Universal reference book for medicines
Product name: KELIX В® (CAELYX В® )

Active substance: doxorubicin

Type: Antitumor antibiotic

Manufacturer: JOHNSON & JOHNSON (Russia) manufactured and packaged by GlaxoSmithKline Manufacturing (Italy) secondary packaging and quality control JANSSEN PHARMACEUTICA (Belgium)

Composition, form of production and packaging
Concentrate for the preparation of a solution for intravenous administration
in the form of a translucent suspension of red color.

1 ml

doxorubicin hydrochloride pegylated liposomal 2 mg

Excipients: phosphatidylcholine, carbomoylmethoximacrogolddystearoylglycerophosphoethanolamine sodium, cholesterol, ammonium sulfate, histidine, sucrose, hydrochloric acid, sodium hydroxide, water d / u.

10 ml - bottles of glass (1) - packs of cardboard.

25 ml - bottles of glass (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2016.

PHARMACHOLOGIC EFFECT

Antitumor drug.
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. The exact mechanism of the antitumor effect 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 implanting doxorubicin between adjacent base pairs of the DNA double helix, which prevents the spiral from unfolding for subsequent replication.
Kelix В® is a pegylated liposomal form of doxorubicin that circulates long in the blood and provides a higher concentration of doxorubicin in the tumor tissue than in normal tissues.
Liposomes contain surface-bound hydrophilic polymers of methoxypolyethylene glycol (MPEG). These linear MPEG groups create a protective shell protruding above the liposome surface, reducing the possibility of interaction between the lipid bilayer membrane and plasma components, which protects liposomes from recognition by the phagocytic system and allows lengthening the circulation time of doxorubicin in the bloodstream. Pegylated liposomes also have a low permeability lipid matrix and an internal aqueous buffer system that, in combination, allows to retain doxorubicin within the liposome while circulating it in the bloodstream. The rather small size of the pegylated liposomes (average diameter of about 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 cumulation in tumors.
PHARMACOKINETICS

With intravenous administration of Kelix В®, the concentration of doxorubicin in plasma and AUC relate predominantly to pegylated liposomal doxorubicin (from 90% to 95% of the measured doxorubicin, respectively), and is significantly higher than when equivalent doses of traditional (non-pegylated non-liposomal) doxorubicin are administered.

The pharmacokinetic profile of doxorubicin indicates that its clearance from plasma is determined by a liposome carrier.
Doxorubicin becomes available only after the release of liposomes from the vascular bed and penetration into the tissues.
In low doses (10-20 mg / m 2 ) the drug shows a linear pharmacokinetics, at higher doses (20-60 mg / m 2 ) - nonlinear.

The pharmacokinetics indices at the dose of 10 to 60 mg / m 2 : clearance of doxorubicin - on average 0.03 l / h / m 2 (0.008-0.152 l / h / m 2 ), V d - 1.93 l / m 2 (0.96- 3.85 l / m 2 ), T 1/2 - 73.9 h (24-231 h).

Pharmacokinetics in special clinical cases

Pharmacokinetic parameters for violations of liver function and hyperbilirubinemia slightly differ from pharmacokinetic parameters of normal concentration of total bilirubin.

Renal failure (KK 30-156 ml / min) does not affect the pharmacokinetic parameters.
There is no data on the pharmacokinetics of the drug in patients with creatinine clearance less than 30 ml / min.
The age of patients (21-75 years) does not significantly affect the pharmacokinetic parameters of Kelix В® .

INDICATIONS

- metastatic breast cancer in the presence of indications for therapy with anthracyclines, including.
in the case of an increased risk of cardiac complications and in the ineffectiveness of therapy with taxanes;
- common ovarian cancer with ineffective chemotherapy with platinum drugs;

- progressive multiple myeloma (in combination with bortezomib) in patients who received at least one line of chemotherapy and who underwent bone marrow transplantation (TCM) or who are not candidates for TCM;

- AIDS-associated Kaposi sarcoma of low CD4 counters (<200 CD4 lymphocyte / mm 3 ) and extensive skin and mucous membrane lesions or visceral organs, other than Kaposi's sarcoma, which can be treated locally or systemically treated with interferon alpha.
Kelix В® can be used as the first or second line of chemotherapy in patients with AIDS-associated Kaposi's sarcoma, insensitive to drugs such as vinca alkaloids, bleomycin and standard doxorubicin (or other anthracyclines).
DOSING MODE

The drug is injected / drip.
The drug can not be injected or undiluted.
Treatment continues until signs of progression or development of unacceptable toxicity.

