Composition, form of production and packaging
Tablets covered with a film coating of white or almost white color, round, biconcave, with the stamp "GX EH3" on one side and "A" on the other; the core of the tablet is white or almost white.
melphalan 2 mg
Excipients: microcrystalline cellulose, crospovidone, silicon dioxide colloid, magnesium stearate.
Composition of the shell: Deficient white YS-1-18097-A (hypromellose, titanium dioxide, macrogol).
25 pcs. - bottles of dark glass (1) - packs of cardboard.
Lyophilized powder for solution for injections of white or almost white color; The applied solvent is a clear, colorless solution with an alcohol smell; when dissolved in 10 ml of the solvent, practically contains no visible particles.
melphalan (in the form of hydrochloride) 50 mg
Excipients: povidone K12, hydrochloric acid.
Solvent: sodium citrate, propylene glycol, ethanol, water d / u.
Glass vials (1) complete with a solvent (10 ml - С„Р».) - plastic pens (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
The description of the drug was approved by the manufacturer for the 2006 print edition.
Antitumor preparation, bifunctional alkylating compound. The alkylation process consists in the covalent bonding of carbon intermediate compounds formed from two bis-2-chloroethyl groups with guanine 7-nitrogen in DNA and cross-linking of two DNA chains, which leads to a disruption in cell replication.
The intravenous administration of Alkera in the form of monotherapy or in combination with other cytotoxic drugs is also effective in multiple myeloma, as is the oral administration of Alkera. The intravenous administration of Alkerane in high doses (with or without hemopoietic stem cell transplantation) as the first line of therapy or for the consolidation of remission after standard cytostatic chemotherapy leads to complete remission in 50% of patients with multiple myeloma.
Alkeran in high doses (with or without stem cell transplantation) was used either as monotherapy or in combination with radiotherapy and / or other cytotoxic drugs, to consolidate remission after standard treatment with prevalent neuroblastoma in children.
In / in the introduction of Alkera in the form of monotherapy and in combination with other cytotoxic drugs, it is possible to achieve an objective effect in about 50% of patients with advanced ovarian adenocarcinoma.
Taking the drug in the form of monotherapy or in combination with other drugs has a significant therapeutic effect in a number of patients with advanced breast carcinoma; In addition, melphalan has been used as part of adjuvant therapy after surgery for breast carcinoma.
Effective in treating patients with true polycythemia.
In 13 patients who received melphalan orally in a dose of 0.6 mg / kg body weight, the absorption was characterized by great variability - both in time before the first appearance of the drug in the plasma (range from 0 to 336 min) and in the value of C max in plasma (range from 70 to 63 ng / ml). In 5 patients who received an equivalent dose of melphalan IV, the mean absolute bioavailability was 56 В± 27%.
The pharmacokinetics of melphalan for intravenous administration in standard and high doses corresponds to the bi-exponential two-chamber model.
. In 18 patients who received melphalan orally in doses from 0.2 to 0.25 mg / kg body weight, Cmax in plasma (range from 87 to 350 ng / ml) was achieved within 0.5-2.0 hours. When taking melphalan tablets immediately after meals, time until the C max in the plasma increased, and the AUC decreased by 39 - 45%.
After administration of the drug in the form of a two-minute infusion in doses of 5 to 23 mg / m 2 body surface (about 0.1-0.6 mg / kg body weight), 10 patients with ovarian cancer or myeloma, the mean V d in equilibrium and the central compartment were 29.1 В± 13.6 l and 12.2 В± 6.5 l, respectively. In 28 patients with various malignant tumors who received the drug in doses from 70 to 200 mg / m 2 of the body surface in the form of 2-20 minute infusions, the average Vd in the equilibrium state and the central compartment were 40.2 В± 18.3 L and 18.2 В± 11.7 L, respectively .
At hyperthermal (39 В° C) perfusion of the lower extremity with melphalan at a dose of 1.75 mg / kg body weight in 11 patients with advanced melanoma, the mean Vd in the equilibrium state and the central compartment were 2.87 В± 0.8 L and 1.01 В± 0.28 L, respectively.
