Келикс

General characteristics. Structure:

Active agent: doxorubicine a hydrochloride pegylated liposomal – 2 mg.

Excipients: карбамоилметоксиполиэтиленгликольдистеароил sodium glycerophosphoethanolamine, phosphatidylsincaline, cholesterol, ammonium sulfate, sucrose, a histidine, Acidum hydrochloricum, sodium hydroxide, water for injections.

Pharmacological properties:

Pharmacodynamics.

Doxorubicine – the cytotoxic anthracycline antibiotic allocated from Streptomyces peucetius var. caesius. The exact mechanism of antineoplastic effect of doxorubicine is not known. Believe that the cytotoxic effect is caused by its ability to inhibit synthesis of DNA, RNA and proteins by implementation of doxorubicine between the next couples of bases of a double helix of DNA that interferes with deployment of a spiral for the subsequent replication.

Drug represents a pegylated liposomal form of doxorubicine, is long higher concentration of doxorubicine circulating in blood and providing in tumoral fabric, than in normal fabrics. Liposomes contain poverkhnostnosvyazanny hydrophilic polymers метоксиполиэтиленгликоля (MPEG). These MPEG linear groups create the protective cover acting over a surface of liposomes reducing a possibility of interaction between the lipidic bilayer membrane and components of plasma that protects liposomes from recognition by phagocytal system and allows to extend time of circulation of doxorubicine in a blood-groove. Pegylated liposomes have also lipidic matrix with low-permeability and internal water buffer system that in a combination allows to hold doxorubicine in a liposome during circulation it in a blood-groove. Rather small size of pegylated liposomes (average diameter about 100 nanometers) allows them to get through defects of blood vessels of a tumor. Results of pilot studies demonstrate penetration of pegylated liposomes from blood vessels and their cumulation in a tumor.

Pharmacokinetics.

At intravenous administration of drug concentration of doxorubicine in plasma and the area under a curve "concentration time", относящиея it is preferential to pegylated liposomal doxorubicine (respectively from 90% to 95% of the measured doxorubicine), is significantly higher, than at introduction of equivalent doses traditional (not pegylated non-liposomal) doxorubicine. The pharmacokinetic profile of drug indicates that the clearance of doxorubicine from a blood plasma is defined by the liposomal carrier. Doxorubicine becomes available only after an exit of liposomes from a vascular bed and their penetration into fabrics.

In low doses (10-20 mg/sq.m) drug shows linear pharmacokinetics, in higher doses (20-60 mg/sq.m) – nonlinear. Pharmacokinetics indicators at introduction in a dose from 10 to 60 mg/sq.m: clearance of doxorubicine – on average 0,030 l/h/sq.m (0,008-0,152 l/h/sq.m); distribution volume – 1,93 l/sq.m (0,96-3,85 l/sq.m); an elimination half-life – 73,9 h (24-231 h).

Pharmacokinetic indicators at an abnormal liver function and a hyperbilirubinemia slightly differ from pharmacokinetic parameters at normal concentration of the general bilirubin.

The renal failure (clearance of creatinine of 30-156 ml/min.) does not exert impact on pharmacokinetic parameters. Patients have no data on drug pharmacokinetics with clearance of creatinine less than 30 ml/min.

The age of patients (21-75 years) has no significant effect on pharmacokinetic indicators of doxorubicine.

Indications to use:

− the Metastatic breast cancer in the presence of indications to therapy by anthracyclines, including in case of the increased risk of cardiological complications and at inefficiency of therapy by taxons;

− Widespread ovarian cancer at inefficiency of the first line of chemotherapy platinum drugs;

− the Progressing multiple myeloma (in a combination with bortezomiby) at the patients who received, at least, one line of chemotherapy and transferred the transplantation of marrow (TM), or not being candidates for TKM;

− the AIDS-associated Kaposha's sarcoma at patients with the low CD4 level (<200 CD4 lymphocyte/mm3) and extensive damages of skin and mucous membranes or visceral bodies, except sarcoma of Kaposha who is giving in to topical treatment or system treatment by interferon an alpha. The drug Keliks® can be used as the first or second line of chemotherapy at patients with the AIDS-associated Kaposha's sarcoma, insensitive to such drugs as periwinkle alkaloids, bleomycin and standard doxorubicine (or to other anthracyclines).

Route of administration and doses:

Intravenously kapelno. The drug cannot be administered struyno or in not divorced look. Treatment is continued before emergence of signs of progressing or development of unacceptable toxicity.

The drug Keliks® has unique pharmacokinetic properties and should not be replaced with other forms of doxorubicine of a hydrochloride. Treatment by the drug Keliks® has to be carried out only under observation of the qualified oncologist having experience of performing cytostatic therapy.

Breast cancer or ovarian cancer. At a breast cancer and ovarian cancer the drug is administered intravenously in a dose of 50 mg/sq.m of 1 times in 4 weeks, to a progression of a disease and so far admissible portability remains.

