Symptoms: severe myelosuppression (mainly leukopenia and thrombocytopenia), toxic effects from the gastrointestinal tract (mucositis).
Treatment acute overdose in patients with severe myelosuppression should be carried out in a hospital and include the administration of antibiotics, transfusion of granulocytes and platelets, and symptomatic therapy of mucositis.
Following the special precautions for storage (see below) the shelf life for the powder for solution for injection is 5 years. The expiration date is printed on the label.
Chemical and physical in-use stability of the reconstituted solution in 0.9% sodium chloride solution has been demonstrated for 7 days at 15-25 C and for 14 days under refrigeration (2-8 C).
Chemical and physical in-use stability of a 0.5 mg/ml solution in water for injections has been demonstrated for 24 hours at temperatures below 25 C.
Chemical and physical in-use stability of solutions in the range 0.05 mg/ml to 5 mg/ml in 0.9% sodium chloride solution has been demonstrated for 7 days at room temperature (15-25 C).
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 C, unless reconstitution has taken place in controlled and validated aseptic conditions.
Acute myelosuppression (including as a result of chemo-or radiation therapy), previous treatment with cumulative doses of pharmorubicin, daunoblastin or even adriblastin, bladder tumors complicated by narrowing of the urethra, urinary tract infections (intravesical instillation), cardiomyopathy (including in the anamnesis).
Hypersensitivity, impaired liver and kidney function, leukopenia, thrombocytopenia, anemia, myocarditis, myocardial infarction, arrhythmia, cystitis (with intravesical use), pregnancy, breast-feeding.
With the combined use of the drug Kelix® No increase in toxicity was found with cyclophosphamide or taxanes in patients with solid tumors (including ovarian cancer and breast cancer). However, it should be taken into account that Kelix® Like other doxorubicin hydrochloride preparations, it may increase the toxic effect of other antitumor agents.
There are reports of exacerbation of cyclophosphamide-induced hemorrhagic cystitis and increased hepatotoxicity of mercaptopurine in patients with AIDS-associated Kaposi's sarcoma when treated with standard doxorubicin hydrochloride. Caution should be exercised when concomitantly using any other cytostatics, especially myelotoxic agents.
The drug should not be mixed with other solutions, except for 5% dextrose solution for infusions.
With the combined use of the drug Doxorub® No increase in toxicity was found with cyclophosphamide or taxanes in patients with solid tumors (including ovarian cancer and breast cancer). However, keep in mind that Doxorub® Like other doxorubicin hydrochloride preparations, it may increase the toxic effect of other antitumor agents.
There are reports of exacerbation of cyclophosphamide-induced hemorrhagic cystitis and increased hepatotoxicity of mercaptopurine in patients with AIDS-associated Kaposi's sarcoma when treated with standard doxorubicin hydrochloride. Caution should be exercised when concomitantly using any other cytostatics, especially myelotoxic agents.
The drug should not be mixed with other solutions, except for 5% dextrose solution for infusions.
It can be used in combination with other chemotherapeutic antitumor agents.
Lactose
Loose, porous mass (powder) or tablet of red color.
Data on adverse reactions observed in clinical trials. The following are the adverse events reported in clinical trials and systematized for each of the organ systems, depending on the frequency of occurrence, using the following classification: very common (≥1/10), common (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated cases.
Adverse events observed in the course of clinical studies of the use of the drug Kelix® for the treatment of breast cancer patients
Infections and infestations: often — pharyngitis, folliculitis, fungal infections, feverish rashes on the skin (non-herpetic), upper respiratory tract infections.
From the blood and lymphatic system: often-leukopenia, anemia, neutropenia, thrombocytopenia, thrombocytemia.
From the nervous system: often-paresthesia, peripheral neuropathy, hot flashes, infrequently-drowsiness.
On the part of the visual organ: often-lacrimation, blurred vision.
From the heart: often-ventricular arrhythmia.
From the respiratory system, chest and mediastinal organs: often-shortness of breath, nosebleeds.
From the side of metabolism and nutrition: very often — anorexia.
From the gastrointestinal tract: very often-nausea, vomiting, stomatitis, often-ulceration of the oral mucosa, abdominal pain, constipation, diarrhea, dyspepsia, pain in the oral cavity.
From the skin and subcutaneous tissues: very often-alopecia, palmar-plantar syndrome, rash, often-erythema, dry skin, pigmentation disorders, itching, discoloration of the skin, bullous rash, dermatitis, erythematous rash, nail lesions, scaly skin.
Musculoskeletal and connective tissue disorders: often-leg cramps, bone pain, muscle pain.
On the part of the reproductive system and breast: often-pain in the mammary gland.
General disorders and reactions at the injection site: very often — fatigue, asthenia, inflammation of the mucous membranes, often-weakness, fever, pain, weight loss, swelling (including in the legs).
Influence on the results of laboratory tests: clinically significant deviations of laboratory parameters (grade III and IV) in this group of breast cancer patients included increases in the concentration of total bilirubin (2.4%) and AST activity (1.6%). The increase in ALT activity was less frequent (<1 %). There was no clinically significant increase in serum creatinine.
Adverse events observed in the course of clinical studies of the use of the drug Kelix® for the treatment of ovarian cancer patients
Infections and infestations: often-infections, candidiasis of the oral mucosa, shingles, urinary tract infections, other infections (including fungal infections, lower respiratory tract infections).
From the blood and lymphatic system: very often — leukopenia, anemia, neutropenia, thrombocytopenia, often-hypochromic anemia.
From the nervous system: often-paresthesia, drowsiness, headache, dizziness, neuropathy, increased blood pressure.
From the respiratory system, chest and mediastinal organs: often — pharyngitis, shortness of breath, increased cough.
From the gastrointestinal tract: very often — stomatitis, constipation, diarrhea, nausea, vomiting, often-abdominal pain, dyspepsia, ulceration of the oral cavity, esophagitis, gastritis, dysphagia, dry mouth, flatulence, gingivitis, perversion of taste.
From the skin and subcutaneous tissues: very often-palmar-plantar syndrome, alopecia, rash, often-dry skin, discoloration of the skin, vesiculobullosis rash, itching, exfoliative dermatitis, skin disorders, maculopapular rash, sweating, acne, skin ulcers.
On the part of the immune system: often-allergic reactions.
From the side of metabolism and nutrition: very often-anorexia, often-dehydration, cachexia.
Mental disorders: often-anxiety, depression, insomnia.
On the part of the visual organ: often-conjunctivitis.
From the heart: often-cardiovascular disorders.
From the side of the vessels: often-vasodilation.
Musculoskeletal and connective tissue disorders: often-back pain, myalgia.
From the kidneys and urinary tract: often-dysuria.
From the genitals and breast: often-vaginitis.
General disorders and disorders at the injection site: very often — asthenia, violation of the mucous membranes, often-fever, pain, chills, chest pain, malaise, peripheral edema.
Influence on the results of laboratory and instrumental studies: often-weight loss. Clinically significant deviations of laboratory parameters observed in patients with ovarian cancer during clinical trials of the drug Kelix®, included an increase in total bilirubin (usually in patients with liver metastases — 5%) and serum creatinine levels (5%). Increases in AST were less frequent (<1%). Sepsis in leukopenia was observed infrequently (<1%).
Adverse events observed in the course of clinical studies of the use of the drug Kelix® for the treatment of patients with multiple myeloma
Infections and infestations: often — herpes simplex, shingles, nasopharyngitis, oral candidiasis, pneumonia, upper respiratory tract infection.
From the blood and lymphatic system: very often — anemia, neutropenia, thrombocytopenia, often-febrile neutropenia, leukopenia, lymphopenia.
From the side of metabolism and nutrition: very often-anorexia, often - decreased appetite, dehydration, hyperkalemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia.
Mental disorders: often-anxiety, insomnia.
From the nervous system: very often-headache, neuralgia, peripheral sensory neuropathy, often-dizziness, dysesthesia, dysgeusia, hypesthesia, lethargy, neuropathy, paresthesia, peripheral neuropathy, polyneuropathy, fainting.
On the part of the visual organ: often-conjunctivitis.
From the side of the vessels: often-hot flashes, low blood pressure, increased blood pressure, orthostatic hypotension, phlebitis.