The data obtained in vivo and in vitro suggest that the main factor determining T 1/2 of the drug in humans is spontaneous degradation, not enzymatic degradation.
In 13 patients after oral administration of melphalan at a dose of 0.6 mg / kg of body weight, the mean T 1/2 of the final phase was 90 В± 57 minutes, with 11% of the drug detectable in 24 hours in urine.
In 8 patients after a single bolus administration of Alkeran 0.5-0.6 mg / kg T 1/2 in the initial and terminal phases were 7.7 В± 3.3 and 108 В± 20.8 min, respectively.After parenteral administration of melphalan in the plasma, its metabolites - monohydroxymelphalan and dihydroxymethylphalan, whose concentration reached the maximum levels by 60 and 105 min, respectively - were determined. T 1/2 with the addition of melphalan to the patient serum in vitro at 37 В° C was similar to that in vivo and was 126 В± 6 min. This suggests that the main factor determining the duration of T 1/2 in the human body is, rather, its spontaneous degradation, rather than enzymatic metabolism.
After administration of the drug in the form of a two-minute infusion in doses of 5 to 23 mg / m 2 body surface (about 0.1-0.6 mg / kg body weight), 10 patients with ovarian cancer or myeloma T 1/2 in the initial and terminal phases were 8.1 В± 6.6 and 76.9 В± 40.7 minutes, and the average clearance is 342.7 В± 96.8 ml / min.
In 15 children and 11 adults who received high-dose (140 mg / m 2 body surface) iv melfalan therapy against forced diuresis, mean T 1/2 in the initial and terminal phases were 6.5 В± 3.6 and 41.4 В± 16.5 min, respectively. In 28 patients with various malignant tumors who received the drug in doses from 70 to 200 mg / m 2 of the body surface in the form of 2-20-minute infusions, mean T 1/2 in the initial and terminal phases were 8.8 В± 6.6 and 73.1 В± 45.9 min, respectively , and the average clearance is 564.6 В± 159.1 ml / min.
At hyperthermic (39 В° C.) perfusion of the lower extremity with melphalan at a dose of 1.75 mg / kg body weight in 11 patients with advanced melanoma, mean T 1/2in the initial and terminal phases were respectively 3.6 В± 1.5 and 465 В± 17.2 min, respectively, and the average clearance - 55.0 В± 9.4 ml / min.
In 18 patients who received melphalan orally in a dose of 0.2-0.25 mg / kg body weight, the mean T 1/2 left 1.12 В± 0.15 h.
For parenteral use
Regional arterial perfusion is indicated when:
- localized melanoma of the limbs;
- a localized sarcoma of the soft tissues of the extremities.
IV dose in standard doses is applied when:
- multiple myeloma;
- advanced ovarian cancer
I / O administration in high doses is used to treat:
- multiple myeloma;
- a common neuroblastoma in children.
For oral administration
- multiple myeloma;
- common adenocarcinoma of the ovary.
Can be used for:
- breast carcinoma;
- the true polycythemia.
Alkeran should be prescribed only by physicians with experience in performing cytostatic therapy for malignant neoplasms.
Adults with multiple myeloma for parenteral administration of Alkerain for injection is administered in an intermittent mode, either as monotherapy or in combination with other cytotoxic agents, at a dosage range of 8 to 30 mg / m 2 body surface, at intervals of 2 to 6 weeks . In some treatment regimens, prednisolone is additionally included. More detailed treatment schemes are given in the literature. With iv monotherapy, the usual dosing regimen for Alkoker is 0.4 mg / kg body weight (16 mg / m 2 ) with repeated administration at appropriate intervals (for example, once every 4 weeks), provided that peripheral blood values вЂ‹вЂ‹are restored during this period. When used in high-dosage therapy, Alkeran is administered once / at a dose of 100 to 200 mg / m 2 (approximately 2.5 to 5.0 mg / kg body weight). When applying the drug at doses of more than 140 mg / m 2 of the body surface, it is very important to carry out transplantation of hematopoietic stem cells.If the renal function is impaired, the dose of the drug should be reduced by 50 . Given the pronounced myelosuppressive effect with IV therapy in high doses, this therapy should be carried out only in specialized centers under the supervision of experienced specialists.
