Eriblius^® (Solution) Instructions for Use

Marketing Authorization Holder

R-Pharm JSC (Russia)

Manufactured By

R-OPRA LLC (Russia)

ATC Code

L01XX41 (Eribulin)

Active Substance

Eribulin (Rec.INN registered by WHO)

Dosage Form

Eriblius®

Solution for intravenous administration 0.5 mg/ml

Dosage Form, Packaging, and Composition

Solution for intravenous administration

2 ml – vials – cardboard packs – By prescription

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; other antineoplastic agents

Pharmacological Action

Eribulin is an antineoplastic agent of the halichondrin group, a non-taxane microtubule dynamics inhibitor. Structurally, the drug is a simplified synthetic analogue of halichondrin B, a natural substance isolated from the marine sponge Halichondria okadai.

Eribulin inhibits the growth phase of microtubules without affecting the shortening phase, leading to the formation of tubulin aggregates that lack functional activity. The antineoplastic action of eribulin is realized through a tubulin-mediated antimitotic mechanism, leading to cell cycle arrest in the G₂/M phases and disruption of mitotic spindle formation, which ultimately results in apoptotic cell death due to prolonged mitotic blockade.

Eribulin also affects the tumor microenvironment and its phenotype through mechanisms not related to its antimitotic effect. These additional effects of eribulin include: (I) remodeling of the tumor vasculature, improving perfusion of the central part of the tumor and reducing its hypoxia, and (II) phenotypic transition of more aggressive mesenchymal phenotypes to less aggressive epithelial ones through reversal of the epithelial-mesenchymal transition.

Pharmacokinetics

The pharmacokinetic parameters of eribulin are independent of dose or time in the range from 0.22 to 3.53 mg/m².

The pharmacokinetics of eribulin is characterized by a rapid distribution phase, followed by a prolonged elimination phase with a mean terminal T_1/2 of about 40 hours. The drug has a large V_d (mean from 43 to 114 L/m²).

At plasma concentrations in humans from 100 to 1000 ng/ml, the binding of eribulin to plasma proteins ranges from 49% to 65%.

After administration of ¹⁴C-labeled eribulin to patients, the unchanged drug fraction in plasma was predominant. Metabolite concentrations accounted for less than 0.6% of the original eribulin, confirming that no significant metabolites of eribulin are formed in the human body.

The clearance of eribulin averages from 1.16 to 2.42 L/h/m². With weekly administration of eribulin, no significant accumulation is observed.

Eribulin is eliminated primarily in the bile. The transport protein responsible for the excretion of the drug in the bile is currently unknown. Preclinical studies indicate the involvement of P-glycoprotein in this process. However, it has been shown that at clinically significant concentrations, Eribulin is not an inhibitor of P-glycoprotein in vitro.

In vivo, concomitant administration of ketoconazole, a P-glycoprotein inhibitor, does not affect the pharmacokinetic parameters of eribulin (AUC and C_max).

In vitro studies have shown that Eribulin is not a substrate of the organic cation transporter (OCT1).

After administration of ¹⁴C-labeled eribulin to patients, approximately 82% of the dose was excreted in the feces and 9% in the urine. The majority of the radioactive label in feces and urine is unchanged Eribulin.

In patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment associated with liver metastases, eribulin exposure was 1.8 and 3 times higher, respectively, compared to patients with normal liver function.

Administration of eribulin at a dose of 1.1 mg/m² in patients with mild hepatic impairment and at a dose of 0.7 mg/m² in patients with moderate hepatic impairment provided approximately the same exposure as administration of 1.4 mg/m² in patients with normal liver function.

In patients with moderate and severe renal impairment, a 1.5-fold increase in dose-adjusted AUC was observed.

Indications

Locally advanced or metastatic breast cancer in patients who have previously received at least one chemotherapy regimen for advanced disease. Prior therapy should have included anthracyclines and taxanes in the adjuvant setting or for metastatic disease (except for those patients for whom such drugs could not be prescribed).

Unresectable liposarcoma in patients who have previously received anthracycline-based chemotherapy for advanced or metastatic disease (except for those patients for whom such drugs could not be prescribed).

ICD codes

Dosage Regimen

Administer Eriblius^® as an intravenous infusion over 2 to 5 minutes.

The recommended dose is 1.4 mg/m² administered on day 1 and day 8 of each 21-day treatment cycle.

Calculate the dose based on the patient’s body surface area at the start of the first cycle. Recalculate only after a significant change in body weight.

Do not administer as an intravenous bolus. Do not mix with other medicinal products or dilute in glucose solution.

Dose adjustments are mandatory for management of toxicities, primarily hematological and non-hematological adverse reactions.

Withhold the day 8 dose for any of the following: ANC below 1×10⁹/L, platelets below 75×10⁹/L, or grade 3 or 4 non-hematological toxicities.

Resume treatment only when ANC is ≥1.5×10⁹/L, platelets are ≥100×10⁹/L, and non-hematological toxicities resolve to ≤ grade 2.

For patients with moderate hepatic impairment (Child-Pugh B), reduce the recommended dose to 1.1 mg/m².

For patients with moderate renal impairment (CrCl 30-49 mL/min), reduce the recommended dose to 1.1 mg/m².

Permanently reduce the dose to 1.1 mg/m² for occurrences of febrile neutropenia, grade 4 neutropenia lasting >7 days, or other specific grade 3/4 toxicities.

Permanently reduce the dose further to 0.7 mg/m² if toxicities recur after the first dose reduction.