At a calculated dose less than 90 mg a concentrate part in 250 ml of solution 5% of a dextrose for infusions; at a dose of 90 mg and more – in 500 ml of solution of 5% of a dextrose for infusions. For decrease in risk of development of infusional reactions the first introduction is carried out with a speed no more than 1 mg/min. In the absence of reactions the subsequent infusions can be carried out within 60 min.

Patients at whom infusional reactions to the previous introduction were noted should carry out repeated administration of drug as follows: 5% of a calculated dose enter slowly within 15 min. In the absence of reactions introduction is continued with the doubled speed within 15 more min. At good tolerance infusion is continued within the next hour (the general time of introduction – 90 min.).

The subsequent infusions of the drug Keliks® can be carried out within 60 minutes.

Multiple myeloma.

At treatment of a multiple myeloma the drug is administered in a dose 30 mg/sq.m for the 4th day of a three-week cycle in combination with bortezomiby (1,3 mg/sq.m in 1, 4, 8 and 11 days). The drug is administered right after a bortezomib within 1 hour. Performing therapy is shown until the effect of the carried-out treatment at its admissible portability is observed.

At a calculated dose less than 90 mg a concentrate part in 250 ml 5% (50 mg/ml) of dextrose solution for infusions; at a dose of 90 mg and more – in 500 ml of 5% (50 mg/ml) of dextrose solution for infusions.

Intravenous catheter and system of drop introduction between introduction of a bortezomib and doxorubicine it is necessary to wash out solution 5% of a dextrose. At impossibility of administration of doxorubicine and a bortezomib for the 4th day of a cycle their introduction can be postponed for 48 h. If introduction of a bortezomib is made after time designated by the scheme of therapy, then the subsequent introduction of a bortezomib had to be carried out not earlier than in 72 hours after introduction of the last dose of drug. The first infusion of the drug Keliks® can be appointed within 90 minutes according to the scheme:

• To 10 ml there are first 10 min.;

• 20 ml are the next 10 minutes;

• 40 ml are the next 10 minutes;

• then the remained amount of solution within 60 minutes.

In the subsequent the dose of the drug Keliks® can be entered within 1 hour. If emergence of reactions to performing infusion is noted by the drug Keliks®, infusion is stopped and after disappearance of symptoms appoint the drug Keliks® according to the following scheme:

• 10 ml in the first 10 min.;

• 20 ml in the next 10 min.;

• 40 ml in the next 10 min.;

• then the remained amount of solution in 60 minutes.

Infusion can be entered through the central or peripheral venous catheter.

The AIDS-associated Kaposha's sarcoma.

The drug is administered intravenously in a dose of 20 mg/sq.m of 1 times each 2-3 weeks, to a progression of a disease and so far admissible portability remains. It is necessary to avoid intervals between dosing less than 10 days as in this case accumulation of drug in an organism and increase in its toxicity is possible. For achievement of therapeutic effect the course of treatment has to make 2 – 3 months. Treatment should be continued for maintenance of therapeutic effect. A concentrate dissolve in 250 ml 5% of solution of a dextrose for infusions and enter in the form of intravenous infusions within 30 min.

All patients. If the patient has initial symptoms or signs of reaction to administration of drug, infusion is immediately stopped, carry out premedication antihistaminic drugs and/or high-speed glucocorticosteroids and resume infusion at slower speed.

It is impossible to administer the drug in the form of bolyusny injections or in the form of not divorced solution. When performing infusions drug Keliks® solution association through extreme port of intravenous infusion with aqueous solution of 5% of a dextrose for achievement of further dissolution and reduction of risk of development of thromboses and developing of bruises is recommended. Infusion can be carried out through a peripheral vein. The drug Keliks® should not be administered intramusculary or subcutaneously, it is impossible to use infusional systems with the built-in filters.

For decrease in manifestations of some side effects, such as a palmar bottom syndrome (eritrodizesteziya), stomatitis or hematologic toxicity, a dose of drug it can be reduced or cancelled.

Modification of the mode of dosing.

Instructions on change of the mode of dosing of doxorubicine are given in tables below. The toxicity degrees given in tables are based on a scale of toxicity of National institute of malignant new growths, the USA.

Table 1. Modification of the mode of dosing at development of a palmar and bottom syndrome and stomatitis.

Palmar and bottom syndrome.

Toxicity degree after the previous administration of drug of Keliks / Dose adjustment of drug of Keliks.

The I degree (weak erythema, hypostasis, or the desquamation which are not influencing daily activity) / Administration of drug is possible in 4-hnedelny time from the moment of the previous introduction or can be postponed for 1 week. If at the patient 3 – 4 degree of toxicity were noted earlier, it is necessary to postpone treatment for 2 weeks (to wait in addition week) and to resume therapy in the dose reduced by 25%, observing an initial 4-hnedelny interval between introductions. 

