Kelix - instructions for use, dose, side effects, contraindications

sodium carbamoylmethoxy polyethylene glycol distearoyl-glycerophosphoethanolamine, phosphatidylcholine, cholesterol, ammonium sulfate, sucrose, histidine, hydrochloric acid, sodium hydroxide, water for injection.

Description:A semitransparent suspension of red color.

Pharmacotherapeutic group:Antitumor agent, antibiotic

ATX: & nbsp

L.01.D.B.01 Doxorubicin

Pharmacodynamics:Doxorubicin - cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. The exact mechanism of the antitumor effect of doxorubicin is not known. 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.

The drug is a pegylated liposomal form of doxorubicin, circulating long in the blood and providing 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 water buffer system, which in combination allows to retain doxorubicin inside 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 the drug, the concentration of doxorubicin in the plasma and the area under the concentration-time curve, which are predominantly related to pegylated liposomal doxorubicin (from 90% to 95% of the measured doxorubicin, respectively)than with the administration of equivalent doses of traditional (non-pegylated non-liposomal) doxorubicin. The pharmacokinetic profile of the drug indicates that the clearance of doxorubicin from the blood plasma is determined by a liposome carrier. Doxorubicin becomes accessible only after the release of liposomes from the vascular bed and penetration into the tissues.

In low doses (10-20 mg /m²) the drug demonstrates a linear pharmacokinetics, at higher doses (20-60 mg /m²) is nonlinear. The pharmacokinetic parameters when administered at a dose of 10 to 60 mg /m²: clearance of doxorubicin - an average of 0.030 l / h /m²(0.008-0.152 L / h /m²); volume distribution - 1.93 l /m²(0.96-3.85 l /m²); the half-life is 73.9 hours (24-231 hours).

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

Renal failure (creatinine clearance 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 have a significant effect on the pharmacokinetic parameters of doxorubicin.

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 first-line 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's sarcoma in patients with a low CD4 count (<200 CD4 lymphocyte /mm³) and extensive lesions of the skin and mucous membranes or visceral organs, except for Kaposi's sarcoma, which is amenable to topical treatment or systemic treatment with interferon alpha. Kelix® 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).

Contraindications:

- hypersensitivity to any of the components of the drug;

- children's age till 18 years;

- pregnancy;

- the period of breastfeeding;

- Kaposi's Sarcoma, amenable to topical treatment or systemic treatment with interferon alfa.

Carefully:

- circulatory insufficiency;

- previous use of other anthracyclines;

- simultaneous use with drugs that have a cytotoxic (especially myelotoxic) effect;

- oppression of bone marrow hematopoiesis (including bone marrow infiltration by tumor cells, previous chemotherapy or radiation therapy), parasitic and infectious diseases of viral, fungal or bacterial nature (currently or recently transferred, including recent contact with the patient): herpes simplex , herpes zoster (viremic phase), chicken pox, measles, amoebiasis, strongyloidiasis (established or suspected), gout (including in history), urate nephrourolythiasis (including in history), heart disease (cardiotitis classically effect can be observed at lower total doses), hepatic failure; diabetes.

Pregnancy and lactation:

The use of Kelix® during pregnancy is not recommended.Women of childbearing age should use contraceptive methods if the patient or her partner receives Kelix® therapy and within 6 months after the end of treatment.

It is not known whether the drug is excreted in breast milk, so to prevent potential severe infant reactions to Kelix®, women should stop breastfeeding during Kelix® therapy.

Dosing and Administration:

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

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

Treatment with Kelix® should only be performed 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 /m² 1 every 4 weeks, before the progression of the disease and while tolerable tolerance remains.

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® can be performed for 60 minutes.

Multiple myeloma

In the treatment of multiple myeloma, the drug is administered at a dose of 30 mg / m² on the 4th day

a three-week cycle in combination with bortezomib (1.3 mg /m² on days 1, 4, 8 and 11). 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® can be prescribed for 90 minutes according to the scheme:

- 10 ml first 10 min

- 20 ml the next 10 minutes

- 40 ml the next 10 minutes

- then the remaining amount of solution for 60 minutes.

