2010/09/17

Alkeran

Composition, structure and packing

Tablets, coated in white or almost white, round, biconvex, with the stigma of "GX EH3" on one side and "A" - on the other.

1 tab. melphalan 2 mg.

Excipients: microcrystalline cellulose, krospovidon, silica colloidal anhydrous, magnesium stearate.

The composition of the shell: gipromelloza, titanium dioxide, macrogol. 25 pcs. - Dark glass bottles (1) - packs cardboard. Lyophilized powder for solution for injection in white or nearly white; attached solvent transparent, colorless solution with an alcohol odor, dissolving in 10 ml solvent contains almost no visible particles. 1 vial. melphalan (in the form of hydrochloride) 50 mg

Excipients: povidone K12, hydrochloric acid. Solvent: sodium citrate, propylene glycol, ethanol, water, d / and. Glass Bottles (1) together with the solvent (10 ml - vials.) - Plastic Packaging (1) - bundle pasteboard.

Clinico-pharmacological group: The antitumor drug.

Pharmacological action

The antitumor drug, bifunctional alkylating agents. The process of alkylation is covalent formed from two bis-2-chloroethyl groups of carbon intermediate compounds with 7-nitrogen of guanine in DNA and cross-linking of the two strands of DNA that leads to disruption of cell replication. In / in the introduction Alkerana as monotherapy or in combination with other cytotoxic drugs is also effective in multiple myeloma, as well as oral Alkerana. In / in the introduction Alkerana in high doses (with transplantation of hematopoietic stem cells or not) as first-line treatment or for consolidation of remission after standard cytotoxic chemotherapy leads to complete remission in 50% of patients with multiple myeloma. Alkeran in high doses (with hematopoietic stem cell transplantation with or without) was used as a monotherapy and in combination with radiation therapy and / or other cytotoxic drugs for consolidation of remission after standard treatment for widespread neuroblastoma in children. In / in the introduction Alkerana as monotherapy and in combination with other cytotoxic drugs can achieve the objective effect of around 50% of patients with common adenocarcinoma of the ovary. Acceptance of the drug as monotherapy or in combination with other drugs has a significant therapeutic effect in some patients with widespread carcinoma of the breast, in addition, melphalan was used in the adjuvant therapy after surgery for breast carcinoma. It is effective in treating patients with polycythemia.

Pharmacokinetics

Absorption

In 13 patients treated with oral melphalan at a dose of 0.6 mg / kg body weight, absorption was characterized by high variability - both in time before the first appearance of the drug in plasma (range from 0 to 336 min) and for Cmax value in plasma (range from 70 to 63 ng / ml). In 5 patients who received an equivalent dose of melphalan was administered in / in, the average absolute bioavailability was was 56 ± 27%. The pharmacokinetics of melphalan in in / in the introduction of standard and high-dose corresponds to a bi-exponential dual-chamber model. . In 18 patients treated with oral melphalan in doses from 0.2 to 0.25 mg / kg, Cmax in plasma (range from 87 to 350 ng / ml) achieved within 0.5-2.0 h. When you receive melphalan tablets immediately after a meal time to achieve Cmax in plasma increased, and the AUC decreased by 39 - 45%.

Distribution

After injection of the drug in the form of two minutes infusion in doses ranging from 5 to 23 mg/m2 body surface (about 0.1-0.6 mg / kg body weight) 10 patients with ovarian cancer or multiple myeloma average Vd in the equilibrium state and the central compartment were 29.1 ± 13.6 l and 12.2 ± 6.5 l, respectively. In 28 patients with various malignant tumors, at doses ranging from 70 to 200 mg/m2 body surface in the form of 2-20-minute infusion, the average Vdv equilibrium state and the central compartment were equal, respectively, 40.2 ± 18.3 L and 18.2 ± 11.7 liters.

