Padtsev Onko (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Astellas Pharma Europe B.V. (Netherlands)

Manufactured By

Baxter Oncology, GmbH (Germany)

ATC Code

L01FX13 (Enfortumab vedotin)

Active Substance

Enfortumab vedotin (Rec.INN registered by WHO)

Dosage Forms

	Padtsev Onko	Lyophilisate for preparation of solution for infusion 20 mg
		Lyophilisate for preparation of solution for infusion 30 mg

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of concentrate for solution for infusion

20 mg – vials – cardboard packs – By prescription

Lyophilisate for preparation of concentrate for solution for infusion

30 mg – vials – cardboard packs – By prescription

Pharmacotherapeutic Group

Antineoplastic agents; monoclonal antibodies and their drug conjugates; other monoclonal antibodies and their drug conjugates

Pharmacological Action

Enfortumab vedotin is an antibody-drug conjugate (ADC) directed against nectin-4 (an adhesion protein located on the surface of urothelial tumor cells).

It is a fully human IgG1 kappa antibody conjugated to a microtubule-disrupting agent (MMAE) via a protease-cleavable maleimidocaproylvaline-citrulline linker.

Preclinical data indicate that the antitumor activity of enfortumab vedotin is due to the binding of the ADC to nectin-4-expressing cells, followed by internalization of the ADC-nectin-4 complex and release of MMAE via proteolytic cleavage.

MMAE disrupts the microtubule network inside the cell, which subsequently induces cell cycle arrest and leads to apoptotic cell death.

MMAE released from enfortumab vedotin-targeted cells can diffuse into nearby cells with low nectin-4 expression, leading to cytotoxic cell death.

Pharmacokinetics

The mean estimated steady-state V_d of the ADC after administration of enfortumab vedotin at a dose of 1.25 mg/kg was 12.8 L.

The binding of MMAE to human plasma proteins in vitro ranged from 68% to 82%.

The likelihood of displacement of MMAE from plasma protein binding by other highly plasma protein-bound drugs, and vice versa, is low.

In vitro studies have shown that MMAE is a substrate of P-glycoprotein.

A small portion of MMAE released from enfortumab vedotin undergoes metabolism.

In vitro studies have shown that MMAE metabolism occurs primarily via oxidation involving the CYP3A4 isoenzyme.

The mean clearance of the ADC and unconjugated MMAE in patients was 0.11 L/h and 2.11 L/h, respectively.

The ADC exhibits polyexponential concentration decline upon elimination, with a T_1/2 of 3.6 days.

The elimination of MMAE is limited by its rate of release from enfortumab vedotin.

MMAE exhibits polyexponential concentration decline upon elimination, with a T_1/2 of 2.6 days.

Excretion of MMAE occurs primarily in feces and to a lesser extent in urine.

After a single administration of another MMAE-containing ADC, approximately 24% of the administered MMAE was excreted in feces and urine unchanged within 1 week.

The majority of MMAE was excreted in feces (72%). A similar MMAE excretion profile is expected after enfortumab vedotin administration.

Indications

As monotherapy for locally advanced or metastatic urothelial cancer (mUC) in patients who have previously received a programmed cell death receptor-1 (PD-1) or programmed cell death ligand-1 (PD-L1) inhibitor and a platinum-containing chemotherapy regimen.

ICD codes

Dosage Regimen

Treatment with this agent should be initiated and conducted under the supervision of a physician experienced in the use of antineoplastic agents. Good venous access must be established prior to initiation of treatment.

Administer intravenously as an infusion. Enfortumab vedotin must not be administered as an intravenous push or bolus.

The recommended dose of enfortumab vedotin is 1.25 mg/kg (maximum 125 mg for patients with body weight ≥100 kg) as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 28-day cycle until disease progression or unacceptable toxicity occurs.

Dose adjustments are made according to a specific schedule in case of adverse reactions.

Adverse Reactions

Blood and lymphatic system disorders very common – anemia; frequency unknown – neutropenia, febrile neutropenia, decreased neutrophil count.

Metabolism and nutrition disorders very common – hyperglycemia, decreased appetite, weight loss.

