Xavbobin - instructions for use, dose, side effects, contraindications

Components	Amount, mg
Active substance
Capecitabine	150,0	500,0
Excipients
Croscarmellose sodium	7,5	25,0
Microcrystalline cellulose	18,0	60,0
Hypromellose 5cR	7,5	25,0
Silica colloidal dioxide	1,8	6,0
Magnesium stearate	4,2	14,0
Casing of the tablet
Hypromellose 5cR	3,115	9,967
Titanium dioxide	1,279	3,987
Talc	0,262	0,839
Macrogol 400	0,328	1,049
Iron Oxide Red Dye Oxide	0,015	0,136
Dye iron oxide yellow	0,002	0,021

Description:

Dosage of 150 mg:

Oval biconvex tablets covered with a filmy coating of light pink with a yellowish tint of color with an embossed inscription "150" on one side.

On the cross section, the core of the tablet is white or almost white in color.

Dosage 500 mg:

Capsule-shaped tablets covered with a pink film cover with a yellowish tint of color with an embossed inscription "500" on one side.

On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:Antitumor agent - antimetabolite

ATX: & nbsp

L.01.B.C.06 Capecitabine

Pharmacodynamics:

Capecitabine is a derivative of fluoropyrimidine carbamate, an oral cytotoxic agent that activates in the tumor tissue and exerts a selective cytotoxic effect on it.

In vitro capecitabine does not have a cytotoxic effect, in vivo turns into fluorouracil (FU), which undergoes further metabolism. The formation of FU occurs predominantly in the tumor tissue under the action of a tumor angiogenic factor - thymidine phosphorylase, which minimizes the systemic effect of FU on healthy body tissues.

Sequential enzymatic biotransformation of capecitabine in FU creates higher drug concentrations in tumor tissues than in surrounding healthy tissues.

After oral administration of capecitabine to patients with colorectal cancer (N= 8) the concentration of FU in the tumor tissue is 3.2 times greater than its concentration in the adjacent healthy tissues (range from 0.9 to 8.0).

The ratio of FU concentrations in the tumor and plasma tissues is 21.4 (range from 3.9 to 59.9), the ratio of its concentration in healthy tissues and in plasma is 8.9 (range from 3 to 25.8).

The activity of thymidine phosphorylase in the primary colorectal tumor is also 4 times higher than in the adjacent healthy tissues.

In tumor cells in patients with breast, stomach, colorectal cancer, cervical and ovarian cancer, there is a higher level of thymidine phosphorylase, capable of converting 5'-deoxy-5-fluorouridine (5-DFUR) to 5-FU than in the corresponding healthy tissues.

Both healthy and tumor cells metabolize FU into 5-fluoro-2-deoxyuridine monophosphate (FUDF) and 5-fluorouridine triphosphate (FUTF). These metabolites damage the cells through two different mechanisms. First, FUUM and the folate cofactor N^5-10-methylenetetrahydrofolate bind to thymidylate synthase (TC) to form a covalently bound tertiary complex. This binding inhibits the formation of thymidylate from uracil.Thymidylate is a necessary precursor of thymidine triphosphate, which in turn is extremely important for DNA synthesis, so the lack of this substance can lead to inhibition of cell division.

Secondly, in the process of RNA synthesis, the transcriptional enzymes of the nucleus can erroneously include FUTM in it instead of uridine-triphosphate (UTP). This metabolic "error" disrupts RNA processing and protein synthesis.

Pharmacokinetics:

Suction

After oral administration capecitabine quickly and completely absorbed, after which it is transformed into the metabolites of 5'-deoxy-5-fluorocytidine (5'-DFTST) and 5'-DFUR. Food reduces the absorption rate of capecitabine, but the area under the concentration-time curve (AUC) 5'-DFUR and the next metabolite FU affects slightly. When capecitabine is administered after a meal at a dose of 1250 mg / m² on the 14th day the maximum concentrations in plasma (C_mOh) capecitabine, 5'-DFTST, 5'-DFUR, FU and FBAL were respectively 4.47, 3.05, 12.1, 0.95 and 5.46 μg / ml, respectively. The time to reach the maximum concentration (T_mOh) were 1.50, 2.00, 2.00, 2.00 and 3.34 hours. AUC_0-∞ were 7.75, 7.24, 24.6, 2.03 and 36.3 μg * h / ml, respectively.

Distribution (binding with proteins)

Study in vitro in human blood plasma showed that for capecitabine, 5'-DFTST, 5'-DFUR and FU, binding to proteins (mainly albumin) is 54%, 10%, 62% and 10%, respectively.

Metabolism

Primarily metabolized in the liver under the influence of carboxyl esterase to the metabolite 5'-DFTST, which is then transformed into 5'-DFUR under the action of cytidine deaminase, located mainly in the liver and tumor tissues. Further transformation to the active cytotoxic metabolite FU occurs predominantly in tumor tissue under the action of tumor angiogenic factor - thymidine phosphorylase.

AUC for FU in plasma is 6-22 times less than after intravenous bolus administration of FU at a dose of 600 mg / m². Metabolites of capecitabine become cytotoxic only after conversion to FU and metabolites of FU.

Further FU is catabolized with the formation of inactive metabolites of dihydro-5-fluorouracil (FUN₂), 5-fluoroureidopropionic acid (FCCC) and α-fluoro-β-alanine (FAL); this process occurs under the influence of dihydropyrimidine dehydrogenase (DPD), whose activity limits the reaction rate.

