Milanfor

General characteristics. Structure:

Active ingredient: 3,5 mg of a bortezomib.

Excipients: D-Mannitolum, nitrogen.

Solvent: sodium chloride of 0,9%, water for injections.

The drug used for treatment of a multiple myeloma and a mayntiynokletochny lymphoma.

Pharmacological properties:

Pharmacodynamics. Бортезомиб is a reversible high-selection inhibitor of activity of a 26S-proteasoma of cells of mammals and represents the modified boric acid. 26S – the proteasoma, is present at a kernel and cytosol of all eukaryotic cells and is the key component catalyzing splitting of the main proteins participating in management of a life cycle of cells. Бортезомиб inhibits himotripsinopodobny action of a proteasoma, causes braking of proteolysis and leads to apoptosis. Myeloma cells (in vitro) almost in one thousand times are more susceptible to the apoptosis caused bortezomiby, than normal cells of plasma. The major factor explaining ability of inhibitor of a proteasoma of a bortezomib to destroy myeloma cells is its ability to block NF-kB activation. In normal cells of NF-kB (which exists as p50-p65 dimeasures) it is connected with the inhibiting protein of LkB which holds it in an inactive form in cytosol. Some tumors contain the activated NF-kB forms, and the proteasoma plays an important role in this activation since it catalyzes proteolytic generation of subgroup of NF-kB p50 from the inactive predecessor of p50 and destruction of the inhibiting protein of LkB. The activated NF-kB, getting into a kernel, helps a cell to survive and proliferate. Inhibiting proteasy and therefore, slowing down NF-k activation, бортезомиб promotes reduction of quantity of antiaptozny factors, inflammatory molecules, molecules of cellular adhesion (which allow connecting cells to be attached to marrow cells) and cytokines (which stimulate growth of cells of a myeloma). In vivo бортезомиб caused delay of growth of many experimental models of human tumors, including a multiple myeloma.

Pharmacokinetics. After single intravenous administration concentration of a bortezomib in a blood plasma decreases on the two-phase curve which is characterized by a bystry initial phase of distribution and longer final phase of removal. The drug elimination half-life in an initial phase of distribution fluctuates from 5 to 15 hours. System influence of a bortezomib has dozozavisimy character in the range of doses from 1,45 to 2,0 mg/m? and in the range of doses of 1,0-1,3 mg/m? system influence increases in proportion to a dose.

After single or repeated introduction in doses of 1,0 and 1,3 mg/m? the average volume of distribution of a bortezomib at patients with a multiple myeloma makes 1659–3294 l (489–1884 l/sq.m). It allows to assume that it бортезомиб is intensively distributed in peripheral fabrics. At concentration of a bortezomib of 100-1000 ng/ml linkng of drug with proteins of a blood plasma averages 83%. In the conditions of in vitro metabolism of a bortezomib is preferential carried out by P450 cytochrome isoenzymes — CYP3A4, CYP2C19 and CYP1A2. Only a small amount of not changed substance is removed with urine, and in bile and Calais not changed бортезомиб it is not found.

Ways of removal of a bortezomib of in vivo were not studied.

Indications to use:

Drug is intended for treatment:

-   a multiple myeloma (as a part of a combination therapy of the 1st line).
-   a multiple myeloma at the patients who earlier received therapy of the 1st line (therapy of the 2nd line);
-   a mantiynokletochny lymphoma at the patients who earlier received therapy of the 1st line.

Route of administration and doses:

Monotherapy. The drug is administered in/in struyno during 3-5 sec.

The recommended initial dose of a bortezomib makes 1.3 mg/sq.m of surface area of a body 2 times a week within 2 weeks (days 1, 4, 8 and 11) with the subsequent 10-day break (days 12-21). The cycle of treatment makes 21 days. Between introduction of consecutive doses of Milanfor there have to pass not less than 72 h.

Degree of the clinical answer is recommended to be estimated after carrying out 3 and 5 cycles of treatment.

In case of achievement of the full clinical answer carrying out 2 additional cycles of treatment is recommended.

Lasting treatment more than 8 cycles Milanfor it is possible to apply according to the standard scheme or according to the scheme of a maintenance therapy - weekly within 4 weeks (days 1,8, 15, 22) with the subsequent 13-day period of rest (days 23-35).

