Халавен®

General characteristics. Structure:

Active ingredient: 0,5 mg of an eribulin of a mezilat.

Excipients: ethanol, Acidum hydrochloricum and sodium hydroxide, water for injections.

Pharmacological properties:

Pharmacodynamics. Eribulin treats the inhibitors of dynamics of microtubules of a netaksanovy row belonging to galikhondrinovy group of antineoplastic means. On the structure drug represents the simplified synthetic analog of a galikhondrin In, the natural substance emitted from a sea sponge of Halichondriaokadai. Eribulin brakes a growth phase of microtubules, without influencing a shortening phase that leads to formation of the tubulinovy units which do not have functional activity. Antineoplastic action of an eribulin is implemented via the tubulin-mediated antimitotic mechanism leading to blockade of a cellular cycle G2/M vfaza (a stage of the cellular cycle GAP 2/mitosis) and to disturbance of formation of mitotic spindles that, as a result, leads to apoptotic death of cells as a result of long blocking of a mitosis.

Pharmacokinetics. Distribution. The pharmacokinetics of an eribulin is characterized by the bystry phase of distribution replaced by a long phase of removal with a final elimination half-life (Тш), on average, about 40 h. Drug has the large volume of distribution (on average, varying from 43 to 114 l/sq.m).

Eribulin poorly contacts proteins of plasma. At concentration in plasma of the person from 100 to 1000 ng/ml, the share of the eribulin connected with proteins of plasma makes from 49% to 65%.

Metabolism. In primary culture of hepatocytes of the person the inducing potential of an eribulin concerning isoenzymes 1A or ZA (in concentration to 5 dm), and also 2C9 or 2C19 (to 10 dm) P450 cytochrome was not revealed.

After introduction to patients of a 14C-mechenny eribulin, the fraction of not changed drug in plasma was overwhelming. Concentration of metabolites corresponded less than 0.6% of an initial eribulin, confirming the fact that significant metabolites of an eribulin in a human body are not formed.

Removal. Eribulin has low value of clearance (on average, varying from 1,16 to 2,42 l/h/sq.m). At weekly introduction of an eribulin of significant cumulation it is not observed. Pharmacokinetic parameters of an eribulin do not depend on a dose or time in the range from 0,22 to 4,0 mg/sq.m.

It is removed эрибулин, mainly, with bile. The transport protein which is responsible for drug excretion with bile is unknown now. Preclinical trials indicate participation in this process of the R-glycoprotein. After introduction to patients of a 14C-mechenny eribulin about 82% of a dose also 9% - with urine were removed with a stake that says that the renal clearance is not a significant way of removal of drug. Represented the most part of a radioactive label in Calais and urine not changed эрибулин.

Pharmacokinetics at a liver failure. Assessment of pharmacokinetics of an eribulin at patients with easy (a class A on Chayld-Pyyu) or moderated (a class B on Chayld-Pyyu) a liver failure, in comparison with patients with normal function of a liver (п =6), showed that exposure of an eribulin in the first two groups of patients was higher, respectively, in 1,8 and 2,5 times. Drug use Halaven in a dose of 1,1 mg/sq.m to patients with a slight liver failure and in a dose of 0,7 mg/sq.m - to patients with a moderate liver failure provided approximately the same exposure, as at use of 1,4 mg/sq.m to patients with normal function of a liver.

Halaven was not studied at patients with a heavy liver failure (a class C on Chayld-Pyyu).

Pharmacokinetics at a renal failure. Special researches of pharmacokinetics of an eribulin at patients with a renal failure were not conducted. According to available data it is supposed that compound values of the indicators of system exposure normalized on a dose at patients with easy renal failures (clearance of creatinine - KK, 50-80 ml/min.) will correspond to values at patients with normal function of kidneys. Nevertheless, at patients with moderate renal failures (KK of 30-50 ml/min.) compound values of the indicators of system exposure normalized on a dose increased twice in comparison with data of patients with normal function of kidneys.

Influence of age, sex or race on pharmacokinetics. Data of the population analysis showed lack of clinically significant influence of age, sex or race on pharmacokinetic parameters of an eribulin.

Indications to use:

Monotherapy at the patients with a locally-spread or metastatic breast cancer who received earlier not less than two various modes of chemotherapy concerning a widespread disease. The previous therapy has to include anthracyclines and taxons, except for those patients to whom these drugs could not be appointed.

Route of administration and doses:

Intravenously. Treatment by drug Halaven should be carried out only under control of the doctor having the corresponding experience of use of cytotoxic medicines. Antiemetics are recommended in case of emergence at the patient of nausea and vomiting.