Excretion

Half-life from the body (T_1/2) capecitabine, 5'-DFTST, 5'-DFUR, FU and FBAL are 0.85, 1.11, 0.66, 0.76 and 3.23 hours, respectively. The pharmacokinetics of capecitabine were studied in doses ranging from 502 to 3514 mg / m² per day. The pharmacokinetic parameters of capecitabine, 5'-DFTST and 5'-DFUR on the 1 st and 14 th day were the same. AUC FU increased by day 14 to 30-35% and did not increase (day 22). In the range of therapeutic doses, the pharmacokinetic parameters of capecitabine and its metabolites, with the exception of FU, were dose-dependent.

After taking capecitabine, its metabolites are excreted mainly in the urine. Most (95%) of the accepted dose of capecitabine is excreted in the urine. Excretion with feces is minimal (2.6%). The main metabolite in urine is FBAL, which accounts for 57% of the dose taken. About 3% of the dose is excreted unchanged in the urine.

Combination Therapy

No effect of capecitabine on the pharmacokinetics of docetaxel or paclitaxel (C_mOh and AUC) And docetaxel or paclitaxel impact on the pharmacokinetics of 5'-DFUR (a metabolite of capecitabine ground) is detected.

Pharmacokinetics in special clinical groups

Sex, the presence or absence of metastases in the liver before the start of treatment, the index of the patient's general condition, the concentration of total bilirubin, serum albumin, the activity of ALT and ACT did not have a statistically significant effect on the pharmacokinetic properties of 5'-DFUR, FU, and FBAL.

Patients with hepatic insufficiency due to metastatic liver damage

In patients with mild to moderate liver function disorders caused by metastases, there is no clinically significant change in bioactivation and pharmacokinetics of capecitabine. Data on pharmacokinetics in patients with severe impairment of liver function are absent.

Patients with impaired renal function

The results of the pharmacokinetic study show that at varying degrees (from mild to severe) of renal failure, the pharmacokinetics of the unchanged drug and FU does not depend on creatinine clearance (CC). QC affects the magnitude AUC 5'-DFUR is the immediate precursor of FU (increase AUC by 35% with a decrease in CK by 50%) and FBAL (increase AUC by 114% with a decrease in QC by 50%). FBAL is a metabolite that does not possess antiproliferative activity; 5'-DFUR is the immediate precursor of FU.

Elderly patients

Age does not affect the pharmacokinetics of 5'-DFUR and 5-FU. AUC FBAL increased with age (an increase in the patient's age by 20% was accompanied by an increase AUC FBAL by 15%), which is probably due to changes in kidney function.

Indications:

Mammary cancer

- combined therapy with docetaxel of locally advanced or metastatic breast cancer with ineffective chemotherapy, including an anthracycline-based drug;

- monotherapy of locally advanced or metastatic breast cancer, chemotherapy-resistant taxanes or anthracycline-based drugs, or in the presence of contraindications to them.

Colorectal cancer

- adjuvant therapy for colon cancer III stage after surgical treatment;

- therapy of metastatic colorectal cancer.

Stomach cancer

- first-line therapy of advanced stomach cancer.

Contraindications:

- Hypersensitivity to capecitabine or any other components of the drug;

- hypersensitivity to fluorouracil or when there are reported cases of unexpected or severe adverse reactions to fluoropyrimidine derivatives in the history;

- established dihydropyrimidine dehydrogenase deficiency (DPD), as well as for other fluoropyrimidines;

- simultaneous administration of sorivudine and its structural analogues of brivudine type;

- severe hepatic impairment;

- leukopenia;

- severe renal failure (CC below 30 ml / min);

- initial neutrophil count <1.5 x 10⁹/ l and / or platelets <100 x 10⁹/ l;

- if there are contraindications to one of the drugs of combination therapy, it should not be used;

- pregnancy;

- the period of breastfeeding;

- children's age (efficacy and safety of use not established).

Carefully:

With ischemic disease (CHD), arrhythmia and angina in history, renal failure of moderate severity or liver failure, hypo- or hypercalcemia, diseases of the central and peripheral nervous system, diabetes mellitus and violations of water-electrolyte balance, age over 60 years, simultaneous application with oral coumarin anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Pregnancy and lactation:

Contraindicated the appointment of the drug during pregnancy and during breastfeeding.

Women of childbearing age during drug therapy Xalvobin and at least 3 months after the end, reliable methods of contraception should be used.If the pregnancy occurred during the period of therapy, the patient should be aware of the potential threat to the fetus.

Dosing and Administration:

For oral administration. After washing with water, not later than 30 minutes after eating.

Standard dosing regimen

Monotherapy

Colorectal cancer, colon cancer and breast cancer

At 1250 mg / m² 2 times a day - morning and evening (total daily dose of 2500 mg / m²) for two weeks followed by a seven-day break.

Combination Therapy

Mammary cancer

At 1250 mg / m² 2 times a day for two weeks followed by a seven-day break, in combination with docetaxel at a dose of 75 mg / m² 1 every 3 weeks as an intravenous infusion for 1 hour.

Premedication is performed before docetaxel is administered in accordance with the instructions for its use.

Colorectal cancer and stomach cancer

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

As a part of combined therapy with irinotecan (mode XELIRI) the recommended dose of the drug Xalvobin is 800 mg / m² 2 times a day for 14 days followed by a 7-day break. The addition of bevacizumab to combination therapy does not affect the initial dose of the drug Xavolbin.

Antiemetics and premedication to ensure adequate hydration are prescribed before the administration of cisplatin and oxaliplatin according to the instructions for the use of cisplatin and oxaliplatin when used in combination with the drug Xavolbin.

