Xalvobin, 500 mg 120 pcs

Antitumor agent. It has a selective cytotoxic effect. In tumor tissue capecitabine is converted into 5-fluorouracil under the action of thymidine phosphorylase (tumor angiogenic factor). Thymidine phosphorylase activity in primary tumor is 4 times higher than in healthy tissue, so the concentration of 5-fluorouracil in tumor tissue is higher than in healthy tissue and in plasma.

In both healthy and tumor cells, 5-fluorouracil is metabolized to form 5-fluoro-2-deoxyuridine monophosphate and 5-fluoruridine triphosphate, which have cytotoxic effects.

Indications

Active ingredient

Composition

Shell composition: hypromellose 5cP – 9.967 mg, titanium dioxide – 3.987 mg, talc – 0.839 mg, macrogol 400 – 1.049 mg, iron oxide red dye – 0.136 mg, iron oxide yellow dye – 0.021 mg.

How to take, the dosage

To be taken orally. Drinking with water, no later than 30 minutes after a meal.

The standard dosing regimen

Monotherapy

Colorectal cancer, colorectal cancer and breast cancer.

It is 1250 mg/m2 twice daily, morning and evening (total daily dose 2500 mg/m2) for two weeks, followed by a seven-day break.

Combination therapy

Breast cancer

To 1250 mg/m2 twice daily for two weeks followed by a seven-day break, in combination with docetaxel at a dose of 75 mg/m2 once every 3 weeks as an intravenous infusion for 1 hour.

Premedication is given before administration of docetaxel according to its instructions for use.

Colorectal cancer and gastric cancer

In combination therapy (except for therapy with irinotecan) the dose of Xalvobin is up to 800-1000 mg/m2 2 times daily for two weeks followed by a seven-day break or up to 625 mg/m2 2 times daily in continuous regimen.

In combination therapy with irinotecan (XELIRI regimen), the recommended dose of Xalvobin is 800 mg/m2 2 times daily for 14 days followed by a 7-day break. Adding bevacizumab to combination therapy does not affect the starting dose of Xalvobin.

The anti-emetics and premedication to ensure adequate hydration are administered prior to the administration of cisplatin and oxaliplatin according to the instructions for use of cisplatin and oxaliplatin when used in combination with Xalvobin.

In adjuvant therapy of stage III colorectal cancer, the recommended duration of therapy with Xalvobin is 6 months, i.e. 8 courses.

In combination with cisplatin

Prescribed at 1000 mg/m2 2 times a day for two weeks followed by a seven-day break in combination with cisplatin (80 mg/m2 once every 3 weeks, IV infusion for 2 h, first infusion administered on the first day of the cycle). The first dose of Xalvobin is administered in the evening on the first day of the therapy cycle, the last dose on the morning of day 15.

In combination with oxaliplatin or with oxaliplatin and bevacizumab

Appointed at 1000 mg/m2 twice daily for two weeks followed by a seven-day break in combination with oxaliplatin or with oxaliplatin and bevacizumab. The first dose of Xalvobin is administered in the evening on the first day of the therapy cycle and the last dose on the morning of day 15. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, by IV infusion for 30-90 minutes, with the first infusion starting on the first day of the cycle. After bevacizumab, oxaliplatin is administered at a dose of 130 mg/m2, IV infusion for 2 h.

In combination with epirubicin and platinum-based drug

In combination with irinotecan or with irinotecan and bevacizumab

The recommended dose of Xalvobin is 800 mg/m2 twice daily for two weeks followed by a seven-day break in combination with irinotecan or with irinotecan and bevacizumab.

Irinotecan is administered at a dose of 200 mg/m2 once every 3 weeks, by IV infusion for 30 minutes, the first infusion on the first day of the cycle.

Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, IV infusion for 30-90 minutes, with the first infusion starting on the first day of the cycle.

