Composition, form of production and packaging
Liofilizate for the preparation of a suspension for s / c injection as a powder or a porous mass of white; the prepared suspension is white.
azacitidine 100 mg
Excipients: mannitol - 100 mg.
Vials of colorless glass with a capacity of 30 ml (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
Antitumor drug. Antimetabolite. The antitumor effect of azacitidine is due to a variety of mechanisms, including cytotoxicity against pathologically altered hematopoietic bone marrow cells and DNA hypomethylation. Mechanisms involved in the realization of the cytotoxic action of azacitidine include inhibition of DNA, RNA and protein synthesis, incorporation of the drug into DNA and RNA, and activation of DNA damage pathways. Non-proliferating cells are practically insensitive to azacitidine. The incorporation of azacitidine into DNA leads to the inactivation of methyltransferase DNA, resulting in DNA hypomethylation. Hypomethylation of DNA in aberrantly methylated genes, present in the regulatory cycle of normal cells, their differentiation and cell death, can cause re-expression of the gene and restoration of tumor growth suppression properties in the cancer cells themselves. The clinical significance of the mechanism of DNA hypomethylation in comparison with the cytotoxic and other effects of azacitidine has not yet been established.
Clinical efficacy and safety of Vaidazy was confirmed by the results of a multicenter, randomized Phase III study. In patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myelogenous leukemia, Vaidaza therapy was superior to modern conventional therapy in all criteria of effectiveness, including life expectancy and the overall response rate.
After sc administration, azacitidine is rapidly absorbed, reaching C max of 750 В± 403 ng / ml 0.5 h after administration. Absolute bioavailability of azacitidine with n / k introduction is 89% with respect to this indicator with iv introduction based on the results of the AUC determination.
The results of the in vitro study showed that isozymes of the cytochrome P450 system, UDP-glucuronyltransferase, sulfotransferase and glutathione transferase do not participate in the metabolism of azacitidine. Azacitidine is metabolized by spontaneous hydrolysis and deamination, which is induced by cytidine deaminase.
Azacitidine is rapidly excreted from the body, its T 1/2 after the SC administration is 41 В± 8 min. Most of the azacitidine (50-85%) and / or its metabolites is excreted by the kidneys. Less than 1% of the drug is excreted through the intestine. There is no data on the introduction of azacitidine into breast milk.
Pharmacokinetics in special clinical cases
The effect of impaired liver or kidney function, as well as age, gender or race on the pharmacokinetic parameters of azacitidine, has not been studied.
Treatment of adult patients who can not undergo transplantation of hematopoietic stem cells:
- Myelodysplastic syndrome (MDS) with a high or intermediate-2 risk level in accordance with the IPSS scale (International Prediction Scoring System);
acute myeloid leukemia;
- chronic myelomonocytic leukemia without signs of MDS.
Vaidaz drug is injected into the shoulder, hip, or abdomen. Place the injection alternating. Place for the next injection should be more than 2.5 cm from the previous one. Vaidase should not be injected into damaged, hyperemic, dense or painful skin areas (including areas of skin with hemorrhages).
Before the introduction of Vaidazy it is recommended to prescribe antiemetic drugs.
The recommended initial dose of Vaidas preparation for the first cycle of therapy for all patients, regardless of the initial hematological parameters, is 75 mg / m 2 ofthe body surface and is administered daily for 7 days followed by a break of 21 days (28-day therapeutic cycle).
At least 6 therapeutic cycles should be performed. Treatment is continued as long as its effectiveness remains or until symptoms of disease progression appear.
During the observation of patients, the response from the blood counts and possible manifestations of toxicity, in particular from the blood and kidneys, which may require postponement of the next course of treatment or correction of the dose of the drug, are evaluated. Below are the possibilities of modifying the dose of Vaidaz preparation for the development of various types of toxicity.
Modification of dose in detecting symptoms of hematological toxicity
Hematological toxicity is the maximum reduction in the number of cells during a given treatment cycle (nadir) if the platelet count drops to 50 Г— 10 9 / L and below and / or the absolute number of neutrophils decreases to 1 Г— 10 9 / L and below.
