ADCETRIS POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION 50MG/VIAL

Product Information

Registration Status: Active

ADCETRIS POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION 50MG/VIAL is approved to be sold in Singapore with effective from 2014-08-01. It is marketed by TAKEDA PHARMACEUTICALS (ASIA PACIFIC) PTE LTD, with the registration number of SIN14477P.

This product contains Brentuximab Vedotin 50mg/vial in the form of INJECTION, POWDER, FOR SOLUTION. It is approved for INTRAVENOUS DRIP use.

This product is manufactured by BSP PHARMACEUTICALS S.P.A in ITALY, andPIERRE FABRE MEDICAMENT PRODUCTION in FRANCE.

It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Brentuximab Vedotin

Description

Brentuximab vedotin, also known as Adcetris®, is an antibody-drug conjugate that combines an anti-CD30 antibody with the drug monomethyl auristatin E (MMAE). It is an anti-neoplastic agent used in the treatment of Hodgkin's lymphoma and systemic anaplastic large cell lymphoma. Brentuximab vedotin was initially approved in 2011. In January 2012, the drug label was revised with a boxed warning of a condition known as progressive multifocal leukoencephalopathy and death due to opportunistic JC virus infection post treatment [L1737]. The U.S. Food and Drug Administration approved Adcetris in March 2018 to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy [L1737]. Adcetris has also been previously approved by the FDA to treat Hodgkin's lymphoma after relapse, Hodgkin's lymphoma after stem cell transplantation when a patient has a high risk of relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after the failure of other treatment regimens, and primary cutaneous ALCL after failure of other treatment regimens [L1737]. Lymphoma is a malignancy that begins in the lymphatic system, which helps to combat infection and disease. Lymphoma may begin anywhere in the body and can spread to nearby lymph nodes. The two main types of lymphoma are Hodgkin lymphoma (also called Hodgkin disease) and non-Hodgkin lymphoma. Most individuals with Hodgkin's lymphoma have the classical type. In this type of lymphoma, large, abnormal lymphocytes (a type of white blood cell) are found in the lymph nodes called Reed-Sternberg cells. With early diagnosis and intervention, patients with Hodgkin lymphoma normally experience long-term remission [L1737]. The ECHELON-1 study results demonstrated superior efficacy of the drug combined with a chemotherapy regimen when it is compared to the previous standard of care. Importantly, removing the drug bleomycin, a highly toxic agent, was completely removed from the regimen. This demonstrates meaningful progress in treatment for patients affected by this disease [L1739].

Indication

Seattle Genetics Announced FDA Approval of ADCETRIS® (Brentuximab Vedotin) in combination with chemotherapy for adults with previously untreated stage III or IV Classical Hodgkin Lymphoma in March 2018 [L1737, L1739]. Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates [FDA label], [L1737]. Systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen [FDA label].

Mechanism of Action

Brentuximab vedotin is composed of 3 parts: a chimeric human-murine IgG1 that selectively targets CD30, monomethyl auristatin E (MMAE), which is a microtubule-disrupting agent, and a protease-susceptible linker that links the antibody and MMAE. The IgG1 antibody enables Brentuximab vedotin to target tumor cells expressing CD30 on their surface. Following this Brentuximab vedotin enters the cell. Once inside, the linker is cleaved releasing MMAE which binds disrupts the microtubule network [FDA label]. The antibody component of this drug is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting particle. MMAE is covalently attached to the antibody by a linker. Data suggest that the anticancer activity of Adcertris is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the subsequent release of MMAE by proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptotis of the malignant cells [FDA label].