In adjuvant therapy for colon cancer, stage III, the recommended duration of drug therapy Xalvobin is 6 months, i.е. 8 courses.

In combination with cisplatin

Assign to 1000 mg / m² 2 times a day for two weeks followed by a seven-day break in combination with cisplatin (80 mg / m² 1 every 3 weeks, intravenous infusion for 2 hours, the first infusion is given on the first day of the cycle). The first dose of the drug Xalvobin is appointed in the evening on the first day of the therapy cycle, the latter on the morning of the 15th day.

In combination with okcaliplatin or with oxaliplatin and bevacizumab

Assign to 1000 mg / m² 2 times a day for two weeks followed by a seven-day break in combination with oxaliplatin or with oxaliplatin and bevacizumab.The first dose of the drug Xalvobin is appointed in the evening on the first day of the therapy cycle, the latter on the morning of the 15th day. Bevacizumab is administered at a dose of 7.5 mg / kg once every 3 weeks, IV infusion for 30-90 minutes, the first infusion starts on the first day of the cycle. After bevacizumab is introduced oxaliplatinum in a dose of 130 mg / m², intravenous infusion for 2 hours.

In combination with epirubicin and a platinum-based drug

Assign to 625 mg / m² 2 times a day in a continuous mode in combination with epirubicin (50 mg / m² 1 every 3 weeks, iv bolus starting from the first day of the cycle) and a platinum-based drug. The drug is based on platinum (cisplatin in a dose of 60 mg / m²or oxaliplatinum in a dose of 130 mg / m²) should be entered on the first day of the cycle in the form of IV infusion for 2 hours, then 1 every 3 weeks.

In combination with irinotecan or with irinotecan and bevacizumab

The recommended dose of the drug Xalvobin is 800 mg / m² 2 times a day 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 1 every 3 weeks, 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 every 3 weeks, intravenous infusion for 30-90 minutes, the first infusion begins on the first day of the cycle.

The following tables show examples of calculating the standard and reduced dose of the drug Xalvobin for an initial dose of 1250 mg / m² or 1000 mg / m².

Table 1. Standard and reduced doses of Xabvobin for an initial dose of 1250 mg / m², calculated depending on the surface area of the body

	Dose - at 1250 mg / m² 2 times a day
	The total dose of 1250 mg / m²	The number of tablets 150 mg and / or 500 mg per reception (for each intake 2 times a day - in the morning and in the evening)		Reduced dose of 950 mg / m² (75% of the initial dose)	Reduced dose of 625 mg / m² (50% of the initial dose)
Body surface area (m²)	Dose for admission (mg)	150 mg	500 mg	Dose for admission (mg)	Dose for admission (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	-	5	1950	1300
2,07-2,18	2650	1	5	2000	1300
≥2,19	2800	2	5	2150	1450

Table 2. Standard and reduced doses of Xalvobin for an initial dose of 1000 mg / m², calculated depending on the surface area of the body.

	The dose of 1000 mg / m² 2 times a day
	The total dose of 1000 mg / m²	Number of tablets 150 mg and / or 500 mg appointment (for every reception 2 times a day - in the morning and in the evening)		Reduced dose of 750 mg / m² (75% of the initial dose)	Reduced dose of 500 mg / m² (50% of the initial dose)
Body surface area (m²)	Dose for admission (mg)	150 mg	500 mg	Dose for admission (mg)	Dose for admission (mg)
≤1,26	1150	1	2	800	600
1,27-1,38	1300	2	2	1000	600
1,39-1,52	1450	3	2	1100	750
1,53-1,66	1600	4	2	1200	800
1,67-1,78	1750	5	2	1300	800
1,79-1,92	1800	2	3	1400	900
1,93-2,06	2000	-	4	1500	1000
2,07-2,18	2150	1	4	1600	1050
≥2,19	2300	2	4	1750	1100

Correction of dose during treatment

General recommendations

Toxic effects of the drug Xalvobin can be eliminated by symptomatic therapy and / or dose adjustment (interrupting treatment or reducing the dose of the drug). If the dose had to be reduced, you can not increase it later.

If the toxic effect of the drug is estimated by the attending physician Xalvobin does not carry a serious or life-threatening sick character, treatment can be continued at the initial dose without reducing it or interrupting therapy.

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

With the disappearance of signs of toxicity or a decrease in the last to Poi degree, drug therapy Xalvobin can be resumed in a full dose or adjusted according to the recommendations in Table 3.

With the development of signs of toxicity of the 4th degree, treatment should be stopped or temporarily interrupted until the symptoms are reduced or reduced to 1 degree, after which the use of the drug can be resumed at a dose equal to 50% of the initial level. The patient should immediately inform the doctor about the unwanted events that develop in him. Immediately stop taking the drug Xalvobin if severe or moderate to severe.

If, due to toxic effects, several medications were missed Xalvobin, these doses are not replenished.

Hematological toxicity

Do not administer capecitabine therapy to patients who have an initial level of neutrophils <1.5 x 10⁹/ l and / or initial platelet count <100 x 10⁹/ l.

Drug therapy Xalvobin should be interrupted if, during an unplanned evaluation of laboratory indicators, the number of neutrophils decreased below 1.0 x 10⁹/ l, and the number of platelets decreased below 75 x 10⁹/ l (haematological toxicity 3rd or 4th degree).

The table below shows recommendations for changing the dose of the drug Xalvobin in the case of development of toxic phenomena associated with its use.