The restoration is the increase in the number of cells in the cell line (s) by at least half the difference between the initial cell count and the nadir (i.e., the number of cells recovered> nadir + (0.5? ([Original number - nadir] ).
Patients with baseline (before Vaidazy therapy) WBC count> 3 Г— 10 9 / L, absolute neutrophil count> 1.5 Г— 10 9 / L, platelet count> 75 Г— 10 9 / L
If, against the background of treatment with Vaidaz, these patients develop symptoms of hematologic toxicity, the next cycle of treatment with the drug is postponed until the platelet count and the absolute number of neutrophils are restored to their original values. If the duration of the recovery period does not exceed 14 days, no modification of the dose of the drug is required. If the number of blood cells has not increased to the required level within 14 days, the dose should be reduced as recommended below. When using a modified dose, the duration of the therapy cycle should be restored to 28 days.
Number of blood cells % of the initial dose for the next cycle, if recovery * of the number of blood cells required more than 14 days
Absolute number of neutrophils Number of platelets
? 1? 10 9 / L? 50? 10 9 / L 50%
> 1 Г— 10 9 / L> 50 Г— 10 9 / L 100%
* Recovery = quantity (number)? Minimal amount of + (0.5? [Initial quantity - minimum quantity])
Patients with baseline (before the beginning of Vaidaz therapy), white blood cell count <3 Г— 10 9 / L, absolute neutrophil count <1.5 Г— 10 9 / L, platelet count <75 Г— 10 9 / L.
If a reduction in the number of white blood cells or an absolute number of neutrophils or platelets less than or equal to 50% of their baseline values, or more than 50%, is observed before the next course of treatment with Vaidaz, but if there are signs of improvement in the differentiation of any cell germ, the Vaidaz drug administration schedule and dose must change.
Patients in whom the number of blood cells did not exceed 50% of the threshold from the baseline in the absence of signs of improvement in differentiation of cell sprouts, the next course of treatment with Vaidaz should be delayed until the absolute number of neutrophils and platelets is restored. If the recovery process took no more than 14 days, a dose adjustment of Vaidaz is not required. If the number of blood cells did not reach the desired level within 14 days, it is necessary to determine the cellular saturation of the bone marrow. With a cell saturation index> 50%, no dose change is required. If the cellular saturation of the bone marrow? 50%, the administration of Vaidaz should be delayed and the dose reduced according to the recommendations given in the table:
Cellular bone marrow saturation, % of the initial dose for the next cycle, if recovery * of the number of blood cells took more than 14 days
Recovery *? 21 day Recovery *> 21 days
15-50% 100% 50%
<15% 100% 33%
* Recovery = quantity (number)? Minimal amount of + (0.5? [Initial quantity - minimum quantity])
After the modification of the dose, the cycle time must be restored to 28 days.
An example of calculating an individual dose of azacitidine is shown in the table below:
m 2 body surface 100% of the recommended initial dose (75 mg / m 2 ) 50% of the recommended initial dose (37.5 mg / m 2 ) 33% of the recommended initial dose (25 mg / m 2 )
Daily dose Volume of solution Daily dose Solution volume Daily dose Volume of solution
1.4 105 mg 4.2 ml ** 52.5 mg 2.1 ml * 35 mg 1.4 ml *
1.5 112.5 mg 4.5 ml ** 56.25 mg 2.25 ml * 37.5 mg 1.5 ml *
1.6 120 mg 4.8 ml ** 60 mg 2.4 ml * 40 mg 1.6 ml *
1.7 127.5 mg 5.1 ml ** 63.75 mg 2.55 ml * 42.5 mg 1.7 ml *
1.8 135 mg 5.4 ml ** 67.5 mg 2.7 ml * 45 mg 1.8 ml *
1.9 142.5 mg 5.7 ml ** 71.25 mg 2.85 ml * 47.5 mg 1.9 ml *
* 1 vial containing 100 mg of azacitidine ** 2 vials containing 100 mg of azacitidine
Peculiarities of application in separate groups of patients
In patients with impaired renal function, no special studies have been performed. Patients with severe renal failure require careful monitoring to monitor adverse events. It is not necessary to change the initial dose of the drug in patients with impaired renal function (for example, the baseline serum creatinine level or urea concentration in the blood is 2 times higher than the VGN or the bicarbonate concentration is less than 20 mmol / l). The subsequent modification of the dose is based on the results of the study of hematological parameters and indicators of kidney function. With an unexplained decrease in serum bicarbonate concentration of less than 20 mmol / L, the dose for the next cycle of therapy should be reduced by 50%. If there is an unexplained increase in serum creatinine concentration or a concentration of urea nitrogen in the blood 2 or more times from baseline values вЂ‹вЂ‹or higher than ULN, the next cycle of therapy should be postponed until these parameters are restored to normal or baseline values, and the dose of the drug in the next cycle should be reduced on 50%.