Recommendations about dose adjustment and mode of introduction of Milanfor. At development of any not hematologic toxic effect of the 3rd degree or hematologic toxicity of the 4th degree, except for a neuropathy, treatment by Milanfor should be suspended. After disappearance of symptoms of toxicity treatment by Milanfor can be resumed in the dose lowered by 25% (the dose of 1.3 mg/sq.m is reduced to 1 mg/sq.m, the dose of 1 mg/sq.m is reduced to 0.7 mg/sq.m). If symptoms of toxicity do not disappear or appear again at the minimum dose, then it is necessary to consider the possibility of cancellation of Milanfor if only the advantage of its use obviously does not exceed risk.

At emergence of the neyropatichesky pain connected using Milanfor and/or a peripheral neuropathy the dose of drug is changed according to the table. At patients with a heavy neuropathy in the anamnesis Milanfor it is possible to apply only after careful assessment of the relation risk/advantage.

Table 1. The recommended change of a dose at development of the neyropatichesky pain caused by Milanfor and/or a peripheral touch or motive neuropathy

Weight of a peripheral neuropathy	Change of a dose and frequency of introduction
1 degree (paresthesia and/or fading of reflexes) without pain or defunctionalization	The dose and the mode of introduction do not demand correction
1 degree with pain or the 2nd degree (dysfunction, but not daily activity)	To lower a dose to 1 mg/sq.m
2 degree with pain or the 3rd degree (disturbance of daily activity)	To suspend Milanfor's use before disappearance of symptoms of toxicity. After that to resume treatment, having lowered Milanfor's dose to 0.7 mg/sq.m and having reduced introduction frequency to 1 time a week
4 degree (the touch neuropathy resulting in disability or a motive neuropathy, life-threatening or leading to paralysis)	To stop Milanfor's use

Extent of disturbance of functions of kidneys does not influence Milanfor's pharmacokinetics. Therefore for patients with a renal failure of dose adjustment it is not required. As dialysis can reduce concentration of a bortezomib in blood, the drug should be administered after carrying out dialysis.

Combination therapy. Milanfor enter in/in struyno during 3-5 sec. into combinations with Melphalanum and Prednisonum accepted inside. Carry out nine 6 weeks cycles, as shown in the table. In cycles 1-4 Milanfor apply 2 times a week (days 1, 4, 8, 11, 22, 25, 29 and 32), and in cycles 5-9 - once a week (days 1, 8, 22 and 29).

Table 2. The recommended scheme of dosing of Milanfor applied in a combination with Melphalanum and Prednisonum at patients with earlier not a treated multiple myeloma

Milanfor 2 times in a week (cycles 1-4)

1 week.	2 weeks.	3 weeks.	4 weeks.	5 weeks.	6 weeks.
Milanfor (1.3 mg/sq.m)
1st day 4th day	8th day 11th day	Rest period	22nd day 25th day	29th day 32nd day	Rest period
Melphalanum (9 mg/sq.m) + Prednisonum (60 mg/sq.m)
1st day 2nd day 3rd day 4th day	-	Rest period	-	-	Rest period

Milanfor once a week (cycles 5-9)

1 week.	2 weeks.	3 weeks.	4 weeks.	5 weeks.	6 weeks.
Milanfor (1.3 mg/sq.m)
1st day	8th day	Rest period	22nd day	29th day	Rest period
Melphalanum (9 mg/sq.m) + Prednisonum (60 mg/sq.m)
1st day 2nd day 3rd day 4th day	-	Rest period	-	-	Rest period

Dose adjustment and schemes of treatment at Milanfor's use together with Melphalanum and Prednisonum
Before a new cycle of treatment:

the maintenance of thrombocytes has to be> 70 000/mkl, and the absolute maintenance of neutrophils (AMN)> 1000/mkl;

negematologicheskaya toxicity has to decrease to 1 degree or to initial level.
Table 3. Dose adjustment at the subsequent cycles of treatment