In Hyperthermia (39 ° C) perfusion of the lower extremity melphalan at a dose of 1.75 mg / kg of body weight in 11 patients with advanced melanoma Average Vdv equilibrium state and the central compartment, respectively, were equal to 2.87 ± 0.8 l and 1.01 ± 0.28 liters.

Metabolism

Data obtained in vivo and in vitro, suggest that the primary determinant of T1 / 2 of the drug in humans, is the spontaneous degradation, rather than enzymatic.

Withdrawal

13 patients after oral administration of melphalan at a dose of 0.6 mg / kg body weight average T1 / 2 final phase is 90 ± 57 min, while for 24 h in urine was detected 11% of the drug. 8 patients after a single bolus dose of 0.5-0.6 Alkerana mg / kg, T1 / 2 in primary and terminal phase were respectively 7.7 ± 3.3 and 108 ± 20.8 min. After parenteral administration of melphalan in plasma were determined by its metabolites - monogidroksimelfalan and digidroksimelfalan, whose concentration reached maximum levels at 60 and 105 min, respectively. T1 / 2 by adding to the serum of patients melphalan in vitro at 37 ° C was similar to that in vivo and was 126 ± 6 min. This suggests that the main factor determining the duration of T1 / 2 in the human body is, rather, its spontaneous degradation, rather than enzymatic metabolism. After injection of the drug in the form of two minutes infusion in doses ranging from 5 to 23 mg/m2 body surface (about 0.1-0.6 mg / kg body weight) 10 patients with ovarian cancer or multiple myeloma T1 / 2 in primary and terminal phase were respectively 8.1 ± 6.6 and 76.9 ± 40.7 minutes, and the average clearance - 342.7 ± 96.8 ml / min. In 15 children and 11 adults treated by high-(140 mg/m2 body surface area) in / melphalan therapy on the background of forced diuresis, mean T1 / 2 in primary and terminal phase were respectively 6.5 ± 3.6 and 41.4 ± 16.5 min. In 28 patients with various malignant tumors, at doses ranging from 70 to 200 mg/m2 body surface in the form of 2-20-min infusion average T1 / 2 in primary and terminal phase were respectively 8.8 ± .6 and 73.1 ± 45.9 min, and Average clearance - 564.6 ± 159.1 ml / min. In Hyperthermia (39oS) perfusion of the lower extremity melphalan at a dose of 1.75 mg / kg of body weight in 11 patients with advanced melanoma mean T1 / 2 in primary and terminal phase were respectively 3.6 ± 1.5 and 465 ± 17.2 min, respectively, while the average clearance - 55.0 ± 9.4 ml / min. In 18 patients treated with oral melphalan at a dose of 0.2-0.25 mg / kg of body weight, mean T1 / 2 left 1.12 ± 0.15 h.

Statement

For parenteral

The regional arterial perfusion is indicated for:
localized melanoma of the limbs;
localized soft tissue sarcoma of extremities. In / in the introduction to the standard doses used in:
multiple myeloma;
disseminated ovarian cancer in the / in the introduction to the high doses used to treat: - multiple myeloma;
widespread neuroblastoma in children.

For oral

Showed at:
multiple myeloma;
common adenocarcinoma of the ovary.

Can be used for:
carcinoma of the breast;
polycythemia vera.

Dosage regimen

Alkeran should be appointed only by doctors who have experience of cytostatic therapy of malignant neoplasms.

Adults with multiple myeloma for parenteral administration Alkerana solution for injection in the intermittent mode is assigned as a monotherapy and in combination with other cytotoxic drugs, in doses ranging from 8 to 30 mg/m2 body surface, at intervals ranging from 2 to 6 weeks.

In addition, some regimens included prednisolone. More detailed treatments are given in the literature.

When i / in monotherapy the usual dosing regimen Alkerana is 0.4 mg / kg (16 mg/m2) with repeated administration at appropriate intervals (eg once every 4 weeks), subject to recovery for the period of peripheral blood.

When used in the mode of high-therapy Alkeran injected once into / in a dose of 100 to 200 mg/m2 (approximately 2.5 to 5.0 mg / kg body weight).