Table 3. Scheme of dose adjustment Xalvobin

Toxicity to NCIC *	Dose variation during the course of therapy	Correction of dose during the next cycle of therapy (% of the initial dose)
Degree 1	Continue in the same dose	Continue in the same dose
Degree 2
1 appearance	Interrupt therapy before resolution to grade 0-1	100%
2 appearance	Interrupt therapy before resolution to grade 0-1	75%
3 appearance	Interrupt therapy before resolution to grade 0-1	50%
4 appearance	Completely stop therapy	Not applicable
Degree 3
1 appearance	Interrupt therapy before resolution to grade 0-1	75%
2 appearance	Interrupt therapy before resolution to grade 0-1	50%
3 appearance	Completely stop therapy	Not applicable
Degree 4
1 appearance	Completely discontinue therapy OR, if the doctor believes that it is in the patient's interest to continue treatment, discontinue therapy until resolution to grade 0-1	50%
2 appearance	Completely stop therapy	Not applicable

* In accordance with the general toxicity criteria of the Clinical Research Unit of the National Cancer Institute of Canada (NCIC CTG, version 1) or the common terminology criteria for adverse events of the Antitumor Evaluation Program of the National Cancer Institute (USACA, version 3). The criteria for toxicity of the palmar-plantar syndrome and hyperbilirubinemia are described in detail in the "Special instructions" section.

General recommendations for combination therapy

In case of occurrence of toxicity in combination therapy, the recommendations for dose adjustment should be followed Xalvobinmentioned in table 3 above, and the corresponding recommendations in the instructions for the use of other drugs.

At the beginning of the therapy cycle, if a delay is expected with taking the drug Xalvobin or other drug (s), all drugs should be deferred until the conditions for resumption of therapy with all drugs have been reached.

If, during the combination therapy cycle, the toxicity phenomena, according to the doctor, are not related to the use of the drug Xavolbin, then drug therapy Xalvobin should be continued, and the dose of another drug should be adjusted in accordance with the recommendations of the instructions for its use.

If the other drug (s) have to be canceled, the drug treatment Xalvobin can be continued when meeting the requirements for the resumption of therapy with the drug Xavolbin.

These recommendations are applicable to all indications and all special patient groups.

Correction of the dose in special cases

Violation of liver function in patients with liver metastases

There is no need to change the initial dose in patients with liver metastases and a mild or moderate liver function disorder.However, these patients should be carefully monitored. The use of the drug in patients with severe hepatic insufficiency has not been studied.

Impaired renal function

It is recommended that the initial dose be reduced to 75% from 1250 mg / m² in patients with initial moderate renal insufficiency (KK 30-50 ml / min, according to the formula Cockroft-Gault), do not require dose adjustment at an initial dose of 1000 mg / m².

In patients with mild renal insufficiency (KK 51-80 ml / min) correction of the initial dose is not required.

In case the patient develops an undesirable phenomenon of the 2nd, 3rd or 4th degree of severity, careful monitoring and immediate interruption of the therapy should be performed with a view to correcting the dose of the drug in accordance with the recommendations indicated in Table 3. If the calculated CC decreased during the therapy to less than 30 ml / min, drug therapy Xalvobin should be discontinued. Recommendations for correcting the dose of the drug for renal insufficiency of moderate severity apply both to monotherapy and to combination therapy. Calculation of the dose is indicated in Tables 1 and 2.

Childhood

Safety and efficacy of the drug Xalvobin in children was not studied.

Patients of elderly and senile age

Correction of the initial dose with monotherapy drug Xalvobin not required. However, severe adverse events of 3rd and 4th degree associated with ongoing therapy developed in patients older than 80 years more often than in younger patients.

When using the drug Xalvobin in combination with other antineoplastic agents in elderly patients (≥65 years of age), unwanted reactions of the 3rd and 4th degree of severity, as well as undesirable reactions requiring discontinuation of therapy, were noted more often than in younger patients. A thorough monitoring of the condition of elderly patients is recommended.

In the treatment in combination with docetaxel in patients aged 60 years and older there was an increase in the incidence of adverse events 3rd and 4th degree and serious adverse events associated with therapy. For patients aged 60 years and older who will receive a combination of the drug Xalvobin with docetaxel, it is recommended to lower the initial dose of the drug Xalvobin up to 75% (950 mg / m² 2 times a day). Calculation of the dose is given in Table 1.In the absence of toxicity, the dose may be increased to 1250 mg / m² 2 times a day.

Side effects:

The frequency of development of unwanted reactions is stated in accordance with the following gradation: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely ≥1 / 10000 and <1/1000), very rarely (<1/10000, including individual cases). The undesirable reactions listed below are listed in order of clinical significance.

The most common and / or clinically relevant adverse reactions during drug therapy Xalvobin were disorders of the gastrointestinal tract (gastrointestinal tract) (especially diarrhea, nausea, vomiting, abdominal pain, stomatitis), palmar-plantar syndrome, fatigue, drowsiness, anorexia, manifestations of cardiotoxicity, increased renal failure in patients with impaired renal function anamnesis, thrombosis / embolism.

Monotherapy with Xalvobin

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

Benign, malignant and unspecified neoplasms: infrequently - a lipoma.

Violations of the blood and lymphatic system: often - neutropenia, anemia; infrequently - febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, increased international correlation (INR), prolongation of prothrombin time.

Immune system disorders: infrequent - increased sensitivity.

Disorders from the metabolism and nutrition: very often - anorexia; often - dehydration, decreased appetite, weight loss; infrequently diabetes mellitus, hypokalemia, indigestion, hypertriglycercardia.