Kelix В® has unique pharmacokinetic properties and should not be replaced by other forms of doxorubicin hydrochloride.

Treatment with Kelix В® should be performed only under the supervision of a qualified oncologist who has experience with cytostatic therapy.

Breast cancer or ovarian cancer

In breast cancer and ovarian cancer, the drug is administered intravenously at a dose of 50 mg / m 2 once every 4 weeks, until the disease progresses and tolerability is maintained for the time being.

At a calculated dose of less than 90 mg concentrate is diluted in 250 ml of a solution of 5% dextrose for infusion;
at a dose of 90 mg or more - in 500 ml of a solution of 5% dextrose for infusion.
To reduce the risk of developing infusion reactions, the first administration is performed at a rate of no more than 1 mg / min. In the absence of reactions, subsequent infusions can be performed 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, administration is continued at a doubled rate for another 15 minutes. With good tolerability, the infusion is continued for the next hour (total time of administration is 90 minutes).
Subsequent infusions of Kelix В® can be performed for 60 minutes.

Multiple myeloma

In the treatment of multiple myeloma, the drug is administered at a dose of 30 mg / m 2 on the 4th day of a three-week cycle in combination with bortezomib (1.3 mg / m 2 at 1, 4, 8 and 11 days).
The drug is administered immediately after bortezomib for 1 hour. The therapy is shown until the effect of the treatment is observed with its tolerable tolerance.
At a calculated dose of less than 90 mg, concentrate is diluted in 250 ml of 5% (50 mg / ml) dextrose solution for infusion;
at a dose of 90 mg or more in 500 ml of a 5% (50 mg / ml) solution of dextrose for infusion.
An intravenous catheter and a drip system between the administration of bortezomib and doxorubicin should be washed with a solution of 5% dextrose.
If it is not possible to administer doxorubicin and bortezomib on day 4 of the cycle, their administration can be postponed for 48 hours. If bortezomib was administered later than the time indicated by the therapy regimen, the subsequent administration of bortezomib should be performed no earlier than 72 hours after the last dose of the drug. The first infusion of Kelix В®can be prescribed for 90 minutes according to the scheme:
-10 ml first 10 minutes;

-20 ml for the next 10 minutes;

-40 ml for the next 10 minutes;

for the remaining amount of the solution for 60 minutes.

Subsequently, the dose of Kelix В® can be administered within 1 hour.
If there is a reaction to infusion with Kelix В® , the infusion is stopped and, after the disappearance of the symptoms, Kelix В® is prescribed according to the following scheme:
-10 ml for the first 10 min;

-20 ml for the next 10 min;

-40 ml for the next 10 min;

then the remaining amount of solution in 60 minutes;

Infusion administration can be performed through a central or peripheral venous catheter.

AIDS-associated Kaposi's sarcoma

The drug is administered intravenously at a dose of 20 mg / m 2 once or twice every 2-3 weeks, until the disease progresses and while tolerable tolerance remains.
Avoid intervals between doses of less than 10 days, since in this case, the accumulation of the drug in the body and increase its toxicity. To achieve therapeutic effect, the course of treatment should be 2 - 3 months. Treatment should be continued to maintain therapeutic effect.
Concentrate is diluted in 250 ml of 5% dextrose solution for infusion and administered as an IV infusion for 30 min.

All patients

If the patient develops initial symptoms or signs of reaction to the drug, the infusion is immediately stopped, premedication is performed with antihistamines and / or high-speed glucocorticosteroids and the infusion is resumed at a slower rate.

