Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
Carfilzomib is an antineoplastic agent belonging to the pharmacological class of proteasome inhibitors.
Carfilzomib is approved by the FDA for the treatment of relapsed or refractory multiple myeloma.
Carfilzomib is absorbed quickly and entirely throughout the systemic circulation when administered intravenously. It rapidly undergoes metabolism, mainly through peptidase cleavage and epoxide hydrolysis, and enters all tissues except the brain. It is primarily excreted through Urine.
The most common side effects of Carfilzomib include nausea, fatigue, and fever.
Carfilzomib is available as a powder for injection.
The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.
Carfilzomib is an antineoplastic agent belonging to the pharmacological class of proteasome inhibitors.
Carfilzomib is composed of four rearranged peptides. Carfilzomib selectively and irreversibly binds to the 20S proteasome's N-terminal threonine-containing active sites, the proteolytic core particle comprising the 26S proteasome. The three catalytic active sites in this 20S core are trypsin, chymotrypsin, and caspase-like sites. Carfilzomib (β5 and β5i subunits) is the most effective target for inhibiting the chymotrypsin-like site, ultimately leading to cell cycle arrest and apoptosis of cancerous cells. Carfilzomib inhibits the trypsin and caspase-like sites at higher doses.
Carfilzomib attains peak plasma concentration at 4232 ng/mL (27 mg/m²) and 2079 ng/mL (56 mg/m²).
AUC of Carfilzomib is 379 ng·hr/mL (27 mg/m²) and 948 ng•hr/mL (56 mg/m²).
Carfilzomib is available as a powder for injection.
Powder for injection: To use Carfilzomib powder for injection, it should be reconstituted and then further diluted before administration.
- Indicated for those adults with relapsed or refractory multiple myeloma who have undergone 1-3 prior lines of therapy, either in combination with dexamethasone, lenalidomide plus dexamethasone, or daratumumab plus dexamethasone.
- As a single agent, it is indicated for relapsed or refractory multiple myeloma in the adults who received ≥1 line.
- Hypersensitivity to Carfilzomib or any of the excipients.
- Concomitant use with melphalan and prednisone.
- Cardiac Toxicities: It is advised to monitor for signs of cardiac failure or ischemia vigilantly. Promptly withhold Kyprolis and conduct a thorough evaluation.
- Serum creatinine levels are regularly monitored to detect potential acute renal failure.
- Tumor Lysis Syndrome (TLS): Administer pre-treatment hydration and monitor for TLS. Assess uric acid levels and initiate prompt treatment.
- Pulmonary Toxicity: Acute Respiratory Distress Syndrome, Acute Respiratory Failure, and Acute Diffuse Infiltrative Pulmonary Disease. Promptly withhold Kyprolis and conduct an immediate evaluation.
- Pulmonary Hypertension: Stop Carfilzomib and conduct a thorough evaluation. For severe dyspnea, suspend Carfilzomib and assess promptly.
- Hypertension: Regularly monitor blood pressure. If hypertension is uncontrollable, interrupt Carfilzomib treatment.
- Venous Thrombosis: Thromboprophylaxis is recommended to minimize the risk of venous thrombosis.
- Infusion Reactions: Administer premedication with dexamethasone to mitigate infusion reactions.
- Hemorrhage: Monitor for signs of bleeding, including gastrointestinal, pulmonary, and intracranial. Evaluate promptly if symptoms arise.
- Thrombocytopenia: Monitor platelet counts regularly and adjust Carfilzomib dosing as clinically indicated.
- Hepatic Toxicity and Hepatic Failure: Regularly monitor liver enzymes. Discontinue Carfilzomib if hepatic issues are suspected.
- Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Carfilzomib if thrombotic microangiopathy is suspected.
- Posterior Reversible Encephalopathy Syndrome (PRES): Neuro-radiological imaging should be considered for the onset of visual or neurological symptoms. Discontinue Carfilzomib if PRES is suspected.
- Embryo-Fetal Toxicity: Carfilzomib can cause fetal harm. Females of reproductive potential should avoid getting pregnant during the treatment.
