Composition, form of production and packaging
The solution for intravenous administration is clear, colorless.
1 ml
Erybulin 0.5 mg
Excipients: ethanol - 0.05 ml, hydrochloric acid and sodium hydroxide - up to pH 6.0-9.0, water d / u - up to 1 ml.
2 ml - vials of colorless glass (1) - packs cardboard.
2 ml - vials of colorless glass (6) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
PHARMACHOLOGIC EFFECT
Erybulin refers to the inhibitors of the dynamics of microtubules of the non-anaxane series belonging to the halichondrin group of antitumor agents. By its structure, the drug is a simplified synthetic analogue of halichondrin B, a natural substance extracted from the marine sponge Halichondria okadai.
Eribulin inhibits the growth phase of microtubules, without affecting the shortening phase, which leads to the formation of tubulin aggregates that do not have functional activity. The antitumor effect of erybulin is realized through a tubulin-mediated antimitotic mechanism leading to blockade of the cell cycle in the G 2 / M phases (GAP 2 / mitosis cell cycle stages) and to the formation of mitotic spindles, which ultimately leads to apoptotic cell death as a result of prolonged blocking mitosis.
Erybulin also affects the microenvironment of the tumor and its phenotype by mechanisms that are not associated with its antimitotic effect. These additional effects of erybulin include (i) remodeling the tumor vascular bed, which improves the perfusion of the central part of the tumor and reduces its hypoxia, and (ii) the phenotypic transition of more aggressive mesenchymal phenotypes to less aggressive epithelial by inversion of the epithelial-mesenchymal transition.
Clinical efficacy
Mammary cancer
The efficacy of HalavenВ® in the treatment of locally advanced or metastatic breast cancer has been confirmed in two randomized, phase III comparative trials involving more than 1,800 patients in whom endpoints of efficacy were overall survival and progression-free survival.
Soft tissue sarcomas
The efficacy of HalavenВ® in the treatment of soft tissue sarcomas was confirmed in two phase 2 trials and one randomized phase III trial compared with dacarbazine in 452 patients with locally advanced inoperable and / or metastatic soft tissue sarcomas of one of the following subtypes, leiomyosarcoma or liposarcoma. The end point of the efficacy assessment was overall survival.
Application in combination
The use of erybulin in combination with trastuzumab and capecitabine has been studied in two studies of the second phase
PHARMACOKINETICS
Distribution
The pharmacokinetics of erybulin is characterized by a rapid phase of the distribution, replaced by a prolonged elimination phase with a finite T 1/2 , on average, about 40 h. The preparation has a large volume of distribution (on average, varying from 43 to 114 l / m 2 ).
Erybulin weakly binds to plasma proteins. At human plasma concentrations from 100 to 1000 ng / ml, the fraction of protein-bound plasma of eribulin is 49% to 65%.
Metabolism
After administration of 14 C-labeled erybulin to patients, the fraction of unchanged drug in plasma was suppressive. The concentrations of metabolites corresponded to less than 0.6% of the original erybulin, confirming the fact that significant metabolites of erybulin in the human body are not formed.
Excretion
Erybulin has a low clearance value (on average, varying from 1.16 to 2.42 l / h / m 2 ). With a weekly administration of erybulin, no significant cumulation is observed. The pharmacokinetic parameters of erybulin do not depend on the dose or time in the range from 0.22 to 3.53 mg / m 2 .
Erybulin is excreted, mainly with bile. Transport protein, responsible for the excretion of the drug with bile, is currently unknown. Preclinical studies indicate the involvement of the P-glycoprotein in this process. However, it has been shown that at clinically significant concentrations, erybulin is not an inhibitor of P-glycoprotein in vitro .
In vivo, the concomitant administration of ketoconazole, which is an inhibitor of the P-glycoprotein, has no effect on the pharmacokinetic parameters of erybulin (AUC and C max ).
In vitro studies have shown that eribulin is not a substrate for the organic cation transport (OCT1).
After the administration of 14 C-labeled erybulin to patients, approximately 82% of the dose was excreted with feces and 9% with urine, which indicates that renal clearance is not an important route of excretion. Most of the radioactive label in the feces and urine was unchanged erybulin.
