Capecitabine

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Dosage and Administration

Adverse reactions

The incidence of adverse reactions is set out according to WHO recommendations: very often (> 10%), often (> 1% and <10%), infrequently (> 0.1% and <1%), rarely (> 0.01% and < 0.1%), very rarely (<0.01%).

The most frequent side effects associated with taking capecitabine were disorders of the gastrointestinal tract (GIT) (diarrhea, nausea, vomiting, abdominal pain, stomatitis), palmar and plantar syndrome, increased fatigue, asthenia, anorexia, cardiotoxicity, renal buildup failure in patients with impaired renal function in history, as well as thrombosis / embolism.

Side effects reported in patients taking capecitabine as monotherapy

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

Benign, malignant and unspecified neoplasms: infrequently - lipoma.

Disorders of the blood and lymphatic system: often - neutropenia; infrequently - febrile neutropenia, granulocytopenia, thrombocytopenia, leukopenia, hemolytic anemia, an increase in the international normalized ratio, lengthening of the prothrombin time.

Immune system disorders: infrequently - hypersensitivity. Metabolic and nutritional disorders: very often - anorexia; often - dehydration, weight loss; infrequently - diabetes, hypokalemia, indigestion, hypertriglyceridemia.

Psychiatric disorders: infrequently - panic attacks, depressed mood, decreased libido.

Nervous system disorders: often - headache, dizziness (except vertigo), lethargy, paresthesias, dysgeusia (taste perversion): not often - aphasia, memory disorder, fainting, imbalance, loss of sensitivity, peripheral neuropathy.

Violations on the part of the organ of vision: often - increased tearing, conjunctivitis; infrequently - decreased visual acuity, diplopia.

Disturbances of the organ of hearing and labyrinth disorders: infrequently - vertigo, pain in the ears.

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

Vascular disorders: often - thrombophlebitis; infrequently - deep vein thrombosis, high blood pressure, petechiae, low blood pressure, "hot flushes", cooling of the distal extremities.

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

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

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

Violations of the skin and subcutaneous tissues: very often - palmar and plantar syndrome (paresthesia, edema, hyperemia, peeling of the skin, blistering), dermatitis; often - hyperpigmentation of skin, macular rash, rash, alopecia, erythema, dry skin; infrequently - blister, skin ulcers, urticaria, palmar erythema, swelling of the face, purpura. In less than 2% of patients in 7 completed clinical studies (N = 949), skin cracks were reported, at least presumably related to capecitabine therapy.

Disorders of the musculoskeletal and connective tissues: often - pain in the limbs, back pain; infrequently - swollen joints, bone pain, facial pain, stiffness, muscle weakness.

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

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

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

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

The following adverse reactions are manifestations of toxicity, known for therapy with fluoropyrimidines; At least an indirect association between the development of such reactions and the use of capecitabine was reported in less than 5% of patients who participated in 7 completed clinical studies (N = 949):

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

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

nervous system disorders: taste disturbance, insomnia, confusion, encephalopathy, cerebellar symptoms (ataxia, dysarthria, imbalance and coordination);

mental disorders: depression;

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

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

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

disorders of the organ of vision: eye irritation;

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

disorders of the musculoskeletal and connective tissues: arthralgia, myalgia, back pain;

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

Capecitabine use in combination therapy

The safety profile did not differ when prescribed for various indications and with various combinations, but the adverse reactions listed in monotherapy can be observed with greater frequency when capecitabine is used in combination therapy.

