Halaven - instructions for use, dose, side effects, contraindications

Active substanceEribulinEribulin

Similar drugsTo uncover

Halaven®

solution in / in

Eysay Europe Limited United Kingdom

Dosage form: & nbspsolution for intravenous administration

Composition:

1 ml of the preparation contains:

active substance: eribulinum mesylate 0.5 mg;

auxiliary substances: ethanol 0.05 ml, hydrochloric acid and sodium hydroxide to pH 6.0-9.0, water for injection up to 1.0 ml.

Description:

clear colorless solution

Pharmacotherapeutic group:antitumor agent

ATX: & nbsp

L.01.X.X Other antineoplastic agents

L.01.X.X.41 Eribulin

Pharmacodynamics:

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 preparation is a simplified synthetic analogue of halichondrin B, a natural substance isolated from a sea 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 via tubulin-mediated antimitotic mechanism leading to blockade of the cell cycle in phases G2/ M (stages of the cell cycle GAP 2 / mitosis) and the formation of mitotic spindles, which ultimately leads to apoptotic cell death as a result of prolonged blockage of mitosis.

Clinical efficacy

The effectiveness of the drug Halaven® in the treatment of locally advanced or metastatic breast cancer has been confirmed in two randomized comparative Phase III trials involving more than 1,800 patients in whom endpoints of efficacy evaluation were overall survival and progression-free survival.

Pharmacokinetics:

Distribution

The pharmacokinetics of erybulin is characterized by a rapid phase of the distribution, followed by a prolonged elimination phase with a finite half-life (T1/2), on average, about 40 h. The preparation has a large volume of distribution (on average, varying from 43 to 114 l / m2).

Eribulin weakly binds from 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 to patients ¹⁴C-labeled eribulin, the fraction of unchanged drug in plasma was overwhelming. 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 / m²).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 / m².

Displayed eribulin, 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 was shown that in clinically significant concentrations eribulin is not an inhibitor of P-glycoprotein in vitro.

In vivo concomitant administration of ketoconazole, which is an inhibitor of P-glycoprotein, does not affect the pharmacokinetic parameters of erybulin (AUC and C_mOh).

Research in vitro showed that eribulin is not a substrate for an organic cation carrier (OCT1).

After administration to patients ¹⁴C-labeled erybulin approximately 82% of the dose was excreted with feces and 9% with urine, which indicates that renal clearance is not a significant way of removing the drug. Most of the radioactive label in feces and urine was unchanged eribulin.

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, in 1.8 and 3 times.

Application of the drug Halaven® in a dose of 1.1 mg / m² patients with mild hepatic insufficiency and in a dose of 0.7 mg / m² - patients with moderate hepatic impairment provided approximately the same exposure as with 1.4 mg / m in patients with normal liver function.

Application of the drug Halaven® 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

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 (CK <30 ml / min) severity was studied in Phase I. Increase in C_max adjusted for the dose was 1.31 times for patients with moderate renal insufficiency and 2.02 times with severe renal failure compared to normal renal function. Also in patients with moderate and severe renal insufficiency, there was an increase in AUC with a dose adjustment of 1.49 times. The severity of renal failure did not exert an additional effect on the effect of erybulin.

Indications:

Halaven® shown to patients with locally advanced or metastatic breast cancer who previously received at least one chemotherapy regimen for a common disease. Pre-existing therapy should include anthracyclines and taxanes, in adjuvant mode or under metastatic conditions forms of the disease, except for those patients who could not be appointed these preparations.

Contraindications:

Hypersensitivity to erysipelin or any of the excipients.

Pregnancy and the period of breastfeeding.

Age to 18 years.

Carefully:

Syndrome of congenital extension of the QT interval.

Diseases of the heart (heart failure, bradyarrhythmia).

Electrolyte imbalance (eg, hypokalemia, hypomagnesemia).

Simultaneous reception of drugs that extend the QT interval (including antiarrhythmic IA and III classes).

Simultaneous reception of drugs that have a narrow therapeutic range and are metabolized predominantly by the isoenzyme CYP3A4 (see section "Interaction with other drugs").

Severe liver failure and liver dysfunction associated with cirrhosis (the use of the drug in this group of patients has not been studied).

Renal failure of moderate and severe severity (see section "Method of administration and dose").