Pharmacokinetics in liver failure
Evaluation of the pharmacokinetics of erybulin in patients with mild hepatic insufficiency (Child-Pugh class A) or moderate (Child-Pugh class B) severity associated with the formation of liver metastases compared to patients with normal liver function (n = 6) , showed that the exposure of erybulin in the first two groups of patients was higher, respectively, 1.8 and 3 times.
The use of the Halaven В® drug at a dose of 1.1 mg / m 2 in patients with mild hepatic insufficiency and at a dose of 0.7 mg / m 2 - for patients with moderate hepatic impairment provided approximately the same exposure as with 1.4 mg / m 2 to patients with normal liver function.
The use of Halaven В® in patients with severe hepatic insufficiency (Child-Pugh class C), as well as with hepatic insufficiency associated with cirrhosis, has not been studied.
Pharmacokinetics in renal failure
In some patients with moderate and severe renal insufficiency, an increase in the exposure of erybulin with a high degree of variability was observed. The pharmacokinetics of erybulin in patients with normal renal function (creatinine clearance> 80 ml / min), with renal insufficiency average (CK 30-50 ml / min) and severe (KK 15- <30 ml / min) severity was studied in Phase 1 study. The QC value was estimated using the Cockcroft-Gault formula. In patients with moderate and severe renal insufficiency, there was an increase in AUC, adjusted for a dose 1.5 times.
INDICATIONS
HalavenВ® is indicated to patients:
- with locally advanced or metastatic breast cancer, previously received at least one chemotherapy regimen for a common disease. Prior therapy should include anthracyclines and taxanes in the adjuvant or metastatic mode of the disease, except for patients who could not be prescribed these drugs;
- with inoperable liposarcoma, previously chemotherapy with anthracyclines for a common or metastatic disease (except for patients who could not be prescribed these drugs).
DOSING MODE
Intravenously.
Treatment with Halaven В® should be done only under the supervision of a doctor who has appropriate experience in the use of cytotoxic drugs.
Antiemetic drugs and GCS are recommended if the patient experiences nausea and vomiting.
The recommended dose of HalavenВ® is 1.4 mg / m 2 . This dose is administered intravenously for 2-5 minutes on the 1 st and 8 th days of each 21-day cycle.
Postponement of the introduction of a regular dose during therapy
The administration of Halaven В® on the first or the 8th day of the therapy cycle should be postponed if any of the following conditions exists:
- Absolute number of neutrophils (ACHN) <1 Г— 10 9 / L
- The number of platelets <75? 10 9 / l
- Non-hematological toxicity 3 or 4 degrees.
The administration of HalavenВ® on the 8th day of the cycle can be delayed for a maximum of 1 week.
- If by 15 day the toxic manifestations are not resolved or their severity has not decreased to 2 degrees or less, the introduction of the next dose of the drug should be skipped.
- In case of resolution or reduction in the severity of toxic manifestations to grade 2 or lower by day 15, HalavenВ® should be administered at a reduced dose, with the next treatment cycle being initiated no earlier than 2 weeks later.
Dose reduction during treatment
Recommendations for calculating the dose when resuming therapy are given in Table 1.
Table 1. Recommendations for reducing the dose of Halaven В® .
Undesirable reactions after previous administration of HalavenВ® The recommended dose
Hematological:
Neutropenia <0.5 Г— 10 9 / L, lasting more than 7 days 1.1 mg / m 2
Neutropenia <1 Г— 10 9 / L, complicated by fever or infection
Thrombocytopenia <25 Г— 10 9 / L
Thrombocytopenia <50 Г— 10 9 / L, complicated by bleeding or requiring a blood transfusion / platelet mass
Non-hematological:
Any unwanted reactions of 3 or 4 degrees in the previous cycle
Recurrence of any of the above hematologic or non-hematologic adverse reactions
Despite a reduction in the dose to 1.1 mg / m 2 0.7 mg / m 2
Despite a reduction in the dose to 0.7 mg / m 2 The discontinuation of therapy with the drug Halaven В®
After lowering the dose of eribulin, its reverse increase in subsequent cycles is not recommended.
