Capecitabine, 500 mg 120 pcs

Breast Cancer

– Combination therapy with docetaxel for locally advanced or metastatic breast cancer when chemotherapy including an anthracycline drug is ineffective;

Monotherapy of locally advanced or metastatic breast cancer that is resistant to chemotherapy with taxanes or anthracycline-type drugs or if there are contraindications to them.

Colorectal cancer

– Adjuvant therapy of stage III colorectal cancer after surgical treatment;

The therapy of metastatic colorectal cancer.

Gastric cancer

– First-line therapy for advanced gastric cancer.

Active ingredient

Composition

Active ingredient:

accompanies:

lactose 91.11 mg,

How to take, the dosage

Orally with water, no later than 30 minutes after a meal.

The standard dosing regimen

Monotherapy

Colorectal cancer, colorectal cancer and breast cancer

By 1250 mg/m2 2 times a day, morning and evening.

It is 1250 mg/m2 twice daily, morning and evening (total daily dose 2500 mg/m2) for 14 days, followed by a 7-day break.

Combination therapy

Breast cancer

To 1250 mg/m2 2 times daily for 14 days followed by a 7-day break, in combination with docetaxel at a dose of 75 mg/m2 once every 21 days as an intravenous infusion for 1 hour.

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

Colorectal cancer and gastric cancer

As part of combination therapy, the dose of capecitabine should be reduced to 800-1000 mg/m2 2 times daily for 14 days followed by a 7-day break or to 625 mg/m2 2 times daily with a continuous regimen.

The addition of bevacizumab to combination therapy does not affect the starting dose of capecitabine.

Antidiarrheals and premedication to ensure adequate hydration are administered prior to the administration of cisplatin and oxaliplatin in accordance with the instructions for use of cisplatin and xaliplatin when used in combination with capecitabine.

In adjuvant therapy for colorectal cancer, the recommended duration of therapy with capecitabine is 6 months, which is 8 courses.

In combination with cisplatin

At 1000 mg/m2 2 times per day for 14 days followed by a 7-day break in combination with cisplatin (80 mg/m2 once every 3 weeks, IV infusion for 2 h, first infusion administered on day 1 of cycle).

The first dose of capecitabine is administered in the evening on day 1 of the therapy cycle, the last dose on the morning of day 15.

In combination with oxaliplatin or with oxaliplatin and bevacizumab

At 1000 mg/m2 twice daily for 14 days followed by a 7-day break in combination with oxaliplatin or with oxaliplatin and bevacizumab.

The first dose of capecitabine is given in the evening on day 1 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 day 1 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

At 625 mg/m2 2 times per day continuously in combination with epirubicin (50 mg/m2 once every 3 weeks, by IV bolus starting on day 1 of cycle) and platinum-based drug.

The platinum-based drug (cisplatin at a dose of 60 mg/m2 or oxaliplatin at a dose of 130 mg/m2) should be given on day 1 of the cycle as an IV infusion for 2 h, then once every 3 weeks.

In combination with irinotecan or with irinotecan and bevacizumab

At 800 mg/m2 twice daily for 14 days followed by a 7-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, IV infusion for 30 minutes, first infusion on day 1 of the cycle. Bevacizumab is administered at a dose of 7.5 mg/kg once every 3 weeks, IV infusion for 30-90 min, first infusion beginning on cycle day 1.

General recommendations

The toxic effects of capecitabine 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, the dose should not be increased thereafter.

If the treating physician’s assessment is that the toxic effect of capecitabine is not serious or life-threatening in the patient, treatment can be continued at the initial dose without reduction or discontinuation of therapy.

In 1st-degree toxicity, the dose is not changed. In case of grade 2 or 3 toxicity, therapy with capecitabine should be discontinued.

If signs of toxicity disappear or the latter is reduced to grade 1, therapy with capecitabine may be resumed at the full dose or adjusted as recommended.

If signs of grade 4 toxicity develop, treatment should be discontinued or temporarily interrupted until symptoms subside or decrease to grade 1, after which the drug can be resumed at a dose that is 50% of the initial dose.

The patient should immediately inform the physician about developing adverse events. Capecitabine should be discontinued immediately if severe or moderate toxicity occurs.

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

Hematologic toxicity

Capecitabine should not be used in patients with a baseline neutrophil count of less than 1.5×109/L and/or a baseline platelet count of <100×109/L.

Capecitabine therapy should be discontinued if an unscheduled laboratory evaluation shows a neutrophil count less than 1.0×109/L and a platelet count less than 75 x 109/L (Grade 3 or 4 hematologic toxicity).

General recommendations for combination therapy

If toxicity occurs with combination therapy, recommendations for adjusting the dose of capecitabine should be followed.