Adults with multiple myeloma for oral administration usually appoint 0.15 mg / kg body weight in several doses for 4 days, repeating the cycles at intervals of 6 weeks. However, many other regimes have also been used, which can be studied in detail in the specialized literature. Taking melphalan orally with the simultaneous administration of prednisolone may be more effective than monotherapy with melphalan. Combination therapy is usually given on a discontinuous schedule.
Therapy lasting more than 1 year in patients responding to therapy, apparently, is not accompanied by a higher efficacy.
In the prevalent ovarian adenocarcinoma with intravenous administration in monotherapy, Alkeran is usually used at a dose of 1 mg / kg body weight (approximately 40 mg / m 2 ) at intervals of 4 weeks. When used in combination with other cytotoxic agents, the recommended dose of Alkeran is 0.3 to 0.4 mg / kg body weight (12 to 16 mg / m 2 ) at intervals of 4-6 weeks. When ingestion, usually prescribed 0.2 mg / kg of body weight per day for 5 days, repeating cycles every 4 to 8 weeks or after restoration of the picture of peripheral blood.
In melanoma, hyperthermic regional perfusion with Alkera's solution is used as adjuvant therapy after melanoma removal at an early stage of the disease, as well as as a palliative treatment of the locally advanced stage. Detailed information on the perfusion technique and the recommended doses is given in the literature.
With soft tissue sarcoma, hyperthermic regional perfusion of Alkera's solution is used at all stages of localized soft tissue sarcoma, usually in combination with surgical treatment. Alkeran is also prescribed in combination with actinomycin D. Detailed information on the recommended dosages is given in the literature.
In breast carcinoma, Alkeran is administered orally at a dose of 0.15 mg / kg body weight or 6 mg / m 2 body surface per day for 5 days, repeating the cycles every 6 weeks. At a toxic effect on bone marrow hematopoiesis, the dose is reduced.
With true polycythemia, in order to induce remission, the drug is administered orally at doses of 6 to 10 mg per day for 5-7 days, after which they switch to a dose of 2 to 4 mg per day until sufficient control of the disease is achieved. For maintenance therapy, the drug is prescribed in a dose of 2 to 6 mg once a week
Given the possibility of severe myelosuppression with continuous administration of melphalan, it is important throughout the therapy to regularly examine the blood picture, if necessary adjusting the dose or taking breaks in treatment to maintain good control of the blood picture.
With a common neuroblastoma in children , the Alkera injection solution is administered at doses of 100 to 240 mg / m 2 (sometimes this dose is divided into several equal parts and administered for three consecutive days) both in monotherapy and in combination with radiation therapy and / or with other cytotoxic agents, in combination with transplantation of hematopoietic stem cells.
Melphalan in the traditional dose range is prescribed for children only in rare cases, therefore it is not possible to give clearly defined recommendations for dosing.
Alkerane is often used in elderly and senile patients in standard doses, there is no information on the features of its use in this age group.
The experience of using Alkera in high doses in elderly and senile patients is limited. Before the initiation of high-dose iv therapy with melphalan in patients in this category, an adequate general condition should be achieved.
If the kidney function is impaired, the clearance of melphalan can decrease, although it varies greatly. With iv administration of the drug in standard doses (8-40 mg / m 2 ), patients with moderate or severe renal insufficiency are recommended to reduce the initial dose by 50%, and then select the dose depending on the degree of oppression of bone marrow function.
With iv administration of the drug in high doses (100-240 mg / m 2 ), the need to reduce the dose depends on the degree of renal dysfunction, whether the transplantation of hematopoietic stem cells is carried out, and the therapeutic need. As a rule, when performing high-dose therapy with melphalan without transplantation of hematopoietic stem cells in patients with moderate renal insufficiency (CK 30-50 ml / min), the dose is reduced by 50%. In severe renal failure, high-dose therapy with melphalan without transplantation of hematopoietic stem cells is not recommended.
