Center for Drug Evaluation and Research. More patients and longer follow-up from the ongoing phase I/II clinical study are needed to ascertain these potential advantages.
On October 31, 2017, the Food and Drug Administration granted accelerated approval to acalabrutinib (Calquence, AstraZeneca Pharmaceuticals Inc. under license of Acerta Pharma BV) for treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.Approval was based on Study LY-004, an open-label, phase 2 trial (NCT02213926) enrolling 124 patients with MCL who received at least one prior therapy. BTK inhibitors block BCR-induced BTK activation and its downstream signaling, leading to growth inhibition and cell death in certain malignant white blood cells called B-cells. Médicament avec autorisation temporaire d'utilisation nominative, absence d'information référentielle sur cette spécialité. US Food and Drug Administration. Usual Adult Dose for Lymphoma 100 mg orally every 12 hours until disease progression or unacceptable toxicity Use: Treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy Usual Adult Dose for Leukemia Médicament avec autorisation temporaire d'utilisation nominative, absence d'information référentielle sur cette spécialité. Multiple trials … As of 2019, it was unclear whether it improved outcomes.
Médicament avec autorisation temporaire d'utilisation nominative, absence d'information référentielle sur cette spécialité.
Antineoplastic agent; small-molecule inhibitor of Bruton's tyrosine kinase (BTK).Treatment of mantle cell lymphoma in patients who have received at least one prior therapy;Current indication based on overall response rate; clinical benefit (e.g., increased survival) not established.In the principal efficacy trial (ACE-LY-004 trial), the investigator-assessed overall response rate was 81%; 40% of patients achieved a complete response.Acalabrutinib can potentially interact with drugs affecting gastric acidity, including antacids, histamine HObtain acalabrutinib through specialty pharmacies and distributors.Administer acalabrutinib capsules orally twice daily, approximately 12 hours apart, without regard to meals.If a dose is missed by >3 hours, skip that dose and take the next dose at the regularly scheduled time.If grade 3 or greater nonhematologic toxicity, grade 3 thrombocytopenia with bleeding, grade 4 thrombocytopenia, or grade 4 neutropenia lasting >7 days occurs, interrupt therapy.Dosage Modification after Recovery from Toxicity – (Starting Dosage = 100 mg twice daily)No special dosage recommendations; most patients in pivotal efficacy study were geriatric.Serious hemorrhagic events, including fatal cases, observed.Increased risk of hemorrhagic events with concomitant use of acalabrutinib and antiplatelet or anticoagulant therapies.Consider potential benefits and risks of withholding acalabrutinib therapy for 3–7 days prior to and following surgery.Serious and sometimes fatal infections, including bacterial, fungal, viral, or other opportunistic infections, observed.Most commonly reported grade 3 or 4 infection was pneumonia.Consider antimicrobial prophylactic therapy in patients at increased risk for opportunistic infections.Monitor for signs and symptoms of infection during therapy and treat as medically appropriate.Cytopenias, including neutropenia, anemia, and thrombocytopenia, reported.Second primary malignancies, including non-skin carcinomas, reported in 11% of acalabrutinib-treated patients.Monitor for development of atrial fibrillation and flutter and manage appropriately.If used during pregnancy, apprise of potential fetal hazard.Acalabrutinib and its active metabolite (ACP-5862) distribute into milk in animals.In clinical studies in patients with mantle cell lymphoma, approximately 65% of patients were ≥65 years of age and approximately 26% were ≥75 years of age.Mild or moderate hepatic impairment does not substantially alter pharmacokinetics.Not studied in patients with severe hepatic impairment.Mild to moderate renal impairment does not substantially alter pharmacokinetics of acalabrutinib; the drug is minimally excreted in urine.Not studied in patients with severe renal impairment or in patients with renal impairment undergoing dialysis.Principally metabolized by CYP3A and, to a minor extent, by glutathione conjugation and amide hydrolysis.Acalabrutinib is a weak inhibitor of CYP3A4/5, 2C8, and 2C9; does not inhibit CYP isoenzymes 1A2, 2B6, 2C19, and 2D6; and is a weak inducer of CYP isoenzymes 3A4, 1A2, and 2B6.Acalabrutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); not a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, and organic anion transport proteins (OATP) 1B1 and OATP1B3.Possible pharmacokinetic interaction (increased plasma acalabrutinib concentrations and risk of toxicity).Possible pharmacokinetic interaction (decreased plasma acalabrutinib concentrations and reduced efficacy).Avoid concomitant use with potent CYP3A inducers, if possible; if concomitant use cannot be avoided, increase acalabrutinib dosage to 200 mg twice daily.Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely at clinically relevant concentrations.Possible pharmacokinetic interaction (increased exposure to BCRP substrates due to inhibition of intestinal BCRP).Potential pharmacokinetic interaction (decreased solubility of acalabrutinib may result in decreased plasma concentrations and reduced efficacy) with drugs that increase gastric pH.Possible decreased plasma concentrations and reduced efficacy of acalabrutinibCalcium carbonate: Decreased acalabrutinib AUC by 53%Antacids may be used as an alternative to proton-pump inhibitors; if concurrent use is necessary, separate antacid and acalabrutinib doses by ≥2 hoursPossibly decreased plasma concentrations and reduced efficacy of acalabrutinibAvoid concomitant use; if concomitant use unavoidable, increase acalabrutinib dosage to 200 mg twice dailyAntifungals, azole (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)Possibly increased peak plasma concentrations and systemic exposure of acalabrutinibItraconazole: Increased acalabrutinib peak plasma concentrations and AUC by 3.9- and 5.1-fold, respectivelyPotent CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole): Avoid concomitant use; if concomitant use of the antifungal is short term (≤7 days), withhold acalabrutinib therapy during administration of the antifungalModerate CYP3A inhibitors (e.g., fluconazole): Reduce acalabrutinib dosage to 100 mg once dailyPossible decreased plasma concentrations and reduced efficacy of acalabrutinibRifampin: Decreased acalabrutinib peak plasma concentration and AUC by 68 and 77%, respectivelyAvoid concomitant use; if concomitant use unavoidable, increase acalabrutinib dosage to 200 mg twice dailyPossibly increased peak plasma concentrations and systemic exposure of acalabrutinibPossible decreased plasma concentrations and reduced efficacy of acalabrutinibPossibly increased peak plasma concentrations and systemic exposure of acalabrutinibErythromycin: Expected to increase peak plasma concentration and systemic exposure of acalabrutinib by twofold to almost threefoldPotent CYP3A inhibitors (e.g., clarithromycin): Avoid concomitant use; if concomitant use of the macrolide is short term (≤7 days), withhold acalabrutinib therapy during administration of the macrolideModerate CYP3A inhibitors (e.g., erythromycin): Reduce acalabrutinib dosage to 100 mg once dailyPossible increased exposure to methotrexate (a BCRP substrate)Possible decreased plasma concentrations and efficacy of acalabrutinibExhibits almost linear pharmacokinetics over a dosage range of 75–250 mg and dose proportionality.Median steady-state binding of acalabrutinib to BTK (BTK occupancy) of ≥95% is maintained over a 12-hour dosing interval.High-fat, high-calorie meal did not substantially alter AUC; peak plasma concentrations decreased by 73% and time to achieve peak concentrations delayed by 1–2 hours compared with administration under fasting conditions.Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: In a hepatic impairment study, exposure increased by less than twofold.Severe hepatic impairment (Child-Pugh class C or total bilirubin concentrations 3–10 times the ULN with any AST concentration): Not studied.Mild or moderate renal impairment (estimated GFR ≥30 mL/minute per 1.73 mSevere renal impairment (estimated GFR <29 mL/minute per 1.73 mAge, body weight, gender, and race do not have clinically important effects on pharmacokinetics.Acalabrutinib and its active metabolite ACP-5862 distribute into milk in animals; not known whether the drug and/or its active metabolite distributes into human milk.Metabolized principally by CYP3A and, to a minor extent, by glutathione conjugation and amide hydrolysis.Eliminated in feces (84%) and urine (12%), mainly as metabolites; <1% excreted as unchanged drug.Acalabrutinib: Median of 0.9 hours (range: 0.6–2.8 hours).Selectively and irreversibly inhibits BTK, an essential signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways.Acalabrutinib and its active metabolite (ACP-5862) bind covalently with a cysteine residue in the BTK active site resulting in inhibition of BTK enzymatic activity.Within B cells, BTK signaling results in activation of pathways involved in cell proliferation, trafficking, chemotaxis, and adhesion.Inhibition of BTK also reduces plasma concentrations of cytokines and chemokines, which may lead to decreased cell adhesion and mobilization of cells from tissues.Unlike ibrutinib (another BTK inhibitor used to treat mantle cell lymphoma), acalabrutinib does not appear to irreversibly target kinases other than BTK, including epidermal growth factor receptor (EGFR), tyrosine kinase expressed in hepatocellular carcinoma (TEC), and interleukin 2-inducible T-cell kinase (ITK).Importance of instructing patients to read the manufacturer's patient information.Importance of advising patients to take acalabrutinib as directed by their clinician.Importance of advising patients to swallow acalabrutinib capsules whole with a glass of water and not to open, break, or chew the capsules.Possible risk of developing a second primary malignancy (e.g., skin cancer).Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.Importance of advising women to avoid breast-feeding while receiving acalabrutinib and for ≥2 weeks after discontinuance of therapy.Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., anticoagulant or antiplatelet drugs, antacids, histamine HImportance of informing patients of other important precautionary information.2.
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