Subsequently, a dose of Kelix® can be administered within 1 hour. If there is a reaction to infusion with Kelix®, the infusion is stopped and, after the disappearance of the symptoms, Kelix® is prescribed as follows:

- 10 ml for the first 10 min

- 20 ml over the next 10 min

- 40 ml over the next 10 min

- then the remaining amount of solution in 60 minutes

Infusion can be administered through a central or peripheral venous catheter.

AIDS-associated Kaposi's sarcoma

The drug is administered intravenously in a dose of 20 mg / m² 1 time every 2-3 weeks, until the progression of the disease and while permissible 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 a 5% dextrose solution for infusion and administered as an intravenous infusion for 30 minutes.

All the patients.

If the patient has initial symptoms or signs of reaction to the drug, the infusion is immediately stopped, premedication with antihistamine drugs and / or high-speed glucocorticosteroids and resume infusion at a slower rate. Do not administer the drug in the form of bolus injections or as an undiluted solution. When carrying out infusions, it is recommended to combine Kelix® solution through the outermost portintravenous infusion with an aqueous solution of 5% dextrose to achieve further dissolution and reduce the risk of thrombosis and bruising. Infusion can be carried out through the peripheral vein. Kelix® 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 and stomatitis

Palmar-plantar syndrome

Toxicity after	Correction of Kelix® dose
previous administration of Kelix®
I degree (mild erythema, edema,	Administration of the drug is possible in 4 weeks
or desquamation that does not affect	period from the date of the previous introduction or
on daily activities)	can be delayed for another week. If the patient has previously had 3-4 toxicity levels, 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,	Postpone the treatment for 2 weeks or until
Desquamation, edema affecting	reduce toxicity to
day-to-day physical	degree 0-1. Then treatment can be continued in
activity, but not	the original dose and in the previous regime. If
limiting it; small	after 2 weeks of toxicity reduction not
blisters or ulceration	it is noted, the therapy to resume in a reduced
(<2 cm in diameter))	at a 25% dose, following 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.

Table 2. Modification of the dosing regimen in the development of stomatitis

	Stomatitis
The degree of toxicity after the previous administration of Kelix®	Correction of Kelix® dose
I degree	Administration of the drug is possible within 4 weeks from
(painless sores,	of the previous introduction or may be
erythema or poorly	delayed for another week.
expressed	If the patient has previously noted grade 3-4
soreness)	toxicity, it is necessary to postpone treatment for 2 weeks (wait an additional week) and resume therapy in a 25% reduced dose, observing the initial 4-week interval between administrations or discontinuing treatment as decided by the doctor.
II degree (painful	Postpone the treatment for 2 weeks before decreasing
erythema, edema or ulcers,	intensity of toxicity to the degree of 0-1.
but the patient can eat)	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 treatment for 2 weeks or until toxicity decreases to 0-1.

If no toxicity is observed after 2 weeks, treatment with Kelix® should be discontinued.

IV degree (the condition requires parenteral or enteral nutrition)

Postpone treatment for 2 weeks or until toxicity decreases to 0-1.

If no toxicity is observed after 2 weeks, treatment with Kelix® should be discontinued.

Table 3. Modification of the dosing regimen with the development of hematological toxicity (for breast cancer, ovarian cancer)

Hematological toxicity
Power	Neutrophils (in 1 μl)	Platelets (in 1 μl)	Changing the dosing regimen
I	1500-1900	75000- 150000	Continuation of therapy without dose reduction
II	1000-<1500	50000- <75000	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	25000- <50000	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 25000	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

Correction of doses of doxorubicin and bortezomib in patients with multiple myeloma
Patient's condition	Kelix®	Bortezomib
Increase body temperature> 38 ° C and the number of neutrophils <1000 / μL	Do not administer the drug in this cycle if an undesirable 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 of the drug after the 1st day of each cycle: Platelet count 25000 / μl Hemoglobin <8 g / dL Number of neutrophils 500 / μL	Do not administer the drug in this cycle if an undesirable 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	Dose correction is not required	See the application bortezomiba

* For more information on the use of bortezomib and its dose adjustment,in 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® and bortezomib, develops the 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 of the regimen in the development of stomatitis").