The tables below show examples of standard and reduced dose calculations for Xalvobin for an initial dose of 1250 mg/m2 or 1000 mg/m2.

Table 1. Standard and reduced doses of Xalvobin for an initial dose of 1250 mg/m2, calculated as a function of body surface area

The standard and reduced doses of Xalvobin for an initial dose of 1250 mg/m2table cellspacing=”0″ cellpadding=”0″>

The dose is 1250 mg/m2 2 times a day

The full dose of 1250 mg/m2

Number of tablets 150 mg and/or 500 mg per administration (for each administration 2 times daily – morning and evening)

Reduced dose 950 mg/m2 (75% of initial dose)

Reduced dose 625 mg/m2 (50% of initial dose)

Body surface area (m2)

Dose per administration (mg)

150 mg

500 mg

Dose per administration (mg)

Dose per administration (mg)

≤1.26

1500

3

1150

800

1.27-1.38

1650

1

3

1300

800

1.39-1.52

1800

2

3

1450

950

1.53-1.66

2000

–

4

1500

1000

1.67-1.78

2150

1

4

1650

1000

1.79-1.92

2300

2

4

1800

1150

1.93-2.06

2500

–

1,950

1,300

2.07-2.18

2650

1

5

2000

≥2.19

2800

2

5

2150

1450

Table 2. Standard and reduced doses of Xalvobin for an initial dose of 1000 mg/m2, calculated as a function of body surface area.

The dose is 1000 mg/m2 2 times daily

Full dose of 1000 mg/m2

Number of tablets 150 mg and/or 500 mg per administration (for each administration 2 times a day – morning and evening)

Reduced dose of 750 mg/m2 (75% of initial dose)

Reduced dose of 500 mg/m2 (50% of initial dose)

Body surface area (m2)

Dose per administration (mg)

150 mg

500 mg

Dose per administration (mg)

Dose per dose (mg)

≤1.26

1150

1

2

800

600

800

1.67-1.78

1750

5

2

1300

800

1.79-1.92

1800

3

1400

900

1.93-2.06

2000

–

4

2.07-2.18

2150

1

4

1600

1050

≥2.19

2300

2

4

1750

1100

Dose adjustment during treatment

General guidelines

The toxic effects of Xalvobin can be managed with symptomatic therapy and/or by adjusting the dose of the drug (by interrupting treatment or reducing the dose of the drug). If the dose has had to be reduced, it should not be increased thereafter.

If the treating physician’s assessment is that the toxic effects of Xalvobin are not serious or life-threatening, treatment may be continued at the initial dose without reduction or interruption of therapy.

In 1st degree toxicity, the dose is not changed. In case of 2nd and 3rd degree toxicity, therapy with Xalvobin should be interrupted.

If signs of toxicity disappear or are reduced to Grade 2 toxicity, Xalvobin therapy may be resumed at the full dose or adjusted according to the recommendations in Table 3.

If signs of Grade 4 toxicity develop, treatment should be discontinued or temporarily interrupted until symptoms subside or decrease to Grade 1, at which time the drug may be resumed at a dose that is 50% of the initial dose. The patient should immediately inform the physician about the developed adverse events. Xalvobin should be discontinued immediately in case of severe or moderate toxicity.

If several doses of Xalvobin have been missed due to toxicity, these doses are not replenished.

Hematologic toxicity

Capecitabine therapy should not be administered to patients who have an initial neutrophil count <1.5 x 109/L and/or an initial platelet count <100 x 109/L.

The therapy with Xalvobin should be discontinued if at an unscheduled laboratory evaluation the neutrophil count has decreased below 1.0 x 109/L and the platelet count has decreased below 75 x 109/L (Grade 3 or 4 hematologic toxicity).

The table below provides recommendations for changing the dose of Xalvobin if toxic events associated with its use develop.