Pregnancy and lactation:

Pregnancy

Data on the use of the drug Halaven® in pregnant women there. In preclinical studies eribulin had embryotoxic, fetotoxic and teratogenic effects. Halaven® should not be used during pregnancy.

Women of childbearing age should be informed of the need to protect themselves from pregnancy when using them or their partners with Halaven®, as well as mandatory use of effective methods of contraception during the treatment with Halaven® and within 3 months after its completion.

Lactation

There are no data on the penetration of erybulin or its metabolites into human milk or animals. Since the risk to newborns and infants can not be ruled out, Halaven® should not be used during breastfeeding.

Fertility

In preclinical studies, the testicular toxicity of the drug was observed. Before starting treatment, male patients should seek advice on the preservation of sperm, since the treatment with the drug Halaven® there is a possibility of developing irreversible infertility.

Dosing and Administration:

Intravenously.

Treatment with Halaven® should be carried out only under the supervision of a physician with relevant experience in the use of cytotoxic drugs.

Antiemetic drugs, including glucocorticosteroids, are recommended in case the patient experiences nausea and vomiting.

Recommended dose of drug Halaven® is 1.4 mg / m². 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

Administration of the drug Halaven® in the 1 st or 8 th day of the therapy cycle, it is necessary to postpone if any of the following conditions exist:

- Absolute number of neutrophils (AFN) <1 x 10⁹/ l

- The number of platelets <75 x 10⁹/ l

- Non-hematological toxicity 3 or 4 degrees.

Dose reduction during treatment

Recommendations for calculating the dose when resuming therapy are given in Table 1.

Table 1.

Undesirable reactions after previous administration of the drug Halaven	Recommended dose
Hematological:
Neutropenia <0.5 x 10⁹/ l, lasting more than 7 days	1.1 mg / m²
Neutropenia <1 x 10⁹/ l, complicated by fever or infection
Thrombocytopenia <25 x 10⁹/ l
Thrombocytopenia <50 x 10⁹/ l, complicated by bleeding or requiring 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 / m²	0,7 mg / m²
Despite the reduction in the dose to 0.7 mg / m²	Cessation of therapy with Halaven®

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:

Recommended dose of drug Halaven® for patients with mild hepatic insufficiency (Child-Pugh class A) is 1.1 mg / m² intravenously for 2-5 minutes in the 1st and 8th days of the 21-day treatment cycle.

Recommended dose of drug Halaven® for patients with hepatic insufficiency moderate severity (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.

Application of the drug Halaven® in patients with severe hepatic insufficiency (Child-Pugh class C) has not been studied, but it is expected that a more significant decrease in the dose of the drug Halaven®.

Dysfunction of the liver 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 patients with moderate or severe renal insufficiency (CC <40 mL / min), an initial dose reduction may be required.

Use in children

Safety and efficacy data for Halaven® patients under the age of 18 years are absent.

Application in the elderly

Special recommendations "for the elderly are not provided for dose changes.

Instructions for reconstitution before introduction

Halaven® dilute 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. Halaven® does not have an irritant or necrotizing effect at the injection site. In the case of extravasage, treatment should be symptomatic.

Side effects:

The most common adverse reactions with Halaven therapy® include 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 therapy with the drug Halaven®. Other side effects include fatigue, alopecia, increased hepatic enzyme levels, sepsis and musculoskeletal pain.

Table 2 shows the incidence of adverse events observed in 1503 patients with breast cancer who received the recommended dose of the drug Halaven® in five Phase II studies and two Phase III studies.

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); rarely (> 1/10000, <1/1000); very rarely (<1/10000).