From the respiratory system, chest and mediastinal organs: often-cough, shortness of breath, nosebleeds, shortness of breath during exercise.
From the gastrointestinal tract: very often-nausea, vomiting, diarrhea, stomatitis, constipation, often-abdominal pain, dyspepsia, pain in the upper abdomen, ulceration of the oral cavity, dry mouth, dysphagia, aphthous stomatitis.
From the skin and subcutaneous tissues: very often-palmar-plantar syndrome, rash, often-dry skin, itching, papular rash, allergic dermatitis, erythema, hyperpigmentation of the skin, petechiae, alopecia, drug rash.
Musculoskeletal and connective tissue disorders: often-arthralgia, muscle spasms, muscle weakness, musculoskeletal pain in the chest, musculoskeletal pain, myalgia, pain in the extremities.
On the part of the reproductive system and breast: often-erythema of the scrotum.
General disorders and disorders at the injection site: very often — asthenia, fatigue, pyrexia, often-chills, hyperthermia, flu-like disease, malaise, peripheral edema.
Influence on the results of laboratory and instrumental studies: often — an increase in ALT activity in the blood, an increase in AST activity in the blood, an increase in the concentration of creatinine in the blood, a decrease in the ejection fraction, a decrease in body weight.
Adverse events observed in the course of clinical studies of the use of the drug Kelix® for the treatment of patients with AIDS-associated Kaposi's sarcoma
Infections and infestations: often-candidiasis of the oral cavity.
From the blood and lymphatic system: very often — neutropenia, anemia, leukopenia, often-thrombocytopenia.
From the side of metabolism and nutrition: often-anorexia.
Mental disorders: often-confusion.
From the nervous system: often-dizziness, infrequently-paresthesia.
On the part of the visual organ: often-retinitis.
From the side of the vessels: often-vasodilation.
From the respiratory system, chest and mediastinal organs: often-shortness of breath.
From the gastrointestinal tract: very often-nausea, often-diarrhea, stomatitis, vomiting, ulceration of the oral mucosa, abdominal pain, glossitis, constipation, nausea and vomiting.
From the skin and subcutaneous tissues: often — alopecia, rash, infrequently-palmar-plantar syndrome.
General disorders and disorders at the injection site: often-asthenia, fever, acute reactions to the infusion.
Influence on the results of laboratory and instrumental studies: often — weight loss.
Hematological toxic events may require dose reduction or suspension of therapy. It is necessary to temporarily suspend therapy with the drug Kelix® in patients with an absolute neutrophil count <1000 / mm3 and / or platelet count <50000 / mm3 G-CSF (or GM-CSF) can be used in concomitant therapy to maintain the number of shaped elements at an absolute neutrophil count of <1000 / mm.3 in subsequent cycles.
Respiratory side effects have been reported frequently (≥5%) in clinical trials of the drug Kelix® and may be associated with opportunistic infections in the AIDS patient population. Opportunistic infections (OI) were observed in patients with AIDS-associated Kaposi's sarcoma after the use of the drug Kelix®, and are often observed in patients with HIV-related immunodeficiency. The most frequently reported OI in clinical studies were: candidiasis, CMV infection, herpes simplex, pneumonia caused by Pneumocystis carinii and the complex Mycobacterium avium. Clinically significant laboratory disorders were frequently observed (≥5%) in clinical trials of the drug Kelix®. These included an increase in the activity of alkaline phosphatase, an increase in the activity of AST and the concentration of bilirubin, which were considered to be associated with the underlying disease, and not with the use of the drug Kelix®. Decreases in hemoglobin and platelet count were rare (<5%). Sepsis associated with leukopenia was rare (<1%). Some of the described deviations could be associated with the presence of HIV infection, and not with taking the drug Kelix®.
Post-registration surveillance data
Adverse reactions observed during post-marketing use of the drug Kelix® and systematized with respect to each of the organ systems depending on the frequency of occurrence, using the following classification are given below: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, <1/1000), very rarely (<1/10000), including isolated cases.
From the side of the vessels: patients with malignant tumors have an increased risk of developing thromboembolism. Infrequently — in patients taking the drug Kelix®, there are cases of thrombophlebitis and venous thrombosis, as well as pulmonary embolism.
From the skin and subcutaneous tissues: very rarely — serious skin disorders, including polymorphic erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Secondary neoplasms of the oral cavity: very rarely — with prolonged (more than one year) use of the drug Kelix® or if the total dose of the drug Kelix is reached® more than 720 mg / m2 patients have had cases of secondary oral cancer.
Data on adverse reactions observed in clinical trials. The following are the adverse events reported in clinical trials and systematized for each of the organ systems, depending on the frequency of occurrence, using the following classification: very common (≥1/10), common (≥1/100, <1/10), infrequent (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated cases.
Adverse events observed in the course of clinical studies of the use of the drug Doxorub® for the treatment of breast cancer patients
Infections and infestations: often — pharyngitis, folliculitis, fungal infections, feverish rashes on the skin (non-herpetic), upper respiratory tract infections.
From the blood and lymphatic system: often-leukopenia, anemia, neutropenia, thrombocytopenia, thrombocytemia.
From the nervous system: often-paresthesia, peripheral neuropathy, hot flashes, infrequently-drowsiness.
On the part of the visual organ: often-lacrimation, blurred vision.
From the heart: often-ventricular arrhythmia.
From the respiratory system, chest and mediastinal organs: often-shortness of breath, nosebleeds.
From the side of metabolism and nutrition: very often — anorexia.
From the gastrointestinal tract: very often-nausea, vomiting, stomatitis, often-ulceration of the oral mucosa, abdominal pain, constipation, diarrhea, dyspepsia, pain in the oral cavity.
From the skin and subcutaneous tissues: very often-alopecia, palmar-plantar syndrome, rash, often-erythema, dry skin, pigmentation disorders, itching, discoloration of the skin, bullous rash, dermatitis, erythematous rash, nail lesions, scaly skin.
Musculoskeletal and connective tissue disorders: often-leg cramps, bone pain, muscle pain.
On the part of the reproductive system and breast: often-pain in the mammary gland.
General disorders and reactions at the injection site: very often — fatigue, asthenia, inflammation of the mucous membranes, often-weakness, fever, pain, weight loss, edema (including in the legs).
Influence on the results of laboratory tests: clinically significant deviations of laboratory parameters (grade III and IV) in this group of breast cancer patients included increases in the concentration of total bilirubin (2.4%) and AST activity (1.6%). The increase in ALT activity was less frequent (<1 %). There was no clinically significant increase in serum creatinine.
Adverse events observed in the course of clinical studies of the use of the drug Doxorub® for the treatment of ovarian cancer patients
Infections and infestations: often-infections, candidiasis of the oral mucosa, shingles, urinary tract infections, other infections (including fungal infections, lower respiratory tract infections).
From the blood and lymphatic system: very often — leukopenia, anemia, neutropenia, thrombocytopenia, often-hypochromic anemia.
From the nervous system: often-paresthesia, drowsiness, headache, dizziness, neuropathy, increased blood pressure.
From the respiratory system, chest and mediastinal organs: often — pharyngitis, shortness of breath, increased cough.
From the gastrointestinal tract: very often — stomatitis, constipation, diarrhea, nausea, vomiting, often-abdominal pain, dyspepsia, ulceration of the oral cavity, esophagitis, gastritis, dysphagia, dry mouth, flatulence, gingivitis, perversion of taste.
From the skin and subcutaneous tissues: very often-palmar-plantar syndrome, alopecia, rash, often-dry skin, discoloration of the skin, vesiculobullosis rash, itching, exfoliative dermatitis, skin disorders, maculopapular rash, sweating, acne, skin ulcers.
On the part of the immune system: often-allergic reactions.
From the side of metabolism and nutrition: very often-anorexia, often-dehydration, cachexia.
Mental disorders: often-anxiety, depression, insomnia.
On the part of the visual organ: often-conjunctivitis.
From the heart: often-cardiovascular disorders.
From the side of the vessels: often-vasodilation.
Musculoskeletal and connective tissue disorders: often-back pain, myalgia.
From the kidneys and urinary tract: often-dysuria.
From the genitals and breast: often-vaginitis.
General disorders and disorders at the injection site: very often — asthenia, violation of the mucous membranes, often-fever, pain, chills, chest pain, malaise, peripheral edema.