The recommended drug dose Halaven makes 1,4 mg/sq.m. This dose is entered intravenously within 2-5 minutes in the 1st and 8th days of each 21-day cycle. A delay of introduction of the next dose during therapy

• Administration of drug Halaven in the 1st or 8th day of a cycle of therapy needs to be postponed in the presence of any of the following states:
◦ Absolute Number of Neutrophils (ANN) <1 x 109/l
◦ Quantity of thrombocytes <75 x 109/l
◦ Not hematologic toxicity 3 or 4 degrees.
• Administration of drug Halaven for the 8th day of a cycle can be postponed at most for 1 week.
◦ If by 15th day toxic manifestations were not allowed or them
◦ Expressiveness did not decrease to the 2nd degree less, introduction of the next dose of drug should be missed.
◦ in case of permission or decrease in expressiveness of toxic manifestations to the 2nd degree or is lower by 15th day, the drug Halaven has to be administered in a reduced dose, at the same time carrying out the following cycle of treatment has to be begun not earlier than in 2 weeks.

Dose decline during treatment. Recommendations about calculation of a dose when resuming therapy are provided in Table 1.

Table 1. Recommendations about a drug dose decline Halaven.

After a dose decline because of toxicity its return increase in the subsequent cycles is not recommended.

Special actions in case of treatment cancellation by drug Halaven are not required.

Use for patients with a liver failure the Recommended drug dose Halaven for patients with a slight liver failure (a class A on Chayld-Pyyu) makes 1,1 mg/sq.m intravenously within 25 minutes in the 1st and 8th days of a 21-day medical cycle. The recommended drug dose Halaven for patients with a moderate liver failure (a class B on Chayld-Pyyu) makes 0,7 mg/sq.m intravenously within 2-5 minutes in the 1st and 8th days of a 21-day cycle of therapy.

Experience of use of drug Halaven at patients with a heavy liver failure (a class C on Chayld-Pyyu) is absent.

Use for patients with a renal failure. Patients with a slight renal failure have no special recommendations about change of a dose. The recommended drug dose Halaven for patients with a moderate renal failure (KK of 30-50 ml/min.) makes 1,1 mg/sq.m intravenously within 2-5 minutes in the 1st and 8th days of a 21-day medical cycle. Safety of use of drug of Halaven for patients with a heavy renal failure (KK <30 ml/min.) was not studied.

Use for children. Data on safety and efficiency of drug Halaven at patients more young are absent than 18 years.

Use for elderly people. Special recommendations for elderly people about change of a dose are not provided.

Instructions for cultivation of drug before introduction. Drug Halaven is dissolved in aseptic conditions no more than in 100 ml by 0,9% of solution of sodium of chloride for injections. Drug cannot be mixed with other medicines, and also to part in 5% dextrose solution.

Before introduction it is necessary to provide good access to peripheral veins or to the central vein. Halaven has no the irritating or necrotizing effect in an injection site. In case of an ekstravazation treatment has to be symptomatic.

Features of use:

Hematologic. Miyelosupressiya is dozozavisimy and, first of all, is expressed as a neutropenia. Average time to the expected minimum of number of neutrophils (nadir) made 13 days, and average time before recovery after a heavy neutropenia (<0,5 x 109/l) made 8 days. At each patient before introduction of any dose of drug Halaven it is necessary to carry out clinical blood test. Halavenmozhno's drug to begin treatment only at AChN higher than 1,5 x 10 9/l and number of thrombocytes higher than 100 h109/l.

Less than at 5% of the patients receiving Halaven the febrile neutropenia was observed. At development in the patient of a febrile neutropenia, and also at a heavy neutropenia or thrombocytopenia, it is necessary to correct treatment according to the stated above recommendations.

At activity of ALT or ACT exceeding the upper bound of norm more than three times at the patient the risk of development of a neutropenia 4 degrees and a febrile neutropenia increases. At the values of bilirubin exceeding the upper bound of norm more than by one and a half times, the risk of development of a neutropenia 4 degrees and a febrile neutropenia also increases though the data confirming this dependence are limited. At a heavy neutropenia according to the decision of the attending physician and according to the existing recommendations the granulotsitarny colony stimulating factor (G-KSF) or its analog can be appointed.

Peripheral neuropathy. It is necessary to conduct constant observation of possible symptoms of peripheral motor or touch neuropathy at patients.

In clinical practice it was shown that at patients with the neuropathy which was available prior to therapy by drug Halaven the bigger risk of development new or deteriorations in already available its symptoms, unlike the patients who did not have peripheral neuropathy prior to therapy by drug Halaven was not observed.