Patients with impaired liver 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, 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 prescribed to patients with metastases in the liver with concomitant hyperbilirubinemia and increased activity of "liver" 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, alkaline phosphatase, bilirubin.

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 on the use of Kelix® for the treatment of this group of patients, the use of Kelix® in these patients is not recommended.

Children

Limited safety data from Phase I studies I testify that doses up to 60 mg / m every 4 weeks are well tolerated in pediatric practice, nevertheless, the effectiveness of Kelix® treatment for patients under the age of 18 years is not established.

Adult patients

In patients aged 21 to 75 years, no significant differences in the pharmacokinetics of Kelix® were found.

Rules for the preparation and administration of a solution for infusions

Do not use the drug with signs of precipitation or presence of suspended particles.

When using the drug, it is necessary to follow the rules of working with antitumor drugs. Use gloves. In case of contact with the skin or mucous membranes, immediately flush this area with soap and water.

Determine the dose of doxorubicin needed for administration. The required volume of the drug is typed in a sterile syringe. All manipulations should be carried out with strict adherence to the rules of aseptic (the drug does not contain preservatives and bacteriostatic additives).

It is recommended to inject the drug through the side port of the infusion system, through which a solution of 5% dextrose is injected to achieve greater dilution and minimize the risk of thrombosis and extravasation. Infusion can be carried out in the peripheral vein.

The drug can not be administered intramuscularly or subcutaneously.

DO NOT USE FOR PREPARATION KELIX® INFUSION SYSTEMS WITH BUILT-IN FILTER.

It is recommended to administer Kelix® immediately after dilution with a 5% dextrose solution for infusion. 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.

Side effects:

Data on adverse reactions observed during clinical trials

The following are undesirable phenomena noted during clinical trials and systematized for each of the organ systems, depending on the frequency of occurrence, using the following classification:

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.

The adverse events observed in the clinical trials of the use of Kelix® for the treatment of breast cancer patients:

Infections and infestations:

Often: pharyngitis, folliculitis, fungal infections, febrile rashes on the skin (not herpetic), infections of the upper respiratory tract. Disorders from the blood and lymphatic system:

Often: leukopenia, anemia, neutropenia, thrombocytopenia, thrombocythemia Nervous system disorders:

Often: paresthesia, peripheral neuropathy, hot flashes

Infrequently: drowsiness

Disorders from the side of the organ of vision:

Often: lacrimation, blurred vision Heart disorders:

Often: ventricular arrhythmia

Disturbances from the respiratory system, chest and mediastinal organs:

Often: shortness of breath, nosebleeds

Disorders from the metabolism and nutrition:

Very often: anorexia

Disorders 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

Disturbances from the skin and subcutaneous tissues:

Very often: alopecia, palmar-plantar syndrome, rash

Often: erythema, dry skin, impaired pigmentation, itching, discoloration of the skin, bullous rash, dermatitis, erythematous rash, nail lesions, scaly skin.

Disorders from the musculoskeletal and connective tissues:

Often: leg cramps, bone pain, muscle pain

Disorders from the reproductive system and breast:

Often: pain in the mammary gland.

General disorders and reactions at the site of administration:

Very often: fatigue, asthenia, inflammation of the mucous membranes Often: weakness, fever, pain, weight loss, edema, edema in the leg area Clinically significant deviations in laboratory indicators (grades III and IV) inThis group of patients with breast cancer included increased concentrations of total bilirubin (2.4%) and activity of aspartate aminotransferase (1.6%). An increase in alanine aminotransferase activity was noted less frequently (<1%). There was no clinically significant increase in serum creatinine.