In applying the drug in doses of 140 mg/m2 body surface is very important to the transplantation of hematopoietic stem cells.

In violation of renal function dose should be reduced to 50. Given the expressed mielosupressivnogo actions when in / therapy in high doses, this therapy should be conducted only in specialized centers under the supervision of experienced professionals.

Adults with multiple myeloma Oral is usually prescribed to 0.15 mg / kg of body weight in divided doses for 4 days, repeating cycles with intervals of 6 weeks. However, used, and many other modes, which can be found in detail in the literature.

Receiving melphalan inside with simultaneous appointment of prednisolone may be more effective than monotherapy with melphalan. Combination therapy is usually appointed by a broken diagram. Therapy longer than 1 year in patients responding to therapy, apparently not accompanied by higher efficiency.
In common with adenocarcinoma of the ovaries in / in the introduction as monotherapy Alkeran usually used in doses of 1 mg / kg body weight (approximately 40 mg/m2) with an interval of 4 weeks.
When used in combination with other cytotoxic drugs recommended doses Alkerana ranges from 0.3 to 0.4 mg / kg body weight (from 12 to 16 mg/m2) with an interval of 4-6 weeks.
If ingestion is usually prescribed for the 0.2 mg / kg body weight per day for 5 days, repeating the cycle every 4 - 8 weeks or after a pattern of peripheral blood.
In melanoma, hyperthermic regional perfusion solution Alkerana used as adjuvant therapy after removal of melanoma at an early stage of disease, as well as a palliative treatment of locally advanced stage.
When soft tissue sarcoma hyperthermic regional perfusion solution Alkerana applied at all stages of localized soft tissue sarcoma, usually in combination with surgical treatment. Alkeran also given in combination with actinomycin D.
In carcinoma of the breast Alkeran prescribe oral dose of 0.15 mg / kg of body weight or 6 mg/m2 body surface per day for 5 days, repeating the cycle every 6 weeks.
The toxic effect on bone marrow hemopoiesis lower dose.
In polycythemia vera for remission induction drug prescribe oral doses of 6 to 10 mg / day for 5-7 days and then transferred to a reception at a dose of 2 to 4 mg per day to achieve adequate control of the disease.

For maintenance therapy the drug is prescribed in doses of 2 to 6 mg once a week Because of the possibility of severe myelosuppression when receiving continuous melphalan, it is very important throughout the therapy on a regular basis to investigate the blood picture, if necessary, adjusting the dose or by making breaks in treatment to maintain good control of the picture blood.

With widespread neuroblastoma in children Alkerana solution for injections administered in doses ranging from 100 to 240 mg/m2 (sometimes this dose is divided into several equal parts and injected for three consecutive days) as a monotherapy and in combination with radiotherapy and / or with other cytotoxic drugs, in combination with transplantation of hematopoietic stem cells. Melphalan at conventional dose range is assigned to children only in rare cases, therefore, to give clear guidance on dosing is not possible. Alkeran is often used in patients of elderly in standard doses, information about the features of its use in this age subgroup no. Experience with Alkerana in high doses in patients of elderly is limited. Before starting of high-in / melphalan therapy in patients in this category must achieve adequate general condition.

In case of violation of renal function melphalan clearance can be reduced, although highly variable.

When i / v injection of the drug in standard doses (8-40 mg/m2) in patients with moderate or severe renal insufficiency is recommended to reduce initial dose by 50%, and further to select the dose depending on the degree of suppression of bone marrow function.

When i / v injection of the drug in high doses (100-240 mg/m2) the need for dose reduction depends on the degree of renal dysfunction, whether that asks whether the transplantation of hematopoietic stem cells, and the therapeutic necessity. Typically, during the treatment of high-melphalan without hematopoietic stem cell transplantation in patients with moderate renal insufficiency (CC 30-50 ml / min) dose reduced by 50%.

