Adcetris
Adsetris: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Use in the elderly
- 14. Drug interactions
- 15. Analogs
- 16. Terms and conditions of storage
- 17. Terms of dispensing from pharmacies
- 18. Reviews
- 19. Price in pharmacies
Latin name: Adcetris
ATX code: L01XC12
Active ingredient: brentuximab vedotin (brentuximab vedotin)
Manufacturer: BSP Pharmaceuticals S.r.l. (Italy), Pierre Fabre Medicament Production (France)
Description and photo update: 2018-27-11
Adcetris is an antineoplastic drug.
Release form and composition
The drug is produced in the form of a lyophilisate for the preparation of a concentrate for the preparation of a solution for infusion: a porous mass or powder of white or almost white color, after recovery, a slightly opalescent or transparent solution from colorless to yellowish is formed (50 mg each in glass bottles without color, in a cardboard box with first opening control 1 bottle and instructions for use of Adsetris).
1 bottle contains:
- active substance: brentuximab vedotin [conjugate consisting of a CD30-directed monoclonal antibody (cAC10) covalently linked to MMAE (monomethylauristatin E) (SGD-1006)] - 50 mg (the amount of brentuximab vedotin, including an excess of 10%, is 55 mg; after reconstitution, 1 ml of solution contains 5 mg of active substance);
- auxiliary components: citric acid monohydrate, sodium citrate dihydrate, α, α-trehalose dihydrate, polysorbate 80.
Pharmacological properties
Pharmacodynamics
Adcetris is an antineoplastic drug, the action of which is due to the properties of the active substance - brentuximab vedotin. Being an artificially synthesized compound containing monoclonal antibodies and an antitumor substance, brentuximab vedotin, after delivery to the malignant cells expressing the CD30 antigen, induces their selective apoptosis. The biological activity of a drug is the result of a multi-stage process. The impetus for the development of endocytosis on the cell surface is the binding of the conjugate of the antibody and antitumor agent to the CD30 antigen. Once inside the cell, the complex formed from the conjugate and CD30 is transported to the lysosomes. The active component of MMAE is released inside the cell as a result of proteolytic cleavage. The binding of MMAE to tubulin causes the destruction of the network of intracellular microtubules,inhibition of the cell cycle and death of a CD30-expressing tumor cell.
In classic Hodgkin's lymphoma and systemic ALCL (anaplastic large cell lymphoma), the expression of the CD30 antigen occurs on the surface of tumor cells and does not depend on the stage of the disease, previous therapy or transplantation. The CD30-directed mechanism of action provides brentuximab vedotin with the ability to overcome chemotherapy resistance, since the CD30 antigen is consistently expressed in patients refractory to multicomponent chemotherapy, regardless of previous transplantation status.
It is possible that antibodies have additional mechanisms of action due to their other properties. The biological rationale for the use of Adcetris in the treatment of recurrent or refractory Hodgkin's lymphoma and systemic ALCL without or with prior autologous stem cell transplantation are the following factors: CD30-directed mechanism of drug action, stable expression of CD30 in patients with classic Hodgkin's lymphoma and systemic ALCL, therapeutic spectrum the use and clinical evidence of the efficacy of brentuximab vedotin for the treatment of these two CD30-positive tumors, including in the setting of several previous lines of therapy.
Pharmacokinetics
The maximum plasma concentration (C max) of brentuximab vedotin is reached at the end of the infusion procedure, or at the sampling point closest to the end of the procedure.
A multi-exponential decrease in serum concentrations of the active substance was observed with a final T 1/2 (half-life) of approximately 4-6 days. The concentrations were roughly proportional to the doses administered.
The minimal or no accumulation of brentuximab vedotin observed at multiple doses every three weeks is consistent with the estimated terminal half-life.
According to the phase 1 study, against the background of a single injection of brentuximab vedotin at a dose of 1.8 mg per 1 kg of the patient's weight, the C max was 31.98 μg / ml, AUC (total concentration) - 79.41 μg / ml per day.
The main metabolite of brentuximab vedotin is MMAE. According to the phase 1 study, after a single injection of Adcetris at a dose of 1.8 mg per 1 kg of patient weight, the median is: C max - 4.97 ng / ml, AUC - 37.03 ng / ml per day, T max (time to reach maximum plasma concentration of brentuximab vedotin) - 2.09 days.
Against the background of multiple doses of the drug, the concentration of MMAE decreases to 50–80% of the level of the first dose. Further, MMAE is metabolized mainly to a metabolite with equivalent activity. Its exposure is an order of magnitude lower than that of MMAE, therefore, the activity of the metabolite does not significantly affect the manifestation of systemic effects.
