Adcetris® [Brentuximab vedotin]

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Adcetris® [Brentuximab vedotin]

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Intravenous, in the form of infusions.

The drug should be used under the supervision of a physician with experience in the use of anticancer drugs. A clinical blood test should be performed before each dose. Patients should be closely monitored during and after 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 weight of 100 kg should be used when calculating the dose.

Severe renal failure

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

Liver failure

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

Patients with hepatic impairment must be strictly monitored (see the Pharmacological Properties section).

Duration of therapy

When a stable state is achieved or when the disease is positive, the patient should undergo at least 8, but not more than 16 cycles of treatment (approximately 1 year).

Dose calculation

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

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

Calculation of the required number of drug vials:

Total dose of the drug (ml) for administration / Total volume in one vial (10 ml / vial) = Required number of vials

Tab. 1. Examples of calculations for patients with a body weight from 60 kg to 120 kg. The recommended dose of the drug is 1.8 mg / kg.

The body weight of the patient (kg)	Total dose = patient body weight multiplied by recommended dose [1.8 mg / kgbut ]	Total volume for breedingb = total dose divided by the concentration of the solution reconstituted in the vial [5 mg / ml]	Required number of vials = total volume for dilution divided by total volume in one vial [10 ml / vial]
60 kg	108 mg	21.6 ml	2,16 bottles
80 kg	144 mg	28.8 ml	2,88 bottles
100 kg	180 mg	36 ml	3.6 bottles
120 kgat	180 mgg	36 ml	3.6 bottles

^but. In the case of a reduced dose, a value of 1.2 mg / kg is used in the calculations.

^b. For dilution in 150 ml of the solution and the introduction of the method of intravenous infusion for 30 minutes every 3 weeks.

^at. If the patient's body weight exceeds 100 kg, the weight of 100 kg should be used when calculating the dose.

^year The maximum recommended dose is 180 mg.

Dose adjustment

Neutropenia

If neutropenia is detected during treatment, the intervals between doses should be extended to control it. Relevant recommendations for dosing are given in Table. 2 (see also the section “Special Instructions”).

Tab. 2. Dosing recommendations for neutropenia

The severity of neutropenia (signs and symptoms [abbreviated description of CTCAEa ])	Changing the dosing regimen
Grade 1 (3 9 / l) or Degree 2 (<1500 -="" 1000="" mm="" sup="">3 <1,5 – 1,0 × 109 / l)	Continue the treatment according to the same regimen and with the same dosage.
Grade 3 (<1000 -="" 500="" mm="" sup="">3 <1,0 – 0,5 × 109 / l) or Grade 4 (<500 mm="" sup="">3<0,5 × 109 / l)	Stop the treatment until the severity of neutropenia returns to ≤ Grade 2 or baseline, then continue the treatment according to the previous regimen and with the same dosageb . With the development of neutropenia of 3 or 4 degrees of severity, the additional appointment of recombinant hemopoietic factors G-CSF or GM-CSF is possible

^but. The classification is based on the “Common terminology of adverse reaction criteria” (CTCAE) c. 3.0 National Cancer Institute (NCI)

^b. With the development of lymphopenia 3 and 4 severity, patients can continue treatment without changes.

Peripheral Neuropathy

In the event of the occurrence or aggravation of peripheral sensory or motor neuropathy during the treatment period, the following dosing recommendations should be followed (Table 3).

Tab. 3Dosing recommendations for newly diagnosed or progressive sensory or motor neuropathy

Severity of progressive sensory or motor neuropathy (signs and symptoms [abbreviated description of CTCAEbut ])	Changing the dosing regimen
Grade 1 (paresthesia and / or loss of reflexes, without loss of functionality)	Continue the treatment according to the same regimen and with the same dosage.
Grade 2 (impaired functionality, but without obvious effect on daily activities) Grade 3 (daily activity difficulty)	Stop treatment until the severity of neuropathy returns to ≤ Grade 1 or baseline, then restart treatment using a reduced dosage of 1.2 mg / kg every 3 weeks
Grade 4 (sensory neuropathy resulting in incapacity, or motor neuropathy, life-threatening or paralysis)	Stop treatment

^but. The classification is based on the “Common terminology of adverse reaction criteria” (CTCAE) c. 3.0 National Cancer Institute (NCI)

Elderly patients

The safety and efficacy of the drug in elderly patients (65 years and older) have not been established. No data available.

Children's population

The safety and efficacy of the drug in children under 18 years have not been established. No data available.

Preparation of infusion solution

General Precautions

During use of the drug must comply with aseptic conditions.

Instructions for the preparation of the recovered solution

1. The contents of a single vial for single use must be dissolved in 10.5 ml of sterile water for injection to obtain a solution of 11 ml (including dissolved solids) with a final concentration of 5 mg / ml of bentuximab Vedotine. Direct the jet along the wall of the bottle. Do not direct the spray directly onto the lyophilized mass or powder.