Use in patients with hepatic impairment
Dysfunction of the liver associated with the formation of metastases
The recommended dose of HalavenВ® for patients with mild hepatic insufficiency (Child-Pugh class A) is 1.1 mg / m 2 intravenously for 2 to 5 minutes on the 1st and 8th days of the 21-day treatment cycle
The recommended dose of Halaven for patients with moderate hepatic impairment (Child-Pugh class B) is 0.7 mg / m intravenously for 2-5 minutes on days 1 and 8 of the 21-day therapy cycle.
The use of HalavenВ® in patients with severe hepatic insufficiency (Child-Pugh class C) has not been studied, but it is expected that a greater reduction in the dose of HalavenВ® may be required.
Liver dysfunction associated with cirrhosis
The use of the drug in this group of patients has not been studied. The above doses can be used for patients with mild and moderate hepatic impairment, provided that the monitoring is carefully monitored. a further dose reduction may be required.
Use in patients with renal insufficiency
In some patients with moderate or severe renal insufficiency (CK <50 ml / min), an increase in the exposure of the erybulin may be observed, and as a consequence, an initial dose reduction may be required. For all patients with renal failure, additional precautions and monitoring of adverse events are recommended.
Use in children
The use of the drug in children and adolescents according to the indication of "breast cancer" is not provided.
The safety and efficacy of HalavenВ® in patients under the age of 18 with soft tissue sarcomas has not been evaluated to date.
Application in the elderly
There are no special recommendations for elderly people on dose changes
Instructions for reconstitution before introduction
The drug Halaven В® is diluted in aseptic conditions in not more than 100 ml of a 0.9% solution of sodium chloride for injection. The drug should not be mixed with other drugs, and diluted in a 5% solution of dextrose.
Before the introduction, you should provide good access to the peripheral veins or to the central vein. Halavene В® does not have an irritant or necrotizing effect at the injection site. In the case of extravasation, treatment should be symptomatic.
SIDE EFFECT
The most common adverse reactions in the treatment with HalavenВ® include the suppression of bone marrow function, expressed in neutropenia, leukopenia, anemia and thrombocytopenia with concomitant infections. Also, new manifestations or worsening of previously existing peripheral neuropathy were reported.Gastrointestinal toxicity, manifested in the form of anorexia, nausea, vomiting, diarrhea, constipation and stomatitis also refers to the side effects of HalavenВ® therapy. Other side effects include fatigue, alopecia, increased hepatic enzyme activity, sepsis and musculoskeletal pain.
The safety profile of the combination of HalavenВ® with trastuzumab or capecitabine corresponds to the known safety profile of each of these preparations alone.
Table 2 shows the incidence of side effects observed in patients with breast cancer and soft tissue sarcomas who received the recommended dose of HalavenВ® in monotherapy in Phase 2 and Phase 3 clinical trials.
To indicate the frequency of adverse events, the following classification is used: very often (? 1/10 cases); often (? 1/100, <1/10); infrequently (? 1/1000, <1/100) and rarely (? 1/10000, <1/1000). Within each group, side effects are presented in descending order of frequency. If applicable, the total and summary incidence of 3rd and 4th degree incidence are shown.
Table 2.