Table 3. Xalvobin dose adjustment chart

The NCIC grade of toxicity*

Dose change during therapy cycle

Dose adjustment during next therapy cycle (% of initial dose)

Stage 1

Continue at the same dose

Continue at the same dose

Grade 2

1 appearance

Interrupt therapy until resolution to grade 0-1

100%

2 occurrence

Interrupt therapy until resolution to grade 0-1

/p>

75%

3 occurrence

Interrupt therapy until resolution to grade 0-1

/p>

50%

4 occurrence

Completely discontinue therapy

Not applicable

Grade 3

3 appearance

Discontinue therapy completely

Not applicable

Degree 4

1 occurrence

Completely discontinue therapy OR, if the physician believes it is in the patient’s best interest to continue treatment, interrupt therapy until resolution to grade 0-1

50%

2 occurrence

Completely discontinue therapy

Not applicable

*In accordance with the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG, version 1) general toxicity criteria or the U.S. National Cancer Institute’s Program for Antitumor Therapy Evaluation (STCAE, version 3) general adverse event criteria. Criteria for palpebral toxicity and hyperbilirubinemia are described in detail in the Special Guidelines section.

General recommendations for combination therapy

If toxicity occurs with combination therapy, the dose adjustment recommendations for Xalvobin in Table 3 above and the corresponding recommendations in the instructions for use of the other drugs should be followed.

At the beginning of a therapy cycle, if Xalvobin or other drug(s) are expected to be delayed, all medications should be delayed until conditions for resuming therapy with all medications are met.

If, during the combination therapy cycle, toxicity does not appear to be related to the use of Xalvobin, the therapy with Xalvobin should continue, and the dose of the other drug should be adjusted according to the recommendations in the drug’s instructions for use.

If the other drug(s) have to be discontinued, treatment with Xalvobin can be continued if the requirements for resumption of Xalvobin therapy are met.

The guidelines apply for all indications and all special patient groups.

Dose adjustment in special cases

Hepatic impairment in patients with liver metastases

There is no need to change the starting dose in patients with liver metastases and mild to moderate hepatic impairment. However, these patients should be monitored closely. The use of the drug in patients with severe hepatic impairment has not been studied.

Renal dysfunction

It is recommended that the initial dose be reduced to 75% of 1250 mg/m2 in patients with baseline moderate renal impairment (CKR 30-50 ml/min, according to the Cockroft-Gault formula); no dose adjustment is required for an initial dose of 1000 mg/m2.

In patients with mild renal impairment (CKR 51-80 ml/min), no adjustment of the starting dose is required.

If an adverse event of grade 2, 3 or 4 occurs in a patient, close monitoring is required and immediate discontinuation of current therapy for subsequent dose adjustment of the drug according to the recommendations in Table 3. If calculated CK decreased to less than 30 ml/min during therapy, therapy with Xalvobin should be discontinued. Recommendations on dose adjustment of the drug in moderate renal insufficiency refer to both monotherapy and combination therapy. Dose calculations are listed in Tables 1 and 2.

Children

The safety and effectiveness of Xalvobin in children has not been studied.

Elderly and elderly patients

The initial dose adjustment is not required with Xalvobin monotherapy. However, severe therapy-related grade 3 and 4 adverse events developed more frequently in patients older than 80 years than in younger patients.

When using Xalvobin in combination with other anticancer drugs in elderly patients (aged ≥65 years) adverse reactions of 3rd and 4th degree severity, as well as adverse reactions requiring withdrawal of therapy, were observed more frequently than in younger patients. Close monitoring of elderly patients is recommended.

When treated in combination with docetaxel, an increased incidence of grade 3 and 4 adverse events and serious adverse events associated with therapy was noted in patients aged 60 years and older. For patients 60 years of age and older who will receive a combination of Xalvobin with docetaxel, it is recommended that the starting dose of Xalvobin be reduced to 75% (950 mg/m2 2 times daily). The dose calculation is given in Table 1. If there are no manifestations of toxicity, the dose may be increased to 1250 mg/m2 2 times daily.