Do not administer the drug in the form of bolus injections or as an undiluted solution.
When infusions are recommended, the combination of the KelixВ® solution through the terminal port of intravenous infusion with an aqueous solution of 5% dextrose is recommended to achieve further dissolution and reduce the risk of thrombosis and bruising.Infusion can be carried out through the peripheral vein. Kelix В® should not be administered intramuscularly or subcutaneously, nor should infusion systems with built-in filters be used.
To reduce the appearance of some side effects, such as palmar-plantar syndrome (erythrodysesthesia), stomatitis or hematologic toxicity, the dose of the drug can be reduced or canceled.

Modification of the dosing regimen

Guidance on changing the doxorubicin dosage regimen is given in the tables below.
The toxicity levels given in the tables are based on the toxicity scale of the National Institute of Malignancies, USA.
Table 1. Modification of the dosing regimen in the development of palmar-plantar syndrome

Palmar-plantar syndrome

Degree of toxicity after previous administration of Kelix В® Correction of Kelix В® dose

I degree (mild erythema, edema, or desquamation that does not affect daily activities) The drug can be administered within 4 weeks from the date of the previous administration or may be postponed for 1 week.
If the patient has previously had a 3-4 toxicity level, it is necessary to postpone the treatment for 2 weeks (wait an additional week) and resume therapy in a 25% reduced dose, observing the initial 4-week interval between administrations.
II degree (erythema, desquamation, edema affecting, but not limited to, daily physical activity, small blisters or ulceration (<2 cm in diameter)) Postpone treatment for 2 weeks or until toxicity decreases to 0-1.
Then the treatment can be continued in the original dose and in the previous regime. If no toxicity is observed after 2 weeks, the therapy should be resumed in a 25% reduced dose, observing the initial interval between administrations. If patients previously had toxicity of 3-4 degrees, therapy should be resumed in a 25% reduced dose, observing the initial interval between administrations.
III degree (blisters, ulceration, swelling that interfere with walking or daily activities, the patient can not wear regular clothes and shoes) Postpone the treatment for 2 weeks before reducing the intensity of toxicity to 0-1.
If no toxicity is observed after 2 weeks, treatment with KelixВ® should be discontinued.
IV degree (diffuse or local processes leading to infectious complications, bed rest or hospitalization) Postpone treatment for 2 weeks or until toxicity decreases to 0-1.
If no toxicity is observed after 2 weeks, treatment with KelixВ® should be discontinued.
Table 2. Modification of the dosing regimen in the development of stomatitis

Stomatitis

Degree of toxicity after previous administration of Kelix В® Correction of Kelix В® dose

I degree (painless ulcers, erythema or mild tenderness) Administration of the drug is possible within 4 weeks from the date of the previous introduction or may be postponed for another 1 week.
If the patient has previously had 3-4 toxicity, it is necessary to postpone the treatment for 2 weeks (wait an additional week) and resume therapy in a 25% reduced dose, observing the initial 4-week interval between the administrations or stopping the treatment according to the doctor's decision.
II degree (painful erythema, swelling or ulcers, but the patient can eat). Postpone the treatment for 2 weeks before reducing the intensity of toxicity to 0-1.
If no toxicity is observed after 2 weeks, the therapy should be resumed in a 25% reduced dose, observing the initial interval between the administrations or discontinuing the treatment according to the doctor's decision.
III degree (painful erythema, swelling or ulcers, the patient can not eat) Postpone the treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-1.
If no toxicity is observed after 2 weeks, treatment with KelixВ® should be discontinued.
IV degree (the condition requires parenteral or enteral nutrition) Postpone the treatment for 2 weeks or until the intensity of toxicity decreases to a degree of 0-1.
If no toxicity is observed after 2 weeks, treatment with KelixВ® should be discontinued.
Table 3. Modification of the dosing regimen with the development of hematological toxicity (for breast cancer, ovarian cancer)

Hematologic toxicity

Degree of Neutrophil (in 1 Ојl) Platelets (in 1 Ојl) Changing the dosing regimen

I 1500-1900 75 000-150 000 Continuation of therapy without dose reduction

II 1000 - <1500 50 000- <75 000 When restoring the number of neutrophils to 1500 and more and platelets to 75 000 or more continue treatment without reducing the dose.

