Adcetris, lyophilizate 50 mg

Brentuximab vedotin is a conjugate of a monoclonal antibody and an antitumor agent that is delivered to tumor cells expressing the CD30 antigen and causes their selective apoptosis. In preclinical studies it was found that the biological activity of brentuximab vedotin is the result of a multistep process. Binding of antibody and antitumor agent conjugate with CD30 antigen on the cell surface starts the process of endocytosis due to which “conjugate-CD30” complex enters the cell and is transported to lysosomes. Inside the cell, the active component of MMAE is released as a result of proteolytic cleavage. Binding of MMAE to tubulin leads to destruction of the microtubule network inside the cell, inhibition of the cell cycle, and ultimately death of the CD30-expressing tumor cell.

In patients with classical Hodgkin lymphoma and systemic anaplastic large cell lymphoma (systemic ACCL), the CD30 antigen is expressed on the surface of tumor cells. This expression is independent of the stage of the disease, previous therapy, and transplantation. Because of its CD30-directed mechanism of action, brentuximab vedotin is able to overcome chemotherapeutic resistance because patients refractory to multicomponent chemotherapy invariably express the CD30 antigen, regardless of prior transplant status.

Additional mechanisms of antibody action due to their other properties cannot be excluded. The CD30-directed mechanism of action of branduximab vedotin, stable CD30 expression in patients with classic Hodgkin lymphoma and systemic ACCL, and the therapeutic spectrum of use and clinical evidence of efficacy of the drug for treating these two CD30-positive tumors, even after several prior lines of therapy, provide the biological rationale for using this drug in patients with relapsed or refractory Hodgkin lymphoma and systemic ACCL with and without prior autologous stem transplantation

Indications

Cancer

The treatment of patients with relapsed/refractory CD30+ Hodgkin lymphoma after autologous stem cell transplantation or after at least two lines of prior therapy, when autologous stem cell transplantation or combination chemotherapy is not considered as a treatment option.

The treatment of patients with relapsed/refractory ACCL.

Active ingredient

Brentuximab vedotin

Composition

• active ingredient: Brentuximab vedotin (conjugate consisting of CD30-directed monoclonal antibody (cAC10) covalently bound to monomethylauristatin E (MMAE) (SGD-1006)) 50 mg*;
• excipients: citric acid monohydrate 2.1 mg, sodium citrate dihydrate 56.1 mg, α,α-trehalose dihydrate 700 mg, polysorbate 80 2.0 mg.

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How to take, the dosage

Intravenously, as an infusion.

The drug should be used under the supervision of a physician experienced in the use of antitumor drugs. A clinical blood test should be done before each dose is administered. Patients must be closely monitored during and after the infusion.

Dosage

The recommended dose is 1.8 mg/kg as an intravenous infusion for 30 minutes every 3 weeks.

If the patient’s body weight exceeds 100 kg, the value of 100 kg should be used when calculating the dose.

Severe renal failure

For patients with severe renal failure, the recommended starting dose is 1.2 mg/kg, administered intravenously as an infusion for 30 minutes every 3 weeks. Patients with renal insufficiency should be closely monitored (see section “Pharmacological properties”).

Hepatic Impairment

In patients with hepatic impairment, the recommended starting dose is 1.2 mg/kg, administered intravenously as an infusion for 30 minutes every 3 weeks.

Patients with hepatic insufficiency should be under close monitoring (see section on Pharmacological properties).

Length of therapy

At least 8, but no more than 16 cycles of therapy (approximately 1 year) must be completed if the patient becomes stable or has a positive course of disease.

Dose calculation

Calculate the total volume (ml) of the drug solution for further dilution:

Dose of drug (mg/kg) × patient body weight (kg) / Concentration of solution reconstituted in vial (5 mg/ml) = Total dose of drug (ml) for further dilution

Calculating the number of vials of drug required:

The total drug dose (ml) to be administered / Total volume in one vial (10 ml/vial) = Number of vials required

Calculating the number of vialsPreparation of the infusion solution

General precautions

Aseptic conditions must be observed during the use of the drug.

Instructions for preparing the reconstituted solution

1. The contents of one single-use vial should be dissolved in 10.5 ml of sterile water for injection to produce an 11 ml solution (including dissolved solids) with a final concentration of 5 mg/ml of brentuximab vedotin. Direct the jet along the wall of the vial. Do not direct the jet directly onto the lyophilized mass or powder.

2. twist the vial gently to facilitate dissolution. DO NOT SHAKE.