Influence on the results of laboratory and instrumental studies: often-weight loss. Clinically significant deviations of laboratory parameters observed in patients with ovarian cancer during clinical trials of the drug Doxorub®, included an increase in total bilirubin (usually in patients with liver metastases — 5%) and serum creatinine levels (5%). Increases in AST were less frequent (<1%). Sepsis in leukopenia was observed infrequently (<1%).
Adverse events observed in the course of clinical studies of the use of the drug Doxorub® for the treatment of patients with multiple myeloma
Infections and infestations: often — herpes simplex, shingles, nasopharyngitis, oral candidiasis, pneumonia, upper respiratory tract infection.
From the blood and lymphatic system: very often — anemia, neutropenia, thrombocytopenia, often-febrile neutropenia, leukopenia, lymphopenia.
From the side of metabolism and nutrition: very often-anorexia, often - decreased appetite, dehydration, hyperkalemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia.
Mental disorders: often-anxiety, insomnia.
From the nervous system: very often-headache, neuralgia, peripheral sensory neuropathy, often-dizziness, dysesthesia, dysgeusia, hypesthesia, lethargy, neuropathy, paresthesia, peripheral neuropathy, polyneuropathy, fainting.
On the part of the visual organ: often-conjunctivitis.
From the side of the vessels: often-hot flashes, low blood pressure, increased blood pressure, orthostatic hypotension, phlebitis.
From the respiratory system, chest and mediastinal organs: often-cough, shortness of breath, nosebleeds, shortness of breath during exercise.
From the gastrointestinal tract: very often-nausea, vomiting, diarrhea, stomatitis, constipation, often-abdominal pain, dyspepsia, pain in the upper abdomen, ulceration of the oral cavity, dry mouth, dysphagia, aphthous stomatitis.
From the skin and subcutaneous tissues: very often-palmar-plantar syndrome, rash, often-dry skin, itching, papular rash, allergic dermatitis, erythema, hyperpigmentation of the skin, petechiae, alopecia, drug rash.
Musculoskeletal and connective tissue disorders: often-arthralgia, muscle spasms, muscle weakness, musculoskeletal pain in the chest, musculoskeletal pain, myalgia, pain in the extremities.
On the part of the reproductive system and breast: often-erythema of the scrotum.
General disorders and disorders at the injection site: very often — asthenia, fatigue, pyrexia, often-chills, hyperthermia, flu-like disease, malaise, peripheral edema.
Influence on the results of laboratory and instrumental studies: often — an increase in ALT activity in the blood, an increase in AST activity in the blood, an increase in the concentration of creatinine in the blood, a decrease in the ejection fraction, a decrease in body weight.
Adverse events observed in the course of clinical studies of the use of the drug Doxorub® for the treatment of patients with AIDS-associated Kaposi's sarcoma
Infections and infestations: often-candidiasis of the oral cavity.
From the blood and lymphatic system: very often — neutropenia, anemia, leukopenia, often-thrombocytopenia.
From the side of metabolism and nutrition: often-anorexia.
Mental disorders: often-confusion.
From the nervous system: often-dizziness, infrequently-paresthesia.
On the part of the visual organ: often-retinitis.
From the side of the vessels: often-vasodilation.
From the respiratory system, chest and mediastinal organs: often-shortness of breath.
From the gastrointestinal tract: very often-nausea, often-diarrhea, stomatitis, vomiting, ulceration of the oral mucosa, abdominal pain, glossitis, constipation, nausea and vomiting.
From the skin and subcutaneous tissues: often — alopecia, rash, infrequently-palmar-plantar syndrome.
General disorders and disorders at the injection site: often-asthenia, fever, acute reactions to the infusion.
Influence on the results of laboratory and instrumental studies: often — weight loss.
Hematological toxic events may require dose reduction or suspension of therapy. You should temporarily suspend therapy with Doxorub® in patients with an absolute neutrophil count <1000 / mm3 and / or platelet count <50000 / mm3 G-CSF (or GM-CSF) can be used in concomitant therapy to maintain the number of shaped elements at an absolute neutrophil count of <1000 / mm.3 in subsequent cycles.
Respiratory side effects were frequently reported (≥5%) in clinical trials of Doxorub® and may be associated with opportunistic infections in the AIDS patient population. Opportunistic infections (OI) have been reported in patients with AIDS-associated Kaposi's sarcoma after administration of Doxorub®, and are often observed in patients with HIV-related immunodeficiency. The most frequently reported OI in clinical studies were: candidiasis, CMV infection, herpes simplex, pneumonia caused by Pneumocystis carinii and the complex Mycobacterium avium. Clinically significant laboratory abnormalities were frequently reported (≥5%) in clinical trials of Doxorub®. These included an increase in the activity of alkaline phosphatase, an increase in the activity of AST, and the concentration of bilirubin, which were considered to be associated with the underlying disease, and not with the use of the drug Doxorub®. Decreases in hemoglobin and platelet count were rare (<5%). Sepsis associated with leukopenia was rare (<1%). Some of the described abnormalities could be associated with the presence of HIV infection, and not with taking the drug Doxorub®.
Post-registration surveillance data
Adverse reactions observed during post-marketing use of Doxorub® and systematized with respect to each of the organ systems depending on the frequency of occurrence, using the following classification are given below: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, <1/1000), very rarely (<1/10000), including isolated cases.
From the side of the vessels: patients with malignant tumors have an increased risk of developing thromboembolism. Infrequently — in patients taking the drug Doxorub®, there are cases of thrombophlebitis and venous thrombosis, as well as pulmonary embolism.
From the skin and subcutaneous tissues: very rarely — serious skin disorders, including polymorphic erythema, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Secondary neoplasms of the oral cavity: very rarely — with prolonged (more than one year) use of the drug Doxorub® or if the total dose of Doxorub is reached® more than 720 mg / m2 patients have had cases of secondary oral cancer.
With intravenous administration — myelosuppression, cardiac disorders, sometimes manifested a few weeks after discontinuation of therapy (heart failure), alopecia (in 85% of patients), cessation of hair growth (including beard), stomatitis (5-10 days after the first administration) with painful erosions, especially on the lateral surfaces of the tongue, in the sublingual area, nausea, vomiting, diarrhea, etc.gastrointestinal disorders, severe tissue damage, including necrosis (when the solution enters the tissues, especially repeated use of the same vein), venous sclerosis.
When administered inside the bladder — burning in the bladder and urethra, urination disorders (soreness, difficulty, frequency, etc.), hematuria.
Stomatitis, nausea, vomiting, alopecia, heart failure, heart pain, red urine staining, leukopenia, thrombocytopenia, anemia, allergic reactions.
There are no preclinical safety data of relevance to the prescriber which are additional to those already stated in other sections of the SPC.
metastatic breast cancer in the presence of indications for anthracycline therapy, including in the case of an increased risk of cardiac complications and in the case of ineffective therapy with taxanes,
common ovarian cancer with ineffective platinum-based chemotherapy,
progressive multiple myeloma (in combination with bortezomib) in patients who have received at least one line of chemotherapy and have undergone a bone marrow transplant (TCM) or are not candidates for TCM,
AIDS-associated Kaposi's sarcoma in patients with low CD4 levels (<200 CD4 lymphocytes / mm3) and extensive lesions of the skin and mucous membranes or visceral organs, other than Kaposi's sarcoma, amenable to local treatment or systemic treatment with interferon alpha. The drug Kelix® It can be used as a 1st or 2nd line of chemotherapy in patients with AIDS-associated Kaposi's sarcoma who are insensitive to drugs such as periwinkle alkaloids, bleomycin, and standard doxorubicin (or other anthracyclines).
metastatic breast cancer in the presence of indications for anthracycline therapy, including in the case of an increased risk of cardiac complications and in the case of ineffective therapy with taxanes,
common ovarian cancer with ineffective platinum-based chemotherapy,
progressive multiple myeloma (in combination with bortezomib) in patients who have received at least one line of chemotherapy and have undergone a bone marrow transplant (TCM) or are not candidates for TCM,
AIDS-associated Kaposi's sarcoma in patients with low CD4 levels (<200 CD4 lymphocytes / mm3) and extensive lesions of the skin and mucous membranes or visceral organs, other than Kaposi's sarcoma, amenable to local treatment or systemic treatment with interferon alpha. The drug Doxorub® It can be used as a 1st or 2nd line of chemotherapy in patients with AIDS-associated Kaposi's sarcoma who are insensitive to drugs such as periwinkle alkaloids, bleomycin, and standard doxorubicin (or other anthracyclines).