Interaction

Coumarin anticoagulants

Cytochrome Р450 substrates

Special studies of drug interaction of capecitabine with other drugs metabolized by cytochrome Р450 system isoenzyme 2C9 have not been conducted. Caution should be exercised when prescribing Xalvobin with these drugs.

Phenytoin

Antacids

When evaluating the pharmacokinetic parameters of Xalvobin when concomitantly taken with antacids containing aluminum hydroxide and magnesium hydroxide, a slight increase in plasma concentration of capecitabine and one of its metabolites (5′-DPCT) was noted. The three main metabolites of capecitabine (5′-DFUR, FU and FBAL) were not affected by the studied agents.

Allopurinol

Combined administration of allopurinol and capecitabine should be avoided because the effectiveness of fluorouracil may decrease due to interaction of fluorouracil with allopurinol.

Interferon alfa

The maximum tolerated dose of capecitabine in combination with interferon 2-alpha (3 international mU/m2/day) was 2000 mg/m2/day, whereas the maximum tolerated dose of capecitabine as monotherapy was 3000 mg/m2/day.

Radiation therapy

. The maximum tolerated dose of capecitabine in combination with radiotherapy in the treatment of patients with rectal cancer was 2,000 mg/m2 per day (with continuous therapy or with Monday through Friday regimen and a 6-day course of radiotherapy), whereas the maximum tolerated dose of capecitabine as monotherapy was 3,000 mg/m2 per day (intermittent regimen).

Calcium folinate (Leucovorin)

Calcium folinate does not affect the pharmacokinetic properties of capecitabine and its metabolites. However, it is possible to increase the toxic effect of capecitabine due to the effect of calcium folinate on the pharmacodynamics of capecitabine.

Sorivudine and its analogues

The literature describes a clinically significant drug interaction between sorivudine and 5-FU based on the inhibitory effect of sorivudine on DPD. This interaction may lead to fatal enhancement of fluoropyrimidine toxicity. Therefore, Xalvobin should not be administered simultaneously with sorivudine or its structural analogues like brivudine. At least a four-week interval between the end of therapy with sorivudine or its structural analogues (including brivudine) and the beginning of treatment with Xalvobin should be observed.

Oxaliplatin

There is no clinically significant difference in exposure to capecitabine or oxaliplatin metabolites (free platinum or total platinum) when capecitabine and oxaliplatin are combined, regardless of the presence of bevacizumab.

Bevacizumab

There were no clinically significant effects of bevacizumab on the pharmacokinetics of capecitabine or its metabolites.

Special Instructions

Dose-limiting adverse reactions of the drug include diarrhea, abdominal pain, nausea, stomatitis, and palmar-squamous syndrome.

There should be close medical monitoring of toxicity in patients treated with Xalvobin.

The majority of adverse events are reversible and do not require complete withdrawal of the drug, although adjustment of the dose or temporary withdrawal of the drug may be necessary.

Diarrhea

The treatment with Xalvobin may cause diarrhea, sometimes severe. Patients with severe diarrhea should be monitored closely, and rehydration or reimbursement of electrolyte loss should be performed if dehydration develops. Standard antidiarrheals (e.g., loperamide) should be given as early as medically advisable. Grade 2 diarrhea is defined by the National Cancer Institute of Canada (NCIC STS, version 2) as increased frequency of stools of 4-6 times per day or nighttime stools, grade 3 diarrhea as increased stools of 7-9 times per day or incontinence and malabsorption, grade 4 diarrhea as increased stools of 10 or more per day, visible blood in the stool, or a need for parenteral maintenance therapy. The dose of Xalvobin should be reduced if necessary.

Dehydration

Dehydration should be prevented or corrected at the onset. Dehydration can occur quickly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea.

Dehydration may cause acute renal failure, in some cases with fatal outcome, especially in patients with impaired renal function at the start of therapy or if the patient is taking capecitabine concomitantly with drugs that have nephrotoxic effects.