Nervous system disorders : very common – peripheral sensory neuropathy, dysgeusia; common – peripheral neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia, hypesthesia, gait disturbance, muscle weakness; uncommon – demyelinating polyneuropathy, polyneuropathy, neurotoxicity, motor dysfunction, dysesthesia, muscle atrophy, neuralgia, peroneal nerve palsy, loss of sensation, skin burning sensation, burning sensation.

Eye disorders very common – dry eye syndrome.

Respiratory, thoracic and mediastinal disorders: common – pneumonitis; uncommon – interstitial lung disease.

Gastrointestinal disorders very common – diarrhea, vomiting, nausea, increased ALT, increased AST.

Skin and subcutaneous tissue disorders very common – alopecia, pruritus, rash, maculopapular rash, dry skin; common – drug eruption, skin exfoliation, conjunctivitis, bullous dermatitis, blistering, stomatitis, palmar-plantar erythrodysesthesia syndrome, eczema, erythema, erythematous rash, macular rash, papular rash, pruritic rash, vesicular rash; uncommon – generalized exfoliative dermatitis, erythema multiforme, exfoliative rash, pemphigoid, maculovesicular rash, dermatitis, allergic dermatitis, contact dermatitis, intertrigo, skin irritation, stasis dermatitis, blood blister; frequency unknown – toxic epidermal necrolysis, Stevens-Johnson syndrome, epidermal necrosis, symmetrical drug-related intertriginous and flexural exanthema.

General disorders and administration site conditions very common – fatigue; common – infusion site extravasation.

Contraindications

Hypersensitivity to enfortumab vedotin, childhood and adolescence under 18 years of age, pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Women of childbearing potential should be advised to undergo a pregnancy test within 7 days prior to initiating treatment with enfortumab vedotin and to use effective contraception during treatment and for at least 12 months after its discontinuation.

Men receiving this agent are advised to avoid fathering a child during treatment and for 9 months after the last dose.

Breastfeeding should be discontinued during treatment and for at least 6 months after the last dose.

Use in Hepatic Impairment

No dose adjustment is required in patients with mild hepatic impairment (total bilirubin level from 1 to 1.5 × ULN and any AST level or total bilirubin concentration ≥ ULN and AST > ULN). Enfortumab vedotin has been studied only in a limited number of patients with moderate hepatic impairment and has not been studied in patients with severe hepatic impairment.

Use in Renal Impairment

No dose adjustment is required in patients with mild renal impairment (CrCl > 60-90 ml/min), moderate renal impairment (CrCl 30-60 ml/min), or severe renal impairment (CrCl 15-30 ml/min). Enfortumab vedotin has not been studied in patients with end-stage chronic kidney disease (CrCl <15 ml/min)/

Pediatric Use

Safety and efficacy in children from 0 to 18 years of age have not been established to date. No data available.

Geriatric Use

No dose adjustment is required in patients aged ≥ 65 years.

Special Precautions

Patients should be monitored for the development of skin reactions starting from the first cycle and throughout the entire treatment.

Patients should be medically monitored during treatment for signs and symptoms of pneumonitis/ILD, such as hypoxia, cough, dyspnea, and interstitial infiltrates on radiographic imaging.

Cases of hyperglycemia occurred more frequently in patients with pre-existing hyperglycemia and in patients with a high body mass index (≥30 kg/m²). Blood glucose levels should be monitored in patients with diabetes or at risk for diabetes, and in patients with hyperglycemia, prior to initiation of treatment and periodically throughout the course of treatment as clinically indicated.

Patients should be monitored for the emergence or worsening of peripheral neuropathy symptoms, as they may require temporary therapy interruption, dose reduction, or discontinuation of enfortumab vedotin.

Patients should be monitored to detect eye disorders. Consider prescribing artificial tear preparations and referral for ophthalmological examination to prevent dry eyes if symptoms persist or worsen.

If extravasation occurs, the infusion should be discontinued and the patient observed for adverse reactions.

Drug Interactions

Caution should be exercised in case of concomitant treatment with CYP3A4 isoenzyme inhibitors. Patients who are concurrently receiving strong CYP3A4 isoenzyme inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) should be monitored more closely for manifestations of toxicity.

Strong CYP3A4 isoenzyme inducers (e.g., rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort (Hypericum perforatum)) may moderately reduce exposure to unconjugated MMAE.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°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.