III 500- <1000 25 000- <50 000 When restoring the number of neutrophils to 1500 and more and platelets to 75 000 or more continue treatment without reducing the dose.

IV Less than 500 Less than 25 000 When restoring the number of neutrophils to 1500 and more and platelets to 75 000 or more, continue treatment, reducing the dose by 25%, or continue treatment at the same dose with the support of colony-stimulating factors.

Table 4. Modification of the dosing regimen for multiple myeloma

Patient status Kelix В® Bortezomib

Fever-38 В° C and neutrophil count <1000 / ОјL Do not administer the drug in this cycle if an undesired reaction occurs before the 4th day.
If it is observed after the 4th day, then the next dose is reduced by 25%. The next dose is reduced by 25%
On any day of application, after the 1st day of each cycle: Platelet number <25 000 / ОјL Hemoglobin <8 g / dl Number of neutrophils <500 / ОјL Do not administer the drug in this cycle if an undesired 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 because of hematologic toxicity. * Do not administer the drug; if the cycle does not introduce 2 or more doses, then in the following cycles, reduce the dose by 25%.
Non-hematological toxicity 3-4 degrees Do not administer the drug until toxicity decreases to <2 degrees;
all the following doses lower by 25%. Do not administer the drug until toxicity decreases to <2 degrees; all the following doses lower by 25%.
Neuropathic pain or peripheral neuropathy No dose adjustment needed See the instructions for bortezomib

* For more information about the regimen for the administration of bortezomib and the correction of its dose, see the instructions for the use of bortezomib in the "Method of administration and dose" section.

If a patient with multiple myeloma receiving combination therapy with Kelix В® and bortezomib develops a palmar-plantar syndrome or stomatitis, the dose of the drug should be adjusted as indicated in Tables 1 and 2 (Modification of the Regimen in the Development of the Palmar-Plantar Syndrome and Modification regime in the development of stomatitis ").

Patients with impaired hepatic function

With a serum bilirubin content of 1.2 to 3 mg / dL, the calculated dose is reduced by 25%.
If the bilirubin content exceeds 3.0 mg / dl, the calculated dose is reduced by 50%. If the patient has successfully undergone the administration of this dose (without hyperbilirubinemia or increased activity of hepatic enzymes in the blood serum), then the next dose is raised to the previous level (ie, when the dose is reduced by 25%, it is raised to the full dose, with a 50% - increase to 75% of the total dose). With good tolerability in subsequent cycles, the dose can be increased to the full dose. The drug can be administered to patients with metastases in the liver with concomitant hyperbilirubinemia and increased activity of hepatic enzymes up to 4 times higher than the upper limit of the norm. Before the introduction of doxorubicin, a clinical and laboratory study of liver function should be performed, including the determination of ALT / AST, APP, bilirubin activity.
Patients with impaired renal function

Correction of the dosing regimen is not required.
Data on the pharmacokinetics of the drug in patients with creatinine clearance less than 30 ml / min are absent.
Patients with AIDS-associated Kaposi's sarcoma and splenectomy

Since there is currently no clinical data are Keliks preparation В® to treat these patients, the use of the drug Keliks В® in these patients is not recommended.
Children

Limited data security obtained during phase 1 studies testify that the dose to 60 mg / m 2 every 4 weeks well perenosyatsyav pediatric practice, however, the effectiveness of the drug Keliks В® to treat patients molozhe18 years is not installed.
Adult patients
In patients aged between 21 and 75 years of significant differences in the pharmacokinetics of the drug Keliks В® were found.
Rules for formulation and administration of the solution for infusion
is impossible to use the drug with signs of precipitation or by the presence of suspended particles.
When using the drug you must abide by the rules of working with anticancer drugs. You must use gloves. In the case of getting the drug to the skin or mucous membranes of the rinse immediately with soap and water.
Determine the dose of doxorubicin required for administration. The required amount of the drug is typed into a sterile syringe. All manipulations should be carried out with strict aseptic conditions (formulation does not contain preservatives and bacteriostatic additives).
Recommended to inject medication through the side port of the infusion system through which is introduced a solution of 5% dextrose to achieve greater dilution and to minimize the risk of thrombosis and extravasation. Infusion may be carried out in a peripheral vein.
The drug should not be administered intramuscularly or subcutaneously.
Can not be used for injection Keliks В® infusion system with built-in filter.
Recommended administered Keliks В® immediately after dilution with 5% dextrose for infusion. In cases where this is not possible, the prepared solution can be stored at 2-8 В° C and used within 24 hours.
SIDE EFFECT