Breast, thyroid, lung, bladder (including superficial tumors), ovarian, osteosarcoma, soft tissue sarcoma, lymphogranulomatosis, non-Hodgkin's lymphoma, neuroblastoma, Wilms tumor, acute lymphoblastic leukemia, acute myeloblastic leukemia.
Breast and thyroid cancer, soft tissue sarcoma, osteogenic sarcoma, lymphosarcoma, acute leukemia, cervical and endometrial cancer, testicular cancer, prostate cancer, head and neck cancer, lung cancer, bladder cancer, myeloma, Hodgkin's disease and non-Hodgkin's lymphoma, neuroblastoma.
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. The exact mechanism of the antitumor action of doxorubicin is unknown. It is believed that the cytotoxic effect is due to its ability to inhibit the synthesis of DNA, RNA and proteins by introducing doxorubicin between adjacent base pairs of the DNA double helix, which prevents the helix from unfolding for subsequent replication. Kelix® it is a pegylated liposomal form of doxorubicin that circulates in the blood for a long time and provides a higher concentration of doxorubicin in tumor tissue than in normal tissues. Liposomes contain surface-bound hydrophilic polymers of methoxypolyethylene glycol (MPEG). These linear groups of MPEGs create a protective shell protruding above the surface of the liposomes, reducing the possibility of interaction between the lipid bilayer membrane and plasma components, which protects the liposomes from recognition by the phagocytic system and allows you to extend the circulation time of doxorubicin in the bloodstream. Pegylated liposomes also have a low-permeability lipid matrix and an internal water buffer system, which in combination allows you to keep doxorubicin inside the liposome during its circulation in the bloodstream. The relatively small size of the pegylated liposomes (the average diameter is approximately 100 nm) allows them to penetrate through the defects of the blood vessels of the tumor. The results of experimental studies indicate the penetration of pegylated liposomes from blood vessels and their accumulation in tumors
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. The exact mechanism of the antitumor action of doxorubicin is unknown. It is believed that the cytotoxic effect is due to its ability to inhibit the synthesis of DNA, RNA and proteins by introducing doxorubicin between adjacent base pairs of the DNA double helix, which prevents the helix from unfolding for subsequent replication. Doxorub® it is a pegylated liposomal form of doxorubicin that circulates in the blood for a long time and provides a higher concentration of doxorubicin in tumor tissue than in normal tissues. Liposomes contain surface-bound hydrophilic polymers of methoxypolyethylene glycol (MPEG). These linear groups of MPEGs create a protective shell protruding above the surface of the liposomes, reducing the possibility of interaction between the lipid bilayer membrane and plasma components, which protects the liposomes from recognition by the phagocytic system and allows you to extend the circulation time of doxorubicin in the bloodstream. Pegylated liposomes also have a low-permeability lipid matrix and an internal water buffer system, which in combination allows you to keep doxorubicin inside the liposome during its circulation in the bloodstream. The relatively small size of the pegylated liposomes (the average diameter is approximately 100 nm) allows them to penetrate through the defects of the blood vessels of the tumor. The results of experimental studies indicate the penetration of pegylated liposomes from blood vessels and their accumulation in tumors
Along with antitumor, it has an immunosuppressive effect.
With intravenous administration of the drug Kelix® The plasma concentration of doxorubicin and AUC, which are mainly related to pegylated liposomal doxorubicin (90 to 95% of the measured doxorubicin, respectively), are significantly higher than with equivalent doses of traditional (non-pegylated non-liposomal) doxorubicin.
Pharmacokinetic profile of the drug Kelix® indicates that the clearance of doxorubicin from the blood plasma is determined by the liposomal carrier. Doxorubicin becomes available only after the liposomes leave the vascular bed and enter the tissues.
In low doses (10-20 mg / m2) Kelix® demonstrates linear pharmacokinetics, at higher doses (20-60 mg / m2) - non-linear. Pharmacokinetic parameters when administered at a dose of 10 to 60 mg / m2: doxorubicin clearance-average 0.03 l / h / m (0.0080,152 l/h/m2), Vd - 1.93 l / m2 (0.96-3.85 l / m2), T1/2 - 73.9 hours (24-231 hours).
Pharmacokinetic parameters in patients with impaired liver function and hyperbilirubinemia differ slightly from the pharmacokinetic parameters of the normal concentration of total bilirubin.
Renal insufficiency (creatinine Cl 30-156 ml/min) does not affect the pharmacokinetic parameters. There are no data on the pharmacokinetics of the drug in patients with creatinine Cl less than 30 ml / min.
The age of patients (21-75 years) does not significantly affect the pharmacokinetic parameters of the drug Kelix®.
With intravenous administration of the drug Doxorub® The plasma concentration of doxorubicin and AUC, which are mainly related to pegylated liposomal doxorubicin (90 to 95% of the measured doxorubicin, respectively), are significantly higher than with equivalent doses of traditional (non-pegylated non-liposomal) doxorubicin.
Pharmacokinetic profile of Doxorub® indicates that the clearance of doxorubicin from the blood plasma is determined by the liposomal carrier. Doxorubicin becomes available only after the liposomes leave the vascular bed and enter the tissues.
In low doses (10-20 mg / m2) Doxorub® demonstrates linear pharmacokinetics, at higher doses (20-60 mg / m2) - non-linear. Pharmacokinetic parameters when administered at a dose of 10 to 60 mg / m2: doxorubicin clearance-average 0.03 l / h / m (0.0080,152 l/h/m2), Vd - 1.93 l / m2 (0.96-3.85 l / m2), T1/2 - 73.9 hours (24-231 hours).
Pharmacokinetic parameters in patients with impaired liver function and hyperbilirubinemia differ slightly from the pharmacokinetic parameters of the normal concentration of total bilirubin.
Renal insufficiency (creatinine Cl 30-156 ml/min) does not affect the pharmacokinetic parameters. There are no data on the pharmacokinetics of the drug in patients with creatinine Cl less than 30 ml / min.
The age of patients (21-75 years) does not significantly affect the pharmacokinetic parameters of the drug Doxorub®.
April 2005
Doxorub
Pharmachemie B.V.
Swensweg 5
PO Box 552
2003 RN Haarlem
The Netherlands.
At a temperature of 15-25 °C.
Keep out of reach of children.
Shelf life of the drug Adriblastin® instantlyophilizate for the preparation of a solution for intravascular and intravesical administration of 10 mg — 4 years. 5 years-solvent.
lyophilizate for the preparation of a solution for intravascular and intravesical administration of 50 mg — 4 years.
Do not use after the expiration date indicated on the package.
| Lyophilized powder for preparation of solution for injection | 1 fl. |
| doxorubicin hydrochloride | 10 mg |
| excipients: lactose, methylparaben, water for injection |
in vials of 10 mg, complete with solvent (water for injection in ampoules of 5 ml), in a pack of cardboard 1 set.
| Lyophilized powder for preparation of solution for injection | 1 fl. |
| doxorubicin hydrochloride | 50 mg |
| excipients: lactose, methylparaben, water for injection |
in vials of 50 mg, in a pack of cardboard 1 bottle.
Doxorubin 10 mg: PL 4946/0001
Doxorubin 50 mg: PL 4946/0002
Doxorubicin
General precautions
Doxorubicin should only be used under supervision of a physician who is experienced in cytotoxic therapy. Nausea, vomiting and mucositis are often severe and should be treated appropriately.
Doxorubicin should not be administered intramuscularly or subcutaneously.
The total dose of doxorubicin administered to the individual patient should take into account any previous or concomitant therapy with related compounds such as daunorubicin.
Extravasation
Extravasation results in a severe and progressive tissue necrosis. If extravasation occurs, the injection should be terminated immediately and restarted in another vein. Flooding with normal saline, local infiltration with corticosteroids with or without sodium hydrogen carbonate solution (8.4%), and application of dimethylsulfoxide have been reported with varying success. The advice of a plastic surgeon should be sought, and wide excision of the involved area should be considered.