Pharmacokinetics

Absorption
Steady-state of the ADC is achieved within 21 days with every 3-week dosing of Adcetris. Minimal to no accumulation of ADC is observed with multiple doses at the every 3-week schedule. The time to maximum concentration for MMAE ranges from approximately 1 to 3 days. Similar to the ADC, steady-state of MMAE is achieved within 21 days with every 3-week dosing of Adcetris. MMAE exposures decrease with continued administration of Adcetris with about 50% to 80% of the exposure of the first dose being observed at future doses. The AUC of MMAE was measured to be approximately 2.2-fold higher in patients with hepatic impairment in comparison with patients with normal hepatic function [FDA label].
Distribution
MMAE is unlikely to displace or to be displaced by highly protein-bound drugs. In vitro studies show that MMAE is a substrate of P-gp and was not a potent inhibitor of P-gp [FDA label].
Metabolism
Data in both animals and humans suggest that only a small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5. In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP isoforms. MMAE did not induce any major CYP450 enzymes in primary cultures of human hepatocytes [FDA LABEL].
Elimination

Clearance

The liver is the primary route of clearance for MMAE. The pharmacokinetics and safety of Brentuximab vedotin and MMAE were examined after the administration of 1.2 mg/kg of Adcetris to patients with mild, moderate, and severe hepatic impairment. In patients with moderate and severe hepatic impairment, the rate of ≥Grade 3 adverse reactions was 6/6 (100%) compared to 3/8 (38%) in patients with normal hepatic function [FDA label]. It is recommended to avoid use in patients with severe renal impairment (CrCl <30mL/min) [L1742].

Toxicity

The most severe toxic reaction seen in patients is progressive multifocal leukoencephalopathy [FDA label]. Progressive multifocal leukoencephalopathy (PML) follows infection by the JC virus (which is not related to Creutzfeldt-Jakob disease). Symptoms of this condition begin insidiously and usually worsen progressively. The symptoms vary depending on which region of the brain is infected. In about two out of three patients, mental function deteriorates rapidly, leading to dementia. Speaking and walking may become increasingly difficult. Vision may be impaired, and total blindness may occur. Rarely, headaches and seizures can occur, mainly in immunocompromised patients. The most serious sequela of this condition is death [L1743]. Common adverse effects of Adcetris may include: neutropenia, anemia, peripheral neuropathy, nausea, fatigue, constipation, diarrhea, vomiting, and fever. In one trial, neutropenia occurred in 91 percent of patients treated with Adcetris plus chemotherapy, which was associated with a 19 percent rate of febrile neutropenia (neutropenia and fever) [L1737]. Preventive treatment with G-CSF, a growth factor for the bone marrow to produce white blood cells, is recommended with Adcetris plus chemotherapy for the first-line treatment of Stage III or IV cHL [L1737]. Adcetris has a boxed warning that emphasizes the risk of John Cunningham virus infection leading to progressive multifocal leukoencephalopathy, or PML, a rare but serious brain infection that may be lethal. Serious risks of Adcetris include peripheral neuropathy; severe allergic (anaphylaxis) or infusion-site reactions; damage to the blood, lungs and liver (hematologic, pulmonary and hepato-toxicities); severe/opportunistic infections; metabolic abnormalities (tumor lysis syndrome); dermatologic reactions and gastrointestinal complications. Adcetris may cause harm to the fetus and newborn baby; women should be warned of the potential risk to the fetus and to use effective contraception, and to avoid breastfeeding while taking Adcetris [L1737]. MMAE was found to be genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting drug. Fertility studies with Brentuximab vedotin or MMAE have not been conducted. Despite this, results of repeat-dose toxicity studies in rats suggest the potential for Brentuximab vedotin to have a negative effect on male reproductive function and fertility. In a 4-week repeated-dose toxicity study in rats with weekly dosing at 0.5, 5 or 10 mg/kg brentuximab vedotin, seminiferous tubule degeneration, Sertoli cell vacuolation, reduced spermatogenesis, and aspermia were observed [L1737]. Effects in animals were seen mostly at 5 and 10 mg/kg doses of brentuximab vedotin. These dosages are approximately 3 and 6-fold the human recommended dose of 1.8 mg/kg, respectively, based on individual body weight [FDA label].

Active Ingredient/Synonyms

cAC10-vcMMAE | Brentuximab vedotin |


Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.

References

  1. Health Science Authority of Singapore - Reclassified POM
  2. Drugbank