In the first cycle, an increase in the level of MMAE correlates with an absolute decrease in the number of neutrophils.
The binding of MMAE to plasma proteins (in vitro) is 68–82%. It is assumed that drugs with a high degree of binding to plasma proteins will not displace MMAE; in turn, MMAE will not displace these drugs. MMAE is a substrate of P-glycoprotein and does not inhibit it in the range of clinical concentrations.
At equilibrium concentration of Adcetris, the average V d (volume of distribution) is 6–10 liters. The apparent V d is: V d of the VM metabolite - 7.37 L, V d in the peripheral compartment of the VMP - 36.4 L.
Presumably, brentuximab vedotin is catabolized in the same way as a protein, with excretion of the amino acid component or recycling.
According to in vivo studies, only a small fraction of MMAE released from brentuximab vedotin is metabolized.
MMAE is a substrate for CYP3A4 and possibly CYP2D6. MMAE metabolism is mainly carried out by oxidation with the help of CYP3A4 / 5. MMAE has an inhibitory effect on CYP3A4 / 5 only in concentrations that significantly exceed those allowed for clinical use. MMAE does not inhibit other isoforms.
Brentuximab vedotin is eliminated through catabolism. Its clearance is 1.457 liters per day, T 1/2 - 4-6 days.
The rate of elimination of MMAE depends on the period of its release from the conjugate with a monoclonal antibody, the characteristic clearance of MMAE is 19.99 L per day, T 1/2 - 3-4 days.
Within 7 days after the administration of Adcetris, up to 24% of MMAE is excreted, of which 72% through the intestines, 28% through the kidneys.
The results of a population pharmacokinetic analysis indicate a significant effect of the baseline concentration of serum albumin on the clearance of MMAE. In patients with serum albumin concentrations less than 3 g / dl, the clearance of MMAE is reduced by 2 times compared with patients with normal serum albumin concentrations.
In hepatic insufficiency, the period of MMAE excretion is increased by approximately 2.3 times compared with patients in whom liver function is not impaired.
In severe renal failure, the excretion of MMAE increases by about 1.9 times compared with patients with normal renal function.
Currently, data from clinical trials of brentuximab vedotin in patients over the age of 65 years do not allow to distinguish differences in response to treatment when compared with younger patients.
The pharmacokinetics of Adcetris in patients under 18 years of age has not been established.
Indications for use
The use of Adcetris is indicated for the treatment of the following diseases:
- recurrent or refractory systemic anaplastic large cell lymphoma;
- Recurrent or refractory CD30 + Hodgkin's lymphoma in patients who have undergone autologous stem cell transplantation or at least two lines of prior therapy for whom combination chemotherapy or autologous stem cell transplantation is not considered a treatment option;
- CD30 + Hodgkin's lymphoma in patients with one of the factors of increased risk of disease recurrence or progression during autologous stem cell transplantation. Factors at increased risk of recurrence or progression of Hodgkin's lymphoma include resistance to first-line therapy, relapse or progression of the disease within 12 months after the end of the first line of therapy, and the presence of extranodal lesions (including spread to vital organs of nodal masses) with relapse before autologous transplantation hematopoietic stem cells.
Contraindications
- concomitant therapy with bleomycin due to pulmonary toxicity;
- period of pregnancy;
- breast-feeding;
- age up to 18 years;
- hypersensitivity to the components of the drug.
Adcetris should be used with caution in case of impaired liver function, severe renal failure.
Adsetris, instructions for use: method and dosage
The finished solution of the drug Adcetris is administered intravenously in the form of infusions.
The infusion solution is prepared under aseptic conditions.
To restore the solution, 10.5 ml of sterile water for injection should be added to the contents of the vial, directing the stream not to the lyophilized mass, but along the wall of the vial. To facilitate dissolution, the bottle is gently turned without shaking. The reconstituted solution should be colorless, transparent or slightly opalescent, free of any foreign mechanical impurities and have a final acidity index of 6.6. The volume of the resulting concentrate is 11 ml, the content of brentuximab vedotin is 5 mg in 1 ml.
If a visual examination of the reconstituted solution reveals a color change and / or structural damage, the solution must be destroyed.
To prepare a solution for intravenous administration, you can use 0.9% sodium chloride solution, 5% glucose solution for injection, or Ringer's lactate solution for injection. The required dose of the concentrate is taken from the vial (or vials) and added to an infusion bag with a minimum volume of 100 ml of 0.9% sodium chloride solution for injection (or another solution approved for use). Its amount should correspond to the volume required to obtain the concentration of Adcetris, corresponding to 0.4-1.8 mg / ml. To stir the solution, gently turn the bag over without shaking.