2. Carefully rotate the vial 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 equal to 6.6.

4. The reconstituted solution must be inspected for the absence of extraneous mechanical impurities and / or discoloration. In case of detection of extraneous mechanical impurities and / or discoloration, the solution must be destroyed.

Instructions for preparing the solution for administration

The required amount of the reconstituted solution of the drug should be removed from the vial (s) and add to the infusion bag a minimum volume of 100 ml containing 9 mg / ml sodium chloride solution for injection (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 a 5% glucose solution for injection or Ringer's lactate solution for injection.

Gently invert the bag to mix the drug solution.

DO NOT SHAKE.

It is not allowed to add other drugs to the prepared infusion solution or intravenous infusion system. The infusion system should be washed with a solution of sodium chloride for injection 9 mg / ml (0.9%), or with a 5% glucose solution for injection or Ringer's lactate solution for injection.

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

The total storage time of the solution from the moment of dissolution to the receipt of the infusion by the patient should not exceed 24 hours at a temperature of 2 to 8 ºС, since the preparation does not contain preservatives.

Mode of application

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

Instructions for dilution and dilution before the introduction of the drug are given in the subsection "Preparation of the infusion solution".

It is not allowed to administer the drug solution by intravenous jet or bolus administration.The solution of the drug should be administered through a separate intravenous catheter, while it can not be mixed with other drugs. Treatment should be discontinued in the event of disease progression or unwanted toxicity.

Data on the use of brentuximab vedotin in pregnant women do not. Animal studies have shown reproductive toxicity. Brentuximab vedotin should not be used during pregnancy unless the expected benefit to the mother exceeds the potential risk to the fetus. If it is necessary to use the drug during pregnancy, the patient should be informed about the potential risk to the fetus.

There are no data on the penetration of brentuximab vedotin or its metabolites into breast milk. Therefore, the risk to breastfed babies cannot be ruled out. The decision to stop breastfeeding or stop / abstain from treatment with this drug is made taking into account the potential risk to the child and the benefits of drug therapy for the woman.

Progressive multifocal leukoencephalopathy

Brentuximab treatment with vedotine can cause reactivation of the JC virus (John Cunningham virus), which causes the development of PML and leads to death. The occurrence of PML was noted in patients who received this drug after undergoing several courses of chemotherapy. PML is a rare demyelinating disease of the CNS that occurs as a result of reactivation of the latent JC virus and often ends in death.
Patients should be carefully monitored to identify any new or worsening existing neurological, cognitive, or behavioral symptoms or signs that may indicate PML. Brentuximab treatment with vedotine should be suspended if PML is suspected. In this case, it is recommended to undergo an examination, which should include a consultation by a neurologist, a magnetic resonance imaging of the brain with the introduction of gadolinium and an analysis of the CSF for JC DNA of the virus by PCR or a brain biopsy to confirm the diagnosis of PML. Negative polymerase chain reaction does not exclude the possibility of PML disease. It is worth conducting an additional examination if it is impossible to establish an alternative diagnosis. When confirming the diagnosis of PML, the treatment of brentuximab vedotin should be permanently discontinued. The physician should pay particular attention to the symptoms of PML that the patient may not pay attention to (for example, neurological, cognitive, or psychiatric symptoms).

Pancreatitis

Acute pancreatitis is observed in patients receiving Adzetris. Lethal outcomes have been reported.Patients should closely monitor new or worsening abdominal pain, which presumably may be a symptom of acute pancreatitis. Examination of patients may include physical examination, laboratory evaluation of serum amylase and serum lipase, and visualization of the abdominal cavity, for example, ultrasound and other relevant diagnostic measures. Application Adsetris should be discontinued if the diagnosis of acute pancreatitis is confirmed.

Pulmonary toxicity

Lung toxicity has been reported in patients receiving brentuximab vedotin. Although a cause-and-effect relationship with brentuximab vedotinene has not been established, the risk of possible pulmonary toxicity should not be excluded. In the event of new or worsening existing pulmonary symptoms (for example, coughing, shortness of breath), an immediate diagnostic evaluation should be performed and patients should receive appropriate treatment.

Serious infections or opportunistic infections

In patients who were administered brentuximab vedotin, cases of serious infections, such as pneumonia, staphylococcal bacteremia and shingles, as well as opportunistic infections, such as pneumocystis pneumonia, candidiasis, were recorded. During treatment, patients should be supervised by a physician in the event of serious and opportunistic infections.

Infusion Reactions

Noted reactions to the infusion both during the infusion and after its completion, anaphylaxis cases have been reported. During and after the infusion, patients must be under the supervision of a physician. For anaphylaxis, the administration of brentuximab vedotin should be immediately stopped and appropriate treatment should be prescribed.