If dehydration of the 2nd degree or higher develops, treatment with Xalvobin should be immediately interrupted and rehydration should be performed. Treatment should not be resumed until rehydration is completed and the factors which caused it are eliminated or corrected. The dose of the drug should be modified in accordance with the recommendations for adverse events that led to dehydration.

The spectrum of cardiotoxicity with treatment with capecitabine is similar to that with other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, heart failure and ECG changes. These adverse events are more common in patients with a history of CHD. Caution should be exercised in patients with a history of arrhythmias and angina pectoris. During therapy with capecitabine the development of hypo- or hypercalcemia has been noted. Caution should be exercised in patients with previously diagnosed hypo- or hypercalcemia.

Patients with central and peripheral nervous system disorders (e.g., presence of brain metastases and neuropathy) as well as patients with diabetes mellitus and electrolyte balance disorders should be treated with caution since these diseases may worsen during treatment with capecitabine.

In rare cases, unexpected severe toxicities (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with FP are due to insufficient DPD activity. Thus, the association between reduced DPD activity and more severe, potentially lethal toxicity of FU cannot be excluded.

Patients should be monitored for ophthalmic complications such as keratitis or corneal pathology, especially if there is a history of visual impairment. If visual complications develop, appropriate treatment must be prescribed.

The drug Xalvobin may cause serious skin reactions such as Stevenson-Johnson syndrome and toxic epidermal necrolysis. If severe skin reactions develop against the background of Xalvobin use, the drug should be discontinued and not resumed.

The manifestation of cutaneous toxicity of the drug Xalvobin is the development of palmar-todermal syndrome (synonyms: palmar-todermal erythrodisesthesia or acral erythema caused by chemotherapy). The median time to development of manifestations of toxicity in patients receiving Xalvobin monotherapy is 79 days (range, 11 to 360 days), and the severity ranges from grade 1 to grade 3. Grade 1 palmar-todermal syndrome does not impair the patient’s daily activities and is manifested by numbness, dysesthesia/paresthesias, tingling or redness of the palms and/or soles, and discomfort. Grade 2 palm plantar syndrome is characterized by painful redness and swelling of the hands and/or feet, and the discomfort caused by these symptoms interferes with the patient’s daily activities. Grade 3 palmar-subcutaneous syndrome is defined as moist desquamation, ulceration, blistering and severe pain in the hands and/or feet, as well as severe discomfort that makes it impossible for the patient to perform any activities of daily living. If palmar-todermal syndrome of the 2nd or 3rd degree occurs, therapy with Xalvobin should be interrupted until the symptoms disappear or are reduced to the 1st degree. If Grade 3 syndrome occurs, subsequent doses of Xalvobin should be reduced.

Vitamin B6 (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of palmar plantar syndrome when Xalvobin is prescribed in combination with cisplatin because it may reduce the effectiveness of cisplatin. There are data on the effectiveness of dexpanthenol in the prevention of palmar-todermal syndrome during therapy with capecitabine.

Hyperbilirubinemia

The drug Xalvobin may cause hyperbilirubinemia. If hyperbilirubinemia >3 x BHN (upper limit of normal) or increase of “hepatic” aminotransferases activity (ALT, ACT) >2.5 x BHN is observed in connection with Xalvobin treatment, treatment should be stopped.

The therapy can be resumed when bilirubin levels and “hepatic” aminotransferase activity decrease below these limits.

Simultaneous use with coumarin anticoagulants

In patients who simultaneously take Xalvobin and coumarin-derived oral anticoagulants the coagulation parameters (prothrombin time or INR) should be controlled and the anticoagulant dose should be adjusted accordingly.