Disorders from the psyche: infrequently - confusion, panic attacks, depressed mood, decreased libido.

Disturbances from the nervous system: often - headache, dizziness (except vertigo), lethargy, paresthesia, dysgeusia (perversion of taste); infrequently - aphasia, memory disorder, ataxia, syncope, imbalance, loss of sensitivity, peripheral neuropathy.

Disturbances on the part of the organ of sight: often - increased tear, conjunctivitis; infrequent - reduced visual acuity, diplopia.

Hearing disorders and labyrinthine disorders: infrequently - vertigo, pain in the ears.

Heart Disease: infrequently - angina pectoris, including unstable, arrhythmia, sinus tachycardia, palpitation.

Vascular disorders: often - thrombophlebitis, infrequently - deep vein thrombosis, increased blood pressure, petechiae, lowering of arterial pressure, "hot flashes", cooling of the distal extremities.

Disturbances from the respiratory system, chest and mediastinal organs: often - epistaxis, rhinorrhea; infrequently - pneumothorax, hemoptysis, bronchial asthma, dyspnoea with physical exertion.

Disorders from the gastrointestinal tract: very often - diarrhea, vomiting, nausea, stomatitis (including ulcerative), abdominal pain; often - constipation, epigastric pain, dyspepsia; infrequent - intestinal obstruction, ascites, enteritis, gastritis, dysphagia, pain in the lower abdomen, discomfort in the abdomen, gastroesophageal reflux disease, colitis, blood in the stool.

Disturbances from the liver and bile ducts: often - violations of functional liver tests, hyperbilirubinemia; infrequently, jaundice.

Disturbances from the skin and subcutaneous tissues: very often - palmar-plantar syndrome (paresthesia, edema, flushing, skin peeling, blistering), dermatitis; often - hyperpigmentation of the skin, macular rash, rash, skin pigmentation disorder, alopecia, erythema, dry skin; infrequently - blisters, skin ulcers, hives, palmar erythema, face swelling, purpura. In less than 2% of patients, 7 of the completed clinical trials (N = 949) reported skin cracks, at least presumably associated with capecitabine therapy.

Disturbances from the musculoskeletal system and connective tissue: often - pain in the limbs, back pain; infrequently - swelling of the joints, pain in the bones, pain in the face, stiffness, muscle weakness.

Disorders from the kidneys and urinary tract: infrequently - hydronephrosis, urinary incontinence, hematuria, nocturia, increased content of creatinine in the blood.

Violations of the genitals and mammary gland: infrequently - vaginal bleeding.

General disorders and reactions at the site of administration: very often - fatigue, drowsiness; often - peripheral edema, malaise, chest pain, fever, weakness, asthenia; infrequently - edema, chills, flu-like syndrome, trembling, fever.

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

The following undesirable reactions are manifestations of toxicity, known for therapy with fluoropyrimidines; there has been at least an indirect link between the development of such reactions and the use of capecitabine in less than 5% of patients participating in 7 completed clinical trials (N = 949):

Disorders from the gastrointestinal tract: dry mouth, flatulence, undesirable reactions associated with inflammation / ulceration of the mucous membranes, such as: esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding.

Disorders from the cardiovascular system: 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.

Disturbances from the nervous system: a violation of taste, insomnia, confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, imbalance and coordination).

Disorders from the psyche: 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.

Violations of the blood and lymphatic system: anemia, myelosuppression, pancytopenia.

Disturbances from the skin and subcutaneous tissues: itching, focal skin peeling, hyperpigmentation of the skin, nail changes, photosensitization reactions, radiation dermatitis.

Disorders from the side of the organ of vision: eye irritation.

Disturbances from the respiratory system, chest and mediastinal organs: shortness of breath, cough.

Disturbances from the musculoskeletal system and connective tissue: arthralgia, myalgia, back pain.

General disorders and disorders at the site of administration: pain in the chest (non-cardial etiology), pain in the limbs.

Xalvobin in combination therapy

The safety profile did not differ with the appointment for different indications and with different combinations, however, undesirable reactions listed in monotherapy can be observed with a greater frequency when the drug is used Xalvobin in combination therapy.

Below are the undesirable reactions, which were observed additionally to those with monotherapy.

Infectious and parasitic diseases: often - the candidiasis of the oral mucosa, herpes zoster, urinary tract infection, upper respiratory tract infection, rhinitis, influenza, infection, herpes of the oral cavity.

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

Immune system disorders: often - hypersensitivity.

Disorders from the metabolism and nutrition: very often - decreased appetite, weight loss; often - hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia.

Disorders from the psyche: often - sleep disorders, anxiety.

Disturbances from the nervous system: very often - peripheral neuropathy, peripheral sensory neuropathy, taste disorder, paresthesia and dysesthesia, dysgeusia, headache; often - neurotoxicity, tremor, neuralgia, hypoesthesia.

Disturbances on the part of the organ of sight: very often - lacrimation; often - impaired vision, dry eyes, pain in the eyes, blurred vision.

Hearing disorders and labyrinthine disorders: often - "ringing" in the ears, deafness.

Heart Disease: often - atrial fibrillation, ischemia / myocardial infarction.

Vascular disorders: very often - thrombosis / embolism, increased blood pressure (BP), swelling of the lower limbs; often - hyperemia, lowering blood pressure, hypertensive crisis, "hot flashes", phlebitis.

Disturbances from the respiratory system, chest and mediastinal organs: very often - dysesthesia of the pharynx, sore throat; often - nosebleeds, dysphonia, rhinorrhea, hiccough, pain in the pharynx and larynx.