Data on adverse reactions observed in clinical trials
are listed below adverse events reported in clinical trials and systematic with respect to each of the organ systems, depending on the frequency of occurrence, using the following classification: very common (1/10?), Often (? 1/100, <1/10), uncommon (? 1/1000, <1/100), rarely (? 1/10000, <1/1000), very rare (<1/10000), including isolated cases.
Adverse events observed during clinical trials of the drug Keliks В® to treat breast cancer patients:
Infections and infestations: often - pharyngitis, folliculitis, fungal infection, febrile rash (not herpetic), upper respiratory tract infection.
Blood disorders and lymphatic system: often - leukopenia, anemia, neutropenia, thrombocytopenia, thrombocythemia.
Disorders of the nervous system: often - paresthesia, peripheral neuropathy, hot flashes; rarely - drowsiness.
Violations by the organ of vision: often - tearing, blurred vision.
Violations of the heart: often - ventricular fibrillation.
Violations of the respiratory system, organs, thoracic and mediastinal disorders: often - shortness of breath, nasal bleeding.
Violations by the Metabolism and nutrition: very often - anorexia.
Disorders of the gastrointestinal tract:very often - nausea, vomiting, stomatitis; often - ulceration of the oral mucosa, abdominal pain, constipation, diarrhea, dyspepsia, pain in the oral cavity.
Violations of the skin and subcutaneous tissue disorders: very often - alopecia, hand-foot syndrome, rash; often - erythema, dry skin, pigmentation disorders, itching, changes in skin color, bullous eruption, dermatitis, erythematous rash, nail infections, scaly skin.
Violations by musculoskeletal and connective tissue: often - leg cramps, bone pain, muscle pain.
Violations by the reproductive system and breast cancer: often - pain in the breast.
General disorders and reactions at the injection site:very often - fatigue, asthenia, mucositis; often - fatigue, fever, pain, weight loss, edema, swelling in the legs.
Clinically significant laboratory abnormalities (degrees III and IV) in this group of breast cancer patients included increasing the concentration of total bilirubin (2.4%) and AST activity (1.6%). Increased ALT observed rarely (<1%). There were no clinically significant increases in serum creatinine.
Adverse events observed during clinical trials of the drug Keliks В® for the treatment of ovarian cancer patients
Infections and infestations:often - infection, candidiasis of the oral mucosa, herpes zoster, urinary tract infection, and other infections (including fungal infections, lower respiratory tract infections).
Blood disorders and lymphatic system: very often - leukopenia, anemia, neutropenia, thrombocytopenia; often - hypochromic anemia.
Disorders of the nervous system: often - paresthesia, drowsiness, headache, dizziness, neuropathy, increased blood pressure.
Violations of the respiratory system, organs, thoracic and mediastinal disorders: often - faringitfaringit, shortness of breath, increased cough.
Disorders of the gastrointestinal tract: \very often - stomatitis, constipation, diarrhea, nausea, vomiting; often - abdominal pain, dyspepsia, oral ulceration, esophagitis, gastritis, dysphagia, dry mouth, flatulence, gingivitis, taste perversion.
Violations of the skin and subcutaneous tissue disorders: very often - hand-foot syndrome, alopecia, rash; often - dry skin, change in skin color, vesicles, bullous rash, pruritus, exfoliative dermatitis, skin disorder, maculo-papular rash, sweating, acne, skin ulcers.
Disorders of immune system: often - allergic reactions.
Violations by the Metabolism and nutrition: very often - anorexia; often - dehydration, cachexia.
Mental disorders: often - anxiety, depression, insomnia.
Violations by the organ of vision: often - conjunctivitis.
Violations of the heart: often - cardiovascular disorders.
Violations by vessels: often - vasodilatation.
Violations by musculoskeletal and connective tissue disorders: often - back pain, myalgia.
Violations by the kidneys and urinary tract: often - dysuria.
Violations by the genitals and breast: often - vaginitis.
General disorders and at the injection site: very often - asthenia, violation of the mucous membranes; often fever, pain, chills, chest pain, malaise, peripheral edema.
Impact on the results of laboratory and instrumental studies: often - weight loss.
Clinically significant laboratory abnormalities were observed in ovarian cancer patients in clinical trials Keliks preparation В® , included increasing the total bilirubin (usually in patients with liver metastases) (5%) and serum creatinine levels (5%). AST increase occurred less frequently (<1%). Septicemia with leukopenia was observed rarely (<1%).
Adverse events observed during clinical trials of the drug Keliks В® to treat patients with multiple myeloma
Infections and infestations:often - herpes simplex, herpes zoster, nasopharyngitis, oral candidiasis, pneumonia, upper respiratory tract infection.
Blood disorders and lymphatic system: very often - anemia, neutropenia, thrombocytopenia; often - febrile neutropenia, leukopenia, lymphopenia.