Influence on reproductive function. Women of childbearing age have to be informed on need of protection from pregnancy when using by them or their partners препаратаХалавен, and also on obligatory use of effective methods of contraception during treatment by drug Halaven and within 3 months after its end.

In preclinical trials testicular toxicity of drug was observed. Prior to treatment male patients should address for consultation concerning sperm preservation as at treatment by drug Halaven exists probability of development of irreversible infertility.

Lengthening of an interval of Q-T. Lengthening of an interval of Q-T was noted for the 8th day, irrespective of concentration of an eribulin and at normal values of an interval in the 1st day. Against the background of treatment by drug Halaven monitoring of an ECG is recommended to be carried out at patients with heart failure and bradyarrhythmias, and also at a concomitant use of the medicines extending Q-T interval (including antiarrhytmic IA and the III classes). Prior to treatment by drug Halaven is recommended to eliminate an electrolytic imbalance (for example, a hypopotassemia, a hypomagnesiemia), and against the background of treatment to monitorirovat the content of these electrolytes in blood.

Halaven is not recommended to appoint the patient having a syndrome of inborn lengthening of an interval of Q-T drug.

Special precautionary measures at utilization and use Preparation and administration of drug can be carried out only by the persons having the corresponding experience with cytostatics.

Halaven represents cytotoxic antineoplastic drug, and during the work with it, as well as with other toxics, it is necessary to show care. It is recommended to use gloves, goggles and protective clothes. In case of drug solution hit on skin, it is necessary to wash out at once carefully this site of skin water with soap. At contact of drug with mucous membranes, the place of contact needs to be washed out carefully water. At pregnancy it is not necessary to work with drug Halaven.

Storage of the opened packaging. From the microbiological point of view Halaven it is necessary to use immediately. Storage of drug after opening of packaging or after its cultivation is not provided, except for those situations when storage of such drug is carried out in the controlled and standardized aseptic conditions. If drug is not used at once after packaging opening, the person working with drug is responsible for terms and conditions of its storage.

If Halaven is not applied in the form of not divorced solution at once after packaging opening, the maximum period of storage at 25 °C on disseminated to light makes 4 h, and in the conditions of the refrigerator (2-8 °C) - 24 h.

Divorced solution of drug Halaven (from 0,02 mg/ml to 0,2 mg/ml in 0,9% chloride sodium solution for injections) can be stored in concentration no more than 24 h at a temperature of 2-8 °C, except for those situations when cultivation of initial solution was carried out in the standardized controlled aseptic conditions. The unused remains of drug and used dressing materials should be utilized according to the requirements existing in the Russian Federation.

Influence on ability of driving and work with mechanisms. At administration of drug Halaven such side effects as fatigue or dizziness which can make weak or moderate impact on an opportunity to drive the car or to use mechanisms can be observed. Patsiyentov it is necessary to inform that at emergence of feeling of fatigue or dizziness he cannot be driven the car or to use mechanisms.

Use at pregnancy and during breastfeeding. Pregnancy. Pregnant women have data on drug use no Halaven. In preclinical trials эрибулин had embriotoksichesky, fetotoksichesky and teratogenic effect. Halaven it is not necessary to apply at pregnancy. Lactation

There are no data on penetration of an eribulin or its metabolites in breast milk of the person or animals. As the risk for newborns and babies cannot be excluded, Halaven it is not necessary to apply during breastfeeding.

Side effects:

For designation of frequency of the undesirable phenomena the following classification is used: very often (> 1/10 cases); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000) it is also unknown (frequency cannot be determined from the available data).

Disturbances from blood and lymphatic system. Very often: neutropenia, leukopenia, anemia. Often: febrile neutropenia, thrombocytopenia, lymphopenia.

Disturbances from metabolism Very often: loss of appetite. Often: hypopotassemia, hypomagnesiemia, dehydration, hyperglycemia, hypophosphatemia.

Mental disturbances. Often: sleeplessness, depression.

Disturbances from a nervous system. Very often: peripheral neuropathy (touch, motor and sensomotor neuropathy), paresthesias, polyneuropathy (including demyelinating polyneuropathy), a headache. Often: dysgeusia, dizziness, hypesthesia, lethargy, neurotoxicity.

Disturbances from an organ of sight. Often: increase in a slezootdeleniye, conjunctivitis.

Disturbances from an acoustic organ and labyrinth disturbances. Often: the dizziness connected with disturbance of a vestibular mechanism. Infrequently: a ring in ears.

Disturbances from cardiovascular system. Often: "inflows", tachycardia. Infrequently: thrombosis (including a deep vein thrombosis and a thromboembolism of a pulmonary artery).