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

Disturbances from the liver and bile ducts: often - a violation of liver function;

Disturbances from the skin and subcutaneous tissues: very often - alopecia, nail change; often - hyperhidrosis, erythematous rash, hives, night sweats.

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

Disorders from the kidneys and urinary tract: often - hematuria, proteinuria, decreased creatinine clearance, dysuria.

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

In clinical studies and in the postmarketing period, cases of hepatic insufficiency and cholestatic hepatitis were recorded. Causation with the drugs capecitabine is not established.

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

Below you will find information on individual adverse reactions.

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 revealed covariates that were statistically associated with an increased risk of diarrhea: an increase in the initial dose of capecitabine (in grams), an elongation of the study period of therapy (in weeks), an increase in age for every 10 years) and female sex. Covariates statistically associated with a reduced risk of diarrhea: an increase in the cumulative dose of capecitabine (0.1 x kg), an increase in the relative intensity of the dose in the first 6 weeks of therapy (seesection "Special instructions").

Cardiotoxicity

As a result of the analysis of the safety profile of seven clinical trials with the participation of 949 patients who received capecitabine as a monotherapy, the following undesirable reactions (frequency less than 0.1%) were detected: cardiomyopathy, heart failure, sudden cardiac arrest and ventricular extrasystole (see section "Special instructions").

Encephalopathy

Encephalopathy was also associated with the administration of capecitabine as monotherapy (frequency less than 0.1%).

Undesirable reactions in specific clinical groups

Elderly patients

In the analysis of the safety profile in patients aged ≥60 years who received capecitabine in combination with docetaxel, and also as monotherapy, an increase in the number of serious adverse reactions and undesired reactions of grade 3 and 4 toxicity associated with treatment was found compared with patients <60 years of age. Patients aged ≥60 years who received capecitabine in combination with docetaxel, were also previously withdrawn from the study due to the development of unwanted reactions, compared with patients <60 years of age.As a result of a meta-analysis of 14 clinical trials involving more than 4,700 patients, it was found that with increasing patient's age (for every 10 years) the risk of palmar-plantar syndrome and diarrhea increased, while the risk of developing neutropenia, on the contrary, decreased see section "Method of administration and dose").

Floor

As a result of meta-analysis, 14 clinical trials involving more than 4,700 patients who received capecitabine, it was found that in female patients the risk of developing the palmar-plantar syndrome and diarrhea was higher, while the risk of developing neutropenia, on the contrary, decreased.

Patients with renal insufficiency (see also sections "Methods of administration and doses", "Special instructions")

In the analysis of the safety profile in patients with renal insufficiency who received capecitabine as monotherapy (colorectal cancer), an increase in the incidence of adverse events of grade 3 and 4 toxicity was found to be higher than in patients with normal renal function (36% (n= 268) patients with normal renal function compared with 41% (n= 257) patients with mild renal insufficiency and 54% (n= 59) patients with moderate renal insufficiency) (see section "Pharmacological properties"). Among patients with moderate renal insufficiency, the most frequent occurrence was a reduction in the dose of capecitabine (44%) compared with patients with normal renal function (33%) and patients with mild renal insufficiency (32%). There was also an increase in the number of patients who left the study at an early stage (21% of patients who left the study during the first two cycles) compared with patients with normal renal function (5%) and patients with mild renal insufficiency (8%).

Changes in laboratory indicators

Decreased number of neutrophils, decreased number of granulocytes, decreased number of lymphocytes, decreased platelet count, decreased hemoglobin, hyperbilirubinemia, increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase (AF), hypercreatininaemia, hyperglycemia, hypo- / hypercalcemia, hyponatremia, hypokalemia.

Post-market observations

During post-marketing useI preparations of capecitabine the following undesirable reactions were detected:

Disorders from the kidneys and urinary tract: rarely - acute renal failure as a consequence of dehydration, including fatal.

Disturbances from the nervous system: frequency unknown - toxic leukoencephalopathy.

Disturbances from the liver and bile ducts: very rarely - liver failure, cholestatic hepatitis.

Disturbances from the skin and subcutaneous tissues: very rarely - cutaneous form of lupus erythematosus, such severe skin reactions as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Disturbances on the part of the organ of sight: very rarely - stenosis of lacrimal tubule, unspecified; corneal damage, including keratitis; rarely - spot keratitis.

Violations from the heart and blood vessels: rarely - ventricular fibrillation; interval lengthening QT; arrhythmia ventricular tachysystolic type "pirouette"; bradycardia, vasospasm.

If any of the side effects indicated in the manual are aggravated, or if you notice any side effects not listed in the instructions, inform the doctor about it.

Overdose:

Symptoms acute overdose include nausea, vomiting, diarrhea, mucositis, irritation of the gastrointestinal tract and bleeding, as well as suppression of bone marrow function.

Treatment overdose should include a standard set of therapeutic and supportive measures aimed at correcting clinical symptoms and preventing possible complications.

Interaction:

Coumarin anticoagulants

In patients taking capecitabine simultaneously with anticoagulants coumarinic series (warfarin and fenprokumone), reports of coagulation and / or bleeding disorders were reported in a few days or months after initiation of capecitabine therapy, and in several cases within one month after its completion.

In the study of drug interaction after a single administration of warfarin in a dose of 20 mg capecitabine increased the AUC S-warfarin by 57%, and the value of the international normalized ratio (INR) - by 91%. In patients taking the drug simultaneously Xalvobin and anticoagulants of the coumarin series, it is necessary to carefully monitor the clotting indices (prothrombin time or INR), the dose of anticoagulant should be selected in accordance with these indices.