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

Systems bodies	Highly often	Often	Infrequently	Rarely
Infectious and parasitic diseases		Infection Urinary tract (8,0%) (G3 / 4 0,5%) Pneumonia (1,2%) (G3 / 4 0,8%) Candidiasis oral cavity Herpes mucous shells oral cavity Infection upper respiratory tract Nasopharyngitis Rhinitis	Sepsis (0,5%) (G3 / 4 0,2%)^a Neutropenic sepsis (0,1%) (G3 / 4 0,1%) Shingles
Violations of the blood and lymphatic system	Neutropenia (57.0%) (G3 / 4 49,7%) Leukopenia (29.3%) (G3 / 4 17,3%) Anemia (20,6%) (G3 / 4 2.0%)	Lymphopenia (4.9%) (G3 / 4 1,4%) Febrile neutropenia (4.7%) (G3 / 4 4,5%)^a Thrombocytopenia (4.3%) (G3 / 4 0,7%)		Disseminated Intravascular blood coagulation^b
Disorders of metabolism and nutrition	Decreased appetite (21.9%) (G3 / 4 0.7%)	Hypokalemia (6.1%) (G3 / 4 1.7%) Hypomagnesemia (2.9%) (G3 / 4 0.2%) Dehydration (2.8%) (G3 / 4 0,5%) Hyperglycaemia Hypophosphatemia
Violations psyche		Insomnia Depression
Infringements from nervous systems	Peripheral neypopathy^c (35,6%) (G3 / 4 7.6%) Headache (17.2%) (G3 / 4 0.8%)	Dysgeusia Dizziness (7,9%) (G3 / 4 0.5%) Hypesesia Lethargy Neurotoxicity
Disturbances on the part of the organ of sight		Increased lacrimation (6,0%) (G3 / 4 0.1%) Conjunctivitis
Hearing and labyrinthine disorders violations		Vertigo	Tinnitus
Heart Disease		Tachycardia
Violations from hand vessels		"Tides"	Thrombosis deep veins Thromboembolism pulmonary arteries
Disturbances from respiratory system, chest and mediastinum	Dispnoe (13,9%) (G3 / 4 3,1%)^a Cough (13,6%) (G3 / 4 0.6%)	Oropharyngeal pain Nasal bleeding Rhinorrhea		Interstitial lung diseases
Disorders from the gastro- intestinal tract	Nausea (33,8%) (G3 / 4 1.1%) Constipation (19,6%) (G3 / 4 0.6%) Diarrhea (17,9%) (G3 / 4 0.8%) Vomiting (17,6%) (G3 / 4 0.9%)	Abdominal pain Stomatitis (9,3%) (G3 / 4 0.8%) Dryness oral cavities Dyspepsia (5,9%) (G3 / 4 0.2%) Gastroesophageal reflux disease Ulceration of the mucosa shells oral cavities Blowing belly		Pancreatitis^b
Disturbances from the liver and bile ducts		Increase activity alanine aminotransferase (ALT) (7,6%) (G3 / 4 2,1 %)^d Increase activity aspartate aminotransferase (ACT) (7,4%) (G3 / 4 1.5%) Increase in activity of gamma glutamyl transferase (1,8%) (G3 / 4 0.9%) Hyperbilirubinemia (1.5%) (G3 / 4 0.3%)	Hepatotoxicity (1.0%) (G3 / 4 0.6%)
Disturbances from the skin of the second subcutaneous tissue	Alopecia	Rash Itching (3.9%) (G3 / 4 0.1%) Defeat nails Night sweating Dryness leather Erythema Hyperhidrosis	The palm- plantar erythrosis	Angioneurotic edema
Disturbances from the musculoskeletal and connective fabrics	Arthralgia and myalgia (19.4%) (G3 / 4 1.1%) Backache (13,0%) (G3 / 4 1.5%) Pain in the extremities (10.0%) (G3 / 4 0.7%)	Pain in the bones (9,6%) (G3 / 4 1.7%) Muscle spasm (5,1%) (G3 / 4 0.1%) Musculo-skeletal pain and pain in the chest Muscular weakness
Disorders from the kidneys and urinary tract		Dizuria	Hematuria Proteinuria Renal failure
General disorders and violations at the site of administration	Fatigue and asthenia (47,9%) (G3 / 4 7.8%) Fever (20,4%) (G3 / 4 0.6%)	Inflammation of mucous membranes (8,3%) (G3 / 4 1.1%)^d Peripheral Edema Pain Chills Chest pain Flu-like syndrome
Laboratory and instrumental data	Decreased body weight (11.3%) (G3 / 4 0.3%)

^a Including 1 or 2 cases of the 5th degree.

^bSpontaneous messages.

^fromIncluding terms: peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, paresthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy, and demyelinating polyneuropathy.

^d Only degree 3.

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 (AFN <0.5 x 10⁹/ l) was 8 days.

In the EMBRACE study, a reduction in the number of neutrophils to <0.5 x 10%, lasting more than 7 days, occurred in 13% 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 eribulin.

Disseminated intravascular coagulation of blood

Cases of disseminated intravascular coagulation, commonly associated with neutropenia and / or sepsis, have been reported.