Adverse events observed during clinical studies of the use of Kelix-for the treatment of patients with ovarian cancer:

Infections and infestations:

Often: infections, candidiasis of the oral mucosa, shingles, urinary tract infections, other infections (including fungal infections, lower respiratory infections paths)

Violations from the blood and lymphatic system:

Very often: leukopenia, anemia, neutropenia, thrombocytopenia

Often: hypochromic anemia

Impaired nervous system:

Often: paresthesia, drowsiness, headache, dizziness, neuropathy, increased blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs:

Often: pharyngitis, dyspnea, increased cough

Disorders from the gastrointestinal tract:

Very often: stomatitis, constipation, diarrhea, nausea, vomiting

Often: abdominal pain, indigestion, ulceration of the oral cavity, esophagitis, gastritis, dysphagia, dry mouth, flatulence, gingivitis, taste perversion.

Disturbances from the skin and subcutaneous tissues:

Very often: palmar-plantar syndrome, alopecia, rash.

Often: skin dryness, skin discoloration, vesicle-bulbous rash, itching, exfoliative dermatitis, skin disorders, maculopapular rash, sweating, acne, skin ulcers

Immune system disorders:

Often: allergic reactions.

Disorders from the metabolism and nutrition:

Very often: anorexia

Often: dehydration, cachexia

Disorders of the psyche:

Often: anxiety, depression, insomnia

Disorders from the side of the organ of vision:

Often: conjunctivitis

Heart Disease:

Often: cardiovascular disorders

Vascular disorders:

Often: vasodilation

Disturbances from the musculoskeletal and connective tissue:

Often: back pain, myalgia

Disorders from the kidneys and urinary tract:

Often: dysuria

Violations of the genitals and breast:

Often: Vaginitis

General disorders and disorders at the site of administration:

Very often: asthenia, impaired mucous membranes

Often: fever, pain, chills, chest pain, malaise, peripheral edema.

Impact on laboratory and instrumental research results:

Often: weight loss.

Clinically significant laboratory abnormalities observed in patients with ovarian cancer during clinical trials of Kelix® included an increase in total bilirubin (usually in patients with liver metastases) (5%) and serum creatinine levels (5%). Increases in ACT were less frequent (<1%). Sepsis in leukopenia was noted infrequently (<1%).

Adverse events observed during clinical trials of Kelix® for the treatment of patients with multiple myeloma. Infections and invasions:

Often: herpes simplex, herpes zoster, nasopharyngitis, oral cavity candidiasis, pneumonia, upper respiratory tract infection

Violations from the blood and lymphatic system:

Very often: anemia, neutropenia, thrombocytopenia

Often: febrile neutropenia, leukopenia, lymphopenia.

Disorders from the metabolism and nutrition:

Very often: anorexia

Often: decreased appetite, dehydration, hyperkalemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia

Disorders of the psyche:

Often: anxiety, insomnia

Impaired nervous system:

Very often: headache, neuralgia, peripheral sensory neuropathy

Often: dizziness, dysesthesia, dysgeusia, hypoesthesia, inhibition, neuropathy, paresthesia, peripheral neuropathy, polyneuropathy, syncope.

Disorders from the side of the organ of vision:

Often: conjunctivitis

Vascular disorders:

Often: hot flashes, lowering blood pressure, increasing blood pressure, orthostatic hypotension, phlebitis

Disturbances from the respiratory system, chest and mediastinal organs:

Often: cough, shortness of breath, epistaxis, shortness of breath during exercise

Disorders from the gastrointestinal tract:

Very often: nausea, vomiting, diarrhea, stomatitis, constipation

Often: abdominal pain, indigestion, pain in the upper abdomen, ulceration of the mouth, dry mouth, dysphagia, aphthous stomatitis

Disturbances from the skin and subcutaneous tissues:

Very often: palmar-plantar syndrome, rash

Often: dry skin, pruritus, papular rash, allergic dermatitis, erythema, hyperpigmentation of the skin, petechiae, alopecia, drug-induced rash

Disturbances from the musculoskeletal and connective tissue:

Often: arthralgia, muscle spasms, muscle weakness, musculoskeletal pain in the thorax, musculoskeletal pain, myalgia, pain in the extremities.