Substrates of cytochrome P450

Special studies of the drug interaction between capecitabine and other drugs metabolized by the 2S9 isoenzyme of the cytochrome P450 system were not carried out. Care should be taken when prescribing the drug Xalvobin together with these drugs.

Phenytoin

With concomitant administration of capecitabine and phenytoin, an increase in plasma concentration in plasma was reported. Special studies of the inter-drug interaction between capecitabine and phenytoin have not been carried out, but it is assumed that the basis of the interaction mechanism is the suppression of the isoenzyme P4502C9 under the influence of capecitabine (see "Coumarin anticoagulants" above). Patients receiving concomitantly phenytoin and drug Xalvobin, it is necessary to regularly monitor the concentration of phenytoin in the plasma.

Antacids

When assessing the pharmacokinetic parameters of the drug Xalvobin while concurrent administration with antacids containing aluminum hydroxide and magnesium hydroxide, there was a slight increase in the concentration of capecitabine and one of the metabolites (5'-DFTST) in blood plasma. The three major metabolites of capecitabine (5'-DFUR, FU and FBAL) did not exert any influence.

Allopurinol

It should avoid simultaneous reception of allopurinol and capecitabine, since it is possible to reduce the effectiveness of fluorouracil due to the interaction of fluorouracil with allopurinol.

Interferon alfa

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

Radiation therapy

The maximum tolerated dose of capecitabine in combination with radiotherapy in the treatment of patients with rectal cancer was 2000 mg / m² per day (with a continuous regimen of therapy or in the regime of therapy from Monday to Friday and a 6-day course of radiotherapy), while the maximum tolerated dose of capecitabine as monotherapy was 3000 mg / m² per day (intermittent mode).

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 influence of calcium folinate on the pharmacodynamics of capecitabine.

Sorivudine and its analogs

Literary sources describe the clinically significant drug interaction between sorivudine and 5-FU, which is based on the inhibitory effect of sorivudine on DPD. This interaction can lead to a fatal increase in the toxicity of fluoropyrimidines. Therefore, do not prescribe the drug Xalvobin simultaneously with sorivudine or its structural analogues such as brivudine. It should be observed 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 the drug Xavolbin.

Oxaliplatin

There was no clinically significant difference in the exposure of capecitabine or metabolites of oxaliplatin (free platinum or total platinum) with the combined use of capecitabine and oxaliplatin, regardless of the presence of bevacizumab.

Bevacizumab

Clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites was not observed.

Special instructions:

Adverse reactions that limit the dose of the drug are diarrhea, abdominal pain, nausea, stomatitis and palmar-plantar syndrome.

It is necessary to carry out thorough medical monitoring of manifestations of toxicity in patients receiving drug therapy Xavolbin.

Most of the undesirable phenomena are reversible and do not require complete discontinuation of the drug, although there may be a need for dose adjustment or temporary withdrawal of the drug.

Diarrhea

Treatment with drug Xalvobin can cause diarrhea, sometimes severe. Patients with severe diarrhea should be carefully monitored, and with the development of dehydration it is necessary to rehydrate or compensate for the loss of electrolytes. Standard antidiarrheal drugs (for example, loperamide) should be prescribed as soon as possible on medical grounds. According to the criteria of the National Cancer Institute of Canada (NCIC CTC, version 2) diarrhea 2 degrees is defined as the increase in stool to 4-6 times a day or stool at night, diarrhea 3 degrees - as a stool up to 7-9 times a day or incontinence and malabsorption syndrome, grade 4 diarrhea-like the increase in stool to 10 or more times a day, the appearance of visible blood in the stool or the need for parenteral maintenance therapy. If necessary, reduce the dose of the drug Xavolbin.

Dehydration

Dehydration should be prevented or eliminated at the outset of the occurrence. Dehydration can develop rapidly in patients with anorexia, asthenia, nausea, vomiting, or diarrhea.

Dehydration can lead to the development of acute renal failure, in some cases with a fatal outcome, especially in patients with renal dysfunction at the time of initiation of therapy or in the case of a patient taking capecitabine simultaneously with drugs that have a nephrotoxic effect.

With the development of dehydration of the 2nd degree or higher, treatment with the drug Xalvobin should immediately be discontinued and rehydrated. Treatment can not be resumed until the completion of rehydration and elimination or correction of the factors that caused it. The dose of the drug should be modified in accordance with the recommendations for adverse events leading to dehydration.

The spectrum of cardiotoxicity in the treatment with capecitabine is similar to that of other fluoropyrimidines and includes myocardial infarction, angina pectoris, arrhythmias, cardiac arrest, heart failure, and ECG changes.These undesirable phenomena are more typical for patients suffering from coronary artery disease in the anamnesis. Care must be taken in patients with arrhythmia and angina in history. During the therapy with capecitabine, development of hypo- or hypercalcemia was noted. Caution should be exercised in patients with previously diagnosed hypo- or hypercalcemia.

Care should be taken in patients with diseases of the central and peripheral nervous system (for example, in the presence of metastases in the brain and neuropathy), as well as in patients with diabetes mellitus and violations of water electrolyte balance, as in the course of treatment with capcitabine, possible aggravation of these diseases.

In rare cases, unexpected severe toxicity events (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with FU are due to inadequate activity of DPD. Thus, it is impossible to exclude the connection between the decreased activity of DPD and the more pronounced, potentially lethal toxicity of FU.