High-dose therapy with melphalan in combination with hematopoietic stem cell transplantation was successfully performed even in patients with terminal stage of renal failure on hemodialysis.
Current data on pharmacokinetics do not allow us to recommend a reduction in the dose of melphalan for oral administration in patients with impaired renal function, however, at the beginning of therapy it may be advisable to reduce the dose to determine the tolerability of the drug.
When prescribing the drug inside, it should be taken into account that since absorption of the drug after ingestion varies, then to ensure the achievement of therapeutic concentrations, a cautious increase in the dose may be required before the development of myelosuppression.
Rules for the preparation of solution for injection
The solution is prepared at room temperature by mixing the lyophilized powder with a solvent that is attached to the Alkane bottle.
In a bottle of lyophilized powder of Alkera, 10 ml of the solvent (one-time) should be added and vigorously shaken until complete dissolution. The resulting solution contains 5 mg of anhydrous melphalan in 1 ml and has a pH of about 6.5.
The prepared Alkkeran injection solution is not sufficiently stable and must be prepared immediately before use. Unused solution should be disposed of. The prepared Alkkeran solution can not be stored in the refrigerator, as this causes the formation of a precipitate.
A solution of Alkeran for injection is administered only IV, except when regional arterial perfusion is indicated.
When in / in use, it is recommended to inject Alkera's solution slowly through special closed access in the infusion system against the background of rapid infusion of another solution. If the introduction directly into the rapidly injected another solution is not possible, then the Alkera solution can be diluted in the infusion tanks.
Alkera solution is recommended to dilute only 0.9% solution of sodium chloride for injection and not to mix with infusion solutions containing dextrose (glucose).
With further dilution of the Alkkeran injection solution in the infusion solution, its stability decreases, and the rate of its degradation increases rapidly with increasing ambient temperature. At room temperature (approximately 25 В° C), the total time from the time of preparation of the Alkera injection solution to the completion of its infusion should not exceed 1.5 hours.
If there is turbidity or crystallization in the prepared or diluted Alkkeran solution, it should be destroyed.
Care must be taken to avoid the possible introduction of Alkkeran not into a vein, but into surrounding tissues. In the case of difficult access to peripheral veins, the drug is injected into the central veins . High doses of Alkeraan (with transplantation of hematopoietic stem cells or without it) are recommended to be injected into the central veins.
When using the drug for regional arterial perfusion, it is recommended to familiarize yourself with the details of the technique in the specialized literature.
Modern clinical data on the incidence of adverse reactions with the use of this drug are absent. The frequency of adverse reactions varies depending on the indications and doses administered, as well as on the use of the drug in combination with other agents.
The following principles were used to classify the frequency of undesirable reactions: very often -? 0.1, often -? 0.01, but <0.1, sometimes -? 0.001, but <0.01, rarely -? 0.0001, but <0.001, very rarely - <0.00001
From the hemopoietic system and lymphatic system : very often - oppression of bone marrow hematopoiesis with the development of leukopenia and thrombocytopenia; rarely - hemolytic anemia.
On the part of the immune system : rarely - allergic reactions (urticaria, edema, skin rash, pruritus and anaphylactic shock in the first and subsequent administrations were noted infrequently, mainly with intravenous Alkeran therapy). There are reports of rare cases of heart failure with allergic reactions to Alkeran.
The respiratory system : rarely - interstitial pneumonia and pulmonary fibrosis (including fatal).
From the digestive system:very often - nausea, vomiting, and diarrhea; using high-dose mode - stomatitis; rarely - liver damage, ranging from changes in the functional activity of liver samples to clinically manifest hepatitis and jaundice, veno-occlusive disease after high-dose therapy, stomatitis when standard doses. For parenteral administration include diarrhea, nausea and vomiting are the dose-limiting toxicity factors in patients receiving I / Alkeran high-dose treatment with transplantation of hematopoietic stem cells. Previous therapy with cyclophosphamide, apparently reduces the severity of symptoms from the gastrointestinal tract due to a high dose Alkeran. The ingestion: reportedly up to 30% of patients receiving melphalan inwardly at standard doses, side effects noted by the digestive system,such as nausea and vomiting.