Toxicity	Correction or delay of a dose
Hematologic toxicity during the previous cycle:
Long neutropenia or thrombocytopenia 4 degrees, or thrombocytopenia with bleeding	In the following cycle the dose of Melphalanum should be reduced by 25%
Maintenance of thrombocytes? 30 000/mkl or ASN? 750/mkl in day of introduction of Milanfor (except the 1st day)	To postpone Milanfor's introduction
Several delays of introduction of Milanfor in one cycle (> 3 times at introduction 2 times a week or? 2 times at introduction once a week)	Milanfor's dose is reduced on 1 step (from 1.3 mg/sq.m to 1 mg/sq.m; from 1 mg/sq.m to 0.7 mg/sq.m)
Negematologicheskaya toxicity> 3 degrees	Milanfor's use is postponed until decrease in not hematologic toxicity to 1 degree or to initial level. After that treatment by Milanfor can be resumed in the dose lowered on 1 step (from 1.3 mg/sq.m to 1 mg/sq.m; from 1 mg/sq.m to 0.7 mg/sq.m). At development of the neyropatichesky pain and/or a peripheral neuropathy connected using Milanfor, introduction of the next dose is postponed and/or adjust a dose as above in table 1 is described.

Additional information on Melphalanum and Prednisonum is provided in materials of producers of these drugs.

Rules of preparation and administration of drug
Milanfor is antineoplastic drug. At preparation and the treatment of drug it is necessary to show care. It is necessary to carry out the corresponding rules of an asepsis. It is recommended to use gloves and other protective clothes for prevention of contact with skin.

Bottle contents (10 ml) dissolve 0.9% of solution of sodium of chloride in 3.5 ml.

The received solution is entered by 3-5-second in a bolyusny injection through a peripheral or central venous catheter which then is washed out by 0.9% chloride sodium solution for injections.

Drug cannot be mixed with other medicines, except for 0.9% of solution of sodium of chloride.

Before introduction solution has to be visually checked for lack of mechanical inclusions and discoloration. Solution of a bortezomib has to be transparent and colourless. At detection of mechanical inclusions or discolorations the prepared solution cannot be used.

Features of use:

Treatment by drug. Milanfor it is necessary to carry out only under observation of the doctor having experience of use of antineoplastic chemotherapy. Prior to the beginning of and during each cycle of therapy it is necessary to carry out an integrated analysis of blood with calculation of a leukocytic formula and the maintenance of thrombocytes. Most often at therapy by drug Milanfor is observed passing thrombocytopenia, at the same time the smallest number of thrombocytes is usually observed for the 11th day of a cycle. Cumulative toxicity concerning thrombocytopenia at drug use 2 times a week in the recommended doses throughout 8 cycles were not observed. At decrease in quantity of thrombocytes <25000/mkl therapy by drug Milanfor should be suspended. At recovery of quantity of thrombocytes treatment should be continued in the reduced doses by careful comparison of possible advantage and risk of treatment. It is possible to apply colony stimulating factors, transfusion to treatment of hematologic toxicity platelet and a packed red cells.

For the purpose of prevention of nausea and vomiting use of antiemetic drugs is recommended. When developing diarrhea appoint anti-diarrheal HP. For prevention or treatment of dehydration by the patient it is necessary to carry out rehydration therapy and to support water and electrolytic balance.

Due to the possible development of impassability of intestines, for patients with locks it is necessary to make dynamic observation. When developing neuropathy carry out a maintenance therapy. Usually the frequency of development of peripheral neuropathy reaches a maximum on the 5th cycle of treatment. At emergence new or strengthening of the available symptoms of peripheral neuropathy the dose decline and change of the mode of administration of drug Milanfor can be required. At patients with spasms or epilepsy in the anamnesis infrequent cases of development of spasms are described. At treatment of the patients having any risk factors of development of spasms extra care is required.

Therapy by drug Milanfor often is followed by orthostatic hypotonia. In most cases she is weak or moderately severe and can be observed during all treatment. Short-term losses of consciousness were seldom noted. At the patients having faints, diabetic neuropathy in the anamnesis, receiving hypotensive drugs and also at patients against the background of diarrhea or vomiting it is necessary to be careful with dehydration. Patients should be instructed about need of the address to the doctor in case of dizziness, or a faint. At development of orthostatic hypotonia hydration, introduction of glucocorticoids and/or sympathomimetics is recommended, if necessary it is necessary to lower a dose of hypotensive drugs.

