, oral dysesthesia, oral paresthesia, oral hypoesthesia, abdominal discomfort.

From the digestive system: often - deviation of the level of functional liver tests.

From the skin and subcutaneous tissue: very often - alopecia, nail disorders; often - hyperhidrosis, erythematous rashes, urticaria, night sweats.

From the musculoskeletal system and connective tissue: very often - arthralgia, myalgia, pain in the extremities; often - jaw pain, muscle spasms, trismus, muscle weakness.

From the kidneys and urinary system: common - hematuria, proteinuria, decreased creatinine clearance by the kidneys, dysuria rare - acute renal failure due to dehydration (see section "Peculiarities of use").

General disorders: very often - increased body temperature, weakness, lethargy *, sensitivity to elevated temperature; often - inflammation of the mucous membranes, pain in the extremities, pain, chills, chest pain, flu-like symptoms, fever *, infusion reactions, injection site reactions, pain at the infusion site, pain at the injection site.

Damage (trauma, wounds), poisoning: often - bruise.

The frequency includes all degrees of severity, with the exception of adverse reactions, which included only grade 3-4 adverse reactions.

Selected adverse reactions

Hand-foot syndrome

When using capecitabine at a dose of 1250 mg/m2 times a day for 2 weeks followed by a one-week break, hand-foot syndrome of all degrees of severity in monotherapy (adjuvant therapy for colon cancer, treatment of metastatic colorectal cancer, treatment of breast cancer) was recorded in 53- 60% of patients and 63% of patients with metastatic breast cancer in the capecitabine/docetaxel treatment group. When using capecitabine at a dose of 1000 mg/m 2 times a day for 2 weeks followed by a one-week break, hand-foot syndrome of all degrees of severity was observed in 22-30% of patients receiving combination treatment with capecitabine.

A meta-analysis of data obtained from more than 4,700 patients in 14 clinical trials showed that hand-foot syndrome of all degrees of severity was observed when capecitabine was used alone or in combination with various chemotherapy regimens for various indications (colon cancer, colorectal cancer, gastric cancer, breast cancer) occurred in 43% (2066) of patients at a mean of 239 days after initiation of capecitabine treatment (95% CI 201-288). The following covariates were statistically significantly associated with an increased risk of developing hand-foot syndrome in all studied combinations: increasing the initial dose of capecitabine (in grams), decreasing the cumulative dose of capecitabine (0.1 * kg), increasing the relative dose intensity in the first 6 weeks of treatment, increasing the duration of treatment (weeks),

Diarrhea

The occurrence of diarrhea during capecitabine therapy was observed in almost 50% of patients. In a meta-analysis of data from more than 4,700 patients in 14 clinical trials, the following covariates were statistically significantly associated with an increased risk of diarrhea for all combinations tested: increasing the initial dose of capecitabine (in grams), increasing the duration of treatment (weeks), increasing patient age (increase by 10 years), female gender. The following covariates were statistically significantly associated with a reduction in the risk of developing diarrhea: an increase in the cumulative dose of capecitabine (0.1 * kg) and relative dose intensity in the first 6 weeks of treatment.

Cardiotoxicity

In addition to these cardiac adverse reactions, the following adverse reactions were reported with an incidence of less than 0.1% with capecitabine monotherapy based on a pooled analysis of safety data obtained from 949 patients enrolled in 7 clinical trials (2 phase III and 5 phase II in metastatic disease). colorectal cancer and metastatic breast cancer): cardiomyopathy, heart failure, ventricular extrasystoles, sudden death.

Encephalopathy

In addition to these adverse reactions, capecitabine monotherapy was associated with encephalopathy with an incidence of less than 0.1% based on a pooled analysis of safety data from 7 clinical studies.

Contact with crushed or cut capecitabine tablets

The following adverse reactions have been reported following contact with crushed or cut capecitabine tablets: eye irritation, eye swelling, skin rash, headache, paraesthesia, diarrhea, nausea, gastric irritation and vomiting.

Adverse reactions in special patient groups

Elderly patients. Patients aged ≥ 60 years treated with capecitabine monotherapy and combination therapy with capecitabine and docetaxel had an increased risk of grade 3 and 4 adverse reactions and treatment-related serious adverse reactions compared with patients aged <60 years. More patients aged ≥60 years receiving combination treatment with capecitabine and docetaxel experienced earlier discontinuation due to adverse reactions compared with patients aged <60 years.

A meta-analysis of data from more than 4,700 patients participating in 14 clinical trials showed that in studies of all combinations with age (increasing age by 10 years), there was a statistically significant increase in the risk of developing hand-foot syndrome and diarrhea, as well as a decrease in the risk of developing neutropenia.

Floor

A meta-analysis of data from more than 4,700 patients enrolled in 14 clinical trials, when data from all studies were pooled, found that female gender was statistically significantly associated with an increased risk of developing hand-foot syndrome and diarrhea, as well as a reduced risk of developing neutropenia.

Patients with impaired renal function

In patients with pre-treatment renal impairment who received capecitabine monotherapy (for colorectal cancer), there was an increased incidence of treatment-related grade 3 and 4 adverse reactions compared with patients with normal renal function (36% in patients without impairment). renal function (N = 268), 41% in patients with mild renal failure (N = 257) and 54% in patients with moderate renal failure (N = 59)). Patients with moderate renal impairment were more likely to require dose reductions (44%) compared with 33% and 32% of patients without and mild renal impairment, respectively.

Special instructions for the use of capecitabine

Women of reproductive age should be treated only if they are using reliable contraception. The drug should be prescribed with caution to patients with mild to moderate liver dysfunction caused by liver metastases and the elderly. If hyperbilirubinemia develops, capecitabine should be discontinued until bilirubin levels normalize. Currently, the safety of use in patients with renal failure has not been established. Prescribe with caution to patients whose activities require increased concentration and speed of psychomotor reactions. Prescription of coumarin anticoagulants is possible no earlier than 1 month after the end of capecitabine therapy due to the high risk of blood clotting disorders and bleeding.