Dermatological reactions : very often - alopecia during high-dose therapy, often - alopecia in the appointment of dosage units; rarely - maculo-papular rash, and itching.
From the urinary system : often - transient significant increase in the level of urea in the blood in patients with multiple myeloma with renal dysfunction.
Other : at parenteral administration is very often - subjective, transient sensation of heat and / or tingling.
- Hypersensitivity to melphalan.
PREGNANCY AND LACTATION
Melphalan should be avoided during pregnancy, especially in the I trimester. In each individual case, the potential risk to the fetus must be related to the expected benefit to the mother.
Women receiving Alkeran should stop breastfeeding.
If any of the partners gets Alkeran should use reliable methods of contraception.
The teratogenic potential of Alkeran has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that Alkeran may cause birth defects in babies born to patients treated with this drug.
A significant number of women who have not reached menopause, Alkeran suppresses ovarian function, causing amenorrhea. Some data suggest the possibility of adverse effects on spermatogenesis Alkeran, therefore, in its application it is possible the development of transient or permanent sterility in men.
APPLICATION FOR FUNCTIONS OF THE LIVER
If the kidney function Melphalan clearance may be reduced, though highly variable. The on / in the drug administered at standard doses (8-40 mg / m 2 ) to patients with moderate or severe renal failure is recommended to reduce the initial dose at 50%, and further adjust the dose according to the degree of suppression of bone marrow function.
The on / in the introduction of the drug at high doses (100-240 mg / m 2) The need to reduce the dose depends on the degree of renal function, whether hematopoietic stem cell transplantation is performed, and the therapeutic need. Typically, during high-dose melphalan without hematopoietic stem cell transplantation in patients with moderate renal impairment (creatinine clearance of 30-50 ml / min) dose reduced by 50%. In severe renal insufficiency without the high-dose melphalan therapy of hematopoietic stem cell transplantation is not recommended.
Immunization with live vaccine can sometimes cause the development of infection in immunocompromised patients. For this reason, the use of live vaccines against the backdrop of melphalan therapy is not recommended.
When extravasation Alkeran injection may cause local damage to the surrounding tissues of the vessel, so it should not be introduced directly into the peripheral vein. Alkeran is recommended to inject the solution slowly against the backdrop of rapid infusion through a special closing access to the infusion system or a central vein.
Given the high risk and the need for complex maintenance therapy in the treatment of drug / in high-dose treatment Alkeran should only be performed in specialized centers with the appropriate conditions, under the supervision of experienced professionals. In patients receiving high-I / Alkeran treatment, you must resolve the issue of appointment of prophylactic antimicrobials and, if necessary, blood components. Before the high-dose melphalan is necessary to ensure an adequate overall health and function of organs.
Alkeran should be used with caution in patients who recently have undergone radiation therapy or chemotherapy, for the opportunity to enhance the toxic effect on bone marrow.
In applying Alkeran should follow the recommendations on the use of cytotoxic drugs.
Withdrawal of melphalan in patients with renal failure can be reduced. Furthermore, inhibition of hemopoiesis kostnogomozgovogo uremic genesis can occur in renal failure. In such cases, you may need to decrease the dose of the drug, and patients should be under close medical supervision.
Patients treated with Alkeran, detected chromosomal aberrations.
Melphalan, like other alkylating agents, can cause the development of leukemia in humans. There are reports of acute leukemia after long-term therapy with melphalan about amyloidosis, melanoma, multiple myeloma, macroglobulinemia, cold agglutinins syndrome and ovarian cancer. Comparative analysis of the ovarian cancer patients treated and not treated with alkylating agents, including melphalan, revealed a significant increase in the incidence of acute leukemia in the first group. Before the appointment of Alkeran is necessary to compare the risk of leukemia with a potential therapeutic effect of the drug.