The II degree (the erythema, desquamation, hypostasis which are influencing daily physical activity, but not limiting it; small blisters or ulcerations (<2 cm in the diameter)) / to Postpone treatment for 2 weeks or before reduction of intensity of toxicity until degree 0-1. Then treatment can be continued in an initial dose and as before. If in 2 weeks of reduction of toxicity it is not noted, therapy to renew in the dose reduced by 25%, observing an initial interval between introductions. If at patients toxicity 3-4 degrees was noted earlier, therapy needs to be resumed in the dose reduced by 25%, observing an initial interval between introductions.

The III degree (the blisters, ulcerations, hypostases preventing walking or daily activity, the patient cannot wear usual clothes and shoes) / to Postpone treatment for 2 weeks before reduction of intensity of toxicity until degree 0-1. If in 2 weeks of reduction of toxicity it is not noted, treatment by the drug Keliks® should be stopped.

The IV degree (the diffusion or local processes leading to infectious complications, a bed rest or hospitalization) / to Postpone treatment for 2 weeks or before reduction of intensity of toxicity until degree 0-1. If in 2 weeks of reduction of toxicity it is not noted, treatment by the drug Keliks® should be stopped.

Table 2. Modification of the mode of dosing at development of stomatitis.

Stomatitis.

Toxicity degree after the previous administration of drug of Keliks / Dose adjustment of drug of Keliks.

The I degree (painless ulcers, erythema or poorly expressed morbidity) / Administration of drug is possible in 4-hnedelny time from the moment of the previous introduction or can be postponed for 1 week. If at the patient 3 – 4 degree of toxicity were noted earlier, it is necessary to postpone treatment for 2 weeks (to wait in addition week) and to resume therapy in the dose reduced by 25%, observing an initial 4-week interval between introductions or to stop treatment according to the decision of the doctor.

The II degree (a painful erythema, hypostases or ulcers, but the patient can eat) / to Postpone treatment for 2 weeks before reduction of intensity of toxicity until degree 0-1. If in 2 weeks of reduction of toxicity it is not noted, it is necessary to resume therapy in the dose reduced for 25%, observing an initial interval between introductions or to stop treatment according to the decision of the doctor. 

The III degree (a painful erythema, hypostases or ulcers, the patient cannot eat) / to Postpone treatment for 2 weeks or before reduction of intensity of toxicity until degree 0-1. If in 2 weeks of reduction of toxicity it is not noted, treatment by the drug Keliks® should be stopped.

The IV degree (the state demands parenteral or an enteroalimentation) / to Postpone treatment for 2 weeks or before reduction of intensity of toxicity until degree 0-1. If in 2 weeks of reduction of toxicity it is not noted, treatment by the drug Keliks® should be stopped.

Table 3. Modifications of the mode of dosing at development of hematologic toxicity (at a breast cancer, ovarian cancer).

Hematologic toxicity.

 Degrees / Neutrophils (in 1 мкл) / Thrombocytes (in 1 мкл) / Change of the mode of dosing.

I / 1500-1900 / 75000– 150000 / Continuation of therapy without reduction of a dose.

II / 1000 – <1500 / 50000– <75000 / At recovery of number of neutrophils to 1500 and more and thrombocytes to 75000 and more to continue treatment without reduction of a dose.

III / 500– <1000/25000-<50000 / At recovery of number of neutrophils to 1500 and more and thrombocytes to 75000 and more to continue treatment without reduction of a dose.

IV / Less than 500 / Less than 25000 / At recovery of number of neutrophils to 1500 and more and thrombocytes to 75000 and more to continue treatment, having reduced a dose by 25%, or to continue treatment in the same dose with support by colony stimulating factors.

Table 4. Modification of the mode of dosing at a multiple myeloma.

Correction of doses of doxorubicine and bortezomib at patients with a multiple myeloma.

State patient / Drug of Keliks/Bortezomib.

Fervescence ≥ 38 ○ C and number of neutrophils <1000/mkl / not to administer the drug in this cycle if undesirable reaction arises till 4th day. If it is observed after the 4th day, then to lower the following dose by 25%. / To lower the following dose by 25%.

In any day of use of drug after the 1st day of each cycle: Number of thrombocytes <25000/mkl Gemoglobin <8 g/dl Number of neutrophils <500/mkl / not to administer the drug in this cycle if undesirable reaction arises till 4th day. If it is observed after the 4th day, then to lower the following dose by 25% if the dose of a bortezomib is lowered from - for hematologic toxicity. * / Not to administer the drug; if in a cycle 2 or more doses are not entered, then in the following cycles to lower a dose by 25%.

Not hematologic toxicity 3-4 degrees / not to administer the drug until toxicity decreases to <2 degrees; to lower all following doses by 25% / not to administer the drug until toxicity decreases to <2 degrees; to lower all following doses by 25%.

Neyropatichesky pain or peripheral neuropathy / Dose adjustments is not required/Cm the application instruction of a bortezomib.

* More detailed information on the scheme of use of a bortezomib and correction of its dose see in the application instruction of a bortezomib in the section "Route of Administration and Doses". If at the patient with a multiple myeloma receiving a combination therapy the drug Keliks® and bortezomiby develops palmar подошвенныйсиндром or stomatitis, then a dose of drug should be adjusted as it is specified in tables 1 and 2 ("Modification of the mode at development of a palmar and bottom syndrome" and "Modification of the mode at development of stomatitis").