Organ systems Very often Often infrequently Rarely
Infectious and parasitic diseases Urinary tract infection (8.5%) (G3 / 4 0.7%) Pneumonia (1.6%) (G3 / 4 1.0%) Candidiasis of the oral cavity Herpes mucosa of the oral cavity Upper respiratory tract infection Nasopharyngitis Rhinitis Shingles Sepsis (0, 5%) (G3 / 4 0.4%) a Neutropenic sepsis (0.2%) (G3 / 4 0.1%)
Disorders of blood and lymphatic system Neutropenia (53.6%) (G3 / 4 46.0%) Leukopenia (27.9%) (G3 / 4 16.9%) Anemia (21.8%) (G3 / 4 3.0%) Lymphopenia (5.7%) (G3 / 4 2.1%) Febrile neutropenia (4.5%) (G3 / 4 4.3%) a Thrombocytopenia (4.2%) (G3 / 4 0.7%) Disseminated intravascular coagulation b
Metabolic and nutritional disorders Decreased appetite (22.5%) (G3 / 4 0.7%) . Hypogalemia (6.8%) (G3 / 4 2.0%) Hypomagnesemia (2.8%) (G3 / 4 0.3%) Dehydration (2.8%) (G3 / 4 0.5%) d Hyperglycemia Hypophosphatemia
Disorders of the psyche Insomnia Depression
Nervous system disorders Peripheral neuropathy with (35.9%) (G3 / 4 7.3%) Headache (17.5%) (G3 / 4 0.7%) Dysgeusia Dizziness (9.0%) (G3 / 4 0.4%) dHypesthesia Lethargy Neurotoxicity
Visual disturbances Increased tearing (5.8%) (G3 / 4 0.1%) d Conjunctivitis
Hearing impairments and labyrinthine disturbances Vertigo Tinnitus in the ears
Impaired Heart Tachycardia
Vascular disorders "Tides" Thromboembolism of the pulmonary artery (1.3%) (G3 / 4 1.1%) a Deep vein thrombosis
Dyspnoea disorders (15.2%) (G3 / 4 3.6%) and Cough (15.0%) (G3 / 4 0.5%) d Oropharyngeal pain Nasal bleeding Rinorrhea Interstitial lung diseases (0.2%) ( G3 / 4 0.1%)
Disturbances from the gastrointestinal tract Nausea (35.7%) (G3 / 4 1.1%) d Constipation (22.3%) (G3 / 4 0.7%) d Diarrhea (18.7%) (G3 / 4 0.8%) Vomiting (18.1%) (G3 / 4 1.0%) Abdominal pain Stomatitis (11.1%) (G3 / 4 1.0%) d Oral dryness Dyspepsia (6.5%) (G3 / 4 0.3%) d Gastroesophageal reflux disease Bloating Stomach ulceration of the oral cavity Pancreatitis (0.1%)
Disturbances from the liver and bile ducts Increased activity of AST (7.7%) (G3 / 4 1.4%) d Increase in ALT activity (7.6%) (G3 / 4 1.9%) d Increase in GGT activity (1.7%) (G3 / 4 0.9% ) d Hyperbilirubinemia (1.4%) (G3 / 4 0.4%) Hepatotoxicity (0.8%) (G3 / 4 0.6%)
Skin and subcutaneous tissue disorders Alopecia Rash (4.9%) (G3 / 4 0.1%) Itching (3.9%) (G3 / 4 0.1%) d Nail lesions Night sweats Dry skin Erythema Hyperhidrosis Palmar-plantar erythrodysesthesia (1.0% ) (G3 / 4 0.1%) d Angioedema (0.1%)
Musculoskeletal and connective tissue disorders Arthralgia and myalgia (20.4%) (G3 / 4 1.0%) Back pain (12.8%) (G3 / 4 1.5%) Pain in the extremities (10.0%) (G3 / 4 0.7% ) d Bone pain (6.7%) (G3 / 4 1.2%) Muscle spasm (5.3%) (G3 / 4 0.1%) d Muscle skeletal pain and chest pain Muscle weakness
Disorders from the kidneys and urinary tract Dysuria Hematuria Proteinuria Renal failure
General disorders and disorders at the site of administration Fatigue / asthenia (53.2%) (G3 / 4 7.7%) Fever (21.8%) (G3 / 4 0.7%) Inflammation of the mucous membranes (6.4%) (G3 / 4 0.9%) Peripheral swelling Pain Chills Chest pain Flu-like syndrome
Laboratory and instrumental data Weight loss (11.4%) (G3 / 4 0.4%) d
a Including 1 or 2 cases of the 5th degree.
b Spontaneous messages.
c Including terms: peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy and demyelinating polyneuropathy.
d Only degree 3
In general, the drug Halaven В® has a similar safety profile when used in breast cancer and with soft tissue sarcomas.