The duration of the infusion is 0.5 hours, the frequency of procedures is 1 time in 21 days.
Recommended dosage: at the rate of 1.8 mg per 1 kg of patient weight. If the patient's weight exceeds 100 kg, then the weight value of 100 kg should be used for the calculation.
To calculate the total volume (ml) of Adcetris solution for infusion, the recommended dose (1.8 mg / kg) must be multiplied by the patient's weight (kg) and divided by the concentration indicator of the solution reconstituted in the vial (5 mg / ml). To determine the required number of vials of the drug for one infusion, the received dose (ml) is divided by 10 ml (the total volume of one vial). Calculation example for a patient weighing 60 kg: 1.8 x 60: 5 = 21.6 ml (2.16 bottles). If a dose reduction is required, 1.2 mg / kg is used in the calculations.
The maximum recommended dose should not exceed 180 mg (36 ml, or 3.6 vials)
Do not mix the prepared infusion solution with other drugs or use the IV infusion system for their administration. It is recommended to flush the infusion set with 0.9% Sodium Chloride Injection or another approved solution.
Infusion should be started immediately after preparation of the solution.
The drug Adcetris does not contain preservatives, therefore the total time from the moment of dissolution to the end of the infusion should not exceed 24 hours at a temperature of 2-8 ° C.
Do not inject a solution of the drug in / in a jet or bolus! The procedure is performed using a separate IV catheter.
The use of Adcetris should be supervised by a physician with experience in anticancer therapy. CBC is recommended before each dose is administered. During and after the infusion, the patient should be under medical supervision.
In case of disease progression or unwanted toxicity, treatment should be discontinued.
Re-treatment of recurrent or refractory Hodgkin's lymphoma or systemic ALCL in patients who have responded to previous therapy with brentuximab vedotin can begin with the last tolerated dose of sludge from the total recommended.
The initial dose for patients with hepatic failure or severe renal failure is 1.2 mg per 1 kg of body weight. Patients should be under the strict supervision of a specialist.
Taking into account clinical indications, the duration of treatment can be:
- recurrent or refractory Hodgkin's lymphoma, systemic ALCL: minimum 8, but not more than 16 infusions. The number of procedures is determined by the doctor, taking into account the dynamics of the disease or the degree of achievement of a stable state;
- Hodgkin's lymphoma in patients with an increased risk of relapse or disease progression after autologous stem cell transplantation: up to 16 courses of therapy. Infusions should be initiated based on a clinical assessment of recovery from autologous stem cell transplantation.
If the results of the analysis before the next infusion indicate the presence of neutropenia of the first or second degree on the CTCAE toxicity scale (General terminology for the criteria for adverse events of the National Cancer Institute), then the treatment is continued at the same dose and according to the same scheme. If the patient has a third or fourth degree of neutropenia, treatment is stopped. During this period, it is possible to additionally prescribe to the patient recombinant hematopoietic factors G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor). After the severity of neutropenia returns to the initial level or the second degree and below, treatment is resumed at the same dose and according to the same scheme. To control neutropenia, it is recommended to increase the interval between doses.
With the development of lymphopenia of the third and fourth degrees of severity, treatment can be continued without changes.
Recommended dosage for patients with newly diagnosed or advanced sensory or motor neuropathy, taking into account the severity of the complication:
- grade 1 (loss of reflexes and / or paresthesia, without loss of functionality): treatment is continued at the same dose according to the same scheme;
- Grade 2 (functional impairment that does not have an obvious effect on daily activities) and Grade 3 (daily activity is difficult): Treatment is stopped. After returning to the initial level or the first degree of severity of neuropathy, treatment is resumed using a dose of 1.2 mg per 1 kg of patient weight every 21 days;
- grade 4 (sensory neuropathy resulting in disability or motor neuropathy that is life-threatening or paralyzed): Treatment with the drug must be discontinued.