In severe renal failure of high-melphalan therapy without hematopoietic stem cell transplantation is not recommended. Of high-melphalan therapy combined with transplantation of hematopoietic stem cells successfully implemented even in patients with end stage renal failure who are on hemodialysis. Current data on the pharmacokinetics not allow us to recommend reducing the dose melphalan for oral administration in patients with impaired renal function, but at the beginning of therapy may be appropriate to reduce the dose to determine tolerability.

In the appointment of the drug inside should be aware that since drug absorption after oral administration varies, for guaranteeing the achievement of therapeutic concentrations may require careful dose increase to development myelosuppression. Terms of cooking solution for injection solution is prepared at room temperature by mixing the dried powder with solvent, which is attached to a bottle of Alkeranom. Into a vial containing the lyophilized powder Alkerana should add 10 ml of solvent (simultaneously) and shake vigorously until completely dissolved. The resulting solution contains 5 mg anhydrous melphalan in 1 ml and has a pH of about 6.5. Prepared solution for injection Alkerana not stable and should be prepared immediately before use. Unused solution should be destroyed. Prepared solution Alkerana be stored in the refrigerator, as it causes the formation of sediment. Alkerana solution for injection is introduced only in / except when shown the regional arterial perfusion. When i / in the application is recommended to introduce a solution Alkerana slowly through a special closed access to the infusion system against a background of rapid infusion of another solution. When injected directly into the rapidly introduced another solution is impossible, the solution can be diluted in Alkerana capacity for infusion. Solution Alkerana encouraged to grow only 0.9% solution of sodium chloride for injection and mixed with infusion solutions containing dextrose (glucose).

With further dilution of the solution Alkerana injection in infusion solutions and its stability decreases, and its rate of degradation increases rapidly with increasing temperature.

At room temperature (approximately 25 ° C) the total time from preparation of the solution Alkerana injection until the end of its infusion should not exceed 1.5 h. When cooked, or in a dilute solution Alkerana appear blurred or crystallization, it should be destroyed. Be careful to avoid the possible introduction of Alkerana not in a vein, and in the surrounding tissue. In case of difficulty of access to peripheral veins of the drug is introduced into the central vein. High doses Alkerana (with transplantation of hematopoietic stem cells or not) is recommended to enter into the central vein.

When using the drug for regional arterial perfusion are encouraged to review the details of methodology in the literature.

Side effect

Recent clinical data on the frequency of adverse reactions when using this drug available. The frequency of adverse reactions varies depending on the indications and doses, as well as the use of the drug in combination with other drugs.

To classify the frequency of adverse reactions used the following guidelines: very often - ≥ 0.1, is often - ≥ 0.01, but <0.1, sometimes - ≥ 0.001, but <0.01, rarely - ≥ 0.0001, but <0.001, very rarely - <0.00001.
On the part of the hemopoietic system and lymphatic system: very often - inhibition of bone marrow hematopoiesis with the development of leukopenia and thrombocytopenia, rarely - hemolytic anemia.
On the part of the immune system: Rarely - allergic reactions (hives, swelling, skin rash, itching and anaphylactic shock in the first and subsequent introduction of observed infrequently, mostly in in / therapy Alkeranom). There are reports of rare cases of heart failure in patients with allergic reactions to Alkeran.
On the part of the respiratory system: rarely - interstitial pneumonia and pulmonary fibrosis (including fatal).
On the part of the digestive system: very often - nausea, vomiting and diarrhea, the use of high-profile - stomatitis; rarely - liver damage, ranging from changes in the activity of functional liver tests before clinically manifest hepatitis and jaundice, veno-occlusive disease after high-therapy, stomatitis in use of standard doses.

For parenteral administration: diarrhea, nausea, vomiting are dozolimitiruyuschimi factors of toxicity in patients receiving to / in therapy of high-Alkeranom with transplantation of hematopoietic stem cells. Previous therapy cyclophosphamide, appears to reduce the severity of symptoms from the gastrointestinal tract, caused by high dose Alkerana.

