lunes, 21 de agosto de 2017

FDA Medication Guides

Drug Safety and Availability > Medication Guides
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has been updated to include the following:

FDA is carefully evaluating prescription opioid medications approved to treat cough in children- Drug Information Update

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The Division of Drug Information (DDI)- serving the public by providing information on human drug products and drug product regulation by FDA.

FDA today announced an upcoming meeting of the Pediatric Advisory Committee that will focus on the use of prescription opioid products containing hydrocodone or codeine for the treatment of cough in pediatric patients, including current treatment practices and benefit-risk considerations. The panel of independent experts will provide valuable input to help inform the agency’s decision-making processes related to these medications.
It is vital we understand the potential complications that can occur when using opioid-containing medications in children, even according to labeled instructions. This is an area that the agency is continuing to evaluate. As part of these efforts, the FDA announced required changes in April 2017 to the labeling of prescription codeine products in order to help better protect children from serious risks associated with these opioid medications, including life-threatening respiratory depression and death. Those changes include adding a contraindication to drug labels alerting that codeine should not be used for any reason, including treatment of cough, in children younger than 12 years. 
The FDA has also provided tips for consumers on how to safely treat a child’s cold as most young children do not need medicines to treat a cough or cold. Caregivers should read labels on non-prescription cough and cold products that may be sold over the counter as these products may contain codeine or may not be appropriate for young children. The FDA is also funding research to develop comprehensive, consumer-centered approaches on best practices for the safe use of pediatric cough and cold medications generally – not just those that contain an opioid.
For more information, please visit: Children’s Prescription Opioid Cough Medications.

Ibrutinib Approved for Graft-Versus-Host Disease - National Cancer Institute

Ibrutinib Approved for Graft-Versus-Host Disease - National Cancer Institute

National Cancer Institute

Ibrutinib Becomes First FDA-Approved Drug for Chronic Graft-Versus-Host Disease


August 11, 2017, by NCI Staff
erythema skin rash caused by graft-versus host disease
Skin changes caused by chronic graft-versus-host disease.
Credit: National Cancer Institute
A drug currently used to treat several forms of blood cancer, ibrutinib (Imbruvica®), has been approved by the Food and Drug Administration (FDA) for the treatment of chronic graft-versus-host disease (cGVHD). The agency’s decision, announced on August 2, makes ibrutinib the first approved therapy for this potentially fatal and common side effect of cancer-related stem cell transplants.
The approval covers the use of ibrutinib in patients with cGVHD that is not responding to other standard treatments, namely corticosteroids.
Ibrutinib is already approved by FDA for the treatment of several types of lymphoma and chronic lymphocytic leukemia. It works primarily by blocking the activity of a protein known as BTK, which is present in B cells and other types of immune cells.
GVHD occurs when transplanted immune cells attack healthy tissues. Chronic GVHD occurs when the condition arises or persists months after the transplant. GVHD can cause multiple, often debilitating symptoms, including widespread skin rashes, painful mouth ulcers, shortness of breath, and limb and joint pain.
The agency’s approval was based on a nonrandomized clinical trial in which nearly half of patients treated with ibrutinib had significant improvement in their GVHD-related symptoms for at least 5 months.
A January 2017 Cancer Currents post described details of the ibrutinib clinical trial and its potential impact on patient care.

Approved Drugs > FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL

Approved Drugs > FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL

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FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL

On Aug. 17, 2017, the U.S. Food and Drug Administration approved inotuzumab ozogamicin (BESPONSA, Wyeth Pharmaceuticals Inc., a subsidiary of Pfizer Inc.) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The approval was based on data from INO-VATE ALL (NCT01564784), a randomized (1:1), open label, international, multicenter study in 326 patients with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. Patients were required to have ≥5% bone marrow blasts and to have received one or two previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome positive B cell precursor ALL were required to have disease that failed treatment with at least one tyrosine kinase inhibitor and standard chemotherapy. 

Patients were randomized to receive inotuzumab ozogamicin (n=164) or investigator’s choice of chemotherapy (n=162). Of the initial 218 randomized patients, 35.8% of those who received inotuzumab ozogamicin experienced complete remission (CR) for a median 8.0 months and 89.7% of those patients achieved minimal residual disease (MRD)-negativity. Of the patients who received chemotherapy, 17.4% experienced CR for a median 4.9 months and 31.6% of those patients achieved minimal residual disease MRD-negativity. 