Additional information on some side effects
Neutropenia
The observed neutropenia was reversible and non-cumulative. The mean time to the expected minimum number of neutrophils (nadir) was 13 days, and the mean time to recovery from severe neutropenia (ACH <0.5 Г— 10 9 / L) was 8 days.
In the EMBRACE study, a reduction in the number of neutrophils to <0.5 Г— 10 9 / L, lasting more than 7 days, occurred in 13% of cases.
In soft tissue sarcomas, neutropenia was less frequent (37.4% of cases) than in breast cancer (57.9% of cases).
In case of severe neutropenia, a granulocyte colony-stimulating factor (G-CSF) or its analogue can be assigned according to the decision of the attending physician and in accordance with current recommendations.
Neutropenia led to the cessation of participation in the study of less than 1% of patients receiving erybulin.
Disseminated intravascular coagulation
were reported cases of disseminated intravascular coagulation, is usually associated with neutropenia and / or sepsis.
Peripheral neuropathy
Among 1559 patients with breast cancer the most common adverse events leading to treatment withdrawal eribulin was peripheral neuropathy (3.4%). Median until peripheral neuropathy of 2 degrees was 12.6 weeks (after 4 cycles). In 2 of the 404 patients with soft tissue sarcomas peripheral neuropathy led to treatment withdrawal eribulin. Median until peripheral neuropathy grade 2 was 18.4 weeks.
The development of peripheral neuropathy grade 3 and 4 occurred in 7.4% of patients with breast cancer and 3.5% of patients with soft tissue sarcomas. In clinical studies it has been shown that patients with neuropathy that occurred before the start of therapy with Halawa В® , there was a greater risk of developing new or worsening of existing symptoms thereof, in contrast to patients without peripheral neuropathy before the start of therapy with Halawa В® .
In patients with breast cancer preceding peripheral neuropathy 1 or 2 degrees of the incidence of grade 3 peripheral neuropathy in the treatment of drug halava В® was 14%.
hepatotoxity
In some patients, there was an increase in liver enzymes in the early treatment of eribulin (usually 1-2 cycles). Although this was likely due to liver adaptation eribulin treatment of hepatotoxicity it has also been reported.
Additional safety information in special patient groups
Elderly patients
The safety profile of eribulin in elderly patients (over 65 years) is similar to the safety profile of the drug in younger populations with the exception of fatigue and asthenia, which increases with age. Specific recommendations to reduce the dose in elderly patients is not.
Patients with hepatic impairment
In the activity of ALT or AST greater than the upper limit of normal more than three times, the patient increases the risk of grade 4 neutropenia and febrile neutropenia. When bilirubin values greater than the upper limit of normal in more than half, also increases the risk of grade 4 neutropenia and febrile neutropenia, although the evidence for this relationship are limited.
Notification of adverse reactions
It is imperative to notify about adverse reactions that occurred during post-marketing use of the drug. This allows you to control the ratio of benefits and risks of the drug. Please inform health professionals about the occurrence of any adverse reactions to the address indicated in this manual
CONTRAINDICATIONS
- eribulin or hypersensitivity to any of the excipients;
- pregnancy
- the period of breastfeeding;
- age to 18 years.
Carefully
Syndrome of congenital QT interval elongation.
Heart disease (heart failure, bradyarrhythmias).
Electrolyte imbalance (e.g., hypokalemia, hypomagnesemia).
Simultaneous administration of drugs prolonging the interval QT (including IA and III antiarrhythmics of classes).
Simultaneous administration of drugs having a narrow therapeutic range and metabolized mainly isoenzyme SYP3A4 (cm. "Drug Interactions" section).
Severe hepatic insufficiency, and liver dysfunction associated with cirrhosis (this group of drug application in patients not studied).
Renal failure secondary to severe (see. "Metering mode").
PREGNANCY AND LACTATION
Pregnancy
Data on the use of the drug Halawa В® in pregnant women do not. In preclinical studies, eribulin has embryotoxic, foetotoxic and teratogenic. Halawa В® should not be used during pregnancy.