Cardiotoxicity
Congestive heart failure and/or cardiomyopathy may be encountered several weeks after discontinuation of doxorubicin therapy. Severe cardiac failure may occur precipitously without antecedent ECG change.
The risk of severe, irreversible and therapy-resistant cardiomyopathy and resulting congestive heart failure gradually increases with increasing dosages. A cumulative dose of 450 mg/m2 should not be exceeded.
Age over 70 or below 15 years and female gender in children should be considered a risk factor, as well as concomitant heart disease. In addition, ECG changes may occur including a reduction in the voltage of the QRS wave, and a prolongation of the systolic time interval, and the ejection fraction may be reduced.
In patients previously treated with other anthracyclines or cyclophosphamide, mitomycin C or dacarbazine, and patients who received radiotherapy to the mediastinal area, cardiotoxicity may occur at doses lower than the recommended cumulative limit. The concurrent use of trastuzumab and anthracyclines (like doxorubicin) is not recommended.
Acute severe arrhythmias have been reported to occur during or within a few hours after doxorubicin administration.
Heart function should be assessed before, during and after doxorubicin therapy, e.g., by ECG, echocardiography or determination of the ejection fraction. If test results indicate change in cardiac function associated with doxorubicin the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.
Myelosuppression
The high incidence of bone marrow depression requires careful haematologic monitoring. The nadir is reached between 10-14 days after administration. Blood values usually return to normal within 21 days after administration. Doxorubicin therapy should not be started or continued when polynuclear granulocyte counts are below 2000/mm3, except in the treatment of acute leukaemia, where lower limits may be applied, depending on the circumstances.
Careful haematologic monitoring is also required because of the risk of secondary leukaemias after treatment with cytotoxic agents. A remission of acute leukaemia can be achieved when detected at an early stage.
Hepatic impairment
Hepatic function (SGOT, SGPT, alkaline phosphatase and bilirubin) should be evaluated before and during therapy.
Hyperuricaemia
Doxorubicin may induce hyperuricemia. The blood uric acid level should be monitored. Sufficient fluid intake should be ascertained (with a daily minimum of 3 l/m2). If necessary, a xanthine-oxidase inhibitor (allopurinol) may be administered.
Discoloration of urine
Doxorubicin may impart a red coloration to the urine.
Due to the frequent occurrence of nausea and vomiting, driving cars and operation of machinery should be discouraged.
In/in, for 2-3 minutes (pre-dissolve the contents of the bottle with 10 mg of the drug in 5 ml of isotonic sodium chloride solution, 50 mg - in 25 ml). Most often-60-75 mg / m2 1 time in 3 weeks or 20 mg / m2 weekly or 20-30 mg / m2 daily (3 days), with a repeat of the course every 3-4 weeks. At a bilirubin level of 12-30 mg / l, the dose should be reduced by 50%, at a level of more than 30 mg/l — by 75%. Total dose-no more than 550 mg / m2, in patients who underwent radiation therapy on the chest area or were treated with cardiotoxic drugs-no more than 400 mg/m2.
Intravesical-30-50 mg for instillation at intervals of 1 week to 1 month (the recommended concentration of the solution is 1 mg / ml of water for injection).
In / in drip. The drug can not be administered in a jet or undiluted form.
Treatment is continued until signs of progression or development of unacceptable toxicity appear.
The drug Kelix® It has unique pharmacokinetic properties and should not be replaced by other forms of doxorubicin hydrochloride. Treatment with Kelix® it should be carried out only under the supervision of a qualified oncologist who has experience in cytostatic therapy.
Breast cancer and ovarian cancer
In breast cancer and ovarian cancer, the drug is administered at a dose of 50 mg / m2 1 time in 4 weeks, until the progression of the disease and while the permissible tolerance is maintained.
At a calculated dose of less than 90 mg, the concentrate is diluted in 250 ml of 5% dextrose solution for infusions, at a dose of 90 mg or more - in 500 ml of 5% dextrose solution for infusions. To reduce the risk of developing infusion reactions, the first administration is carried out at a rate of no more than 1 mg / min. In the absence of reactions, subsequent infusions can be carried out within 60 minutes.
Repeated administration of the drug to patients who had infusion reactions to the previous administration should be carried out as follows: 5%of the calculated dose is administered slowly for 15 minutes. In the absence of reactions, the administration is continued at twice the speed for another 15 minutes. With good tolerability, the infusion is continued for the next hour (the total time of administration is 90 minutes). Subsequent infusions of the drug Kelix® can be held for 60 minutes.
Multiple myeloma
In the treatment of multiple myeloma Kelix® enter in a dose of 30 mg/m2 on the 4th day of the three-week cycle in combination with bortezomib (1.3 mg / m2 on days 1, 4, 8, and 11). Kelix® it is administered immediately after bortezomib for 1 hour. The therapy is indicated as long as the effect of the treatment is observed with its acceptable tolerability.
At a calculated dose of less than 90 mg, the concentrate is diluted in 250 ml of 5% (50 mg/ml) dextrose solution for infusions, at a dose of 90 mg or more — in 500 ml of 5% (50 mg/ml) dextrose solution for infusions.
The intravenous catheter and drip system should be flushed with a 5% dextrose solution between the administration of bortezomib and doxorubicin. If it is impossible to administer Kelix and bortezomib on the 4th day of the cycle, their administration can be postponed for 48 hours. If the administration of bortezomib was made later than the time indicated by the therapy scheme, then the subsequent administration of bortezomib should be carried out no earlier than 72 hours after the last dose. The first infusion of the drug Kelix® it can be assigned within 90 minutes according to the scheme:
- 10 ml first 10 min,
- 20 ml for the next 10 minutes,
- 40 ml for the next 10 minutes,
- then the remaining amount of the solution for 60 minutes.
In the subsequent dose of the drug Kelix® it can be administered within 1 hour If there is an occurrence of reactions to the infusion of the drug Kelix®, the infusion is stopped and after the symptoms disappear, the drug Kelix is prescribed® according to the following scheme:
- 10 ml for the first 10 minutes,
- 20 ml for the next 10 minutes,
- 40 ml for the next 10 minutes,
- then the remaining amount of solution for 60 minutes.
The infusion can be carried out through a central or peripheral venous catheter.
Kaposi's AIDS-associated sarcoma
The drug is administered intravenously at a dose of 20 mg / m2 1 time every 2-3 weeks, until the progression of the disease and while the permissible tolerance is maintained. Intervals between dosing of less than 10 days should be avoided because in this case it is possible to accumulate the drug in the body and increase its toxicity. To achieve a therapeutic effect, the course of treatment should be 2-3 months. Treatment should be continued to maintain the therapeutic effect.
The concentrate is diluted in 250 ml of 5% dextrose solution for infusions and administered as intravenous infusions for 30 minutes.
General rules for all patients. If the patient has initial symptoms or signs of a reaction to the administration of the drug, the infusion is immediately stopped, premedicated with antihistamines and / or fast-acting corticosteroids, and the infusion is resumed at a slower rate. Do not administer the drug in the form of bolus injections or in the form of an undiluted solution. When performing infusions, it is recommended to combine the solution of the drug Kelix® through the extreme port of intravenous infusion with an aqueous solution of 5% dextrose to achieve further dissolution and reduce the risk of thrombosis and bruising. The infusion can be carried out through the peripheral vein.
The drug Kelix® it should not be administered in / m or n / a, you can not use infusion systems with built-in filters.
To reduce the manifestations of certain side effects, such as palmar-plantar syndrome (erythrodysesthesia), stomatitis or hematological toxicity, the dose of the drug can be reduced or canceled.
Modification of the dosage regimen
Instructions for changing the dosage regimen of the drug Kelix® they are shown in the tables. The degrees of toxicity shown in the tables are based on the toxicity scale National Cancer Institute (NCI-CTC).