Patients with an abnormal liver function. At the content of bilirubin in blood serum from 1,2 to 3 mg/dl the calculated dose is lowered by 25%. If the content of bilirubin exceeds 3,0 mg/dl, the calculated dose is lowered by 50%. If the patient well transferred introduction of this dose (without hyperbilirubinemia or increase in activity of "hepatic" enzymes in blood serum), then the following dose is raised to the previous level (i.e. at a dose decline for 25% it is raised to a full dose, at a dose decline for 50% - raise to 75% of a full dose). At good tolerance in the subsequent cycles the dose can be raised to a full dose. Patients can appoint drug with metastasises in a liver with the accompanying hyperbilirubinemia and increase in activity of the "hepatic" enzymes, to 4 times exceeding the upper bound of norm. Before administration of doxorubicine it is necessary to conduct a clinical laboratory research of function of a liver, including definition of activity of ALT/nuclear heating plant, an alkaline phosphatase, bilirubin.

Patients with a renal failure. Correction of the mode of dosing is not required. Data on drug pharmacokinetics at patients with clearance of creatinine less than 30 ml/min. are absent.

Patients with the AIDS-associated Kaposha's sarcoma and a splenectomy. As at the moment there are no clinical data on use of the drug Keliks® for treatment of this group of patients, use of the drug Keliks® for these patients is not recommended.

Children.

The limited data on safety received during the researches of the Phase I I demonstrate that doses to 60 mg/sq.m are well transferred each 4 weeks in pediatric practice, nevertheless, efficiency of use of the drug Keliks® for treatment of patients more young is not established than 18 years.

Adult patients.

At patients aged from 21 up to 75 years of significant differences in pharmacokinetics of the drug Keliks® it is not revealed.

Rules of preparation and administration of solution for infusions. It is impossible to use drug with signs of loss of a deposit or existence of suspended particles.

When using drug it is necessary to follow rules of work with antineoplastic drugs. It is necessary to use gloves. In case of hit of drug on skin or mucous membranes immediately wash out this site water with soap.

Define the doxorubicine dose necessary for introduction. The required volume of drug is gained in the sterile syringe. All manipulations should be carried out with strict observance of rules of an asepsis (drug does not contain preservatives and bacteriostatic additives).

It is recommended to administer the drug through side port of infusional system through which enter solution of 5% of a dextrose for achievement of bigger cultivation and minimization of risk of thrombosis and an ekstravazation. Infusion can be carried out to a peripheral vein.

The drug cannot be administered intramusculary or subcutaneously.

IT IS IMPOSSIBLE TO USE FOR ADMINISTRATION OF THE DRUG KELIKS® INFUSIONAL SYSTEMS WITH THE BUILT-IN FILTER.

It is recommended to enter Keliks® immediately after cultivation by solution of 5% of a dextrose for infusions. The prepared solution can be stored in cases when it is impossible, at a temperature of 2-8 °C and to use during 24 h.

Use at pregnancy and during breastfeeding.

Use of the drug Keliks® at pregnancy is not recommended. Women of childbearing age have to use contraception methods if the patient or her partner receive therapy by the drug Keliks® and within 6 months after the end of treatment.

It is unknown whether drug with breast milk therefore for prevention of potential heavy reactions of the baby to the drug Keliks® of the woman have to stop feeding by a breast during therapy by the drug Keliks® is emitted.

Features of use:

Infusional reactions.

Against the background of drug Keliks® use generally during the first infusion and as a result of interaction with other medicines anaphylactoid reactions, a suffocation attack, asthma, a face edema, vasodilatation, increase or a lowering of arterial pressure, a small tortoiseshell, a dorsodynia, thorax pain, a fever, fever, tachycardia, dyspepsia, nausea, dizziness, breath difficulty, pharyngitis, skin rash, a skin itch, the increased perspiration, spasms (very seldom), and also reactions in an injection site were observed. The temporary termination of infusion usually leads to permission of these symptoms without additional treatment. Nevertheless, at administration of drug the medicines for the purpose of performing symptomatic therapy intended for stopping of infusional reactions have to be prepared (Epinephrinum, antihistamines, anticonvulsants, glucocorticosteroids, etc. Hp for rendering emergency medical service). Practically at all patients receiving the drug Keliks®, therapy can be resumed after permission of all symptoms without recurrence.

At emergence of symptoms of infusional reaction it is necessary to stop immediately infusion and to carry out symptomatic therapy (antihistaminic drugs and/or glucocorticosteroids of short action). Resuming of infusion is possible after full stopping of all symptoms with reduction of rate of administering of doxorubicine. Infusional reactions seldom repeat after carrying out the first cycle of therapy by drug.

Stomatitis.