Women of childbearing age should be informed about the need to prevent pregnancy while using them or their partners, drug Halawa В® , as well as the mandatory application of effective methods of contraception during treatment with Halawa В® and for 3 months after its completion.
Lactation
Information about the penetration of eribulin or its metabolites in breast milk of humans or animals are not present. Since the risk to newborns and infants can not be excluded halava В® should not be applied during breastfeeding.
Fertility
In preclinical studies, there was testicular toxicity of the drug. Prior to the treatment of male patients should seek advice about sperm preservation, because the treatment of drug Halawa В® there is a possibility of irreversible infertility.
APPLICATION FOR FUNCTIONS OF THE LIVER
Specific recommendations to change the dose in patients with mild renal insufficiency not. The recommended dose halava drug for patients with moderate renal impairment (creatinine clearance of 30-50 ml / min) is 1.1 mg / m 2 intravenously over 2-5 minutes in the 1st and 8th days of a 21-day treatment cycle. Safety of halava drug in patients with severe renal failure (creatinine clearance <30 mL / min) was not studied.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
The recommended dose halava drug for patients with mild hepatic impairment (Class A according to Child-Pugh) is 1.1 mg / m 2 intravenously over 2-5 minutes in the 1st and 8th days of a 21-day treatment cycle Recommended dose halava for patients with moderate hepatic failure (class B Child-Pugh) is 0.7 mg / m intravenously over 2-5 minutes in the 1st and 8th days of a 21-day treatment cycle.
Previous applications halava drug in patients with severe liver failure patients (class C Child-Pugh) offline.
APPLICATION FOR CHILDREN
Data on the safety and efficacy of Halawa drug in patients under 18 years are not available.
APPLICATION IN ELDERLY PATIENTS
Special recommendations for elderly patients on dose modification is not provided.
SPECIAL INSTRUCTIONS
Hematologic
Myelosuppression is a dose-dependent and, primarily expressed as neutropenia (cm. "Side effect" section). Each patient prior to administration of any dose Halawa В®should hold CBC. Treatment with Halawa В® can only start when ANC above 1.5 x 10 9 / L and platelet counts greater than 100 Г— 10 9 / L.
Less than 5% of patients receiving halava В® , was observed febrile neutropenia. With the development of febrile neutropenia in patients as well as in severe neutropenia or thrombocytopenia, should adjust the treatment according to the guidelines given in the section "Dosage".
When the activity of ALT or AST greater than the upper limit of normal more than three times, the patient increases the risk of grade 4 neutropenia and febrile neutropenia. When bilirubin values greater than the upper limit of normal in more than half, also increases the risk of grade 4 neutropenia and febrile neutropenia, although the evidence for this relationship are limited.
In severe neutropenia by the decision of the attending physician and in accordance with current recommendations can be assigned to granulocyte colony stimulating factor (G-CSF) or an analogue thereof.
peripheral neuropathy
It is necessary to conduct ongoing monitoring for signs of peripheral motor or sensory neuropathy patients. The development of severe peripheral neuropathy requires a delay or reduction of dose administration.
Patients with peripheral neuropathy preceding over 2 severity were not included in clinical trials. However, in patients with prior neuropathy Grade 1 or 2 severity was observed a greater risk of developing new or worsening of existing symptoms thereof in comparison with the patients included in the study without the condition.
QT interval extension
Lengthening QT interval observed on the 8th day, regardless of the concentration eribulin and at normal interval of 1 day. On the background of treatment halava В®ECG monitoring is recommended in patients with heart failure and bradyarrhythmia and while taking drugs prolonging the interval QT (including IA and III antiarrhythmics of classes). Prior to drug treatment halava В® recommended to remove electrolyte imbalance (e.g., hypokalemia, hypomagnesemia), and during the treatment to monitor the content of electrolytes in the blood.
Not recommended halava drug В® patients having congenital long QT interval syndrome.
The use of combinations
It is found that the use of eribulin in combination with anti-HER2, and capecitabine therapy is safe.
Excipients
halava В® contains a small amount of ethanol (less than 100 mg per dose).
Special precautions for disposal and use of
preparation and administration of the preparation can be carried out only by persons having relevant experience with cytostatics.