The most common adverse reactions occurring in greater than 20% of patients were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia. The most common (≥2%) adverse reactions reported as the reason for permanent discontinuation were infection, thrombocytopenia, hyperbilirubinemia, transaminases increased, and hemorrhage.
For the first cycle, the recommended dose of inotuzumab ozogamicin for all patients is 1.8 mg/m2 per cycle, administered as three divided doses on day 1 (0.8 mg/m2), day 8 (0.5 mg/m2), and day 15 (0.5 mg/m2). The recommended dosing for subsequent cycles depends on response to treatment. Details are available in the full prescribing information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761040s000lbl.pdf
FDA previously granted Orphan Drug and Breakthrough Therapy designations to inotuzumab ozogamicin for the treatment of ALL, as well as priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Follow the Oncology Center of Excellence on Twitter @FDAOncology.disclaimer icon
Check out recent approvals at the OCE’s new podcast, Drug Information Soundcast in Clinical Oncology (D.I.S.C.O.), available at www.fda.gov/DISCO.

Approved Drugs > FDA approves olaparib tablets for maintenance treatment in ovarian cancer

Approved Drugs > FDA approves olaparib tablets for maintenance treatment in ovarian cancer

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FDA approves olaparib tablets for maintenance treatment in ovarian cancer

On Aug. 17, 2017, the U.S. Food and Drug Administration granted regular approval to olaparib tablets (Lynparza, AstraZeneca) for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
With the addition of the new indication, a tablet formulation of olaparib is introduced. FDA approved olaparib capsules in 2014 for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Today, FDA also approved olaparib tablets for this indication. Olaparib tablets and capsules are not interchangeable. Olaparib capsules are being phased out of the U.S. market and will be available only through the Lynparza Specialty Pharmacy Network.
The approval in the maintenance setting was based on two randomized, placebo-controlled, double-blind, multicenter trials in patients with recurrent ovarian cancers who were in response to platinum-based therapy.
SOLO-2 (NCT01874353) randomized 295 patients with recurrent germline BRCA-mutated ovarian, fallopian tube, or primary peritoneal cancer (2:1) to receive olaparib tablets 300 mg orally twice daily or placebo. SOLO-2 demonstrated a statistically significant improvement in investigator-assessed progression-free survival (PFS) in patients randomized to olaparib compared with those who received placebo, with a hazard ratio (HR) of 0.30 (95% CI: 0.22, 0.41; p<0.0001). The estimated median PFS was 19.1 and 5.5 months in the olaparib and placebo arms, respectively. 
Study 19 (NCT00753545) randomized 265 patients regardless of BRCA status (1:1) to receive olaparib capsules 400 mg orally twice daily or placebo. Study 19 demonstrated a statistically significant improvement in investigator-assessed PFS in patients treated with olaparib vs. placebo with a HR of 0.35 (95% CI: 0.25, 0.49; p<0.0001). The estimated median PFS was 8.4 months and 4.8 months in the olaparib and placebo arms, respectively. 
The most common adverse reactions (≥20%) in clinical trials were anemia, nausea, fatigue (including asthenia), vomiting, nasopharyngitis, diarrhea, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, and stomatitis. The most common laboratory abnormalities (≥25%) were decrease in hemoglobin, increase in mean corpuscular volume, decrease in lymphocytes, decrease in leukocytes, decrease in absolute neutrophil count, increase in serum creatinine, and decrease in platelets.
The recommended olaparib tablet dose for both the maintenance therapy and later line treatment setting is 300 mg (two 150 mg tablets) taken orally twice daily with or without food.
FDA granted this application Fast Track status. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Follow the Oncology Center of Excellence on Twitter @FDAOncologydisclaimer icon.
Check out recent approvals at the OCE’s new podcast, Drug Information Soundcast in Clinical Oncology (D.I.S.C.O.), available at www.fda.gov/DISCO.