Table 1
Modification of the dosage regimen in connection with the development of palmar-plantar syndrome and stomatitis
| The degree of toxicity after the previous administration of the drug Kelix® | Correction of the dose of the drug Kelix® |
| Palmar-plantar syndrome | |
| Grade I (moderate erythema, edema, or desquamation that does not affect daily activities) | The administration of the drug is possible within 4 weeks from the date of the previous administration, or it can be postponed for another 1 week. If the patient has previously had a III-IV degree of toxicity, it is necessary to postpone treatment for 2 weeks (wait an additional week) and resume therapy at a 25% reduced dose, observing the initial 4-week interval between injections |
| Grade II (erythema, desquamation, edema affecting but not limiting daily physical activity, small blisters or ulcers (<2 cm in diameter) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. Then the treatment can be continued at the original dose and in the same mode. If there is no reduction in toxicity after 2 weeks, the therapy should be resumed at a dose reduced by 25%, observing the initial interval between injections. If patients have previously had grade III–IV toxicity, therapy should be resumed at a dose reduced by 25%, observing the initial interval between injections |
| Grade III (blisters, ulcers, swelling that interfere with walking or daily activities, the patient can not wear normal clothing and shoes) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If there is no reduction in toxicity after 2 weeks, treatment with Kelix® should be discontinued |
| Grade IV (diffuse or local processes leading to infectious complications, bed rest, or hospitalization) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If there is no reduction in toxicity after 2 weeks, treatment with Kelix® should be discontinued |
| Stomatitis | |
| Grade I (painless ulcers, erythema, or mild soreness) | The administration of the drug is possible within 4 weeks from the date of the previous administration, or it can be postponed for another 1 week. If the patient has previously had a grade III–IV toxicity, it is necessary to postpone treatment for 2 weeks (wait an additional week) and resume therapy at a dose reduced by 25%, observing the initial 4-week interval between injections, or stop treatment at the doctor's decision |
| Grade II (painful erythema, edema, or ulcers, but the patient can eat) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If no reduction in toxicity is observed after 2 weeks, the therapy should be resumed at a dose reduced by 25%, observing the initial interval between injections, or discontinue treatment at the doctor's decision |
| Grade III (painful erythema, edema or ulcers, the patient can not eat) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If there is no reduction in toxicity after 2 weeks, treatment with Kelix® should be discontinued |
| Grade IV (the condition requires parenteral or enteral nutrition) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If there is no reduction in toxicity after 2 weeks, treatment with Kelix® should be discontinued |
Table 2
Modification of the dosage regimen due to the development of hematological toxicity (in breast cancer, ovarian cancer)
| Hematological toxicity | |||
| Degree | Neutrophils (in 1 µl) | Platelets (in 1 µl) | Changing the dosage regimen |
| I | 1500–1900 | 75000–150000 | Continuation of therapy without reducing the dose |
| II | 1000–<1500 | 50000–<75000 | If the number of neutrophils is restored to 1,500 or more and platelets to 75,000 or more, continue treatment without reducing the dose |
| III | 500–<1000 | 25000–<50000 | If the number of neutrophils is restored to 1,500 or more and platelets to 75,000 or more, continue treatment without reducing the dose |
| IV | <500 | <25000 | When the number of neutrophils is restored to 1,500 or more and platelets to 75,000 or more, continue treatment by reducing the dose by 25%, or continue treatment at the same dose with the support of colony-stimulating factors |
Table 3
Modification of the dosage regimen for multiple myeloma
| Correction of doses of Kelix® and bortezomib in patients with multiple myeloma | ||
| Patient's condition | Kelix® | Bortezomib |
| Fever ≥38 °C and neutrophil count <1000 / µl | Do not administer the drug in this cycle if an adverse reaction occurs before the 4th day. If it is observed after the 4th day, then the next dose should be reduced by 25% | Reduce the next dose by 25% |
| On any day of use of the drug after the 1st day of each cycle: the number of platelets <25000 / µl, hemoglobin <8 g/dl, the number of neutrophils <500/µl | Do not administer the drug in this cycle if an adverse reaction occurs before the 4th day. If it is observed after the 4th day, then the next dose should be reduced by 25%, if the dose of bortezomib is reduced due to hematological toxicity* | Do not administer the drug if 2 or more doses are not administered in the cycle, then in the following cycles reduce the dose by 25% |
| Non-hematological drug toxicity of the III–IV degree | Do not administer the drug until the toxicity has decreased to < grade II, all subsequent doses should be reduced by 25% | Do not administer the drug until the toxicity has decreased to < grade II, all subsequent doses should be reduced by 25% |
| Neuropathic pain or peripheral neuropathy | No dose adjustment is required | See the instructions for use of bortezomib |
*For more information about the bortezomib regimen and dose adjustment, see the bortezomib instructions for use ("Dosage and administration").
If a patient with multiple myeloma receiving combination therapy with Kelix® and bortezomib, develops palmar-plantar syndrome or stomatitis, then the dose of the drug Kelix® it should be adjusted as indicated in table 1.
Patients with impaired liver function. When the serum bilirubin content is from 1.2 to 3 mg/dl, the calculated dose is reduced by 25%. If the bilirubin content exceeds 3 mg/dl, the calculated dose is reduced by 50%. If the patient has well tolerated the administration of this dose (without hyperbilirubinemia or an increase in the activity of liver enzymes in the blood serum), then the next dose is increased to the previous level (i.e., if the dose is reduced by 25%, it is increased to the full dose, if the dose is reduced by 50%, it is increased to 75% of the full dose). With good tolerability in subsequent cycles, the dose can be increased to the full dose. Kelix® it can be prescribed to patients with liver metastases with concomitant hyperbilirubinemia and increased activity of liver enzymes, up to 4 times higher than the ULN. Before administration of the drug Kelix® It is necessary to conduct a clinical and laboratory study of liver function, including the determination of the activity of ALT/AST, alkaline phosphatase, and bilirubin.
Patients with impaired renal function. Correction of the dosage regimen is not required. There are no data on the pharmacokinetics of the drug in patients with a creatinine Cl of less than 30 ml/min.
Patients with AIDS-associated Kaposi's sarcoma and splenectomy. Since at the moment there is no clinical data on the use of the drug Akelix® for the treatment of this group of patients, the use of the drug Kelix® in these patients, it is not recommended.
Children. Limited safety data obtained during Phase I studies indicate that doses up to 60 mg / m every 4 weeks are well tolerated in pediatric practice, however, the effectiveness of the drug Kelix® for the treatment of patients under 18 years of age is not established.
Adult patients. In patients aged 21 to 75 years, there are significant differences in the pharmacokinetics of the drug Kelix® not detected.
Rules for the preparation and administration of solution for infusions
Do not use the drug with signs of precipitation or the presence of suspended particles.
When using the drug, it is necessary to follow the rules for working with antitumor drugs. It is necessary to use gloves. In case of ingestion of the drug Kelix® on the skin or mucous membranes, immediately wash this area with soap and water.
Determine the dose of the drug Kelix®, required for the introduction. The required volume of the drug is collected in a sterile syringe. All manipulations should be carried out with strict compliance with the rules of asepsis (the drug does not contain preservatives and bacteriostatic additives).
It is recommended to enter Kelix® through the side port of the infusion system, through which a 5% dextrose solution is injected to achieve greater dilution and minimize the risk of thrombosis and extravasation. The infusion can be carried out in the peripheral vein.
Kelix® you can not enter in / m or p / K.
Do not use for the administration of the drug Kelix® infusion systems with a built-in filter.
It is recommended to enter Kelix® immediately after dilution with 5% dextrose solution for infusions. In cases where this is not possible, the prepared solution can be stored at a temperature of 2-8 °C and used for 24 hours.
In / in drip. The drug can not be administered in a jet or undiluted form.
Treatment is continued until signs of progression or development of unacceptable toxicity appear.
The drug Doxorub® It has unique pharmacokinetic properties and should not be replaced by other forms of doxorubicin hydrochloride. Treatment with Doxorub® it should be carried out only under the supervision of a qualified oncologist who has experience in cytostatic therapy.
Breast cancer and ovarian cancer
In breast cancer and ovarian cancer, the drug is administered at a dose of 50 mg / m2 1 time in 4 weeks, until the progression of the disease and while the permissible tolerance is maintained.
At a calculated dose of less than 90 mg, the concentrate is diluted in 250 ml of 5% dextrose solution for infusions, at a dose of 90 mg or more - in 500 ml of 5% dextrose solution for infusions. To reduce the risk of developing infusion reactions, the first administration is carried out at a rate of no more than 1 mg / min. In the absence of reactions, subsequent infusions can be carried out within 60 minutes.