Halawa В®It is a cytotoxic anticancer drug, and when working with it, as with other toxic substances, caution should be exercised. It is recommended to use gloves, goggles and protective clothing. In the case of contact with the drug solution to the skin must be thoroughly flushed immediately the skin with soap and water. Upon contact of the drug with the mucous membranes, contact point should be thoroughly rinsed with water. If pregnancy should not work with the drug Halawa В® .
Storing unopened package
from the microbiological point of view Halawa В® should be used immediately after opening. If the drug is not used immediately after opening the package, with the terms and conditions of its storage responsible person working with the drug.
If halava В® is not applied immediately after opening the package in undiluted form of a solution , the maximum storage time at 25 of C in diffuse light was 4 hours and in the refrigerator conditions (2-8 В° C) - 24 hours.
The dilution was halava preparation В® ( at concentrations of 0.02 mg / ml to 0.2 mg / ml, not more than 24 hours can be stored in 0.9% sodium chloride solution for injection) at a temperature of 2-8 В° C, except for those situations where the initial dilution of the solution was carried out under standardized controlled aseptic conditions .
Unused drug residues and the materials used should be disposed of in accordance with applicable Russian requirements.
Influence on ability to drive vehicles and work with mechanisms
When receiving the drug Halawa В® may experience side effects such as fatigue or dizziness, which may have a mild to moderate effect on the ability to control a car or operate machinery. Patients should be informed that the appearance of fatigue or dizziness, they should not drive or operate machinery.
OVERDOSE
In one of the cases of overdose patient was administered 8.6 mg erroneously preparation halava В® (approximately 4-fold higher than the planned dose), thereby developed a hypersensitivity reaction of 3 degrees on the 3rd day and neutropenia grade 3 - 7 minutes. Both adverse reactions resolved with the help of supportive therapy. Antidote drug overdose halava В® unknown.
Treatment: in case of overdose is recommended constant monitoring of the patient and the use of symptomatic therapy.
DRUG INTERACTION
Dosage incompatibility
This drug can not be mixed with other drugs.
Injection halava В® not be diluted in 5% dextrose solution for infusion.
Eribulin predominantly (70%) excreted in the bile. Transport protein responsible for this process is not detected. Complete inhibition of transport can in theory lead to increased plasma concentrations more than 3 times. In this regard, it is not recommended simultaneous with eribulin use of drugs (such as cyclosporin, ritonavir, saquinavir, lopinavir, efavirenz, emtricitabine, quinine, quinidine, disopyramide, etc.) That are inhibitors of hepatic transport proteins (organic anion transport protein (OATPs), P-glycoprotein, multidrug resistance proteins (MRPs), etc.).
Not recommended simultaneous with carbamazepine, phenytoin, Hypericum perforatum, because these drugs can lead to a marked decrease in plasma concentrations of eribulin and, accordingly, reduce its effectiveness. When applied simultaneously with rifampicin, are inducers isoenzyme CYP3A4, significant effect on eribulin pharmacokinetic parameters (AUC and C max ) was observed. However, rifampicin, due to its ability to inhibit the transport protein, can neutralize its inducing effect on the excretion of eribulin. Therefore, rifampicin effect can not be extrapolated to other inductors.
Drug interactions with inhibitors of CYP3A4 isoenzyme is expected. Clinically significant differences in eribulin exposure (AUC and C max) When it is used together with ketoconazole (an inhibitor of isozyme SYP3A4 and P-glycoprotein) were observed.
Eribulin influence on the pharmacokinetics of other drugs
According to studies in vitro , eribulin may be a weak inhibitor of isozyme SYP3A4. While the use of drugs having a narrow therapeutic range and metabolized mainly SYP3A4 isoenzyme (e.g., alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), and care should be taken to monitor adverse events.
Eribulin has no inhibitory effect on isozymes CYP1A2, CYP2B6, CYP2S8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 in the therapeutic concentration range.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
Store at a temperature of from 8 В° to 25 В° C. Do not freeze or store in the refrigerator. Keep out of the reach of children. Shelf life - 4 years.