3. The solution reconstituted in the vial should be clear or slightly opalescent, colorless. The final pH should be 6.6.

4. The reconstituted solution should be inspected for foreign mechanical inclusions and/or discoloration. If foreign mechanical inclusions and/or discoloration are found, the solution must be destroyed.

Instructions for preparing the solution for injection

. The required amount of reconstituted solution of the drug should be removed from the vial(s) and added to an infusion bag of a minimum volume of 100 ml containing sodium chloride solution for injection of 9 mg/ml (0.9%) to obtain a final concentration of the drug equal to 0.4-1.8 mg/ml. The reconstituted solution can also be diluted with 5% glucose solution for injection or Ringer’s lactate solution for injection.

Gently invert the bag to stir the drug solution.

Do NOT shake.

Do not add other medications to the prepared infusion solution or intravenous infusion system. The infusion system should be flushed with sodium chloride solution for injection 9 mg/ml (0.9%), or with 5% glucose solution for injection or Ringer’s lactate solution for injection.

Infusion of the drug is carried out immediately after preparation of the solution.

The total storage time of the solution from the time it is dissolved until the patient receives the infusion should not exceed 24 hours at 2 to 8 ºC as the product does not contain preservatives.

To use

The recommended dose of the drug is administered as an infusion over 30 minutes.

The instructions for dissolution and dilution before administering the drug are listed under “Preparation of Infusion Solution”.

The drug solution must not be administered by intravenous jetting or bolus injection. The drug solution should be administered through a separate intravenous catheter and should not be mixed with other drugs. Treatment should be discontinued in case of disease progression or undesirable toxicity.

Interaction

The co-administration of brentuximab vedotin and ketoconazole, a potent CYP3A4 and P-glycoprotein inhibitor, resulted in an approximately 73% increase in antimicrotubulin agent MMAE, while plasma levels of brentuximab vedotin were unchanged. Thus, the use of brentuximab vedotin together with potent CYP3A4 and P-glycoprotein inhibitors may lead to an increased incidence of neutropenia. If neutropenia develops, see Table 2 (Dose recommendations). Table 2 (Dosing recommendations for neutropenia, section “How to use and doses”).

The combined use of brentuximab vedotin and rifampicin, a potent CYP3A4 inducer, did not alter plasma levels of brentuximab vedotin, but there was an approximately 31% decrease in MMAE concentrations.

The combined use of midazolam, a CYP3A4 substrate, and brentuximab vedotin did not alter the metabolism of midazolam. Thus, brentuximab vedotin is not expected to alter drug concentrations metabolized by CYP3A4 enzymes.

Special Instructions

Progressive multifocal leukoencephalopathy

Treatment with branduximab vedotin can cause reactivation of JC virus (John Cunningham virus), which causes PML and leads to death. The occurrence of PML has been noted in patients who received this drug after receiving several courses of chemotherapy. PML is a rare CNS demyelinating disease that results from reactivation of latent JC virus and often ends in death.
Patients should be closely monitored for any new or exacerbated existing neurologic, cognitive, or behavioral symptoms or signs that may be indicative of PML. Treatment with branduximab vedotin should be suspended if PML is suspected. In such a case, an evaluation is recommended, which should include consultation with a neurologist, gadolinium-guided magnetic resonance imaging of the brain, and testing of CSF for JC virus DNA by polymerase chain reaction or brain biopsy to confirm the diagnosis of PML. A negative polymerase chain reaction does not rule out the possibility of PML. Additional testing is worthwhile if no alternative diagnosis can be made. If the diagnosis of PML is confirmed, treatment with brentuximab vedotin should be discontinued permanently. The physician should pay special attention to PML symptoms that the patient may not be aware of (e.g., neurologic, cognitive, or psychiatric symptoms).

Pancreatitis

Acute pancreatitis has been seen in patients receiving Adzetris. Fatal outcomes have been reported. Patients should closely monitor for new or worsening abdominal pain that is suspected to be a symptom of acute pancreatitis. Patient evaluation may include physical examination, laboratory evaluation of serum amylase and serum lipase, and abdominal imaging such as ultrasound and other appropriate diagnostic measures. Adzetris should be discontinued if the diagnosis of acute pancreatitis is confirmed.

Pulmonary toxicity

Pulmonary toxicity has been reported in patients receiving brentuximab vedotin. Although a causal relationship with brentuximab vedotin has not been established, the risk of possible pulmonary toxicity should not be excluded. If new or worsening existing pulmonary symptoms (e.g., cough, dyspnea) occur, an immediate diagnostic evaluation should be performed and patients should receive appropriate treatment.