Stomatitis was noted at the patients receiving continuous infusions of standard doxorubicine of a hydrochloride and often noted at the patients receiving the drug Keliks®, it did not interfere with completion of therapy by patients. Dose adjustment usually is not required, except for cases when stomatitis results in impossibility of meal of the patient. In this case extension of intervals between administrations of drugs for 1-2 weeks or a dose decline is possible.

The palmar and bottom syndrome is characterized by reddish painful macular skin rashes. At the patients noting this phenomenon it is usually observed after two-three cycles of therapy. At most of patients the state passes within one-two weeks at therapy by glucocorticosteroids or without it. To prevention and treatment of this syndrome apply a pyridoxine in a dose of 50-150 mg/days. Other methods of treatment and prevention of a palmar and bottom syndrome begin in 4-7 days after administration of drug. For prevention of this syndrome it is necessary to contain hands and legs in a cool state (trays for brushes and feet and a bathtub for a body with the lowered water temperature, swimming in cool water); also it is necessary to avoid excessive influence of warm/hot water and to try not to wear densely fitting socks, gloves, close footwear not to break blood circulation in legs and hands.

The state is probably connected with a dose and the scheme of use and can be lowered due to increase in an interval of administration of drug at 1-2 weeks or dose declines. Nevertheless, this reaction at some patients washes to be heavy and exhausting and can demand drug withdrawal.

At emergence of symptoms of ekstravazalny hit of drug (burning, reddening) immediately stop infusion and lay over ice an injection site for 30 min. Administration of drug is continued in other vein.

The repeated skin reactions connected with the previous radiation therapy were seldom noted at drug Keliks® use.

Risk of development of cardiovascular complications.

Cardiotoxicity.

All patients receiving therapy by drug are recommended to carry out control of an ECG. Passing changes on an ECG, such as flattening of a tooth of T, decrease in a segment of ST and clinically little significant disturbances of a rhythm are not obligatory indications to doxorubicine cancellation. Specific manifestation of cardiotoxic action is decrease in a voltage of the QRS complex. At emergence of such change, it is necessary to consider the possibility of carrying out a biopsy of a myocardium as most specific test for diagnosis of the injury of a cardiac muscle caused by anthracyclines.

Methods of measurement of fraction of emission of a left ventricle – EhoKG and the MUGA scanning (multientrance arteriography) which is preferable – belong to more specific control methods of a condition of function of heart in comparison with an ECG. These methods should be used before the beginning and during performing therapy by drug. Measurement of fraction of emission of a left ventricle is obligatory at each subsequent administration of drug at the total dose of drug exceeding 450 mg/sq.m.

At suspicion on a cardiomyopathy, i.e. at decrease in fraction of emission of a left ventricle in comparison with this indicator prior to treatment and/or at predictively significant decrease in this indicator (less than 45%) it is necessary to carry out a myocardium biopsy.

The listed research methods anthracyclines on cordial activity are recommended to be applied to identification of possible negative impact of therapy in the following sequence: ECG control, measurement of fraction of emission of a left ventricle, myocardium biopsy.

If by results of inspection it is possible to assume the injury of a myocardium connected with therapy by drug it is necessary to carry out careful assessment of a ratio of estimated advantage of continuation of use of drug and risk of development of cardiotoxicity.

Congestive heart failure owing to a cardiomyopathy can unexpectedly develop, without the previous changes on an ECG, and also can develop in several weeks after the therapy termination.

To patients with the cardiological diseases demanding the corresponding therapy, use of drug is possible only in case the advantage of use of drug exceeds risk for the patient. When calculating a cumulative dose of doxorubicine it is necessary to take any previous or accompanying use of cardiotoxic drugs into consideration (other anthracyclines / anthraquinones or ftoruratsit).

Miyelosupressiya.

During therapy by doxorubicine follows regularly and at least before each administration of drug to control a pattern of peripheral blood with obligatory calculation of number of cells.

Miyelosupressiya who is followed by anemia, thrombocytopenia, a leukopenia and, in rare instances, a febrile neutropenia were noted at the patients receiving the drug Keliks®. The resistant expressed miyelosupressiya can lead to development of superinfection or bleeding.

Secondary hematologic malignant new growths.

At the patients receiving the combined chemotherapy including doxorubicine (as well as at use of other DNA-connecting of antineoplastic drugs) cases of development of a secondary acute miyeloblastny leukosis and a miyelodisplastichesky syndrome in this connection such patients are recommended to carry out control of hematologic indicators periodically were noted.

Diabetes mellitus.

At use of drug for patients with a diabetes mellitus it is necessary to consider that drug contains sucrose and that the drug is administered together with 5% dextrose solution.

Children.

Safety and efficiency of use of drug for patients aged up to 18 years are up to the end not studied. Men and women of childbearing age during treatment, and also within 6 months after its cancellation have to use reliable methods of contraception.

Secondary cancer of an oral cavity.