Alcohol Warning
Breast Feeding Warning
Pregnancy Warning
Food Warning
The adverse reactions related to Carfilzomib can be categorized as:
- Common Adverse Effects: Fatigue, anaemia, nausea, thrombocytopenia, dyspnea, and diarrhoea.
- Less Common Adverse Effects: Pneumonia, acute renal failure, pyrexia, congestive heart failure.
- Rare Adverse Effects: Cardiac toxicities, haemorrhage, acute renal failure, and tumour lysis syndrome (TLS)
Reports on Postmarketing
Gastrointestinal bleeding
Lung infection
Rhinitis
Intracranial hemorrhage
Influenza-like fever
Bronchopneumonia
Sepsis
Gastroenteritis
Malaise
Cold
Nasopharyngitis.
An infection of the urinary tract
Viral infections,
Disorders of the ears and labyrinth: hearing loss, tinnitus
Clostridium difficile colitis and influenza are instances of infections and infestations.
Infection with the cytomegalovirus (viremia, enterocolitis, pneumonitis, and chorioretinitis)
Hemolytic uremic syndrome (HUS)
Gastrointestinal perforation
Reactivation of the Hepatitis B virus
Acute pancreatitis
Progressive multifocal leukoencephalopathy (PML)
Pancreatitis in acute form
The clinically relevant drug interactions of Carfilzomib are briefly summarized here.
- Drug-Drug Interactions: Carfilzomib may interact with immunomodulatory drugs (fingolimod, baricitinib), monoclonal antibodies (adalimumab), vaccines (BCG, Denue), antipsychotic drugs (clozapine), and anabolic steroids (methyltestosterone).
- Drug-Food Interactions: Abstain from alcoholic drinks.
- Drug-Disease Interactions: Carfilzomib may interact with several medical conditions, such as heart disease, pulmonary impairment, bleeding disorders, low or high blood pressure, renal or hepatic impairment, and infections (bacterial, fungal, protozoal, or viral).
The common side effects of Carfilzomib include:
dizziness,
lightheadedness,
nausea,
vomiting,
diarrhoea,
constipation,
tiredness,
anaemia (low number of red blood cells),
fever
- Pregnancy
Pregnancy Category D (FDA): Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.
Based on findings from studies on animals and the drug's mode of action, it may be harmful to fetuses.
Before starting treatment, test for pregnancy in potentially fertile females.
It should be recommended to fertile women to refrain from getting pregnant while undergoing treatment.
During treatment, fertile males should be counselled not to father a child.
There is no data on how drugs affect human fertility. However, therapy may affect either male or female fertility depending on its mode of action.
Animal data
When given intraperitoneally to pregnant rats and rabbits during the organogenesis phase, Carfilzomib at 2 mg/kg/day in rats and 0.8 mg/kg/day in rabbits did not cause teratogenic side effects.
The drug was found to be lethal to the embryos when given to rabbits at doses lower than the clinical dose; at 0.4 mg/kg/day in rabbits, there was an increase in pre-implantation loss, and at 0.8 mg/kg/day in rabbits, there was an increase in early resorptions, post implantation loss, and a decrease in fetal weight. The doses of 0.4 and 0.8 mg/kg/day in all rabbits are about 20% and 40%, respectively, of the dose recommended for humans, which is 27 mg/m2 based on body surface area.
Contraception
Advise women who are fertile to use contraception both during treatment and for six months after the last dose; if the patient becomes pregnant while receiving treatment or if the drug is used during pregnancy, the patient should be informed of the possible risks to the fetus.
Advise male patients who have female partners to avoid getting pregnant during treatment and for at least 90 days after therapy ends by using effective contraceptive methods or refraining from sexual activity.
- Nursing Mothers
Nursing women are advised not to breastfeed during the treatment and for two weeks following treatment because many drugs are excreted in human milk, and there is uncertainty about the possibility of severe adverse reactions in breastfed children. There is no data on the presence of drugs in human milk, their effects on breastfed children, or their production of milk.