Below are the adverse reactions that were observed in addition to those with monotherapy:

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

Disorders of the blood and lymphatic system: very often - neutropenia, anemia, thrombocytopenia, leukopenia, febrile neutropenia; often - myelosuppression;

Immune system disorders: often - hypersensitivity;

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

Mental disorders: often - sleep disorders, anxiety;

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

Disturbances from the organ of vision: very often - lacrimation; often - visual disturbances, dry eyes, pain in the eyes, blurred vision;

Disorders of the organ of hearing and labyrinth disorders: often - tinnitus, hearing loss;

Heart disorders: often - atrial fibrillation;

Vascular disorders: very often - thrombosis / embolism, high blood pressure (BP), lower extremity edema; often - hyperemia, lowering blood pressure, hypertensive crisis, "hot flashes", phlebitis;

Disturbances of the respiratory system, organs of the chest and mediastinum: very often - pharyngeal dysesthesia, sore throat; often - nosebleeds, dysphonia, rhinorrhea, hiccups, sore throat and larynx;

Violations of 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, abdominal pain, dysesthesia, paresthesia and hypoesthesia in the mouth, abdominal discomfort;

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

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

Disorders of the musculoskeletal and connective tissues: very often - myalgia, arthralgia, pain in the limbs; often - pain in the jaw, muscle spasms, trismus, muscle weakness;

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

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

Both in clinical studies and outside of them, cases of liver failure and cholestatic hepatitis were recorded. A causal relationship with capecitabine has not been established.

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

Laboratory and instrumental data:

The following are changes in laboratory parameters observed in clinical trials in patients with adjuvant treatment of colon cancer and in patients with treatment of metastatic breast cancer and metastatic colorectal cancer, regardless of their relationship with capecitabine: neutropenia, granulocytopenia, lymphocytopenia, thrombocytopenia, anemia, hyperbilirubinemia, increased activity of ALT, AST, alkaline phosphatase, hypercreatininemia, hyperglycemia, hypo- / hypercalcemia, hyponatremia, hypoka iemiya.

Post-registration experience with capecitabine

rarely - acute renal failure as a result of dehydration, including fatal, point keratitis, ventricular fibrillation, lengthening of the QT interval, ventricular tachysystolic fibrin tina, pirouette, bradycardia, vasospasm; very rarely - cutaneous lupus erythematosus, severe skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, lacrimal tubular stenosis, unspecified, corneal lesion, including keratitis; very rarely, in clinical studies, cases of hepatic failure and cholestatic hepatitis were also recorded outside of their framework.

Diarrhea

Diarrhea was observed in 50% of patients during therapy with capecitabine. As a result of a meta-analysis of 14 clinical studies involving more than 4,700 patients receiving capecitabine therapy, covariates were identified that were statistically associated with an increased risk of developing diarrhea: an increase in the initial dose of capecitabine (in grams), an increase in the study period of treatment (in weeks), an increase in age of the patient (for every 10 years), female gender. Covariates, statistically associated with a decrease in the risk of developing diarrhea: an increase in the cumulative dose of capecitabine (0.1 kg) and an increase in the relative intensity of the dose in the first 6 weeks of treatment.

Patients with severe diarrhea should be carefully observed, conducting their rehydration and restoring the water-electrolyte balance during dehydration. According to the testimony, it is recommended to take standard antidiarrheal drugs (for example, loperamide) as early as possible.

Cardiotoxicity

In addition to the side effects presented in Tables 4 and 5, with monotherapy with capecitabine, the following adverse reactions were observed with a frequency of occurrence of less than 0.1%: cardiomyopathy, heart failure, sudden death and ventricular extrasystoles.

Encephalopathy

With monotherapy with capecitabine, encephalopathy was observed with a frequency of occurrence of less than 0.1%.

Adverse reactions in special patient groups

Elderly patients

Elderly patients aged> 60 years who received capecitabine as monotherapy or in combination with docetaxel showed an increase in the incidence of severity 3 and 4 severity and serious adverse reactions compared with patients aged <60 years="" most="" patients="" aged=""> 60 years who received the combination therapy with docetaxel showed an earlier cessation of treatment as a result of adverse reactions compared with patients aged <60 years="" as="" a="" result="" of="" meta-analysis="" 14="" clinical="" studies="" involving="" more="" than="" 4="" 700="" patients="" who="" received="" capecitabine="" it="" was="" found="" that="" with="" increasing="" patient="" age="" for="" every="" 10="" the="" risk="" developing="" palm-sole="" syndrome="" and="" diarrhea="" increases="" while="" neutropenia="" on="" contrary="" declined="" p="">

Floor

In female patients, there is a statistically significant increase in the risk of developing palm-sole syndrome and diarrhea, the risk of developing neutropenia is reduced.