The use of the drug in elderly and senile patients

The frequency of gastrointestinal toxic events in patients with colorectal cancer aged 60-79 years who received capecitabine monotherapy did not differ from that in the general patient population. In patients 80 years old and older reversible adverse GI events of 3rd and 4th degree, such as diarrhea, nausea and vomiting, developed more frequently. In patients ≥65 years old who received combined therapy with capecitabine and other antitumor drugs, there was an increased frequency of Grade 3 and 4 adverse reactions and adverse events that led to discontinuation of therapy compared to patients younger than 65 years old.

In an analysis of safety data in patients ≥60 years of age receiving combination therapy with Xalvobin and docetaxel, there was an increased incidence of therapy-related Grade 3 and 4 adverse events, serious adverse events, and early therapy withdrawal due to adverse events compared to those in patients less than 60 years of age.

Renal impairment

Cautions should be taken when prescribing Xalvobin to patients with moderate renal impairment. As in treatment with fluorouracil, the incidence of therapy-associated adverse events of grade 3 and 4 was higher in patients with moderate renal impairment (CKD 30-50 ml/min).

Hepatic impairment

Patients with hepatic impairment should be under close medical supervision during therapy with Xalvobin. The effect of hepatic dysfunction not due to metastatic liver injury or severe hepatic failure on the distribution of Xalvobin is unknown.

Pregnancies and Breastfeeding

Safe contraception should be used during therapy with Xalvobin and for at least 3 months thereafter. If pregnancy occurs during therapy, the patient should be made aware of the potential risk to the fetus.

Side effects

The incidence of adverse reactions is stated according to the following grading: very frequently (≥1/10), frequently (≥1/100 to <1/10), infrequently (≥1/1000 to <1/100), rarely (≥1/10000 and <1/1000), very rarely (<1/10000, including individual cases). The following adverse reactions are listed in order of clinical significance.

. The most common and/or clinically significant adverse reactions during therapy with Xalvobin were gastrointestinal (GI) disorders (especially diarrhea, nausea, vomiting, abdominal pain, stomatitis), palm-squamous syndrome, fatigue, drowsiness, anorexia, manifestations of cardiotoxicity, increased renal failure in patients with a history of renal dysfunction, thrombosis/embolism.

Monotherapy with Xalvobin

Infectious and parasitic diseases: frequent – herpes, viral infection, nasopharyngitis, lower respiratory tract infection; infrequent – sepsis, urinary tract infection, cellulitis, tonsillitis, pharyngitis, oral candiosis, influenza, gastroenteritis, fungal infections, infections, dental abscess.

Benign, malignant and unspecified neoplasms: infrequent – lipoma.

Blood and lymphatic system disorders: frequently – neutropenia, anemia; infrequently – febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increase of international ratio (INR), prolongation of prothrombin time.

Immune system disorders: infrequent – sensitization.

Mechanism and nutrition disorders: very common – anorexia; common – dehydration, decreased appetite, decreased body weight; infrequent – diabetes, hypokalemia, digestive disorders, hypertriglyceridemia.

Psychiatric disorders: infrequent – confusion, panic attacks, depressed mood, decreased libido.

Nervous system disorders: frequently – headache, dizziness (except vertigo), dullness, paresthesia, dysgeusia (perversion of taste); infrequently – aphasia, memory disorder, ataxia, syncope, loss of balance, loss of sensitivity, peripheral neuropathy.

Visual disorders: frequently – increased lacrimation, conjunctivitis; infrequently – decreased visual acuity, diplopia.

Hearing and labyrinth disorders: infrequent – vertigo, pain in the ears.

Cardiac disorders: infrequent – angina pectoris, including unstable, arrhythmia, sinus tachycardia, palpitations.

Vascular disorders: frequently – thrombophlebitis, infrequently – deep vein thrombosis, increased blood pressure, petechiae, decreased blood pressure, “hot flashes”, coldness of distal extremities.

Respiratory system, thoracic and mediastinal disorders: frequently – nasal bleeding, rhinorrhea; infrequently – pneumothorax, hemoptysis, bronchial asthma, dyspnea on physical exercise.