Side effects
- from the hematopoietic system: very often - neutropenia; often - thrombocytopenia, anemia; frequency not established - febrile neutropenia;
- infectious and parasitic diseases: very often - upper respiratory tract infections; often - herpes simplex, herpes zoster, sepsis or septic shock, pneumonia; infrequently - staphylococcal bacteremia, candidal stomatitis, pneumocystis pneumonia; frequency not established - progressive multifocal leukoencephalopathy;
- on the part of the immune system: the frequency has not been established - anaphylactic reaction;
- from the nervous system: very often - peripheral motor neuropathy, peripheral sensory neuropathy; often - dizziness, demyelinating polyneuropathy;
- from the musculoskeletal system: very often - arthralgia, myalgia; often - back pain;
- from the side of metabolism: often - hyperglycemia; infrequently - tumor lysis syndrome;
- from the respiratory system: very often - shortness of breath, cough; the frequency has not been established - interstitial lung disease, pneumonitis, acute respiratory distress syndrome in adults (including those with a fatal outcome);
- from the digestive system: very often - nausea, vomiting, pain in the abdomen, diarrhea, constipation; infrequently - acute pancreatitis; frequency not established - enterocolitis, intestinal obstruction, erosion, ulcer, perforation, neutropenic colitis, bleeding (including fatal);
- from the hepatobiliary system: often - an increase in the activity of alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST); the frequency has not been established - hepatotoxicity (including fatal);
- dermatological reactions: very often - itching, alopecia; often a rash; infrequently - toxic epidermal necrolysis, Stevens-Johnson syndrome;
- general reactions: very often - increased fatigue, fever, chills, infusion reactions (including headache, nausea, vomiting, rash, back pain, itching and coughing, shortness of breath);
- laboratory and instrumental disorders: very often - a decrease in body weight.
Overdose
Symptoms: neutropenia and other adverse reactions.
Treatment: there is no specific antidote. Appointment of symptomatic therapy, careful monitoring of the patient's condition for the timely detection of symptoms of adverse reactions, including neutropenia.
special instructions
Treatment with Adcetris should be accompanied by strict monitoring of the patient's condition in order to identify emerging or worsening signs of behavioral, neurological or cognitive impairment. This is due to the reports in the results of clinical trials that reactivation of the JC virus (John Cunningham virus) may occur against the background of the use of brentuximab vedotin. In patients who have undergone several previous chemotherapy regimens, reactivation of the latent JC virus can lead to the development of a rare demyelinating disease of the central nervous system - PML (progressive multifocal leukoencephalopathy) syndrome, which is often fatal. Therefore, if PML is suspected, drug treatment should be suspended and measures taken to diagnose the detected symptoms. For symptoms of the presence of the JC virus, PML is determined according to a scheme that provides for a consultation with a neurologist, magnetic resonance imaging of the brain with gadolinium-based contrast, brain biopsy or analysis of cerebrospinal fluid for the presence of deoxyribonucleic acid of the JC virus by PCR (polymerase chain reaction) diagnostics. If it was not possible to establish an alternative diagnosis, there is every reason for further observation due to the fact that a negative PCR result does not exclude PML. If the diagnosis of PML is confirmed, treatment should be stopped immediately.a brain biopsy or analysis of cerebrospinal fluid for the presence of deoxyribonucleic acid of the JC virus by PCR (polymerase chain reaction) diagnostics. If it was not possible to establish an alternative diagnosis, there is every reason for further observation due to the fact that a negative PCR result does not exclude PML. If the diagnosis of PML is confirmed, treatment should be stopped immediately.a brain biopsy or analysis of cerebrospinal fluid for the presence of deoxyribonucleic acid of the JC virus by PCR (polymerase chain reaction) diagnostics. If it was not possible to establish an alternative diagnosis, there is every reason for further observation due to the fact that a negative PCR result does not exclude PML. If the diagnosis of PML is confirmed, treatment should be stopped immediately.
The doctor should inform the patient about the possibility of developing adverse reactions and the need to immediately report them to the doctor.
There is a risk of developing acute pancreatitis (including fatal cases), therefore it is recommended to carefully monitor the patient for new-onset or worsening abdominal pain, which may be a sign of acute pancreatitis. Treatment should be suspended in case of suspicion of acute pancreatitis for the period of the examination and completely stopped when the diagnosis is confirmed.
In case of development of toxic epidermal necrolysis or Stevens-Johnson syndrome, the use of Adcetris should be canceled.
Although the relationship of pulmonary toxicity with the use of brentuximab vedotin has not been confirmed, it is nevertheless recommended that when a patient develops cough, dyspnoea and aggravation of other pulmonary symptoms, their appropriate diagnostic assessment should be carried out. The question of the advisability of continuing antitumor therapy until symptomatic improvement of the condition is decided individually.
During the period of treatment with brentuximab vedotin, patients have an increased risk of developing severe forms of pneumonia, staphylococcal bacteremia, shingles, candidal stomatitis, and sepsis. For the timely diagnosis of possible severe and opportunistic infections, patients must be under strict supervision during the treatment period.
The development of anaphylactic reaction against the background of the administration of Adcetris is the basis for the complete cancellation of therapy with brentuximab vedotin.
To prevent the development of infusion reactions, premedication with paracetamol, antihistamines or corticosteroids is necessary.