When administered: the available data, up to 30% of patients receiving melphalan orally in standard doses, side effects noted by the digestive system, such as nausea and vomiting.

Dermatological reactions: very often - alopecia during treatment of high-often - alopecia in the appointment of the standard doses; rarely - Makulo-papular rash and itching.

From the urinary system: often - transient significant increase in the level of urea in the blood of patients with multiple myeloma with renal dysfunction.

Other: for parenteral administration is very often - the subjective transient sensation of heat and / or tingling.

Contraindications
sensitivity to melphalan.

Pregnancy and lactation

It should avoid the use of melphalan in pregnancy, especially in the I trimester. In each individual case, the potential risk to the fetus should be correlated with 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.

Teratogenic potential Alkerana not been studied.

In view of its mutagenic properties and structural similarities to known teratogenic compounds, it is possible that Alkeran may cause congenital malformations in children born to patients treated with this drug. A considerable number of women who have not reached menopause, Alkeran suppresses ovarian function, causing amenorrhea.

Some data indicate the possibility of adverse effects on spermatogenesis Alkerana, therefore, in its application it is possible the development of transient or permanent sterility in men.

Application for violations of renal function

In case of violation of renal function melphalan clearance can be reduced, although highly variable.

When i / v injection of the drug in standard doses (8-40 mg/m2) in patients with moderate or severe renal insufficiency is recommended to reduce initial dose by 50%, and further to select the dose depending on the degree of suppression of bone marrow function.

When i / v injection of the drug in high doses (100-240 mg/m2) the need for dose reduction depends on the degree of renal dysfunction, whether that asks whether the transplantation of hematopoietic stem cells, and the therapeutic necessity. Typically, during the treatment of high-melphalan without hematopoietic stem cell transplantation in patients with moderate renal insufficiency (CC 30-50 ml / min) dose reduced by 50%.

In severe renal failure of high-melphalan therapy without hematopoietic stem cell transplantation is not recommended.

Cautions

Immunization with live vaccine can sometimes cause the development of infection in immunocompromised patients. For this reason, the use of live vaccines during therapy with melphalan is not recommended.

When extravasation Alkerana solution for injection may cause local damage to the surrounding vessel tissue, so it should not be injected directly into the peripheral vein.

It is recommended to enter solution Alkerana slowly against the background of rapid infusion through a special closed 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 / in of high-Alkeranom therapy should be undertaken only in specialized centers, with appropriate conditions, under the supervision of experienced professionals. Patients receiving of high-in / therapy Alkeranom necessary to solve the issue of prophylaxis of antibacterial drugs and, if necessary, components of blood.

Before the therapy of high-melphalan necessary to ensure adequate general condition of the body and the function of organs. Alkeran should be used with caution in patients who have recently undergone a course of radiotherapy or chemotherapy, for the opportunity to enhance the toxic effects on bone marrow.

In applying Alkerana should follow the recommendations on the application of cytotoxic drugs.

Derivation of melphalan in patients with renal insufficiency may be reduced. In addition, renal failure may occur oppression kostnogomozgovogo blood uremic genesis. In such cases, you may need to decrease the dose, and patients should be under careful medical supervision.

In 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 melphalan about amyloidosis, melanoma, multiple myeloma, makroglobulinemii, cold agglyutininovogo syndrome and ovarian cancer. Comparative analysis of patients with ovarian cancer treated and not treated with alkylating agents, including melphalan, showed a significant increase in the incidence of acute leukemia in the first group. Before the appointment Alkerana to compare the risk of leukemia with potential therapeutic effects of the drug.

Monitoring of laboratory parameters

Since Alkeran is mielosupressivnym means, in the course of therapy is very important to regularly determine the number of blood cells, if necessary, adjusting the dose or temporarily postponing the introduction of the drug to avoid possible development of excessive myelosuppression and the risk of irreversible bone marrow aplasia. The number of blood cells may continue to decline after the cessation of the drug, so when the first signs of too sharp decline in the number of white blood cells or platelet therapy should be temporarily discontinued.