Serious infections or opportunistic infections

. Serious infections such as pneumonia, staphylococcal bacteremia, and shingles, as well as opportunistic infections such as pneumocystis pneumonia and candidiasis, have been reported in patients who were administered brentuximab vedotin. Patients should be monitored by a physician during treatment for serious and opportunistic infections.

Reactions to the infusion

Reactions to the infusion were noted both during the infusion and after its completion, cases of anaphylaxis were reported. Patients should be under medical supervision during and after completion of the infusion. If anaphylaxis occurs, brentuximab vedotin should be stopped immediately and appropriate treatment administered.

In the event of a reaction to the infusion, the drug administration should be stopped and appropriate medical procedures should be performed. Once the symptoms have disappeared, the infusion can be resumed, administering the drug at a slower infusion rate. If patients have previously had reactions to infusions, premedication with paracetamol, antihistamines and GCS should be given before the next administration of the drug. Reactions to infusions are more frequent and severe in patients with antibodies to brentuximab vedotin.

Tumor Lysis Syndrome

Tumor Lysis Syndrome (TLS) is known to occur with brentuximab vedotin. Patients with rapidly proliferating tumors are at risk for SLO. Such patients should be monitored by a physician and treated according to the standards of leading medical practices. Treatment of SLOs may include intensive hydration with monitoring of renal function, correction of electrolyte abnormalities, treatment of hyperuricemia and use of supportive therapy.

Peripheral neuropathy

Treatment with brentuximab vedotin causes peripheral neuropathy (predominantly sensory). Cases of motor peripheral neuropathy are also known. Peripheral neuropathy caused by the cumulative effects of brentuximab vedotin is reversible in most cases. According to the results of the phase 2 study, the majority of patients (62%) had improvement or disappearance of symptoms of peripheral neuropathy at the time of the last evaluation. Patients with peripheral neuropathy reported discontinuation of branduximab vedotin treatment in 9% of cases, dose reduction in 8% of cases, and delayed dose administration in 13% of cases. Patients should be monitored by a physician for timely detection of neuropathy symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, burning, neuropathic pain, or weakness. If peripheral neuropathy occurs or worsens, treatment should be suspended and the dose reduced or discontinued completely.

Hematologic toxicity

Brentuximab vedotin may cause grade III or IV anemia, thrombocytopenia, and prolonged neutropenia (>1 week) of grade III or IV severity. A complete blood count should be performed before each dose.

Febrile neutropenia

The treatment of brentuximab vedotin may be accompanied by febrile neutropenia (fever of unknown origin without clinical or microbiological confirmation of infection, absolute neutrophil count9/l, body temperature >38.5°C. A detailed blood count should be performed prior to each dose administration. If febrile neutropenia occurs, patients should be closely monitored by a physician for fever and if febrile neutropenia develops, treatment should be administered according to the standards of leading medical practices.

Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJD) and toxic epidermal necrolysis (TEN) have been reported during Adzetris use. Fatal cases have been reported. If SSD and TEN occur, Adzetris treatment should be stopped and appropriate therapy should be administered.

Hyperglycemia

Hyperglycemia has been known to occur in clinical trials in patients with an elevated body mass index, with or without a history of diabetes mellitus. However, plasma glucose levels should be monitored closely if a patient is found to be hyperglycemic. Appropriate antidiabetic drugs should be prescribed.

Renal and hepatic impairment

There is limited experience with treatment of patients with renal and hepatic impairment. Pharmacological analysis (by FC (pharmacokinetic) parameters) for selected patient groups has shown that moderate to severe renal impairment and low serum albumin concentrations may affect MMAE clearance.

Sodium content of excipients

Adcetris contains a maximum of up to 2.1 mmol (or 47 mg) of sodium in a single dose. This fact must be considered in patients who are on a sodium-controlled diet.

Fertility

Women of childbearing age

. Women of childbearing age need to use two methods of effective contraception during Adzetris treatment and for up to 30 days after treatment.

Men

Preclinical studies have shown that treatment with brentuximab vedotin causes toxic testicular damage and can lead to impaired fertility in men. Studies have also shown that MMAE has aneugenic properties. Men are advised to freeze sperm samples for storage before taking this medication. Men are not recommended to plan to conceive during treatment with this drug and for 6 months after the last dose.

Specific effects of the drug on driving or operating potentially dangerous machinery

Brentuximab Vedotin may slightly affect reaction time when driving or operating other potentially dangerous machinery.

Special precautions for waste disposal and other handling

General precautions

The proper handling and disposal procedures applicable to anticancer drugs must be followed.

Perform proper aseptic methods must be used throughout the handling of this medication.

Waste Disposal

Adcetrispred is for single use only.

The unused portion of the drug must be disposed of in accordance with local regulations.