Gastrointestinal disorders: very common – diarrhea, vomiting, nausea, stomatitis (including ulcerative), abdominal pain; common – constipation, epigastric pain, dyspepsia; infrequent – intestinal obstruction, ascites, enteritis, gastritis, dysphagia, lower abdominal pain, abdominal discomfort, gastroesophageal reflux disease, colitis, blood in stool.

Liver and biliary tract disorders: frequently – disorders of liver function tests, hyperbilirubinemia; rarely – jaundice.

Skin and subcutaneous tissue disorders: very common – palmar-subcutaneous syndrome (paresthesias, edema, hyperemia, skin peeling, blistering), dermatitis; common – hyperpigmentation of the skin, macular rash, rash, skin pigmentation disorders, alopecia, erythema, dry skin; infrequent – blisters, skin ulcers, urticaria, palmar erythema, facial edema, purpura. In less than 2% of patients in 7 completed clinical trials (N=949), cracked skin was reported at least presumably related to capecitabine therapy.

Musculoskeletal and connective tissue disorders: frequent – pain in extremities, back pain; infrequent – joint swelling, bone pain, facial pain, stiffness, muscle weakness.

Recreational and urinary tract disorders: infrequent – hydronephrosis, urinary incontinence, hematuria, nycturia, increased blood creatinine.

Gender and mammary gland disorders: infrequent – vaginal bleeding.

General disorders and reactions at the site of administration: very often – fatigue, somnolence; often – peripheral edema, malaise, chest pain, fever, weakness, asthenia; infrequently – edema, chills, flu-like syndrome, shivering, increased body temperature.

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

The following adverse reactions are manifestations of toxicity known for 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 enrolled in 7 completed clinical trials (N=949):

Gastrointestinal disorders: dry mouth, flatulence, adverse reactions associated with mucosal inflammation/inflammation, such as: esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding.

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

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

Psychiatric disorders: depression.

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

Blood and lymphatic system disorders: anemia, myelosuppression, pancytopenia.

Skin and subcutaneous tissue disorders: itching, focal skin peeling, hyperpigmentation of the skin, nail changes, photosensitization reactions, radiation dermatitis.

Visual organ disorders: eye irritation.

Respiratory system, chest and mediastinum disorders: shortness of breath, cough.

Muscular system and connective tissue disorders: arthralgia, myalgia, back pain.

General disorders and disorders at the site of administration: pain in the chest (noncardiac etiology), pain in the extremities.

The use of Xalvobin in combination therapy

The safety profile did not differ when administered for different indications and in different combinations, but adverse reactions listed for monotherapy may be observed with greater frequency when Xalvobin is used in combination therapy.

The following are the adverse reactions that have been observed in addition to those with monotherapy.

Infectious and parasitic diseases: often – oral mucosal candiosis, herpes zoster, urinary tract infections, upper respiratory tract infections, rhinitis, influenza, infection, oral herpes.

Blood and lymphatic system disorders: very common – neutropenia (including 3-4 degree neutropenia associated with fever over 38 °С), leukopenia, febrile neutropenia, anemia, thrombocytopenia; often – myelosuppression.

Immune system disorders: often – hypersensitivity.

Mechanism and nutrition disorders: very common – decreased appetite, weight loss; common – hypokalemia, hyponatremia, hypomagnesaemia, hypocalcaemia, hyperglycaemia.

Mental disorders: frequently – sleep disorders, anxiety.

Nervous system disorders: very common – peripheral neuropathy, peripheral sensory neuropathy, taste disorders, paresthesia and dysesthesia, dysgeusia, headache; common – neurotoxicity, tremor, neuralgia, hypoesthesia.

Visual organ disorders: very common – lacrimation; common – visual disturbances, dry eyes, pain in the eyes, blurred vision.

Hearing and labyrinth disorders: often – “ringing” in the ears, hearing loss.