Disorders from the reproductive system and breast:

Often: erythema of scrotum

General disorders and disorders at the site of administration:

Very often: asthenia, fatigue, pyrexia

Often: chills, hyperthermia, flu-like illness, malaise,

peripheral edema

Impact on laboratory and instrumental research results:

Often: increasing the activity of alanine aminotransferase in the blood, increasing the activity of aspartate aminotransferase in the blood, increasing the concentration of creatinine in the blood, reducing the ejection fraction, and reducing body weight.

Adverse events observed in the clinical trials of Kelix® for the treatment of patients with AIDS-associated Kaposi's sarcoma:

Infections and infestations:

Often: candidiasis of the oral cavity

Violations from the blood and lymphatic system:

Very often: neutropenia, anemia, leukopenia

Often: thrombocytopenia

Disorders from the metabolism and nutrition:

Often: anorexia

Disorders of the psyche:

Often: confusion

Impaired nervous system:

Often: dizziness

Infrequently: paresthesia.

Disorders from the side of the organ of vision:

Often: retinitis.

Vascular disorders:

Often: vasodilation

Disturbances from the respiratory system, chest and mediastinal organs:

Often: dyspnea

Disorders from the gastrointestinal tract:

Very common: nausea

Often: diarrhea, stomatitis, vomiting, ulceration of the oral mucosa, abdominal pain, glossitis, constipation, nausea and vomiting Skin and subcutaneous tissue disorders:

Often: alopecia, rash

Infrequent: palmar-plantar syndrome

General disorders and disorders at the site of administration:

Often: asthenia, fever, acute reactions to infusion

Impact on laboratory and instrumental research results:

Often: loss of body weight.

Hematologic toxic effects may require a reduction in dose or suspension of therapy.It is necessary to temporarily suspend therapy with Kelix® in patients with an absolute number of neutrophils <1000 / mm3 and / or platelet count <50000 / mm³ . G-CSF (or GM-CSF) can be used for concomitant therapy to maintain the number of uniform elements with an absolute neutrophil count <1000 / mm³ in subsequent cycles. Respiratory side effects were often (> 5%) observed in clinical studies of Kelix® and may be associated with opportunistic infections in the AIDS patient population. Opportunistic infections (OIs) have been observed in patients with AIDS-associated Kaposi's sarcoma after using Kelix®, and are often noted in patients with HIV-mediated immunodeficiency. The most frequently observed OI in clinical trials were candidiasis, cytomegalovirus infection, herpes simplex, pneumonia caused by Pneumocystis carinii and mycobacterium avium complex. Clinically significant laboratory disorders were often (> 5%) observed in clinical studies of Kelix®. They included an increase in the activity of alkaline phosphatase and an increase in ACT activity and bilirubin concentrations that were considered associated with the underlying disease, rather than with the drug intake

Kelix®.Reduction of hemoglobin and platelet count was rare (<5%). Septicemia associated with leukopenia was rare (<1%). Some of the abnormalities described could have been associated with the presence of HIV infection, rather than with Kelix®.

Post-registration data.

Undesirable reactions noted during the course of post-marketing application of the Kelix® preparation and systematized relative 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.

Vascular disorders:

In patients with malignant tumors, there is an increased risk of thromboembolism. In patients taking Kelix®, infrequent cases of thrombophlebitis and vein thrombosis, as well as pulmonary embolism, are rare.

Disturbances from the skin and subcutaneous tissues:

Serious skin disorders, including erythema polymorph, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been very rare.

Secondary neoplasms of the oral cavity:

In patients with prolonged (more than one year) use of Kelix® or in patients who received a total dose of Kelix® more than 720 mg /m² very rare cases of secondary cancer of the oral cavity.

Overdose:

Symptoms: severe myelosuppression (mainly leukopenia and

thrombocytopenia), toxic effects from the gastrointestinal tract (mucositis).

Treatment of acute overdose in patients with severe myelosuppression should be carried out in a hospital and include antibacterial drugs, granulocyte and platelet transfusion and symptomatic therapy of mucositis.

Interaction:

With the combined use of doxorubicin with cyclophosphamide or taxanes in patients with solid tumors (including ovarian cancer and breast cancer) no increase in toxicity was detected. Nevertheless, it should be taken into account that the preparation Kelix®, like other preparations of doxorubicin hydrochloride, can enhance the toxic effect of other antitumor drugs.