Repeated administration of the drug to patients who had infusion reactions to the previous administration should be carried out as follows: 5%of the calculated dose is administered slowly for 15 minutes. In the absence of reactions, the administration is continued at twice the speed for another 15 minutes. With good tolerability, the infusion is continued for the next hour (the total time of administration is 90 minutes). Subsequent infusions of Doxorub® can be held for 60 minutes.
Multiple myeloma
In the treatment of multiple myeloma Doxorub® enter in a dose of 30 mg/m2 on the 4th day of the three-week cycle in combination with bortezomib (1.3 mg / m2 on days 1, 4, 8, and 11). Doxorub® it is administered immediately after bortezomib for 1 hour. The therapy is indicated as long as the effect of the treatment is observed with its acceptable tolerability.
At a calculated dose of less than 90 mg, the concentrate is diluted in 250 ml of 5% (50 mg/ml) dextrose solution for infusions, at a dose of 90 mg or more — in 500 ml of 5% (50 mg/ml) dextrose solution for infusions.
The intravenous catheter and drip system should be flushed with a 5% dextrose solution between the administration of bortezomib and doxorubicin. If it is impossible to administer Doxorub and bortezomib on the 4th day of the cycle, their administration can be postponed for 48 hours. If the administration of bortezomib was made later than the time indicated by the therapy scheme, then the subsequent administration of bortezomib should be carried out no earlier than 72 hours after the last dose. The first infusion of the drug Doxorub® it can be assigned within 90 minutes according to the scheme:
- 10 ml first 10 min,
- 20 ml for the next 10 minutes,
- 40 ml for the next 10 minutes,
- then the remaining amount of the solution for 60 minutes.
In the subsequent dose of the drug Doxorub® it can be administered within 1 hour If there is an occurrence of reactions to the infusion with Doxorub®, the infusion is stopped and after the symptoms disappear, the drug Doxorub is prescribed® according to the following scheme:
- 10 ml for the first 10 minutes,
- 20 ml for the next 10 minutes,
- 40 ml for the next 10 minutes,
- then the remaining amount of solution for 60 minutes.
The infusion can be carried out through a central or peripheral venous catheter.
Kaposi's AIDS-associated sarcoma
The drug is administered intravenously at a dose of 20 mg / m2 1 time every 2-3 weeks, until the progression of the disease and while the permissible tolerance is maintained. Intervals between dosing of less than 10 days should be avoided because in this case it is possible to accumulate the drug in the body and increase its toxicity. To achieve a therapeutic effect, the course of treatment should be 2-3 months. Treatment should be continued to maintain the therapeutic effect.
The concentrate is diluted in 250 ml of 5% dextrose solution for infusions and administered as intravenous infusions for 30 minutes.
General rules for all patients. If the patient has initial symptoms or signs of a reaction to the administration of the drug, the infusion is immediately stopped, premedicated with antihistamines and / or fast-acting corticosteroids, and the infusion is resumed at a slower rate. Do not administer the drug in the form of bolus injections or in the form of an undiluted solution. When performing infusions, it is recommended to combine the solution of the drug Doxorub® through the extreme port of intravenous infusion with an aqueous solution of 5% dextrose to achieve further dissolution and reduce the risk of thrombosis and bruising. The infusion can be carried out through the peripheral vein.
The drug Doxorub® it should not be administered in / m or n / a, you can not use infusion systems with built-in filters.
To reduce the manifestations of certain side effects, such as palmar-plantar syndrome (erythrodysesthesia), stomatitis or hematological toxicity, the dose of the drug can be reduced or canceled.
Modification of the dosage regimen
Instructions for changing the dosage regimen of Doxorub® they are shown in the tables. The degrees of toxicity shown in the tables are based on the toxicity scale National Cancer Institute (NCI-CTC).
Table 1
Modification of the dosage regimen in connection with the development of palmar-plantar syndrome and stomatitis
| Degree of toxicity after previous administration of Doxorub® | Doxorub®dose adjustment |
| Palmar-plantar syndrome | |
| Grade I (moderate erythema, edema, or desquamation that does not affect daily activities) | The administration of the drug is possible within 4 weeks from the date of the previous administration, or it can be postponed for another 1 week. If the patient has previously had a III-IV degree of toxicity, it is necessary to postpone treatment for 2 weeks (wait an additional week) and resume therapy at a 25% reduced dose, observing the initial 4-week interval between injections |
| Grade II (erythema, desquamation, edema affecting but not limiting daily physical activity, small blisters or ulcers (<2 cm in diameter) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. Then the treatment can be continued at the original dose and in the same mode. If there is no reduction in toxicity after 2 weeks, the therapy should be resumed at a dose reduced by 25%, observing the initial interval between injections. If patients have previously had grade III–IV toxicity, therapy should be resumed at a dose reduced by 25%, observing the initial interval between injections |
| Grade III (blisters, ulcers, swelling that interfere with walking or daily activities, the patient can not wear normal clothing and shoes) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If there is no reduction in toxicity after 2 weeks, treatment with Doxorub® should be discontinued |
| Grade IV (diffuse or local processes leading to infectious complications, bed rest, or hospitalization) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If there is no reduction in toxicity after 2 weeks, treatment with Doxorub® should be discontinued |
| Stomatitis | |
| Grade I (painless ulcers, erythema, or mild soreness) | The administration of the drug is possible within 4 weeks from the date of the previous administration, or it can be postponed for another 1 week. If the patient has previously had a grade III–IV toxicity, it is necessary to postpone treatment for 2 weeks (wait an additional week) and resume therapy at a dose reduced by 25%, observing the initial 4-week interval between injections, or stop treatment at the doctor's decision |
| Grade II (painful erythema, edema, or ulcers, but the patient can eat) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If no reduction in toxicity is observed after 2 weeks, the therapy should be resumed at a dose reduced by 25%, observing the initial interval between injections, or discontinue treatment at the doctor's decision |
| Grade III (painful erythema, edema or ulcers, the patient can not eat) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If there is no reduction in toxicity after 2 weeks, treatment with Doxorub® should be discontinued |
| Grade IV (the condition requires parenteral or enteral nutrition) | Postpone treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-I. If there is no reduction in toxicity after 2 weeks, treatment with Doxorub® should be discontinued |
Table 2
Modification of the dosage regimen due to the development of hematological toxicity (in breast cancer, ovarian cancer)
| Hematological toxicity | |||
| Degree | Neutrophils (in 1 µl) | Platelets (in 1 µl) | Changing the dosage regimen |
| I | 1500–1900 | 75000–150000 | Continuation of therapy without reducing the dose |
| II | 1000–<1500 | 50000–<75000 | If the number of neutrophils is restored to 1,500 or more and platelets to 75,000 or more, continue treatment without reducing the dose |
| III | 500–<1000 | 25000–<50000 | If the number of neutrophils is restored to 1,500 or more and platelets to 75,000 or more, continue treatment without reducing the dose |
| IV | <500 | <25000 | When the number of neutrophils is restored to 1,500 or more and platelets to 75,000 or more, continue treatment by reducing the dose by 25%, or continue treatment at the same dose with the support of colony-stimulating factors |
Table 3
Modification of the dosage regimen for multiple myeloma
| Dose adjustment of Doxorub® and bortezomib in patients with multiple myeloma | ||
| Patient's condition | Doxorub® | Bortezomib |
| Fever ≥38 °C and neutrophil count <1000 / µl | Do not administer the drug in this cycle if an adverse reaction occurs before the 4th day. If it is observed after the 4th day, then the next dose should be reduced by 25% | Reduce the next dose by 25% |
| On any day of use of the drug after the 1st day of each cycle: the number of platelets <25000 / µl, hemoglobin <8 g/dl, the number of neutrophils <500/µl | Do not administer the drug in this cycle if an adverse reaction occurs before the 4th day. If it is observed after the 4th day, then the next dose should be reduced by 25%, if the dose of bortezomib is reduced due to hematological toxicity* | Do not administer the drug if 2 or more doses are not administered in the cycle, then in the following cycles reduce the dose by 25% |
| Non-hematological drug toxicity of the III–IV degree | Do not administer the drug until the toxicity has decreased to < grade II, all subsequent doses should be reduced by 25% | Do not administer the drug until the toxicity has decreased to < grade II, all subsequent doses should be reduced by 25% |
| Neuropathic pain or peripheral neuropathy | No dose adjustment is required | See the instructions for use of bortezomib |
*For more information about the bortezomib regimen and dose adjustment, see the bortezomib instructions for use ("Dosage and administration").