Rules of sound management of drug

When dealing with melphalan should follow guidelines for handling cytotoxic drugs in accordance with local recommendations and / or regulations. Solution Alkerana should be prepared under the supervision of an experienced pharmacist who owns the rules for safe handling of medication and familiar with its properties. Solution melphalan should be prepared in aseptic conditions on the special equipment (in a laboratory cabinet with vertical hatch), or, if that is not, in a special isolated room in the pharmacy or clinic.

Personnel who prepare solutions or gives an injection to wear special protective clothing: Disposable gloves surgical latex or PVC good quality (rubber is not suitable), a surgical mask of appropriate quality, safety glasses should be washed thoroughly with water after use, disposable apron.

When you work in aseptic conditions require other clothing.

When spraying or spill solution staff dressed in appropriate protective clothing should be immediately wiped with a damp paper towels, who then immediately be packed into a container for hazardous waste, and then destroyed in accordance with established procedure. The surface on which got the drug, should be washed with plenty of water.

After contact with melphalan solution to the skin immediately and thoroughly rinsed with cold water and soap in such cases it is advisable to see a doctor. In contact with mucous membranes of eyes, rinse immediately with a solution of sodium chloride to the eye and immediately seek medical attention.

In the absence of sodium chloride solution can use a large amount of water.

Rules of sound management of melphalan tablets

When dealing with melphalan dosage forms must comply with instructions on handling cytotoxic drugs available in local recommendations and / or appropriate regulations. If the outer shell tablet or damaged, then treatment with melphalan tablets do not pose a risk. Tablets melphalan should not be burst.

Terms of destruction of the drug

Solution Alkerana must be destroyed in accordance with the requirements. In the absence of such it is subject to the same procedure of destruction, as well as other toxic chemicals, such as high-temperature incineration and deep burial. Destruction of sharps (eg needles, syringes, infusion systems and ampoules) should be in rigid containers with a warning sign of danger. Staff carrying out the destruction, should be aware of the observance of all precautions. Procedures for destruction must comply with local regulatory requirements.

Tablets melphalan destroyed in accordance with local regulatory requirements for the destruction of cytostatics.

Overdose

Symptoms: the first manifestations of acute overdose Alkerana with a / in the introduction are nausea and vomiting, may develop blennosis gastrointestinal tract with diarrhea, sometimes hemorrhagic.

If ingestion is most likely the first symptoms of acute overdose are side effects from the gastrointestinal tract, including nausea, vomiting and diarrhea.

The main toxic effect of melphalan (such as ingestion or parenteral administration) is the suppression of bone marrow hemopoiesis to the development of leucopenia, thrombocytopenia and anemia.

Treatment: If necessary, conduct joint activities supporting character, along with blood transfusions and platelet, as well as solve the problem of hospitalization of patients for therapy against infectious and destination stimulant of hematopoiesis.

Specific antidote exists. We must carefully monitor the performance of peripheral blood for at least four weeks after the overdose, until there are signs of normalcy.

Drug Interactions

In / to the introduction of melphalan in high doses along with nalidixic acid resulted in children to death as a result of the development of hemorrhagic enterocolitis. Patients who prior to transplantation of hematopoietic stem cells in / melphalan was administered at high doses, and subsequently administered cyclosporine to prevent the reaction of the graft versus host ", describes cases of renal dysfunction.

Pharmaceutical incompatibilities

The solution of the drug is incompatible with infusion solutions containing dextrose (glucose). He recommended only in a solution of sodium chloride 0.9% for in / infusions.

Terms and Conditions of storage

Packaging with the drug in the form for parenteral administration should be stored protected from light and away from children at or above 30 ° C. Expiration lyophilized powder for solution - 3 years.

The drug in the form of tablets should be stored out of reach of small children at a temperature of from 2 to 8 ° C. Expiration tablets - 2 years. The drug should not be used after the expiry date stated on the packaging.