Patients should be observed for ocular complications, such as keratitis or corneal pathology, especially if there is a history of eye damage.In case of development of complications from the side of the eye, appropriate treatment should be prescribed.

A drug Xalvobin can cause the development of such serious skin reactions as Stevenson-Johnson syndrome and toxic epidermal necrolysis. With the development of severe skin reactions against the background of the drug Xalvobin The drug should be discontinued and not restarted.

The manifestation of skin toxicity of the drug Xalvobin is the development of the palmar dyspnea syndrome (synonyms: palmar-plantar erythrodysesthesia or erythema acroma caused by chemotherapy). Median time to development of manifestations of toxicity in patients receiving monotherapy with the drug Xalvobin, is 79 days (in the range of 11 to 360 days), and the severity varies from the 1st degree to the third degree. Palmar-plantar syndrome of the 1st degree does not disturb the daily activity of the patient and is manifested by numbness, dysesthesia / paresthesia, tingling or redness of the palms and / or soles, discomfort. Palmar-plantar syndrome of the 2nd degree is characterized by painful reddening and swelling of the hands and / or feet, and the discomfort caused by these symptoms disrupts the daily activity of the patient.Paladno-plantar syndrome of the third degree is defined as wet desquamation, ulceration, blistering and sharp pains in hands and / or feet, and also severe discomfort, making it impossible for the patient to any kinds of daily activities. When a palmar-plantar syndrome occurs in the 2nd or 3rd degree, drug therapy Xalvobin should be interrupted before the symptoms disappear or reduce to 1 st degree. If there is a syndrome of 3rd degree, subsequent doses of the drug Xalvobin should be reduced.

Vitamin AT₆ (pyridoxine) is not recommended for symptomatic or secondary prophylactic treatment of the palmar-plantar syndrome with the administration of the drug Xalvobin in combination with cisplatin, as it can reduce the effectiveness of cisplatin. There are data on the effectiveness of dexpanthenol in the prevention of the development of palmar-plantar syndrome in the therapy with capecitabine.

Hyperbilirubinemia

A drug Xalvobin can cause hyperbilirubinemia. If in connection with drug treatment Xalvobin there is hyperbilirubinemia> 3 x VGN (upper limit of the norm) or increased activity of "hepatic" aminotransferases (ALT, ACT)> 2.5 x VGN, treatment should be interrupted.

The therapy can be resumed with a decrease in the level of bilirubin and the activity of "hepatic" aminotransferases below these limits.

Simultaneous reception with coumarin anticoagulants

In patients taking the drug simultaneously Xalvobin and oral anticoagulants - coumarin derivatives, coagulation factors (prothrombin time or INR) should be monitored and, accordingly, a dose of anticoagulant should be selected.

The use of the drug in elderly and senile patients

The incidence of toxic events on the part of the gastrointestinal tract in patients with colorectal cancer aged 60-79 years who received capecitabine monotherapy did not differ from that in the general population of patients. In patients 80 years and older reversible adverse events from the third and fourth degree gastrointestinal tract, such as diarrhea, nausea and vomiting, developed more often. In patients ≥65 years of age who received combination therapy with capecitabine and other antitumor drugs, there was an increase in the incidence of adverse reactions of 3rd and 4th severity and adverse events that led to discontinuation of therapy compared with patients younger than 65 years of age.

When analyzing safety data in patients ≥60 years of age who received combination therapy with the drug Xalvobin and docetaxel, there was an increase in the incidence of third- and fourth-degree adverse events associated with therapy, serious adverse events and early withdrawal of therapy due to adverse events compared with those in patients younger than 60 years of age.

Renal insufficiency

Care should be taken when prescribing the drug Xalvobin patients with moderate renal insufficiency. As with treatment with fluorouracil, the incidence of adverse events of the 3rd and 4th degree of severity associated with ongoing therapy was higher in patients with moderate renal insufficiency (QA 30-50 ml / min).

Liver failure

Patients with hepatic impairment during drug therapy Xalvobin should be under close medical supervision. Influence of liver dysfunction, not caused by metastatic liver damage or severe hepatic insufficiency, on the distribution of the drug Xalvobin is unknown.

Pregnancy and the period of breastfeeding

During drug therapy Xalvobin and at least within 3 months after its end, reliable methods of contraception should be used. If the pregnancy occurred during the period of therapy, the patient should be aware of the potential threat to the fetus.

Additional Information

Handling of an unused product and an expired product. The ingestion of the medicinal product together with the waste in the environment must be minimized. Do not dispose of the product with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

Effect on the ability to drive transp. cf. and fur:

A drug Xalvobin has little or moderate influence on the ability to drive vehicles, mechanisms. Patients who experience such undesirable effects as dizziness, weakness, or nausea should refrain from controlling vehicles and mechanisms.

Form release / dosage:

Film-coated tablets, 150 mg and 500 mg.

Packaging:

For 10 tablets, film-coated in a blister of Al / PVC / PVDC or Al / PVC / PE / PVDC.

For 6 blisters (for a dosage of 150 mg) or 12 blisters (for a dosage of 500 mg) together with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003806

Date of registration:22.08.2016

Expiration Date:22.08.2021

The owner of the registration certificate:Alvogen IPKo S.A.L.Alvogen IPKo S.A.L. Luxembourg

Manufacturer: & nbsp

REMEDICA, Ltd. Cyprus

Representation: & nbspAlvogen Pharma Trading EuropeAlvogen Pharma Trading Europe

Information update date: & nbsp24.01.2018

Illustrated instructions

Instructions

Xalvobin (Xalvobin )