Very exceptional cases of secondary cancer of oral cavity were registered at patients at long-term (more than one year) treatment by the drug Keliks® or at those who receive the cumulative doses of drug exceeding 720 mg/sq.m. Cases of secondary cancer of oral cavity were diagnosed both during treatment, and within 6 years after reception of the last dose. Patients have to have regularly examination on existence of ulcerations in an oral cavity or any discomfort which can testify to secondary cancer of an oral cavity.

Pharmaceutical interaction.

Presence at infusion solution of bacteriostatic additives, such as benzyl alcohol, can cause drug sedimentation.

The drug Keliks® has to be used under observation of the doctor having experience of performing cytostatic therapy.

As the drug Keliks® has special pharmacokinetic properties, it is not necessary to carry out the alternating therapy cycles by the drug Keliks® and traditional doxorubicine. Influence on ability to driving of the car and to control of mechanisms Though drug directly does not influence ability to driving of the car, nevertheless, at some patients dizziness, drowsiness can be noted. Therefore during treatment these patients need to abstain from driving of the car and control of mechanisms.

Side effects:

Data on the undesirable reactions observed during clinical trials are listed below the undesirable phenomena noted during clinical trials and systematized concerning each of systems of bodies depending on occurrence frequency with use of the following classification:

- Very often (≥1/10);

- Often (≥1/100, <1/10);

- Infrequently (≥1/1000, <1/100);

- Seldom (≥1/10000, <1/1000);

- Very seldom (<1/10000), including isolated cases.

The undesirable phenomena observed during clinical trials of use of the drug Keliks® for treatment of patients with cancer of a mammary gland:

Infections and invasions:

- Often: pharyngitis, folliculitis, fungal infections, feverish enanthesis (not herpetic), upper respiratory tract infections.

Disturbances from blood and lymphatic system:

- Often: leukopenia, anemia, neutropenia, thrombocytopenia, trombotsitemiya.

Disturbances from a nervous system:

- Often: paresthesia, peripheral neuropathy, inflows;

- Infrequently: drowsiness.

Disturbances from an organ of sight:

- Often: dacryagogue, the obscured sight.

Disturbances from heart:

- Often: ventricular arrhythmia.

Disturbances from respiratory system, bodies of a thorax and a mediastinum:

- Often: short wind, nasal bleeding.

Disturbances from a metabolism and food:

- Very often: anorexia.

Disturbances from digestive tract:

- Very often: nausea, vomiting, stomatitis;

- Often: an ulceration of a mucous membrane of an oral cavity, an abdominal pain, a lock, diarrhea, dyspepsia, pain in an oral cavity.

Disturbances from skin and hypodermic fabrics:

- Very often: alopecia, palmar and bottom syndrome, rash;

- Often: erythema, xeroderma, pigmentation disturbance, itch, change of coloring of skin, violent rash, dermatitis, erythematic rash, damages of nails, scaly skin.

Disturbances from skeletal and muscular and connecting fabrics:

- Often: spasms of legs, ostealgia, muscular pain.

Disturbances from reproductive system and a mammary gland:

- Often: mammary gland pain.

The general frustration and reactions in an injection site:

- Very often: fatigue, adynamy, inflammation of mucous membranes;

- Often: weakness, fever, pain, decrease in body weight, swelled, swelled in legs.

Clinically significant deviations of laboratory indicators (degree of III and IV) in this group of patients with cancer of a mammary gland included increases in concentration of the general bilirubin (2,4%) and activities of aspartate aminotransferase (1,6%). Increase in activity of alaninaminotranspherase was noted less often (<1%). Clinically significant increase in level of serumal creatinine was not noted.

The undesirable phenomena observed during clinical trials of use of the drug Keliks® for treatment of suffering from cancer ovaries:

Infections and invasions:

- Often: infections, candidiasis of a mucous membrane of an oral cavity, shingles, infections of urinary tract, other infections (including fungal infections, lower respiratory tract infections).

Disturbances from blood and lymphatic system:

- Very often: leukopenia, anemia, neutropenia, thrombocytopenia;

- Often: hypochromia anemia.

Disturbances from a nervous system:

- Often: paresthesia, drowsiness, headache, dizziness, neuropathy, increase in arterial pressure.

Disturbances from respiratory system, bodies of a thorax and a mediastinum:

- Often: pharyngitis, short wind, strengthening of cough.

Disturbances from digestive tract:

- Very often: stomatitis, lock, diarrhea, nausea, vomiting;

- Often: an abdominal pain, dyspepsia, an oral cavity ulceration, an esophagitis, gastritis, a dysphagy, dryness in a mouth, a meteorism, an ulitis, a food faddism.

Disturbances from skin and hypodermic fabrics:

- Very often: palmar and bottom syndrome, alopecia, rash;

- Often: xeroderma, change of coloring of skin, vezikulobullezny rash, itch, exfoliative dermatitis, skin disturbances, makulopapulyarny rash, perspiration, eels, skin ulcers.

Disturbances from immune system:

- Often: allergic reactions.

Disturbances from a metabolism and food:

- Very often: anorexia;

- Often: dehydration, cachexia.

Disturbances of mentality:

- Often: alarm, depression, sleeplessness.