In patients with impaired liver function, no special studies have been performed. Patients with severe hepatic impairment require careful monitoring to detect undesirable events in a timely manner. This category of patients does not need to change the initial dose of the drug. The subsequent modification of the dose will depend on the results of the blood test.
Older patients do not need a special dosing regimen. Since in this category of patients the probability of renal dysfunction is higher, it is recommended to monitor renal function during treatment.
It is not recommended to appoint Vaidaz to children and adolescents under the age of 18 due to lack of clinical experience.
Rules for solution and injection
The contents of the vial with the drug should be dissolved in 4 ml of water for injection to a concentration of 25 mg / 1 ml. After adding water to the bottle for injection, it must be vigorously shaken to obtain a homogeneous suspension of white color. At the required dose exceeding 100 mg, 2 vials with the drug are used.
Immediately prior to administration, it is necessary to re-translate the contents of the syringe into the suspension state. To do this, vigorously roll the syringe between the palms until a homogeneous white suspension is obtained. The temperature of the suspension during the injection should be 20-25 В° C. Do not use if it contains large particles.
For the purpose of injecting a 25-gauge needle is recommended, the needle should be inserted under the skin of the shoulder, hip or abdomen at an angle of 45-90 В°. In one area should be administered no more than 4 ml of the dissolved drug. Doses greater than 4 ml should be administered in 2 different areas.
The Vaidaz suspension should be prepared immediately before use. The ready suspension should be stored at a temperature of 25 В° C not more than 45 minutes or at a temperature of 2 В° to 8 В° C not more than 8 hours. It is necessary that before the introduction the temperature of the suspension in the syringe reaches 20-25 В° C (but not more than 30 min.). If these time limits are exceeded, the prepared suspension must be disposed of appropriately, and a new suspension must be prepared.
Most often: hematological reactions (71.4%), including thrombocytopenia, neutropenia and leukopenia (usually 3-4 degrees of severity); gastrointestinal complications (60.6%), including nausea and vomiting (usually 1-2 degrees of severity) or local reactions at the injection site (77.1%, severity 1-2); serious adverse reactions - febrile neutropenia (8%), anemia (2.3%), as well as sepsis against neutropenia, pneumonia, thrombocytopenia and bleeding (eg, intracranial).
Determination of the frequency of adverse reactions: very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1/1000, <1/100), rarely (? 1/10 000, <1 / 1000), very rarely (<1/10 000); It is not known (it is impossible to estimate from the available data).
From the hemopoietic system: very often - neutropenia, febrile neutropenia, leukopenia, thrombocytopenia, anemia; often - pancytopenia.
From the digestive system: very often - diarrhea, constipation, nausea, vomiting, abdominal pain, anorexia; often - gastrointestinal bleeding, hemorrhoidal bleeding, stomatitis, bleeding gums, dyspepsia.
From the liver and biliary tract: infrequently - liver failure, progressive hepatic coma.
From the nervous system: very often - dizziness, headache; often - intracranial bleeding, drowsiness,
From the side of the psyche: confusion, anxiety, insomnia.
From the cardiovascular system: often - increase or decrease in blood pressure, hematoma.