- Pediatric Use
As per FDA, the safety and effectiveness of Carfilzomib in the pediatric patients have not been established.
Dose Adjustment in Kidney Impairment Patients:
Mild to severe, or patients on chronic hemodialysis: No starting dose adjustment required.
Patients with end-stage renal disease (ESRD) who are on dialysis: Administer the dose only after the hemodialysis procedure.
Dose Adjustment in Hepatic Impairment Patients:
Mild to moderate (bilirubin >1 to 3x ULN): Lower the dose by 25%
Severe: Not evaluated; No dose recommendation
The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage Carfilzomib.
Signs and Symptoms
Overconsumption of Carfilzomib could lead to acute onset of chills, hypotension, thrombocytopenia, renal insufficiency, and lymphopenia.
Management
There is no specific antidote for Carfilzomib. In the event of an overdose, cease taking the tablets of Carfilzomib acetate, monitor for arrhythmias and cardiac failure, and evaluate liver function, among other general supportive measures.
Pharmacodynamic
When measured in blood an hour after the initial dose, intravenous carfilzomib administration suppressed proteasome chymotrypsin-like (CT-L) activity. Protease CT-L activity was ≥80% inhibited by doses of Carfilzomib≥ 15 mg/m2, with or without lenalidomide and dexamethasone. Moreover, the proteasome's low molecular mass polypeptide 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits showed mean inhibitions ranging from 26% to 32% and 41% to 49%, respectively, when Carfilzomib was administered intravenously at a dose of 20 mg/m2. For every week of dosing, proteasome inhibition persisted for at least 48 hours after the first carfilzomib dosage.
Pharmacokinetics
- Absorption: Carfilzomib enters the systemic circulation wholly and quickly when given intravenously.
- Distribution: It penetrates all tissue except the brain extensively. There is a high degree of binding (97%) to plasma proteins in the distribution volume, about 28 litres.
- Metabolism: Peptidase cleavage and epoxide hydrolysis are the primary metabolic processes Carfilzomib goes through quickly and thoroughly. Its metabolism is mainly unaffected by CYP450-mediated processes.
- Excretion: Most drug elimination occurs through Urine, with less than 1% of the drug remaining unchanged and about 25% excreted as metabolites. Less than 1% of the unchanged drug is excreted in the faeces. For doses equal to or greater than 15 mg/m², the elimination half-life is short, lasting no more than one hour.
- Groen K, van de Donk N, Stege C, Zweegman S, Nijhof IS. Carfilzomib for relapsed and refractory multiple myeloma. Cancer Manag Res. 2019 Apr 2;11:2663-2675. doi: 10.2147/CMAR.S150653. PMID: 31037034; PMCID: PMC6450182.
- Ziogas DC, Terpos E, Kastritis E, Dimopoulos MA. An overview of the role of carfilzomib in the treatment of multiple myeloma. Expert Opin Pharmacother. 2017 Dec;18(17):1883-1897. doi: 10.1080/14656566.2017.1404575. Epub 2017 Nov 20. PMID: 29134824.
- Mushtaq A, Kapoor V, Latif A, Iftikhar A, Zahid U, McBride A, Abraham I, Riaz IB, Anwer F. Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review. Crit Rev Oncol Hematol. 2018 May;125:1-11. doi: 10.1016/j.critrevonc.2018.02.008. Epub 2018 Mar 2. PMID: 29650268; PMCID: PMC5901887.
- Raedler LA. Kyprolis (Carfilzomib) Received New Indications as Combination Therapy for Use in Relapsed and/or Refractory Multiple Myeloma. Am Health Drug Benefits. 2016 Mar;9(Spec Feature):93-6. PMID: 27668053; PMCID: PMC5013842.
- US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Kyprolis® (carfilzomib)
- https://www.ema.europa.eu/en/documents/product-information/kyprolis-epar-product-information_en.pdf
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202714s025lbl.pdf
- https://pubmed.ncbi.nlm.nih.gov/23393020/