Peripheral Neuropathy

Among 1503 patients with breast cancer, peripheral neuropathy (3.3%) was the most common side effect leading to the elimination of eribulin therapy. The median before the appearance of peripheral neuropathy of the 2nd degree was 85.5 days (after 4 cycles). The development of peripheral neuropathy of degree 3 and 4 occurred in 7.7% of patients. In clinical studies, it was shown that in patients with neuropathy prior to initiating therapy with Halaven®, there was no greater risk of developing new or worsening of existing symptoms, in contrast to patients who did not have peripheral neuropathy prior to initiating therapy with Halaven®.

In patients with previous peripheral neuropathy 1 or 2 degrees, the incidence of peripheral neuropathy of grade 3 in the treatment with Halaven® was 14%.

Hepatotoxicity

In some patients, an increase in the activity of hepatic enzymes at the beginning of treatment with erybulin (most often in 1-2 cycles) was observed. Although this was most likely due to the adaptation of the liver to treatment with erybulin, hepatotoxicity was also reported.

Additional safety information for specific patient groups

Elderly patients

The safety profile of eribulin in elderly patients (over 65 years) is similar to the profile of drug safety in a younger population, with the exception of fatigue and asthenia, which increased with age. There are no special recommendations for dose reduction in elderly patients.

Patients with hepatic insufficiency

With ALT or ACT activity exceeding the upper limit of the norm more than three times, the patient has a risk of developing grade 4 neutropenia and febrile neutropenia. At bilirubin values that exceed the upper limit of the norm by more than one and a half times, the risk of developing grade 4 neutropenia and febrile neutropenia also increases, although the data supporting this dependence are limited.

Announcement of unwanted reactions It is extremely important to notify of undesirable reactions that occurred during the post-marketing use of the drug. This will control the ratio of the benefits and risks of the drug. Please inform medical workers of any undesired reactions.

Overdose:

In one of the cases of an overdose, 8.6 mg of Halaven® (approximately 4 times higher than the planned dose) were mistakenly administered to the patient, resulting in a hypersensitivity reaction of grade 3 on day 3 and neutropenia of grade 3 on the 7th. Both adverse reactions were resolved with maintenance therapy. The antidote for an overdose of Halavent® is unknown. In case of an overdose, continuous monitoring of the patient and the use of symptomatic therapy are recommended.

Interaction:

Drug incompatibility

This preparation can not mixed with other medicinal products.

Solution for injection Halaven® not should be diluted in a 5% solution of dextrose for infusion.

Eribulin is predominantly (up to 70%) excreted with bile. The transport protein responsible for this process has not been identified. A complete inhibition of transport may in theory lead to an increase in plasma concentration by more than 3 times. In this regard, it is not recommended to use concomitant drugs with eribulin (for example, ciclosporin, ritonavir, saquinavir, lopinavir, efavirenz, emtricitabine, verapamil, clarithromycin, quinine, quinidine, disopyramide, etc.), which are inhibitors of hepatic transport proteins (organic anion transport beige (OATPs), P-glycoprotein, multiple-drug proteins resistance (MRPs) and etc).

It is not recommended simultaneous administration with carbamazepine, phenytoin, St. John's wort, as these drugs can lead to a significant decrease in the concentration of erybulin in the plasma and, accordingly, a decrease in its effectiveness. When used simultaneously with rifampicin, which is an inducer of the isoenzyme CYP3A4, a significant effect on the pharmacokinetic parameters of erybulin (AUC and C_max) was not observed. But, rifampicin, due to its ability to inhibit transport proteins, can neutralize its inducing effect on the excretion of erybulin.Therefore, the effect of rifampicin can not be extrapolated to other

inducers.

Drug interaction with inhibitors of the isoenzyme CYP3A4 is not expected. Clinically significant differences in the exposure of erybulin (AUC and C_max) when used in conjunction with ketoconazole (an inhibitor of the isoenzyme CYP3A4 and P-glycoprotein) was not observed.

The effect of erybulin on the pharmacokinetics of other drugs

According to research in vitro, Erybulin may be a weak inhibitor of the CYP3A4 isoenzyme. When used simultaneously with drugs that have a narrow therapeutic range and are metabolized predominantly by the isoenzyme CYP3A4 (eg, alfentanil, ciclosporin, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be cautious and monitor

undesirable phenomena.