Violations by the Metabolism and nutrition: very often - anorexia; often - loss of appetite, dehydration, hyperkalemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia.
Mental disorders: often - anxiety, insomnia.
Disorders of the nervous system:very often - headache, neuralgia, peripheral sensory neuropathy; often - dizziness, dysaesthesia, dysgeusia, hypoesthesia, lethargy, neuropathy, paresthesia, peripheral neuropathy, polyneuropathy, fainting.
Violations by the organ of vision: often - conjunctivitis.
Violations by vessels:
often - hot flashes, decrease in blood pressure, increased blood pressure, orthostatic hypotension, phlebitis.
Violations of the respiratory system, organs, thoracic and mediastinal disorders: often - cough, dyspnea, epistaxis, dyspnea on exertion.
Disorders of the gastrointestinal tract:very often - nausea, vomiting, diarrhea, stomatitis, constipation; often - abdominal pain, neuralgia, pain in the upper abdomen, ulceration of oral xerostomia, dysphagia, aphthous stomatitis.
Violations of the skin and subcutaneous tissue disorders: very often - hand-foot syndrome, rash; often - dry skin, itching, papular rash, allergic dermatitis, erythema, skin hyperpigmentation, petechiae, alopecia, drug rash.
Violations by musculoskeletal and connective tissue disorders: often - arthralgia, muscle spasms, muscular weakness, musculoskeletal pain in the chest, musculoskeletal pain, myalgia, pain in the limbs.
Violations by the reproductive system and breast cancer: often - erythema of the scrotum.
General disorders and at the injection site: very often - asthenia, fatigue, pyrexia; often - chills, pyrexia, influenza-like illness, malaise, peripheral edema.
Effect on results of laboratory and instrumental investigations: often - increased ALT activity in blood, increased activity of AST in the blood, increasing concentrations kreatininav blood, decreased ejection fraction, decrease in body weight.
Adverse events observed during clinical trials of the drug Keliks В® to treat patients with AIDS-associated Kaposi's sarcoma
Infections and infestations: often - oral candidiasis.
Blood disorders and lymphatic system:very often - neutropenia, anemia, leukopenia; often - thrombocytopenia.
Violations by the Metabolism and nutrition: often - anorexia.
Mental disorders: often - confusion.
Disorders of the nervous system: often - dizziness; rarely - paresthesia.
Violations by the organ of vision: often - retinitis.
Violations by vessels: often - vasodilatation.
Violations of the respiratory system, organs, thoracic and mediastinal disorders: often - shortness of breath.
Violations of the gastrointestinal tract: often - nausea; often - diarrhea, stomatitis, vomiting, ulceration of the oral mucosa, abdominal pain, glossitis, constipation, nausea and vomiting.
Violations of the skin and subcutaneous tissue disorders: often - alopecia, rash; infrequently - hand-foot syndrome.
General disorders and the site of injection: often - fatigue, fever, acute infusion reactions.
Impact on the results of laboratory and instrumental studies: often - weight loss.
Hematologic toxic effects may require dose reduction or suspension of therapy. It should suspend therapy Keliks drug В® patients with an absolute neutrophil count <1000 / mm 3 and / or platelet count <50,000 / mm 3. G-CSF (or GM-CSF) may be used for concomitant therapy to maintain the amount of formed elements with an absolute neutrophil count <1000 / mm 3 in the subsequent cycles. Respiratory side effects frequently (? 5%) were noted in clinical studies Keliks preparation В® and may be associated with opportunistic infections in AIDS patient population. Opportunistic infection (OI) have been reported in patients with AIDS-related Kaposi's sarcoma after drug application Keliks В® , and are often observed in patients with HIV-related immunodeficiency. The most frequently reported OIs in clinical studies were candidiasis, cytomegalovirus, herpes simplex, pneumonia , caused by Pneumocystis cariniiand complex Mycobacterium avium.
Clinically significant laboratory abnormalities frequently (≥ 5%) observed in clinical studies of the drug Keliks ® . They included increased activity of ALP and elevated AST and bilirubin concentrations that were considered related to the primary disease, but not with the reception Keliks preparation ® . Reduced hemoglobin levels and platelet counts were rare (<5%). Sepsis related to leukopenia was observed infrequently (<1%). Some of the described variations can be associated with the presence of HIV infection and not receiving drug Keliks ® .
These post-marketing surveillance
Adverse reactions noted during application of the post-marketing Keliks preparation В®and systematized with respect to each of the organ systems, depending on the frequency of occurrence, using the following classification: very common (1/10?), common (1/100, <1/10?), rare (1/1000, <1 /? 100), rare (? 1/10 000, <1/1000), very rare (<1/10 000), including isolated cases.
Vascular disorders