Disturbances from a respiratory organs, bodies of a thorax and a mediastinum. Often: short wind, cough, oropharyngeal pain, nasal bleeding, rhinorrhea, nasopharyngitis, rhinitis, upper respiratory tract infection. Infrequently: intersticial diseases of lungs.

Disturbances from the digestive tract (DT). Very often: nausea, lock, diarrhea, vomiting. Often: stomatitis, dryness of an oral cavity, dyspepsia, abdominal pain, gastroesophageal reflux disease, ulceration of a mucous membrane of an oral cavity, кандидиаз oral cavities, abdominal distention.

Disturbances from a liver and biliary tract. Often: increase in activity of alaninaminotranspherase (ALT) and aspartate aminotransferase (ACT) in blood. Infrequently: abnormal liver function, hyperbilirubinemia.

Disturbances from kidneys and urinary tract. Infrequently: dysuria, hamaturia, proteinuria, renal failure, infection of urinary tract.

Disturbances from skin and hypodermic fabrics. Very often: alopecia. Often: rash, itch, damage of nails, night perspiration, palmar and bottom eritrodizesteziya, xeroderma, erythema, hyperhidrosis. Infrequently: Quincke's disease.

Disturbances from musculoskeletal and connecting fabric. Very often: arthralgia, mialgiya. Often: extremity pain, muscular spasm, muscular weakness, muscular pain, dorsodynia, stethalgia, ostealgia.

Others. Very often: fatigue and adynamy, fever. Often: inflammation of mucous membranes, peripheral hypostases, fever, grippopodobny syndrome, decrease in body weight, accession of consecutive infections. Infrequently: pneumonia, neytropenichesky sepsis, herpes of a mucous membrane of an oral cavity, shingles.

Interaction with other medicines:

Medicinal incompatibility. This drug cannot be mixed with other medicines. Solution for injections Halaven should not be dissolved in 5% dextrose solution for infusions.

Eribulin is preferential excreted with bile. The transport protein which is responsible for this process is not revealed. In this regard, use of the drugs (for example, such, as, cyclosporine, ритонавир, саквинавир, лопинавир, эфавиренц, эмтрицитабин, verapamil, кларитромицин, quinine, quinidine, Disopyramidum and др) which are inhibitors of hepatic transport proteins is not recommended simultaneous with eribuliny (organic anion - transport protein (OATPs), the R-glycoprotein, proteins of multiple medicinal resistance (MSP) and др).

The concomitant use with the rifampicin, carbamazepine, Phenytoinum, a St. John's Wort which is made a hole is not recommended as these drugs can lead to noticeable decrease in concentration of an eribulin in plasma.

Medicinal interaction with inhibitors of an isoenzyme CYP3A4 of R-450 cytochrome is not expected. Clinically significant distinctions in exposure of an eribulin (AUC and Sshakh) at its use together with ketokonazoly (CYP3 A4 isoenzyme inhibitor) were not observed.

Eribulin has no inhibiting effect on isoenzymes of CYP1A2, CYP2C9, CYP2C19, CYP2D6, Sur2e1ili CYP3A4 in the therapeutic range of concentration.

Contraindications:

Hypersensitivity to a keribulin or any of excipients. Heavy liver failure (lack of data on use). Heavy renal failure (lack of data on use). Pregnancy and period of breastfeeding. Age up to 18 years.

With care: at a syndrome of inborn lengthening of an interval of Q-T, heart diseases (heart failure, a myocardial infarction, bradycardia), an electrolytic imbalance (for example, a hypopotassemia, a hypomagnesiemia), at a concomitant use of the medicines extending Q-T interval (including antiarrhytmic IA and the III classes).

Overdose:

In one of overdose cases to the patient 8,6 mg of drug Halaven (about 4 times higher than the planned dose) were mistakenly entered therefore hypersensitivity reaction 3 degrees for the 3rd day and a neutropenia 3 degrees - on the 7th developed. Both undesirable reactions were allowed by means of a maintenance therapy.

The antidote at overdose by drug Halaven is unknown. In case of overdose constant observation of the patient and use of symptomatic therapy is recommended.

Storage conditions:

To store at a temperature from 8 to 25 °C. Not to freeze and not to store in the refrigerator. To store in the place, unavailable to children. A period of validity - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous administration, 0,5 mg/ml. On 2 ml of drug in bottles from transparent colourless hydrolytic glass like I (Ф. The USA) with a nominal volume of 5 ml, corked by gray butylrubber traffic jams with a teflon covering (Teflon® 2) and rolled up by the aluminum caps supplied with detachable plastic disks (FLIP OFF) of blue color. On 1 bottle together with the application instruction in a cardboard pack.