At use of a bortezomib development or strengthening of the available congestive heart failure is described. The liquid delay can contribute to development of signs and symptoms of heart failure. Patients with risk factors or with already available cardiovascular diseases have to be exposed to careful observation.

Cases of developing of an acute liver failure at patients who against the background of therapy bortezomiby at the same time accepted numerous other drugs as the accompanying treatment are described. Such phenomena of an abnormal liver function as increase in activity of liver enzymes, a hyperbilirubinemia or hepatitis, usually passed at drug withdrawal. Data on a condition of these patients after resuming of therapy by them Milanfor are limited to drug.

The patients with symptoms of an abnormal liver function receiving treatment bortezomiby have to monitorirovatsya carefully regarding toxicity emergence as бортезомиб it is metabolized by liver enzymes and its clearance can decrease at an abnormal liver function.

In rare instances at drug use Milanfor acute diffusion infiltrative pulmonary diseases of an unknown etiology, such as pneumonia, intersticial pneumonia, pulmonary infiltration and syndrome of acute respiratory insufficiency were observed. Some of these states led to a lethal outcome. In case of symptoms of disorder of function of lungs or deterioration in already available symptoms it is necessary to carry out at once diagnosis and to appoint to patients the corresponding treatment.

Due to the possible development of the hyperuricemia connected with a syndrome of a lysis of a tumor, patients during therapy are recommended to determine the level of uric acid and creatinine in blood serum. For prevention of a hyperuricemia plentiful drink, if necessary — Allopyrinolum and alkalization of urine is recommended.

At drug use Milanfor at the patients who are at the same time accepting peroral hypoglycemic drugs it is necessary to control carefully glucose level in blood and if necessary to carry out dose adjustment of hypoglycemic drugs.

During treatment of any of sexual partners it is recommended to use reliable methods of contraception.

During the work with drug Milanfor it is necessary to follow the standard rules of the treatment of cytotoxic drugs.

Patients need to be warned about a possibility of emergence during treatment of dizziness, a faint or visual frustration. At emergence of these symptoms patients are recommended to refrain from driving and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Undesirable side effects which were regarded as possibly or perhaps connected using a bortezomib are listed below.

Undesirable side effects are grouped in systems and frequency of emergence. Frequency was determined as: very often (> 10%), it is frequent (1-10%), infrequently (0.1-1%), is rare (0.01-0.1%), is very rare (<0.01%), including separate cases.

From system of a hemopoiesis and lymphatic system: very often - thrombocytopenia, anemia, a neutropenia; often - a leukopenia, a lymphopenia; infrequently - a pancytopenia, a febrile neutropenia; seldom - the IDCS.

From the alimentary system: very often - nausea, vomiting, diarrhea, a lock, pains in a stomach, dyspepsia, a loss of appetite; often - pharyngalgias, a gastroesophagal reflux, impassability of intestines, abdominal distention, stomatitis and ulcerations of a mucous membrane of an oral cavity, a dysphagy, hepatitis, increase in the ACT, ShchF, GGT level; infrequently - an eructation, hemorrhagic diarrhea, ulcerations in language, bleeding from upper parts of a GIT, vomiting with blood, paralytic Ilheus, a hyperbilirubinemia, increase in ALT, disturbance of indicators of function of a liver; seldom - ischemic colitis, acute pancreatitis.

From TsNS and peripheral nervous system: very often - a peripheral neuropathy, paresthesia, a dizesteziya, dizziness, a headache; often - a food faddism, a polyneuropathy, spasms, a faint, uneasiness; infrequently - a loss of consciousness, taste loss; seldom - encephalopathy, a vegetative neuropathy.

From acoustic organs: infrequently - a hearing disorder; seldom - bilateral deafness.

From an organ of sight: often - decrease in clearness of sight, an infection and irritations of a conjunctiva.

From cardiovascular system: often - orthostatic hypotonia, decrease in the ABP, arrhythmia, tachycardia, fibrillation of an auricle, heartbeat, a fluid lungs, petechias; infrequently - congestive heart failure, cardiogenic shock, decrease in fraction of emission of a left ventricle, an exacerbation of heart failure, bradycardia, an atrial flutter; seldom - full AV blockade, a cardiac tamponade.