Control of laboratory indicators
Since Alkeran is myelosuppressive agent, the course of therapy is very important to determine the number of blood cells, if necessary, adjusting the dose or temporarily postponing the introduction of the drug in order to prevent the possible development of excessive myelosuppression and the risk of irreversible bone marrow aplasia. The amount of blood cells may continue to decrease after cessation of the drug, therefore, at the first sign is too drastic reduction in the number of leucocytes or platelets, treatment should be temporarily discontinued.
For safe handling of the drug
when handling melphalan should follow guidelines for the handling of cytotoxic agents in accordance with local recommendations and / or regulations.
Alkeran solution should be prepared under the supervision of an experienced pharmacist who owns the safe handling rules with the drug, and are familiar with its properties. Melphalan solution should be prepared aseptically in special equipment (in a laboratory oven with a vertical stretch), or, if that is not in a dedicated isolated room in the pharmacy or clinic. Personnel who prepare solutions or do injections, must wear special protective clothing, disposable surgical gloves made of latex or PVC good quality (rubber are not suitable), a surgical mask of appropriate quality, safety glasses which should be washed thoroughly with water after use, disposable apron.
When working in aseptic conditions need different clothes.
When spraying or spilling solution personnel dressed in suitable protective clothing must immediately wipe the surface moist paper towels, which then immediately folded into a hazardous waste container, and then consume according to established procedure. The surface on which was a preparation should wash with plenty of water.
After contact with the solution of melphalan to the skin immediately and thoroughly rinse with plenty of cold water and soap; in such cases it is advisable to consult a doctor.
Upon contact with the mucous membranes of the eyes immediately wash with sodium chloride solution for the eyes and immediately seek medical attention. In the absence of sodium chloride solution may be to use a large amount of water.
For safe handling of melphalan tablets
when handling the dosage forms of melphalan should be observed for the treatment with cytostatics, available in the local recommendations and / or the relevant regulations.
If the outer shell of the tablet is intact, the treatment of melphalan tablets without risk. Melphalan tablets should not be burst.
Terms of destruction of the drug
solution Alkeran should be destroyed in accordance with the requirements. In the absence of such it is subject to the same procedure destruction, as well as other toxic chemicals such as high-temperature combustion and deep burial.
Destruction of sharps (eg needles, syringes, vials and infusion system) should be carried in rigid containers with a hazard warning sign. Personnel carrying out the destruction, should be aware of all precautions. Destruction procedures must comply with local regulatory requirements.
Melphalan Tablets consume in accordance with local regulatory requirements for the destruction of cytostatics.
Symptoms first manifestations of acute overdose Alkeran at / in the introduction are nausea and vomiting, may develop gastrointestinal mucosa with loss of diarrhea, sometimes haemorrhagic. If ingestion is most likely the first symptoms of an acute overdose are adverse reactions from the gastrointestinal tract, including nausea, vomiting and diarrhea. The main toxic effect of melphalan (as by ingestion or by parenteral administration) is to suppress the development of bone marrow hematopoiesis leukopenia, thrombocytopenia and anemia.
Treatment: if necessary, common arrangements supporting character should be carried out, along with blood transfusions and platelets, as well as solve the problem of patients hospitalized for anti-infective therapy and hematopoietic stimulants destination. There is no specific antidote. It is necessary to carefully monitor the peripheral blood for at least four weeks following overdosage until there are signs of normalization.
B / melphalan administration in high doses simultaneously with nalidixic acid resulted in children due to death of hemorrhagic enterocolitis.
Patients who prior to transplantation of hematopoietic stem cells in / melphalan administered in high doses and subsequently administered cyclosporin to prevent reaction "graft versus host", the cases of renal dysfunction are described.
A solution of the drug is not compatible with infusion solutions containing dextrose (glucose). It is recommended to be administered only in sodium chloride 0.9% for I / infusion.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
Packing a preparation in the form for parenteral administration should be stored protected from light and the reach of children at a temperature not higher than 30 В° C. The shelf life of a lyophilized powder for solution - 3 years.
A preparation in the form of tablets should be kept out of the reach of children at 2 to 8 В° C. The shelf life of tablets - 2 years.
The drug should not be used after the expiry date stated on the package.