In case of a reaction to the infusion, the administration of the drug should be suspended and appropriate medical procedures should be carried out. After the symptoms disappear, the infusion can be resumed by injecting the drug with a slower infusion rate. If patients previously had reactions to infusions, before the next administration of the drug, it is necessary to conduct a premedication involving the use of paracetamol, an antihistamine and GCS. Infusion reactions are more frequent and stronger in patients with antibodies to brentuximab vedotin.

Tumor lysis syndrome

There are cases of tumor lysis syndrome (SLO) caused by the use of brentuximab vedotin. Patients with rapidly proliferating tumors are at risk of developing SLO. Such patients should be under the supervision of a physician and receive treatment in accordance with the standards of leading medical practices. Treatment of SLO may include intensive hydration with monitoring of kidney function, correction of electrolyte disorders, treatment of hyperuricemia, and the use of supportive therapy.

Peripheral Neuropathy

Treatment with brentuximab vedotin causes peripheral neuropathy (mainly sensory). Cases of motorized peripheral neuropathy are also known. Peripheral neuropathy caused by the cumulative effect of brentuximab vedotin is reversible in most cases. According to the results of the phase 2 study at the time of the last evaluation, the majority of patients (62%) noted improvement or disappearance of the symptoms of peripheral neuropathy. In patients with peripheral neuropathy, discontinuation of brentuximab vedotin treatment was observed in 9% of cases, dose reduction in 8% of cases, delayed dose in 13% of cases. Patients should be supervised by a physician in order to promptly identify such neuropathy symptoms as hypoesthesia, hyperesthesia, paresthesia, discomfort, burning, neuropathic pain or weakness.In case of occurrence or exacerbation of peripheral neuropathy, it is necessary to suspend treatment and reduce the dose or completely discontinue treatment.

Hematologic toxicity

Brentuximab vedotin can cause anemia of III or IV severity, thrombocytopenia and prolonged neutropenia (more than 1 week) of III or IV severity. Before each dose, it is necessary to conduct a detailed blood test.

Febrile neutropenia

Treatment with brutuximab vedotin may be accompanied by febrile neutropenia (fever of unknown origin without clinical or microbiological confirmation of infection, absolute neutrophil count <1.0x10⁹/ l, body temperature> 38.5 ° C. Before each dose, it is necessary to conduct a detailed blood test. In the event of febrile neutropenia, patients should be closely monitored by the doctor for fever development and in the case of febrile neutropenia should be prescribed treatment in accordance with the standards of leading medical practices.

Stevens-Johnson syndrome and toxic epidermal necrolysis

During the period of use of Adcetris, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were observed. There were reports of fatal cases. With the appearance of SJS and PET, treatment of Adcetris should be suspended and appropriate therapy should be prescribed.

Hyperglycemia

There are cases of hyperglycemia in clinical trials in patients with an increased body mass index, with or without diabetes mellitus. However, it is necessary to closely monitor the level of glucose in the blood plasma, if the patient has hyperglycemia. Appropriate antidiabetic drugs should be prescribed.

Kidney and liver failure

There is limited experience in treating patients with renal and hepatic insufficiency. Pharmacological analysis (on PK (pharmacokinetic) indicators) for certain groups of patients showed that moderate and severe renal failure, as well as low serum albumin concentrations can affect the clearance of MMAE.

Sodium content in excipients

Adcetris contains a maximum of 2.1 mmol (or 47 mg) of sodium in one dose. This fact must be taken into account for patients who are on a diet with a controlled sodium content.

Fertility

Women of childbearing age

Women of childbearing age must use two methods of effective contraception during the period of treatment with Adsetris and for up to 30 days after treatment.

Men

According to preclinical studies, the treatment of brentuximab vedotin causes toxic damage to the testes and can lead to impaired fertility in men. Studies have also shown that MMAE has aneogenic properties. Before taking this drug, men are advised to freeze semen samples for storage. Men are not recommended to plan the conception of a child during treatment with this drug and for 6 months after the last dose.

Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous machinery

Brentuximab vedotin may have little effect on the reaction rate when driving or working with other potentially dangerous machinery.

Special precautions for waste disposal and other handling.

General Precautions

Appropriate treatment and disposal procedures applicable to anticancer drugs should be applied.

Proper aseptic techniques must be applied throughout the process of handling this drug.

Recycling

It is suitable for single use only.

The unused portion of the preparation must be disposed of in accordance with local legislation.

Symptoms: increased side effects.

Treatment: unknown antidote for overdose Adzetris. In case of overdose, the patient should be closely monitored for the development of adverse reactions, in particular, neutropenia, and supportive treatment should be prescribed.