From respiratory system: very often - short wind, cough; often - nasal bleeding, a pleural exudate, allocations from a nose; infrequently - a pneumorrhagia; seldom - acute diffusion infiltrative damage of lungs, increase in pulmonary pressure.

From an urinary system: often - a renal failure and a renal failure, difficulty of an urination, a hamaturia.

From immune system: very often - infections of lower parts of respiratory tracts and lungs, a nasopharyngitis, herpes, bronchitis; often - infections of upper parts of respiratory tracts, pneumonia, post-herpetic neuralgia, sinusitis, pharyngitis, candidiasis of an oral cavity, an infection of urinary tract, infection of a catheter, sepsis, a hyperemia, a gastroenteritis; infrequently - hypersensitivity to drug; seldom - ophthalmologic herpes; seldom - a herpetic encephalomeningitis, a Quincke's edema.

Dermatological reactions: very often - skin rash, an itch, reddenings, a small tortoiseshell.

From a musculoskeletal system: very often - extremity pain, a mialgiya, an arthralgia.

Metabolic disturbances: often - a hyperglycemia, a hypoglycemia, a hyponatremia.

Local reactions: infrequently - pain in the place of an injection, phlebitis.

Others: very often - increased fatigue, weakness, fervescence, a fever, hypostases of the lower extremities; infrequently - a syndrome of a lysis of a tumor.

Interaction with other medicines:

In the researches in vitro and in vivo бортезомиб showed properties of weak inhibitor of isoenzymes of P450 1A2, 2C9, 2C19, 2D6 and 3A4 cytochrome.

Proceeding from an insignificant contribution of CYP2D6 to metabolism of a bortezomib (7%), at people with low activity of this enzyme change of the general distribution of drug is not expected.

The research of medicinal interaction with active CYP3A inhibitor ketokonazoly showed increase in average AUC values of a bortezomib on average by 35%. Therefore it is necessary to watch carefully the patients receiving at the same time бортезомиб and active CYP3A inhibitor (кетоконазол, ритонавир).

In a research of medicinal interaction with active CYP2C19 inhibitor omeprazoly essential change of pharmacokinetics of a bortezomib is not revealed.

The research of medicinal interaction with a combination Melphalanum Prednisonum showed increase in average AUC values of a bortezomib by 17%. This change is considered clinically not significant.

In clinical trials, at the patients with a diabetes mellitus receiving peroral hypoglycemic drugs cases of a hypoglycemia and a hyperglycemia are registered.

At use of a bortezomib in combination with neurotoxic drugs (Amiodaronum, antiviral means, an isoniazid, nitrofurantoin or statines) and drugs, the reducing ABP, strengthening of peripheral neuropathy and arterial hypotonia respectively is possible.

Contraindications:

- hypersensitivity to a bortezomib, boron, and also to any of the components which are a part of drug;
- pregnancy;
- feeding period breast;
- children's age (lack of experience of use).

With care: heavy disturbances of functions of a liver and kidneys.

Overdose:

One case of overdose bortezomiby (exceeding of the recommended dose more than twice) at the patient with sepsis is described. The overdose was followed by acute falling of the ABP. In case of overdose it is recommended to control carefully indicators of a hemodynamics to carry out an intensive care of hypotonia by infusional therapy and other clinical necessary measures. The specific antidote to a bortezomib is not known.

Storage conditions:

To store in the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. After dissolution to store at a temperature not above 25 °C at normal illumination in an original bottle or in the syringe no more than 8 h. Periods of validity: lyophilisate - 2 years, solvent – 5 years.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for intravenous administration of 3,5 mg in glass bottles of dark glass with a capacity of 10 ml. On 5,0 ml of solvent (sodium chloride solution of 0,9%) in ampoules of neutral glass.

1 bottle with drug, 1 ampoule with solvent (5 ml)  is packed into a blister strip packaging from a film polyvinyl chloride. 1 blister strip packaging and the application instruction are placed in a cardboard pack or in a pack from a cardboard bandbox.