Patients with impaired renal function

Patients with impaired renal function before treatment who received capecitabine monotherapy showed an increase in the incidence of adverse events of grade 3 and 4 associated with treatment compared with patients with normal renal function (36% in patients without renal dysfunction, 41% with mild renal insufficiency and 54% with moderate renal insufficiency). Patients with moderate renal failure more often needed to reduce the dose (44%) compared with 33 and 32% of patients without renal failure with mild renal insufficiency, respectively, and more often marked premature withdrawal of treatment.

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

- hypersensitivity to fluorouracil or in cases of unexpected or severe adverse reactions to the treatment with a history of fluoropyrimidine derivatives;

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

- simultaneous reception of sarivudin or its structural analogs of brivudin type;

- severe liver failure;

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

- severe leukopenia;

- the initial content of neutrophils <1,5x109 / l and / or platelet <100x109 l="" p="">

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

- pregnancy and lactation period;

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

Carefully:

With ischemic heart disease, anemia and angina in history, moderate renal insufficiency or liver failure, hypo-or hypercalcemia, diseases of the central and peripheral nervous system, diabetes mellitus and disorders of water and electrolyte balance, over the age of 60 years, simultaneous use with oral coumarin anticoagulants, hereditary lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Drug interactions

Coumarin Anticoagulants

In patients who took capecitabine concurrently with coumarin anticoagulants (warfarin and fenprocumon), impaired clotting rates and / or bleeding were reported several days or months from the start of capecitabine therapy, and in several cases within one month after termination.

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

CYP2C9 isoenzyme substrates

Special studies of drug interactions of capecitabine with other drugs metabolized by the cytochrome P450 CYP2C9 isoenzyme of the system have not been conducted. Caution should be exercised when applying capecitabine with these drugs.

Phenytoin

While taking capecitabine and phenytoin, an increase in plasma concentration of the latter was reported. There have been no special studies on the interactions interaction between capecitabine and phenytoin, however, it is assumed that the basis of the interaction mechanism is the suppression of the CYP2C9 isoenzyme under the influence of capecitabine (see above "Anticoagulants of the coumarin"). In patients receiving both phenytoin and capecitabine, it is necessary to regularly monitor the concentration of phenytoin in the plasma.

Antacids

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

Calcium folinate (leucovorin)

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

Sorivudin and its analogues

The literature describes the clinically significant drug interaction of sarivudine and FU, which is based on the inhibitory effect of sarivudine on DPD. This interaction can lead to a fatal increase in the toxicity of fluoropyrimidines.Therefore, capecitabine should not be administered at the same time as sorivudine or its structural analogs of brivudine type. There should be at least a four-week interval between the end of therapy with sarivudine or its structural analogues (including brivudine) and the start of treatment with capecitabine.

Oxaliplatin

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

Bevacizumab

The clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine, or its metabolites, is not marked.

Allopurinol

The interaction between allopurinol and FU was noted with a possible decrease in the efficiency of FU. Therefore, the simultaneous use of capecitabine and allopurinol should be avoided.

Interferon alfa

The maximum tolerated dose of capecitabine is 2000 mg / m2 per day while taking it with interferon alpha-2-alpha (3 million IU / m2 per day) compared with a dose of capecitabine 3000 mg / m2 per day with monotherapy.

Radiation therapy

The maximum tolerated dose of capecitabine in monotherapy with a standard dosing regimen is 3000 mg / m2, with combined use of colorectal cancer radiotherapy (with a continuous therapy or 5-day courses from Monday to Friday for 6 weeks) - 2000 mg / m2 in day.

Pregnancy and Lactation

Special instructions

• Brand name: Capecitabine
• Active ingredient: Capecitabine
• Dosage form: pills, film coated light peach color, oval, biconvex; with the engraving "500" on one side; cross-section tabletkat white.
• Manufacturer: Studies and clinical trials of Capecitabine (Click to expand)
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