Мюстофоран®

General characteristics. Structure:

1 bottle with powder contains:
active agent: фотемустин 208 mg
excipients: no
1 ampoule with solvent contains: ethanol of 96% - 3.35 ml, water for injections – enough up to the volume of 4 ml.
Description
Powder of light yellow color. Solvent: the transparent, colourless solution having a characteristic smell of ethanol.

Pharmacological properties:

Pharmacodynamics. Fotemustin is the cytostatic antimitotic drug from group of a nitrozomochevina possessing the alkylating and karbamiliruyushchy action. The expressed antineoplastic activity of a fotemustin was confirmed experimentally.
Is a part of a molecule of a fotemustin alanine bioisosteres (amino-1-ethylphosphonew acid) which promotes penetration of drug into cells and passing through a blood-brain barrier.

Pharmacokinetics. After intravenous infusion, the kinetics of elimination of drug from plasma carries mono - or bieksponentsialny character with a short elimination half-life.
Drug is almost completely metabolized. Linkng with proteins of plasma low (25-30%). Fotemustin gets through a blood-brain barrier.

Indications to use:

• The disseminated malignant melanoma, including metastasises in a brain.
• Malignant tumors of a brain.

Route of administration and doses:

• At monotherapy drug is used as induction therapy in a dose 100 mg/sq.m in 1, 8 and 15 days. Similar courses are repeated at an interval of 4-5 weeks.
• As a maintenance therapy Myustoforan enter in the same dose of 1 times in 3 weeks.
• As a part of the combined chemotherapy the drug is administered in a dose 100 mg/sq.m in the 1 and 8 days.
At the patients receiving Myustoforan before each introduction it is necessary to control quantity of thrombocytes, leukocytes and granulocytes in blood. In case of development of hematologic toxicity a drug dose Myustoforan can be reduced, or administration of drug should be postponed according to the following scheme:
Absolute quantity        Quantity of thrombocytes       of % of the previous dose
neutrophils (in 1 мкл)           (in 1 мкл) 
> 2000 and                                     >                                     100000 100%
2000 ≥ N>                        1500 100 000≥N> 80000                           75%
1500 ≥ N> 1000                                                                                50%
≤                                           1000 N ≤ 80 000                             to Postpone introduction
• Use in a combination with dakarbaziny
At introduction of a fotemustin and dakarbazin in high doses within one days cases of pulmonary toxicity (a respiratory distress syndrome of adults) were noted.
It is necessary to avoid simultaneous use of a dakarbazin and a fotemustin (see the section "Interaction with Other Medicines and Other Forms of Interaction"). In need of the combined use of these drugs the following mode of therapy is recommended:
Induction therapy:
- фотемустин in a dose of 100 mg/sq.m in the 1 and 8 days,
- дакарбазин in a dose of 250 mg/sq.m in 15, 16, 17 and 18 days.
Then it is necessary to take a 5 weeks break in treatment.
Maintenance therapy: each 3 weeks
- фотемустин in a dose of 100 mg/sq.m in 1 day,
- дакарбазин in a dose of 250 mg/sq.m in 2, 3, 4 and 5 days.
Instruction for drug cultivation
Solution should be prepared just before introduction and to use at once after preparation.
Contents of a bottle are dissolved in 4 ml of the enclosed solvent and mixed within 2-3 minutes before full dissolution of powder. For preparation of infusion solution a necessary dose further dissolve in 250 ml 5% of solution of a dextrose (at the patients suffering from a diabetes mellitus, as solution for cultivation it is possible to use 0.9% chloride sodium solution). The received solution is entered intravenously kapelno within 1 hour, protecting from light (a bottle with solution place in an opaque cover).

Features of use:

• Treatment by drug Myustoforan should be carried out only under control of the doctor having experience of use of antineoplastic therapy.
• If after the previous treatment by cytostatic means there passed less than 4 weeks (and in case of treatment by nitrozomochevina drugs – 6 weeks), patients are not recommended to appoint drug.
• Myustoforan it is possible to carry out treatment by drug only at quantity of thrombocytes in peripheral blood not less 100000/mkl and granulocytes – not less 2000/mkl.
• Blood test should be carried out before each next administration of drug with the corresponding dose adjustment depending on hematologic indicators.
• Between the beginning of induction therapy and the beginning of a maintenance therapy the interval - is recommended 8 weeks. Between two cycles of a maintenance therapy the recommended interval - 3 weeks.
• Purpose of a maintenance therapy is possible if quantity of thrombocytes in peripheral blood not less 100000/mkl and granulocytes – not less 2000/mkl.
• It is regularly recommended to carry out assessment of indicators of function of a liver in time and after induction chemotherapy.
• Men and women in time and not less than 6 months after the termination have to use reliable measures of contraception.
• During the work with drug Myustoforan it is necessary to follow necessary rules of use and destruction of cytotoxic drugs. Pregnant women are forbidden to work with Myustoforan. During the work with drug use of latex gloves and masks is recommended. In case of hit of solution on skin or mucous membranes these sites should be washed out carefully water with soap. In case of hit of drug in eyes they should be washed out a large amount of water. It is necessary to avoid drug inhalation.
• Drug contains 80% ethanol solution, i.e. 1,3 g of ethanol on 100 mg of a fotemustin that is equivalent to 32 ml of beer, 13,3 ml of wine. Such amount of ethanol can be dangerous to the patients having alcoholism. At purpose of drug patients with diseases of a liver and epilepsy also should remember that ethanol is its part.
• It is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Most often in clinical trials side effects from system of a hemopoiesis were noted. The delayed toxicity of a fotemustin is shown by anemia (14%), thrombocytopenia (40.3%) and a leukopenia (46.3%) and reaches the maximum expressiveness on 4-5 and 5-6 weeks after the beginning of induction therapy. Development of a pancytopenia is also possible.
Frequency of side reactions which were noted against the background of therapy fotemustiny is specified in a type of the following gradation: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000).
From system of a hemopoiesis
Very often: thrombocytopenia, leukopenia (3-4 degrees), anemia (3-4 degrees).
From system of digestion
Very often: the nausea and vomiting developing during 2 h after the beginning of administration of drug; moderate reversible increase in activity of hepatic transaminases, an alkaline phosphatase and bilirubin in blood serum.
Often: diarrhea, abdominal pain.
From the central and peripheral nervous system
Infrequently: passing neurologic symptoms (disturbance of consciousness, paresthesia, loss of flavoring feelings).
From an urinary system:
Infrequently: passing increase in level of urea in blood serum.
From skin and hypodermic fabrics:
Infrequently: skin itch.
Others:
Often: fever, phlebitis in a drug injection site.
At simultaneous introduction with dakarbaziny cases of pulmonary toxicity (a respiratory distress syndrome of adults) were noted (see the section "Interaction with Other Medicines and Other Forms of Interaction").
Use of antineoplastic drugs, and especially – the alkylating connections, is accompanied by risk of development of a miyelodisplastichesky syndrome and acute myeloleukemia. Exceptional cases of such complications were described when using a fotemustin in high cumulative doses in the mode of monotherapy and in combination with other chemotherapeutic drugs, in combination with radiation therapy and without it.

Interaction with other medicines:

Interaction characteristic of cytotoxic drugs
At patients with malignant new growths the risk of development of thrombosis therefore by it often appoint anticoagulants is increased. Against the background of reception of anticoagulants it is necessary to control more often an indicator of the international normalized relation (INR) as at such patients variability of indicators of coagulant ability of blood which is complicated by risk of interaction of anticoagulants for intake and antineoplastic means is noted.
Combinations of drugs which use is contraindicated
• Vaccine of yellow fever
Risk of fatal system postvaccinal complications (see the section "Contraindications").
Undesirable combinations of drugs
• At co-administration of Phenytoinum, because of decrease in absorption at the level of a digestive tract, concentration of Phenytoinum in blood serum can decrease.
• In time and after treatment (at least within 3 months) it is necessary to avoid vaccination by the "live" and "weakened" vaccines.
For vaccination of such patients it is necessary to use the inactivated vaccines (for example, a poliomyelitis vaccine).
Combinations of drugs which use demands care
The immunodepressants-expressed oppression of immune system and risk of a limfoproliferation.
Interaction specific to a fotemustin
Combinations of drugs which use demands care
• Dakarbazin
At introduction of a fotemustin and dakarbazin in high doses within one days cases of pulmonary toxicity (a respiratory distress syndrome of adults) were noted. It is not necessary to apply фотемустин and дакарбазин at the same time. The recommended interval between introduction of the last dose of a fotemustin and the first dose of a dakarbazin makes 1 week (see the section "Route of Administration and Doses").

Contraindications:

• Hypersensitivity to drugs of group of derivatives of a nitrozomochevina.
• Pregnancy and period of feeding by a breast.
• The combined use with a vaccine of yellow fever (see the section "Interaction with Other Medicines and Other Forms of Interaction").
Use for children and teenagers
It is not recommended to apply at children and teenagers up to 18 years due to the lack of sufficient
number of clinical data.
With care
Drug should be used with care to the patients having alcoholism, to patients with diseases of a liver and epilepsy.

Overdose:

Specific antidotes at Myustoforan's overdose are not known. Treatment consists in the termination of administration of drug and carrying out a maintenance therapy at the strengthened control of hematologic indicators.

Storage conditions:

At a temperature from 2 to 8 °C in protected from light and the place, unavailable to children. Period of validity
2 years. Not to apply after the expiry date specified on packaging. Ready solution has to be used at once after preparation.

Issue conditions:

According to the recipe

Packaging:

Powder for preparation of solution for infusions complete with solvent, 208 mg.
Powder
On 208 mg of powder in a bottle from glass of brown color. The bottle is corked by a stopper from elastomer and rolled by an aluminum cap.
Solvent
On 4 ml in an ampoule of colourless glass with the put ring of a break of white color. The bottle and an ampoule are placed in a blister strip packaging from plastic of white color with a colourless plastic cover, and together with instructions on a medical use invest in a cardboard pack.