Discontinue therapy if toxicities require a dose delay beyond two weeks or for persistent grade 3/4 peripheral neuropathy.

Do not re-escalate the dose after it has been reduced.

Adverse Reactions

Definition of frequency categories of adverse events: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100) and rare (≥1/10,000, <1/1000).

Infections and infestations Common – urinary tract infection, pneumonia, oral candidiasis, herpes simplex stomatitis, upper respiratory tract infection, nasopharyngitis, rhinitis, herpes zoster; Uncommon – sepsis, neutropenic sepsis, septic shock.

Blood and lymphatic system disorders Very common – neutropenia, leukopenia, anemia; Common – lymphopenia, febrile neutropenia, thrombocytopenia; Rare – disseminated intravascular coagulation.

Metabolism and nutrition disorders Very common – weight decreased; Common – hypokalemia, hypomagnesemia, dehydration, hyperglycemia, hypophosphatemia.

Nervous system disorders: Very common – peripheral neuropathy, headache; Common – insomnia, depression, dizziness, hypoesthesia, lethargy, neurotoxicity.

Eye and ear disorders Common – lacrimation increased, conjunctivitis, vertigo, tinnitus.

Cardiac and vascular disorders Common – tachycardia, flushing, pulmonary embolism; Uncommon – deep vein thrombosis.

Respiratory, thoracic and mediastinal disorders Very common – dyspnea, cough; Common – oropharyngeal pain, epistaxis, rhinorrhea; Uncommon – interstitial lung disease.

Gastrointestinal disorders Very common – decreased appetite, nausea, constipation, diarrhea, vomiting; Common – abdominal pain, stomatitis, dry mouth, dyspepsia, gastroesophageal reflux disease, abdominal distension, dysgeusia; Uncommon – mucosal ulceration, pancreatitis.

Hepatobiliary disorders Common – increased AST, increased ALT, increased GGT, hyperbilirubinemia; Uncommon – hepatotoxicity.

Skin and subcutaneous tissue disorders Very common – alopecia; Common – rash, pruritus, nail disorder, night sweats, dry skin, erythema, hyperhidrosis, palmar-plantar erythrodysesthesia; Frequency unknown – Stevens-Johnson syndrome/toxic epidermal necrolysis.

Immune system disorders Uncommon – angioedema.

Musculoskeletal and connective tissue disorders: Very common – arthralgia and myalgia, back pain, pain in extremity; Common – bone pain, muscle spasms, musculoskeletal pain and chest pain, muscle weakness.

Renal and urinary disorders Common – dysuria; Uncommon – hematuria, proteinuria, renal failure.

General disorders and administration site conditions Very common – fatigue/asthenia, pyrexia; Common – mucositis, peripheral edema, pain, chills, chest pain, influenza-like illness.

Contraindications

Pregnancy, lactation (breastfeeding); age under 18 years; hypersensitivity to eribulin.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Women of childbearing potential should be informed about the need to use contraceptive measures during treatment with eribulin, or during treatment of their partners, as well as for 3 months after its completion.

Testicular toxicity of the drug was observed in preclinical studies. Before starting treatment, male patients should seek advice on sperm preservation, as there is a possibility of developing irreversible infertility during treatment with eribulin.

Geriatric Use

The drug is contraindicated for use in elderly patients

Special Precautions

Use with caution in congenital long QT syndrome; heart disease (heart failure, bradyarrhythmia); electrolyte imbalance (e.g., hypokalemia, hypomagnesemia); concomitant use of drugs that prolong the QT interval (including class IA and III antiarrhythmics); concomitant use of drugs with a narrow therapeutic range that are predominantly metabolized by the CYP3A4 isoenzyme; in severe hepatic impairment and liver dysfunction associated with cirrhosis (use of the drug in this group of patients has not been studied); moderate and severe renal impairment.

A complete blood count should be performed in each patient before administration of any dose of eribulin. Treatment with eribulin can only be started if the ANC is above 1.5×10⁹/L and the platelet count is above 100×10⁹/L.

If febrile neutropenia develops, as well as in case of severe neutropenia or thrombocytopenia, treatment should be adjusted.

If ALT or AST activity exceeds the ULN by more than 3 times, the risk of developing grade 4 neutropenia and febrile neutropenia increases. With bilirubin values exceeding the ULN by more than 1.5 times, the risk of developing grade 4 neutropenia and febrile neutropenia also increases, although data confirming this relationship are limited.

In case of severe neutropenia, granulocyte colony-stimulating factor (G-CSF) or its analogue may be prescribed at the discretion of the treating physician and in accordance with current guidelines.

Constant monitoring for possible signs of peripheral motor or sensory neuropathy in patients should be carried out. The development of severe peripheral neuropathy requires a delay in administration or a dose reduction.

During treatment, ECG monitoring is recommended in patients with heart failure and bradyarrhythmias, as well as with concomitant use of drugs that prolong the QT interval (including class IA and III antiarrhythmics). Before starting treatment, electrolyte imbalance (e.g., hypokalemia, hypomagnesemia) should be corrected, and the blood levels of these electrolytes should be monitored during treatment.

Drug Interactions

According to in vitro studies, Eribulin may be a weak inhibitor of the CYP3A4 isoenzyme. In vivo data are not available. When used concomitantly with drugs that have a narrow therapeutic range and are predominantly metabolized by the CYP3A4 isoenzyme (e.g., alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), caution should be exercised and adverse events should be monitored.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.