Patients sozlokachestvennymi tumors observed increased risk of thromboembolism. Patients taking the drug Keliks В® , infrequently observed cases of venous thrombosis and thrombophlebitis, and pulmonary embolism.
Violations of the skin and subcutaneous tissue disorders
Severe skin disorders, including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis, very rarely observed.
Secondary tumors of the oral cavity
in patients with long-term (more than one year) applying the drug Keliks В® or patients receiving a total dose Keliks В® 720 mg / m 2 is very rarely observed cases of secondary oral cancer.
CONTRAINDICATIONS

- hypersensitivity to the components of the drug;

- children's age till 18 years;

- Pregnancy;

- the period of breastfeeding;

- Kaposi's sarcoma, amenable to local treatment or systemic treatment with interferon alpha.
With caution

- circulatory failure;
- previous use of other anthracyclines;
- odnovremennoeprimenenie with drugs having a cytotoxic (especially myelotoxic) effect;
- inhibition of bone marrow hematopoiesis (including bone marrow infiltration by tumor cells, prior chemotherapy or radiotherapy), parasitic and infectious diseases of viral, fungal or bacterial origin (currently or recently transferred, including the recent contact with the patient): easy herpes, herpes zoster (viremicheskaya phase), chicken pox, measles, amoebiasis, strongyloidiasis (or suspected), gout (including history) uratnyynefrourolitiaz (including history), heart disease (kardioto ksicheskoe effect can be observed at lower total doses), hepatic failure;
- diabetes.
PREGNANCY AND LACTATION

Application Keliks preparation В® is not recommended during pregnancy.
Women of childbearing potential must use contraceptive methods, if the patient or her partner is receiving therapy Keliks В® and for 6 months after treatment.
It is not known whether the drug is released in breast milk, so to avoid potential severe reactions to the drug baby Keliks В® women should stop breast-feeding during therapy with Keliks В® .
APPLICATION FOR FUNCTIONS OF THE LIVER

Patients with impaired renal function, adjustment of dosing regimen is necessary.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Patients with impaired liver function during serum bilirubin from 1.2 to 3 mg / dl calculated dose reduced by 25%. If the content of Bi
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