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

If, during the combination therapy cycle, toxicity does not appear to be related to capecitabine, the therapy with capecitabine 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 capecitabine can be continued if the requirements for resumption of capecitabine therapy are met. These recommendations apply for all indications and all special patient groups.

Use in Special Patient Groups

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 to reduce the initial dose to 75% of 1250 mg/m2 in patients with baseline moderate renal impairment (CKR 30-50 ml/min, according to Cockroft- Gault formula). In patients with mild renal insufficiency (CKR 51-80 ml/min), no adjustment of the initial dose is required.

If a patient has an adverse event of grade 2, 3 or 4 severity, its close monitoring and immediate discontinuation of therapy is required in order to further adjust the drug dose according to the recommendations.

If the calculated creatinine clearance decreases to less than 30 ml/min during therapy, therapy with capecitabine should be discontinued. Recommendations for adjusting the dose of the drug in moderate renal failure apply to both monotherapy and combination therapy.

In children

The safety and efficacy of capecitabine in children has not been studied.

Elderly and elderly patients

There is no need to adjust the initial dose with capecitabine monotherapy. However, severe therapy-related grade 3 and 4 adverse events developed more often in patients older than 80 years than in younger patients.

When using capecitabine in combination with other antitumor drugs in elderly patients (aged >65 years) adverse reactions of 3rd and 4th degree severity, as well as adverse reactions that required withdrawal of therapy, were observed more often 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 the combination of capecitabine with docetaxel, it is recommended that the starting dose of capecitabine be reduced to 75% (950 mg/m2 2 times daily).

In the absence of signs of toxicity, the dose may be increased to 1250 mg/m2 2 times per day.

When treated in combination with irinotecan in patients 65 years of age and older, it is recommended that the starting dose of capecitabine be reduced to 800 mg/m2 twice daily.

Interaction

Special Instructions

Contraindications

Hypersensitivity to capecitabine or any other drug components;

Hypersensitivity to fluorouracil or a history of unexpected or severe adverse reactions to treatment with fluoropyrimidine derivatives;

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

Side effects

The frequency of adverse reactions is stated according to WHO recommendations: very common (> 10%), common (> 1% and < 10%), infrequent (> 0.1% and < 1%), rare (> 0.01% and < 0.1%), very rare (< 0.01%).

. The most common side effects associated with administration of capecitabine were gastrointestinal (GI) disorders (diarrhea, nausea, vomiting, abdominal pain, stomatitis), palmar-subcutaneous syndrome, increased fatigue, asthenia, anorexia, cardiotoxicity, increased renal failure in patients with a history of impaired renal function, and thrombosis/embolism.

Side effects reported in patients who took capecitabine as monotherapy

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

Benign, malignant and unspecified neoplasms: infrequently – lipoma.

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

Immune system disorders: infrequent – hypersensitivity. Metabolic and nutrition disorders: very common – anorexia; common – dehydration, weight loss; infrequent – diabetes, hypokalemia, digestive disorders, hypertriglyceridemia.

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

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

Visual organ 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, dysphagia, lower abdominal pain, abdominal discomfort, gasgroesophageal reflux disease, blood in the stool.

Liver and biliary tract disorders: frequently – change of liver function tests; infrequently – 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, alopecia, erythema, dry skin; infrequent – blistering, skin ulcers, urticaria, palmar erythema, facial edema, purpura.

Less than 2% of patients in 7 completed clinical trials (N=949) reported cracked skin at least presumably related to capecitabine therapy.

Muscular 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 plasma creatinine.

Gender and mammary gland disorders: infrequent – vaginal bleeding.

General disorders and disorders 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 capecitabine use has been reported in less than 5% of patients in 7 completed clinical trials (N=949):

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

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

nervous system disorders: taste disorder, insomnia, confusion, encephalopathy, symptoms of cerebellar disorders (ataxia, dysarthria, balance and coordination disorders);

mental 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 flaking, skin hyperpigmentation, nail changes, photosensitization reactions, radiation dermatitis;

visual organ disorders: eye irritation;

respiratory system, thoracic and mediastinal organ disorders: shortness of breath, cough;

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

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

The use of capecitabine in combination therapy

The safety profile did not differ when administered for different indications and in different combinations, but adverse reactions listed in monotherapy may be observed with greater frequency when capecitabine 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 candidiasis, herpes zoster, urinary tract infections, upper respiratory tract infections, rhinitis, influenza, infection, oral herpes;

Blood and lymphatic system disorders: very common – neutropenia, anemia, thrombocytopenia, leukopenia, febrile neutropenia; common – myelosuppression;

Immune system disorders: common – hypersensitivity;

Metabolic and nutrition disorders: very often – weight loss, decreased appetite; often – hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, hyperglycemia;