Disturbances from an organ of sight:

- Often: conjunctivitis.

Disturbances from heart:

- Often: cardiovascular frustration.

Disturbances from vessels:

- Often: vazodilatation.

Disturbances from skeletal and muscular and connecting fabric:

- Often: dorsodynia, mialgiya.

Disturbances from kidneys and urinary tract:

- Often: dysuria.

Disturbances from generative organs and a mammary gland:

- Often: vaginitis.

The general frustration and disturbances in an injection site:

- Very often: an adynamy, disturbance from mucous membranes;

- Often: fever, pain, fever, thorax pain, indisposition, peripheral hypostases.

Influence on results of laboratory and tool researches:

- Often: decrease in body weight.

Clinically significant deviations of laboratory indicators noted at suffering from cancer ovaries during clinical trials of the drug Keliks® included increase in the general bilirubin (usually at patients with metastasises in a liver) (5%) and serum creatinine levels (5%). Increases in nuclear heating plant were noted less often (<1%). Sepsis at a leukopenia was noted infrequently (<1%).

The undesirable phenomena observed during clinical trials of use of the drug Keliks® for treatment of patients with a multiple myeloma.

Infections and invasions:

- Often: herpes simplex, shingles, nasopharyngitis, oral cavity candidiasis, pneumonia, upper respiratory tract infection.

Disturbances from blood and lymphatic system:

- Very often: anemia, neutropenia, thrombocytopenia;

- Often: febrile neutropenia, leukopenia, lymphopenia.

Disturbances from a metabolism and food:

- Very often: anorexia;

- Often: loss of appetite, dehydration, hyperpotassemia, hypocalcemia, hypopotassemia, hypomagnesiemia, hyponatremia.

Disturbances of mentality:

- Often: alarm, sleeplessness.

Disturbances from a nervous system:

- Very often: headache, neuralgia, peripheral touch neuropathy;

- Often: dizziness, dizesteziya, dysgeusia, hypesthesia, block, neuropathy, paresthesia, peripheral neuropathy, polyneuropathy, faints.

Disturbances from an organ of sight:

- Often: conjunctivitis.

Disturbances from vessels:

- Often: inflows, lowering of arterial pressure, increase in arterial pressure, orthostatic hypotension, phlebitis.

Disturbances from respiratory system, bodies of a thorax and a mediastinum:

- Often: cough, short wind, nasal bleeding, an asthma at an exercise stress.

Disturbances from digestive tract:

- Very often: nausea, vomiting, diarrhea, stomatitis, lock;

- Often: an abdominal pain, dyspepsia, pain in an upper part of a stomach, an oral cavity ulceration, dryness in a mouth, a dysphagy, aphthous stomatitis.

Disturbances from skin and hypodermic fabrics:

- Very often: palmar and bottom syndrome, rash;

- Often: xeroderma, itch, papular rash, allergic dermatitis, erythema, hyperpegmentation of skin, petechia, alopecia, medicamentous rash.

Disturbances from skeletal and muscular and connecting fabric:

- Often: an arthralgia, muscular spasms, muscular weakness, musculoskeletal pain in a thorax, musculoskeletal pain, a mialgiya, extremity pain.

Disturbances from reproductive system and a mammary gland:

- Often: scrotum erythema.

The general frustration and disturbances in an injection site:

Very often: adynamy, fatigue, pyrexia;

- Often: fever, hyperthermia, grippopodobny disease, indisposition, peripheral hypostases.

Influence on results of laboratory and tool researches:

- Often: increase in activity of alaninaminotranspherase in blood, increase in activity of aspartate aminotransferase in blood, increase in concentration of creatinine in blood, decrease in fraction of emission, decrease in body weight.

The undesirable phenomena observed during clinical trials of use of the drug Keliks® for treatment of patients with the AIDS-associated Kaposha's sarcoma:

Infections and invasions:

- Often: oral cavity candidiasis.

Disturbances from blood and lymphatic system:

- Very often: neutropenia, anemia, leukopenia;

- Often: thrombocytopenia.

Disturbances from a metabolism and food:

- Often: anorexia.

Disturbances of mentality:

- Often: confusion of consciousness.

Disturbances from a nervous system:

- Often: dizziness;

- Infrequently: paresthesia.

Disturbances from an organ of sight:

- Often: retinitis.

Disturbances from vessels:

- Often: vazodilatation.

Disturbances from respiratory system, bodies of a thorax and a mediastinum:

- Often: asthma.

Disturbances from digestive tract:

- Very often: nausea;

- Often: diarrhea, stomatitis, vomiting, an ulceration of a mucous membrane of an oral cavity, pain in a stomach, a glossitis, a lock, nausea and vomiting.

Disturbances from skin and hypodermic fabrics:

- Often: alopecia, rash;

- Infrequently: palmar and bottom syndrome.

The general frustration and disturbances in an injection site:

- Often: an adynamy, fever, acute reactions on infusion.

Influence on results of laboratory and tool researches:

- Often: loss of body weight.