From the respiratory system: very often - shortness of breath; often - shortness of breath with physical exertion, pain in the larynx and pharynx; rarely - interstitial lung diseases.
From the side of the urinary system: often - hematuria, renal failure, increased concentration of creatinine; infrequently, renal tubular acidosis.
From the skin and subcutaneous fat: very often - petechiae, itching, rash, ecchymosis; often - purpura, alopecia, erythema, spotted rash.
From the musculoskeletal system: very often - arthralgia; often - pain in the bones, myalgia.
From the side of the organ of vision : often - intraocular bleeding, hemorrhage in the conjunctiva.
Infections: very often - pneumonia, nasopharyngitis; often - sepsis against neutropenia, upper respiratory tract infection and urinary tract infections, inflammation of the subcutaneous tissue, sinusitis, pharyngitis, rhinitis, herpes simplex.
From the immune system: infrequently - hypersensitivity reactions.
From the side of metabolism: very often - anorexia, often - hypokalemia; rarely - tumor lysis syndrome.
Local reactions: very often - pain and redness, nonspecific reactions at the injection site; often bleeding, hemorrhage, bruising, densification, inflammation, rash, itching, discoloration of the skin, nodules and soreness at the injection site; rarely - tissue necrosis at the injection site.
Other: very often - weakness, fever, pain in the chest area; often - a decrease in body weight.
- common metastases in the liver;
- lactation (the period of breastfeeding);
- Children's age (lack of data on effectiveness and safety);
- Hypersensitivity to azacitidine or other components of the drug.
With caution should be used in patients with cardiovascular diseases, lung diseases, with kidney and liver disorders, including extensive metastatic liver damage.
PREGNANCY AND LACTATION
The drug is contraindicated in pregnancy and during breastfeeding.
Men and women of childbearing age should use effective methods of contraception during treatment and within 3 months after its termination. Men should be encouraged to consider the possibility of preserving samples of their own sperm before starting treatment.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution in the violation of kidney function.
Special studies in patients with impaired renal function were not performed. Patients with severe renal insufficiency should be carefully monitored to monitor adverse events. It is not necessary to change the initial dose of the drug in patients with impaired renal function (for example, the baseline serum creatinine level or urea concentration in the blood is 2 times the upper limit of the norm (VGN) or the bicarbonate concentration is less than 20 mmol / l). The subsequent modification of the dose is based on the results of the study of hematological parameters and indicators of kidney function. With an unexplained decrease in serum bicarbonate levels of less than 20 mmol / L, the dose for the next cycle of therapy should be reduced by 50%. If there is an unexplained increase in the serum creatinine level or urea nitrogen concentration in the blood 2 or more times from the baseline values вЂ‹вЂ‹or higher than the IGN, the next cycle of therapy should be postponed until these parameters are restored to normal or initial values, and the dose of the drug in the next cycle should be reduced on 50%.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution in the violation of liver function.
Special studies in patients with impaired liver function were not performed. Patients with severe hepatic impairment should be carefully monitored for the timely detection of adverse events. This category of patients does not need to change the initial dose of the drug. Subsequent modification of dose will depend on the results of blood tests.
The treatment azacytidine in patients with advanced metastatic liver lesions, especially when the level of albumin in serum of less than 30 g / l, there were cases of hepatic coma fatal.
APPLICATION FOR CHILDREN
Contraindicated in children (lack of efficacy and safety data).
APPLICATION IN ELDERLY PATIENTS
Elderly patients No special dosage regimen. Because elderly patients the likelihood of renal dysfunction is higher during treatment is recommended to monitor renal function.
Treatment with Vaydaza should be under the supervision of a physician who is experienced in the use of anticancer drugs.
The safety and efficacy Vaydazy in patients with severe congestive heart failure and other severe cardiovascular or pulmonary disease has not been established.
Prior to initiation of therapy and prior to each cycle of the study the functional activity of the liver and serum creatinine are to be obtained, as well as data expanded blood analysis. Regular blood tests are shown for monitoring the efficacy and safety of treatment.