Psychiatric disorders: often – sleep disorders, anxiety;

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

Visual disorders: very common – lacrimation; common – visual disturbances, dry eyes, eye pain, blurred vision;

Hearing and labyrinth disturbances: frequent – tinnitus, hearing loss;

Heart disorders: frequent – atrial fibrillation;

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

Respiratory system, chest and mediastinum disorders: very common – pharyngeal dysesthesia, sore throat; common – nasal bleeding, dysphonia, rhinorrhea, hiccups, pain in the pharynx and larynx;

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

Liver and biliary tract disorders: frequent – disorders of liver function;

Skin and subcutaneous tissue disorders: very frequent – alopecia, nail changes; frequent – hyperhidrosis, erythematous rash, urticaria, night sweats;

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

Renal and urinary tract disorders: frequent – hematuria, proteinuria, decreased creatinine clearance, dysuria;

General disorders and disorders at the site of administration: very frequent – weakness, lethargy, hypersensitivity to high and low temperatures; frequent – fever, pain, mucosal inflammation, chills, chest pain, flu-like syndrome, concussion.

Hepatic failure and cholestatic hepatitis have been reported both in and outside clinical trials. A causal relationship with administration of capecitabine 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).

Laboratory and instrumental findings:

The following are the changes in laboratory parameters observed in clinical trials in patients on adjuvant therapy for colorectal cancer and in patients on therapy for metastatic breast cancer and metastatic colorectal cancer, regardless of their association with capecitabine administration: Neutropenia, granulocytopenia, lymphocytopenia, thrombocytopenia, anemia, hyperbilirubinemia, increased ALT, AST, alkaline phosphatase activity, hypercreatininemia, hyperglycemia, hypo/hypercalcemia, hyponatremia, hypokalemia.

Post-registration experience with capecitabine

rare – acute renal failure as a consequence of dehydration, including fatal, pitting keratitis, ventricular fibrillation, prolonged QT interval, ventricular tachycardia tina “pirouette” arrhythmia, bradycardia, vasospasm; very rare – cutaneous lupus erythematosus, severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, lacrimal duct stenosis unspecified, corneal lesions including keratitis; very rare – cases of liver failure and cholestatic hepatitis were reported both in clinical trials and outside the clinical setting.

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: increased initial dose of capecitabine (in grams), increased study treatment period (in weeks), increased patient age (in every 10 years), female gender.

The covariates statistically associated with decreased risk of diarrhea: increased cumulative dose of capecitabine (0.1 to kg) and increased relative dose intensity in the first 6 weeks of treatment.

Patients with severe diarrhea should be closely monitored with rehydration and restoration of water-electrolyte balance with dehydration. Standard anti-diarrheal medications (e.g., loperamide) are recommended as early as possible if indicated.

Cardiotoxicity

In addition to the adverse effects shown in Tables 4 and 5, the following adverse reactions have been reported with an incidence of less than 0.1% with capecitabine monotherapy: cardiomyopathy, heart failure, sudden death, and ventricular extrasystoles.

Encephalopathy

The development of encephalopathy with an incidence of less than 0.1% has been reported with capecitabine monotherapy.

Adverse reactions in special patient groups

Elderly patients

In elderly patients aged >60 years of age who received capecitabine as monotherapy or in combination with docetaxel, there was an increased incidence of grade 3 and 4 adverse reactions and serious adverse reactions compared with patients aged < 60 years.

The majority of patients aged >60 years who received combination therapy with docetaxel were found to have earlier discontinuation of treatment as a result of adverse reactions compared with patients aged <60 years.

A meta-analysis of 14 clinical trials involving more than 4,700 patients who received capecitabine found that the risk of palpebral syndrome and diarrhea increased with increasing patient age (for every 10 years), while the risk of neutropenia, conversely, decreased.

Gender

Female patients had a statistically significant increased risk of palmar-sandibular syndrome and diarrhea, while the risk of neutropenia decreased.

Patients with impaired renal function

. In patients with impaired renal function prior to treatment with capecitabine monotherapy, an increased incidence of treatment-related grade 3 and 4 adverse reactions was noted compared to patients with normal renal function (36% in patients without renal impairment, 41% in patients with mild renal impairment and 54% in patients with moderate renal impairment).

Patients with moderate renal impairment were more likely to need a dose reduction (44%) compared with 33% and 32% of patients without renal impairment with mild renal impairment, respectively, and premature treatment withdrawal was more common.

Overdose

The symptoms of acute overdose include nausea, vomiting, diarrhea, mucosal inflammation (mucositis), gastrointestinal tract irritation and bleeding, and bone marrow function depression.

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

Pregnancy use

The drug is contraindicated in pregnancy and during breastfeeding.