Erybulin does not have an inhibitory action on isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 in the therapeutic concentration range

Special instructions:

Hematological

Myelosuppression is dose-dependent and, first of all, it is expressed in the form of neutropenia (see section "Side effect").Each patient should undergo a clinical blood test before administering any dose of Halaven®. Treatment with Halavent®

It can be started only with AFN above 1.5 x 109 / L and the number of platelets above 100 x 109 / L.

Less than 5% of patients receiving Halaven® had febrile neutropenia. When the patient develops febrile neutropenia, as well as with severe neutropenia or thrombocytopenia, the treatment should be adjusted in accordance with the recommendations given in the section "Method of administration and dose".

Peripheral Neuropathy

It should be constantly monitored for possible signs of peripheral motor or sensory neuropathy in patients. The development of severe peripheral neuropathy requires delay in the administration or reduction of the dose. Patients with previous peripheral neuropathy more than 2 degrees of severity were not included in the clinical studies. However, in patients with a previous neuropathy of 1 or 2 severity, there was no greater risk of developing new or worsening of its already existing symptoms in comparison with patients included in the study without this condition.

QT interval extension

The prolongation of the QT interval was noted on the 8th day, regardless of the concentration of erybulin and at normal values of the interval on the 1st day. On the background of treatment Halaven® 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 the beginning of treatment is recommended to eliminate Halaven® electrolyte imbalance (eg hypokalemia, hypomagnesemia), and during treatment to monitor the contents of these electrolytes in the blood.

It is not recommended to prescribe the drug Halaven® to patients who have the syndrome of congenital prolongation of the QT interval.

Use in combination with anti-HER2 therapy

Efficacy and safety of eribulin in combination with anti-HER2 therapy is not established.

Excipients

Halaven® contains a small amount of ethanol (less than 100 mg per dose).

Special precautions for disposal and use

Preparation and administration of the drug can be carried out only by persons who have relevant experience with cytostatics.

Halaven® is a cytotoxic antitumor drug and care should be taken when handling it, as with other toxic substances. It is recommended to use gloves, goggles and protective clothing. In case of contact with the solution of the drug on the skin, immediately wash this area of skin with water and soap. When contacting the drug with mucous membranes, the contact area should be thoroughly rinsed with water. In pregnancy, do not work with the drug Halaven®.

Storage of opened packaging

From the microbiological point of view Halaven® should be used immediately after opening.If the drug is not used immediately after opening the package, the person working with the drug is responsible for the terms and conditions of its storage.

If Halaven® is not used immediately after opening the package as an undiluted solution, the maximum shelf life at 25 ° C in diffuse light is 4 hours, and in a refrigerator (2-8 ° C) - 24 hours.

A diluted solution of the drug Halaven® (in concentrations from 0.02 mg / ml to 0.2 mg / ml in a 0.9% solution of sodium chloride for injection) can be stored for no more than 24 hours at a temperature of 2-8 ° C, Situations where dilution of the initial solution was carried out in standardized controlled aseptic conditions.

Unused residues of the preparation and used materials should be disposed of in accordance with the requirements in force in the Russian Federation.

Effect on the ability to drive transp. cf. and fur:

When taking Halaven®, there may be side effects such as fatigue or dizziness, which may have little or moderate effects on the ability to drive or work with machinery. Patients should be informed that,that when you feel tired or dizzy, you can not drive a car or work with machinery.

Form release / dosage:

Solution for intravenous administration, 0.5 mg / ml.

Packaging:

2 ml of the drug in bottles of transparent colorless hydrolytic glass type I (F. USA) with a nominal capacity of 5 ml, sealed with gray butyl rubber plugs with Teflon coating (Teflon® 2) and rolled up with aluminum caps equipped with detachable plastic disks of blue color.

For 1 or 6 bottles together with instructions for use in a cardboard pack.

The places of opening of the cardboard pack are glued with two protective transparent stickers; on the middle part of each sticker there is a drawing in the form of a holographic logo of the company-holder of the RU ("Eisal").

Storage conditions:

Store at a temperature of 8 to 25 ° C.

Do not freeze or store in a refrigerator.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001782

Date of registration:24.07.2012

The owner of the registration certificate:Eysay Europe LimitedEysay Europe Limited United Kingdom

Manufacturer: & nbsp

NERPHARMA, Srl. Italy

Representation: & nbspEYSIY LLCEYSIY LLCRussia

Information update date: & nbsp27.11.2015

Illustrated instructions

Instructions

Halaven® (Halaven®)