The most frequent side effects in the treatment of hematological reactions were azacytidine, including thrombocytopenia, neutropenia and leukopenia (usually Grade 3-4). The highest risk of these reactions observed during the first two cycles of therapy, after which they occur with less frequency in patients with hematological parameters restore. Most hematological reactions is allowed postponing the next cycle of treatment, prophylactic antibiotics and / or colony stimulating factor for neutropenia and transfusions for anemia or thrombocytopenia.
Full blood count should be carried out to monitor the effectiveness of treatment and possible adverse reactions of at least prior to each treatment cycle. After the first treatment cycle for subsequent treatment dosage calculated based on the baseline and their dynamics in the course of treatment.
Medical staff and patients should be instructed about the need to control body temperature (fever) symptoms and allows you to diagnose bleeding.
Myelosuppression may lead to neutropenia and an increased risk of infection. Patients on treatment with azacytidine observed serious adverse reactions such as sepsis of neutropenia (0.8%) and pneumonia (2.5%). In the case of infectious complications can assign etiotrop treatment and colony-stimulating factor for neutropenia.
In patients treated with azacytidine, may develop bleeding, including belonging to the category of serious adverse reactions such as gastrointestinal (0.8%) and intracranial hemorrhage (0.5%). It is necessary to control the symptoms, allowing diagnosis of bleeding, particularly in patients with baseline thrombocytopenia or thrombocytopenia occurred during treatment.
In patients treated with azacytidine, observed hypersensitivity reactions related to the severe category (0.25%). In the case of anaphylactic reactions azacytidine treatment should be stopped immediately and symptomatic treatment is scheduled.
Most of the adverse reactions of the skin and subcutaneous fat were observed at the injection site. Most of these reactions occurred during the first two cycles of treatment, while there was a tendency to reduce them with continued treatment. Such local adverse reactions such as rash, inflammation, itching at the injection site erythema may require assignment of antihistamines, corticosteroids and NSAIDS.
The treatment azacytidine in patients with advanced liver metastases were cases of hepatic coma with a fatal outcome.
Patients treated azacytidine, in rare cases of renal dysfunction observed include various states from increasing creatinine pochechnokanaltsevogo acidosis and renal failure before development, including fatal.
Unexplained reducing serum bicarbonate, unexplained increase in serum creatinine or blood urea concentration in the next cycle of therapy should be delayed until recovery of these parameters to normal or reference values, and the dose in the next cycle to be reduced. Because azacitidine and its metabolites are excreted primarily by the kidneys, patients with renal impairment should be monitored closely for adverse events monitoring.
The treatment azacytidine most frequently observed constipation, diarrhea, nausea and vomiting. These adverse reactions were stopped via symptomatic of: antiemetic - nausea and vomiting, antidiarrheal - diarrhea, and laxatives - constipation.
Vaydaza - is a cytotoxic drug, which, as with other toxic substances, should be handled with care. Any unused or consumables must be disposed of in accordance with local requirements.
Upon contact of the reconstituted solution azacitidine with skin, immediately and thoroughly wash it with soap and water. Upon contact with the mucous membrane - rinse thoroughly with water.
Impact on the ability to drive vehicles and manage mechanisms
Studies on the effects on the ability to drive vehicles and use machinery have not been conducted. Given the possibility of weaknesses in the background of treatment Vaydaza, patients should take special care when driving and operating machinery.
Symptoms reported one case of azacitidine overdose during clinical studies. The patient noted diarrhea, nausea and vomiting after a single intravenous injection at a dose of 290 mg / m 2 , which exceeds the recommended starting dose of about 4 times.
Treatment: it is recommended to monitor the level of the respective blood cells and prescribe, if necessary, supportive care. There is no specific antidote to overdose azacitidine.
Not been targeted clinical studies of azacitidine interaction with other drugs. These in vitro studies demonstrate that the involvement of cytochrome P450 isoenzymes, UDP-glucuronyl transferase, sulfotransferase and glyutationtransferazy metabolism azacytidine unlikely. In this regard, interaction with in vivo data enzymes involved in metabolism, it is not clinically significant.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 4 years.