The hematologic toxic phenomena can demand a dose decline or suspension of therapy. It is necessary to suspend temporarily therapy by the drug Keliks® at patients at absolute quantity of neutrophils <1000/mm3 and/or quantity of thrombocytes <50000/mm3. Can be applied by G-KSF (or GM-KSF) to the accompanying therapy for maintenance of quantity of uniform elements at absolute quantity of neutrophils <1000/mm3 in the subsequent cycles. Respiratory side effects often (≥ 5%) were noted in clinical trials of the drug Keliks® and can be connected with opportunistic infections in population of patients about AIDS. The Opportunistic Infections (OI) were noted at patients with the AIDS-associated Kaposha's sarcoma after drug Keliks® use, and often noted at patients with the immunodeficiency caused by HIV. The most often noted by OI in clinical trials were candidiasis, a Cytomegaloviral infection, a herpes simplex, pneumonia, the caused Pneumocystis carinii and the mycobacterium avium complex.

Clinically significant laboratory disturbances often (≥ 5%) were noted in clinical trials of the drug Keliks®. They included increase in activity of an alkaline phosphatase and increase in activity of nuclear heating plant and concentration of bilirubin which were considered connected with a basic disease, but not with reception препаратаКеликс®. Decrease in level of hemoglobin and number of thrombocytes were noted seldom (<5%). The sepsis connected with a leukopenia was noted seldom (<1%). Some of the described deviations could be connected with existence of HIV infection, but not administration of drug of Keliks®.

Data of post-registration observation. The undesirable reactions noted during post-marketing use of the drug Keliks® and systematized concerning each of systems of bodies depending on occurrence frequency with use of the following classification are given below:

- Very often (≥1/10);

- Often (≥1/100, <1/10);

- Infrequently (≥1/1000, <1/100);

- Seldom (≥1/10000, <1/1000);

- Very seldom (<1/10000), including isolated cases.

Disturbances from vessels:

At patients with malignant tumors increase in risk of development of a thromboembolism is noted. At the patients accepting the drug Keliks® cases of thrombophlebitis and vein thrombosis, and also embolisms of lungs are infrequently noted.

Disturbances from skin and hypodermic fabrics:

Serious skin violations, including a polymorphic erythema, Stephens's syndrome - Johnson and a toxic epidermal necrolysis, were noted very seldom.

Secondary new growths of an oral cavity:

At patients at long (more than one year) use of the drug Keliks® or for the patients who received a total dose of the drug Keliks® more than 720 mg/sq.m very seldom cases of secondary cancer of oral cavity were noted.

Interaction with other medicines:

At combined use of doxorubicine with cyclophosphamide or taxons at patients with solid tumors (including ovarian cancer and a breast cancer) increase in toxicity is not revealed. Nevertheless, it is necessary to consider that the drug Keliks®, as well as other drugs of doxorubicine of a hydrochloride, can strengthen toxic effect of other antineoplastic drugs.

Patients have messages on an exacerbation of the hemorrhagic cystitis induced by cyclophosphamide and increase in a hepatotoxic of Mercaptopurinum with the AIDS-associated Kaposha's sarcoma at therapy by standard doxorubicine a hydrochloride. It is necessary to show care at simultaneous use of any other tsitostatik, especially myelotoxic agents.

Drug cannot be mixed with other solutions, except solution of 5% of a dextrose for infusions.

Contraindications:

− hypersensitivity to any of drug components;

− children's age up to 18 years;

− pregnancy;

− breastfeeding period;

− Kaposha's Sarcoma which is giving in to topical treatment or system treatment by interferon an alpha.

With care:

− circulatory unefficiency; the previous use of other anthracyclines;

− simultaneous use with the drugs having cytotoxic (especially myelotoxic) effect;

− oppression of a marrowy hemopoiesis (including the infiltration of marrow tumor cells previous himio-or radiation therapy), parasitic and infectious diseases of the virus, fungal or bacterial nature (now or recently postponed, including recent contact with the patient): the herpes simplex surrounding herpes (a viremichesky phase), the chicken pox, measles, the amebiasis, a strongyloidosis (established or suspected), gout (including in the anamnesis), uratny нефроуролитиаз (including in the anamnesis), heart diseases (cardiotoxic action can be noted at lower total doses), a liver failure;

− diabetes mellitus.

Overdose:

Symptoms: the heavy miyelosupressiya (preferential a leukopenia and thrombocytopenia), (mukozit) toxic effects from digestive tract.

Treatment of acute overdose at patients with a heavy miyelosupressiya has to be carried out in a hospital and include antibacterial drugs, transfusion of a granulotsitarny and platelet concentrate and symptomatic therapy of a mukozit.

Storage conditions:

At a temperature of 2-8 ºС. Not to freeze. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Concentrate for preparation of solution for intravenous administration of 2 mg/ml. On 20 mg / 10 ml or on 50 mg / 25 ml in bottles. On 1 or on 10 bottles together with the application instruction in a cardboard pack.