If a patient with multiple myeloma receiving combination therapy with Doxorub® and bortezomib, develops palmar-plantar syndrome or stomatitis, then the dose of the drug Doxorub® it should be adjusted as indicated in table 1.
Patients with impaired liver function. When the serum bilirubin content is from 1.2 to 3 mg/dl, the calculated dose is reduced by 25%. If the bilirubin content exceeds 3 mg/dl, the calculated dose is reduced by 50%. If the patient has well tolerated the administration of this dose (without hyperbilirubinemia or an increase in the activity of liver enzymes in the blood serum), then the next dose is increased to the previous level (i.e., if the dose is reduced by 25%, it is increased to the full dose, if the dose is reduced by 50%, it is increased to 75% of the full dose). With good tolerability in subsequent cycles, the dose can be increased to the full dose. Doxorub® it can be prescribed to patients with liver metastases with concomitant hyperbilirubinemia and increased activity of liver enzymes, up to 4 times higher than the ULN. Before administration of Doxorub® It is necessary to conduct a clinical and laboratory study of liver function, including the determination of the activity of ALT/AST, alkaline phosphatase, and bilirubin.
Patients with impaired renal function. Correction of the dosage regimen is not required. There are no data on the pharmacokinetics of the drug in patients with a creatinine Cl of less than 30 ml/min.
Patients with AIDS-associated Kaposi's sarcoma and splenectomy. Since at the moment there is no clinical data on the use of the drug Doxorub® for the treatment of this group of patients, the use of the drug Doxorub® in these patients, it is not recommended.
Children. Limited safety data obtained in Phase I studies indicate that doses up to 60 mg / m every 4 weeks are well tolerated in pediatric practice, however, the effectiveness of the drug Doxorub® for the treatment of patients under 18 years of age is not established.
Adult patients. In patients aged 21 to 75 years, there are significant differences in the pharmacokinetics of Doxorub® not detected.
Rules for the preparation and administration of solution for infusions
Do not use the drug with signs of precipitation or the presence of suspended particles.
When using the drug, it is necessary to follow the rules for working with antitumor drugs. It is necessary to use gloves. In case of ingestion of Doxorub® on the skin or mucous membranes, immediately wash this area with soap and water.
Determine the dose of Doxorub®, required for the introduction. The required volume of the drug is collected in a sterile syringe. All manipulations should be carried out with strict compliance with the rules of asepsis (the drug does not contain preservatives and bacteriostatic additives).
It is recommended to enter Doxorub® through the side port of the infusion system, through which a 5% dextrose solution is injected to achieve greater dilution and minimize the risk of thrombosis and extravasation. The infusion can be carried out in the peripheral vein.
Doxorub® you can not enter in / m or p / K.
Do not use for the administration of the drug Doxorub® infusion systems with a built-in filter.
It is recommended to enter Doxorub® immediately after dilution with 5% dextrose solution for infusions. In cases where this is not possible, the prepared solution can be stored at a temperature of 2-8 °C and used for 24 hours.
In/in, intravesical, in / a.
Adriblastine can be used both as monotherapy and in combination with other cytostatics in different doses, depending on the treatment regimen.
In / in the introduction.
As monotherapy, the recommended standard dose per cycle is 60-75 mg / m2 the surface of the body. Usually, the drug is administered once during the cycle, but the cycle dose can be divided into several injections (for example, administered during the first 3 consecutive days or on the 1st and 8th day of the cycle). The cycles are repeated every 3-4 weeks. A weekly regimen of 10-20 mg/m is also used.2, in combination with other antitumor drugs - in a cyclic dose of 30-60 mg / m2 every 3-4 weeks.
Repeated administration of the drug is possible only when all signs of toxicity (especially gastrointestinal and hematological) disappear.
In patients with impaired liver function with an increased level of bilirubin in the blood serum, the dose of doxorubicin decreases depending on the indicators of the level of total bilirubin: at the level of bilirubin in the blood serum of 1.2–3 mg/dl — by 50%, above 3 mg/dl — by 75%.
It is recommended to prescribe lower doses or increase the intervals between cycles in patients who have previously received massive antitumor therapy, in children, in elderly patients, in obese patients (if the body weight is more than 130% of the ideal, there is a decrease in the systemic clearance of Adriblastin), as well as in patients with tumor infiltration of the bone marrow.
Intravenous administration of Adriblastine should be carried out with caution. To reduce the risk of thrombosis and extravasation, it is recommended to administer Adriblastin through the tube of the system for intravenous administration, during an infusion of 0.9% sodium chloride solution or 5% glucose solution, for 3-5 minutes.
The total dose of doxorubicin should not exceed 550 mg / m2.
In patients who have previously received radiation therapy on the mediastinal area/pericardial area or treated with other cardiotoxic drugs, if necessary, the total dose of doxorubicin exceeds 450 mg / m2 the administration of the drug should be carried out under strict monitoring of heart function.
Introduction to the bladder.
Introduction to the bladder is used in the treatment of superficial tumors of the bladder, as well as as a preventive measure, to reduce the likelihood of relapse after transurethral resection.
Intravesical-the recommended dose is 30-50 mg per instillation, with intervals between injections from 1 week to 1 month, depending on the goals of therapy (treatment or prevention).
The recommended concentration of the solution is 1 mg / ml of water for injection or 0.9% sodium chloride solution. After instillation is complete, patients should roll from side to side every 15 minutes to ensure that the drug has a uniform effect on the bladder mucosa. As a rule, the drug should be in the bladder for 1-2 hours. At the end of instillation, the patient should empty the bladder.
To prevent excessive dilution of the drug in the urine, patients should be warned that they should refrain from taking fluids for 12 hours before instillation. The systemic absorption of Adriblastin during instillation into the bladder is very low.
In cases of local toxic effects (chemical cystitis, which can be manifested by dysuria, polyuria, nycturia, painful urination, hematuria, discomfort in the bladder, necrosis of the bladder wall), the dose intended for instillation should be dissolved in 50-100 ml of saline solution.
Special attention should be paid to problems associated with catheterization (for example, with obstruction of the urethra due to massive intravesical tumors).
B / a introduction.
In patients with hepatocellular cancer, to ensure intensive local exposure while reducing the overall toxic effect, Adriblastin can be administered intravenously into the main hepatic artery at a dose of 30-150 mg/m2 at intervals of 3 weeks to 3 months. Higher doses should be used only in cases where extracorporeal excretion of the drug is carried out simultaneously.
Since this method is potentially dangerous, and when it is used, widespread tissue necrosis can occur, intravenous administration can only be carried out by doctors who are proficient in this technique.
I / v, 75 mg / m2 every 3rd week.
Instructions for reconstitution:
For intravenous injection, Doxorubicin powder for solution for injection should be reconstituted to a concentration of 2 mg/ml in water for injections immediately before use. Alternatively, sodium chloride for injections may be used as a solvent, however, the product may take longer to dissolve.
In order to reconstitute the product, ensure the powder, solutions and equipment are at room temperature, add 5 (25) ml to the 10 (50) mg vial and shake for at least 60 seconds and leave to stand at room temperature for at least 5 minutes before administration to get a clear red mobile liquid. If gelatinous fragments are seen, leave the solution to stand for 5 minutes and shake again. Should the fragments still be visible, discard the solution.
When water for injections is used, immediate dilution to a concentration of less than 0.4mg/ml doxorubicin with 0.9% sodium chloride solution or 5% glucose solution is needed in order to obtain an isotonic solution.
Due to the toxic nature of doxorubicin it is recommended that the following protective measures be taken:
-General instructions for safe use of cytotoxics:
- Training in good techniques for reconstitution and handling should be given to relevant personnel.
- Pregnant staff should be excluded from working with this drug
- Protective clothing should be worn while administering, handling or reconstituting doxorubicin
- Contact with skin or eyes should be avoided. If it occurs, the affected area should be washed immediately with water, soap and water or sodium bicarbonate solution.
- Any spillages should be cleaned with dilute sodium hypochlorite solution.
- All equipment used for the handling, preparation and administration of doxorubicin should be incinerated.
Unused products should be disposed of in a suitable labelled container, marked as hazardous waste.
12-July-1993