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

Vascular disorders: very common – thrombosis/embolism, increased blood pressure (BP), edema of the lower extremities; common – hyperemia, decreased blood pressure, hypertensive crisis, “tides”, phlebitis.

Respiratory system, thoracic and mediastinal disorders: very common – pharyngeal dysesthesia, pain in the throat; common – nasal bleeding, dysphonia, rhinorrhea, hiccups, pain in the pharynx and larynx.

Gastrointestinal disorders: very common – constipation, dyspepsia; common – upper GI bleeding, oral ulcers, gastritis, abdominal bloating, gastroesophageal reflux disease, oral pain, dysphagia, rectal bleeding, lower abdominal pain, dysesthesia, paresthesia and hypersthesia in the mouth, abdominal discomfort.

Liver and biliary tract disorders: often – liver dysfunction;

Skin and subcutaneous tissue disorders: very common – alopecia, altered nails; often – hyperhidrosis, erythematous rash, urticaria, night sweats.

Muscular system and connective tissue disorders: very common – myalgia, arthralgia, pain in the extremities; often – pain in the jaw, muscle spasms, trismus, muscle weakness.

Renal and urinary tract disorders: often – hematuria, proteinuria, decreased clearance of creatinine, dysuria.

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

In clinical trials and in the post-marketing period, cases of hepatic failure and cholestatic hepatitis have been reported. A causal relationship with capecitabine preparations has not been established.

In therapy with capecitabine in combination with other chemotherapeutic agents, cases of hypersensitivity reactions (2%) and myocardial ischemia/infarction (3%) have been reported frequently (but in less than 5% of patients).

Information on individual adverse reactions is provided below.

Diarrhea

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

Cardiotoxicity

Encephalopathy

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

Unwanted reactions in special clinical groups

Elderly patients

These were also associated with the use of capecitabine as monotherapy (incidence less than 1%). A safety profile analysis of patients aged ≥60 years who received capecitabine in combination with docetaxel as well as as monotherapy found an increase in serious adverse reactions and treatment-related grade 3 and 4 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 the development of adverse reactions compared to patients aged <60 years. A meta-analysis of 14 clinical trials involving more than 4,700 patients found that as patient age increased (for every 10 years), the risk of palpebral syndrome and diarrhea increased, while, conversely, the risk of neutropenia decreased.

Gender

Patients with renal impairment

Changes in laboratory parameters

Reduced neutrophil count, lower granulocyte count, lower lymphocyte count, lower platelet count, lower hemoglobin, hyperbilirubinemia, increased alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (ALP) activity, hypercreatininemia, hyperglycemia, hypo/hypercalcemia, hyponatremia, hypokalemia.

Post-marketing observations

The following adverse reactions were found during post-marketing use of capecitabine:

Renal and urinary tract disorders: rarely, acute renal failure as a consequence of dehydration, including fatal.

Nervous system disorders: frequency is unknown – toxic leukoencephalopathy.

Hepatic and biliary tract disorders: very rare – liver failure, cholestatic hepatitis.

Skin and subcutaneous tissue disorders: very rare – cutaneous lupus erythematosus, severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Visual organ disorders: very rare – lacrimal duct stenosis unspecified; corneal lesions, including keratitis; rarely – pitting keratitis.

Heart and vascular disorders: rarely – ventricular fibrillation; prolongation of the QT interval; ventricular tachycardia tachysystolic type “pirouette”; bradycardia, vasospasm.

If any of the side effects listed in the instructions worsen, or if you notice any side effects not listed in the instructions, tell your doctor.

Overdose

Symptoms of acute overdose include nausea, vomiting, diarrhea, mucosal inflammation (mucositis), gastrointestinal irritation and bleeding, and bone marrow suppression.

The treatment of overdose should include a standard set of therapeutic and supportive measures aimed at correction of clinical symptoms and prevention of possible complications.