There are reports of an exacerbation of the induced cyclophosphamide hemorrhagic cystitis and increased hepatotoxicity of mercaptopurine in patientswith AIDS-associated Kaposi's sarcoma during therapy with standard doxorubicin hydrochloride. Caution should be exercised when using any other cytotoxic agents, especially myelotoxic agents.

The drug should not be mixed with other solutions, except for a solution of 5% dextrose for infusion.

Special instructions:

Infusion reactions

On the background of the use of Kelix®, during the first infusion and as a result of interaction with other drugs, anaphylactoid reactions, asthma attack, asthma, facial edema, vasodilation, increased or decreased blood pressure, hives, back pain, pain in the thoracic cage, chills, fever, tachycardia, dyspepsia, nausea, dizziness, difficulty breathing, pharyngitis, skin rash, itching of the skin, excessive sweating, convulsions (very rarely), and reactions at the injection site. Temporary cessation of infusion usually leads to resolution of these symptoms without additional treatment. However, when the drug is administered, medicines should be prepared for the purpose of symptomatic therapy, intended for cupping infusion reactions (epinephrine, antihistamines, anticonvulsants, glucocorticosteroids and other drugs for emergency medical care). Virtually all patients who received Kelix®, therapy can be resumed after resolving all symptoms without relapse.

When symptoms of an infusion reaction appear, stop the infusion immediately and perform symptomatic therapy (antihistamines and / or short-acting glucocorticosteroids). Renewal of infusion is possible after complete relief of all symptoms with a decrease in the rate of doxorubicin administration. Infusion reactions are rarely repeated after the first cycle of drug therapy.

Stomatitis

Stomatitis was noted in patients who received continuous infusions of standard doxorubicin hydrochloride and was often noted in patients receiving Kelix®, this did not prevent patients from completing therapy. Dose adjustments are usually not required, except when the stomatitis leads to the impossibility of eating the patient. In this case, it is possible to extend the intervals between administration of drugs for 1-2 weeks or dose reduction.

Palmar-plantar syndrome characterized by painful macular skin rashes of a reddish color. In patients who report this phenomenon, it is usually observed after two to three cycles of therapy. In most patients, the condition passes for one to two weeks with or without glucocorticosteroid therapy. For the prevention and treatment of this syndrome apply pyridoxine in a dose of 50-150 mg / day. Other methods of treatment and prevention of the palmar-plantar syndrome begin 4-7 days after the administration of the drug. To prevent this syndrome should keep your hands and feet in a cool state (baths for brushes and feet and baths for the body with a lowered temperature of water, swimming in cool water); Also avoid excessive exposure to warm / hot water and try not to wear tight fitting socks, gloves, tight shoes, so as not to disturb blood circulation in the legs and hands.

The condition is probably related to the dose and schedule of application and can be reduced by increasing the medication interval for 1-2 weeks or reducing the dose. However, this reaction in some patients can be severe and debilitating and may require the drug to be discontinued.

When symptoms appear extravasal penetration of the drug (burning, redness) immediately stop the infusion and place the ice on the injection site for 30 minutes. The drug is continued into another vein.

Repeated skin reactions associated with previous radiotherapy were rarely seen with Kelix®.

Risk of development of cardiovascular complications

Cardiotoxicity

All patients receiving therapy with the drug are recommended to carry out ECG monitoring. Transient changes in the ECG, such as flattening of the T wave, a decrease in the ST segment and clinically insignificant rhythm disturbances, are not mandatory indications for the abolition of doxorubicin. A specific manifestation of cardiotoxic action is a decrease in the voltage of the QRS complex. If such a change occurs, the possibility of a biopsy of the myocardium as the most specific test for the diagnosis of damage to the heart muscle caused by anthracyclines should be considered.