The risk of developing tumor lysis syndrome is increased in patients with a large tumor mass and rapidly proliferating tumor. In this regard, the treatment regimen for these patients, in addition to concomitant symptomatic therapy, should include optimal methods of medical practice: control of renal function, antihyperuricemic therapy, active fluid replacement in the body, correction of electrolyte imbalance.
If complications from the gastrointestinal tract appear after a diagnostic examination, it is necessary to begin adequate therapy.
Before starting therapy, liver function should be assessed and its condition should be regularly monitored during the entire period of therapy. Patients with a history of liver disease, concomitant pathologies, or the concomitant use of other drugs are at increased risk of developing hepatotoxicity. If there are signs of hepatotoxicity, therapy should be postponed, the dose of brentuximab vedotin should be changed, or therapy should be discontinued.
Treatment with the drug should be accompanied by regular monitoring of serum glucose levels, regardless of history. An increased body weight index increases the risk of developing hyperglycemia in patients with a history of diabetes mellitus or no diabetes.
It should be borne in mind that the sodium content in one dose is 47 mg.
Dispose of unused product residues and medical waste in accordance with national regulations.
Influence on the ability to drive vehicles and complex mechanisms
Due to the possible development of undesirable phenomena against the background of the use of Adcetris, caution should be exercised when performing potentially hazardous activities, including driving.
Application during pregnancy and lactation
The use of Adcetris is contraindicated during gestation and breastfeeding.
Men and women of reproductive age who are treated with brentuximab with vedotin need to use two methods of effective contraception both during the period of its use and within six months after the last dose of Adcetris. The patient should be informed about the potential threat to the fetus in case of conception during treatment.
The effect of brentuximab vedotin on human spermatogenesis has not been established. Against the background of the use of Adcetris, there is a risk of developing testicular toxicity, which can cause a change in male fertility. Due to the aneogenous effects of MMAE, it is recommended to deposit semen samples prior to treatment. Conception of a child should not be planned for men undergoing treatment with brentuximab vedotin.
Pediatric use
The use of Adcetris is contraindicated for the treatment of patients under the age of 18 years.
With impaired renal function
Adcetris should be used with caution in patients with severe renal impairment.
The recommended dosage for renal failure is: the initial dose for intravenous infusions - at the rate of 1.2 mg per 1 kg of patient weight, the duration of the infusion is 0.5 hours. The frequency of procedures is 1 time in 21 days. Patients must be under strict medical supervision.
For violations of liver function
Adcetris should be used with caution in case of liver dysfunction.
Recommended dosage for hepatic insufficiency: initial dose - at the rate of 1.2 mg per 1 kg of patient weight in the form of intravenous infusion lasting 0.5 hours. Frequency rate of procedures - once every 21 days. Patients must be under strict medical supervision.
Use in the elderly
There is no data on the safety and efficacy of Adcetris for the treatment of patients aged 65 years and older.
Drug interactions
With the simultaneous use of Adcetris:
- ketoconazole causes an increase in the level of the antimicrotubulin substance MMAE by about 73% without altering the plasma concentration of brentuximab vedotin. Thus, the joint administration of the drug with powerful inhibitors of CYP3A4 and P-glycoprotein increases the incidence of neutropenia. In this case, an appropriate correction of the dosage regimen is required;
- rifampicin, being a potent inducer of CYP3A4, does not affect the plasma concentration of brentuximab vedotin. Pharmacokinetic data are limited, therefore, it is assumed that the combination with rifampicin lowers the plasma levels of those MMAE metabolites that are measurable;
- midazolam (a CYP3A4 substrate) does not interact with brentuximab vedotin, therefore, the latter does not adversely affect the metabolism of midazolam.
Analogs
Analogs of Adcetris are: Mabthera, Reditux, Rituxim, Avastin, Vektibiks, Herceptin, Kadsila, Trastuzumab, Erbitux.
Terms and conditions of storage
Keep out of the reach of children.
Store and transport at a temperature of 2–8 ° C in a dark place, do not freeze.
Shelf life is 4 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Adcetris
The few reviews about Adcetris are mostly positive. Nevertheless, there are often comments on the forums about the difficulties associated with finding funds to purchase it. For many, treatment with brentuximab vedotin is the last chance for recovery, when other therapies for recurrent Hodgkin's lymphoma are no longer effective, and they are trying to take advantage of this chance. There are reports that after 3-4 infusions there were side effects that require postponing the date of the next procedure.
The price of Adcetris in pharmacies
The price for Adcetris for a package containing 1 bottle of the drug can range from 227,990 rubles.
Anna Kozlova Medical journalist About the author
Education: Rostov State Medical University, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