Methods for measuring the left ventricular ejection fraction - echocardiography and the preferred MUGA scan (multivariable arteriography) - refer to more specific methods for monitoring cardiac function compared to ECG.These methods should be used before and during drug therapy. Measurement of the left ventricular ejection fraction is mandatory for each subsequent administration of the drug at a total dose of the drug exceeding 450 mg /m².

If there is a suspicion of cardiomyopathy, i.e. with a decrease in the left ventricular ejection fraction compared to this index before the start of treatment and / or with a prognostically significant reduction of this index (less than 45%), a biopsy of the myocardium should be performed.

The listed research methods to identify the possible negative effects of anthracycline therapy on cardiac activity are recommended in the following order: ECG control, measurement of the left ventricular ejection fraction, myocardial biopsy.

If the results of the examination suggest damage to the myocardium associated with drug therapy, a careful assessment of the ratio of the prospective benefit of continuing the use of the drug and the risk of developing cardiotoxicity should be carried out.

Congestive heart failure due to cardiomyopathy can develop unexpectedly, without previous changes on the ECG, and may also appear several weeks after discontinuation of therapy.

Patients with cardiac diseases requiring appropriate therapy, the use of the drug is possible only if the benefit of using the drug exceeds the risk for the patient.

When calculating the cumulative dose of doxorubicin, any prior or concomitant use of cardiotoxic drugs (other anthracyclines / anthraquinones or fluorouracil).

Myelosuppression

During therapy with doxorubicin, a picture of peripheral blood should be monitored regularly and at least before each administration of the drug with a mandatory count of the number of cells.

Myelosuppression, accompanied by anemia, thrombocytopenia, leukopenia and, in rare cases, febrile neutropenia, were noted in patients receiving Kelix®. Persistent expressed myelosuppression can lead to the development of superinfection or bleeding.

Secondary hematologic malignant neoplasms

In patients who received combined chemotherapy, including doxorubicin, (as well as with the use of other DNA-binding antitumor drugs), cases of secondary acute myelogenous leukemia and myelodysplasticsyndrome, in connection with which such patients are encouraged to periodically monitor hematological indicators.

Diabetes

When using the drug in diabetics, it should be taken into account that the preparation contains sucrose, and that the drug is administered together with a 5% solution of dextrose.

Children

The safety and efficacy of the drug in patients under the age of 18 years have not been fully investigated.

Men and women of childbearing age during treatment, and also within 6 months after its abolition should use reliable methods of contraception.

Secondary cancer of the oral cavity

Very rare cases of secondary oral cancer have been reported in patients with long-term (more than one year) treatment with Kelix® or in those who receive aggregate doses of the drug in excess of 720 mg /m². Cases of secondary oral cancer were diagnosed both during treatment and for 6 years after the last dose. Patients should be examined regularly for ulcers in the oral cavity or any discomfort that may indicate secondary cancer of the oral cavity.

Pharmaceutical interaction

The presence of bacteriostatic additives in the infusion solution, such as benzyl alcohol, can cause precipitation of the drug.

Kelix® should be administered under the supervision of a physician with experience in cytostatic therapy.

Since the preparation Kelix® has special pharmacokinetic properties, alternating cycles of therapy with Kelix® and traditional doxorubicin should not be performed.

Effect on the ability to drive transp. cf. and fur:Although the drug does not directly affect the ability to drive a car, nevertheless, some patients may experience dizziness, drowsiness. Therefore, during the treatment period, these patients should refrain from driving the car and controlling the mechanisms.

Form release / dosage:

Concentrate for the preparation of a solution for intravenous administration of 2 mg / ml.

Packaging:

For 20 mg / 10 ml or 50 mg / 25 ml in vials.

For 1 or 10 vials with instructions for use in a cardboard pack.

Storage conditions:

At a temperature of 2-8 ° C. Do not freeze.

Keep out of the reach of children.

Shelf life:

20 months.

Do not use after the expiration date stated on the package

Terms of leave from pharmacies:On prescription

Registration number:П N015921 / 01

Date of registration:15.07.2009 / 18.01.2013

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

BEN VENUE Laboratories, Inc. USA

Information update date: & nbsp13.01.2016

Illustrated instructions

Instructions

Kelix® (Caelyx®)