Yellow fever mosquito, 6 other organisms in July RefSeq genome annotations | NCBI Insights

Yellow fever mosquito, 6 other organisms in July RefSeq genome annotations | NCBI Insights

National Institutes of Health, U.S. National Library of Medicine



08/17/2017 12:46 PM EDT

In July, the NCBI Eukaryotic Genome Annotation Pipeline released new annotations in RefSeq for the following organisms: Papio anubis (olive baboon) Prunus avium (sweet cherry) Aedes aegypti (yellow fever mosquito) Chenopodium quinoa (quinoa) Hevea brasiliensis (a eudicot) Manihot esculenta (cassava) Carlito syrichta (Philippine tarsier) … Continue reading 
08/17/2017 12:00 PM EDT

NCBI regularly organizes hackathons throughout the United States, where participants work in teams to apply their data science experience with public datasets. In this NCBI Minute, you will hear highlights from recent hackathons, see examples of the software created in … Continue reading 
08/17/2017 11:00 AM EDT

By Jill L. Newmak ~ One of the joys of working in the History of Medicine Division of the National Library of Medicine is engaging

Clinical Pharmacology Corner: FDA Approves BESPONSA (Inotuzumab Ozogamicin)

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FDA Approves BESPONSA (Inotuzumab Ozogamicin) for Adults with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

On August 17, 2017, the U.S. Food and Drug Administration (FDA) approved BESPONSA (inotuzumab ozogamicin) for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Hepatotoxicity, including fatal and life-threatening veno-occlusive disease (VOD) occurred in patients with relapsed or refractory ALL who received BESPONSA. The risk of VOD was greater in patients who underwent hematopoietic stem cell transplant (HSCT) after BESPONSA treatment; use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level ≥ upper limit of normal (ULN) before HSCT were significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of BESPONSA treatment cycles. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA. Permanently discontinue treatment if VOD occurs. If severe VOD occurs, treat according to standard medical practice.
There was higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA, resulting in a higher Day 100 post-HSCT mortality rate.
Administer BESPONSA with caution in patients who have a history of or predisposition for QTc prolongation, who are taking drugs that prolong QT interval, and in patients with electrolyte disturbances.
Approved Recommended Dosage
Pre-Medication:
  • Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions. For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count of less than or equal to 10,000/mm3 is recommended prior to the first dose.
Cycle 1:
  • The recommended total dose of BESPONSA for all patients is 1.8 mg/m2 per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Cycle 1 is 21 days in duration, but may be extended to 28 days (i.e., 7-day treatment-free interval starting on Day 21) if the patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity.
Subsequent Cycles:
  • In patients who achieve a CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m2 per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are 28 days in duration. 
  • In patients who do not achieve a CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m2 per cycle given as 3 divided doses on Day 1 (0.8 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). Subsequent cycles are 28 days in duration. Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment.
  • For patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is 2 cycles. A third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease negativity after 2 cycles. 
  • For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered.
Dosage Modifications:
  • Clinical monitoring recommendations and dosage modifications for toxicities with BESPONSA, including hematological, hepatic and other non-hematological, and infusion-related reactions, are described in the full prescribing information linked below.
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) 
  • MOA: Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate. N-acetyl-gamma-calicheamicin is a cytotoxic agent that is covalently attached to the antibody via a linker.
  • General PK: PK of inotuzumab ozogamicin was characterized by a 2-compartment model with linear and time-dependent clearance components. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4 (steady-state).
  • Distribution: N-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro.
  • Elimination: The clearance of inotuzumab ozogamicin at steady state was 0.03 L/h. The terminal half-life was 12.3 days.
  • Metabolism: N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction.
  • Cardiac Electrophysiology: In patients with relapsed or refractory ALL, QTcF ≥ 60 msec from baseline were observed in 3% of patients in the BESPONSA arm and 2% of patients in the Investigator’s choice of chemotherapy arm. The highest mean for QTcF was 15.3 msec and observed at the beginning of Cycle 4 in the BESPONSA arm. 
Drug Interactions 
Discontinue drugs known to prolong QTc or use alternative drugs that do not prolong QTc interval or induce Torsades de Pointes. Concomitant use with BESPONSA may increase the risk of QTc interval prolongation. When it is not feasible to avoid concomitant use of drugs known to prolong QTc, monitor as described in the full prescribing information linked below.
Use in Specific Populations
Body surface area was found to significantly affect inotuzumab ozogamicin disposition.
Age (18-92 years), sex, race, or renal impairment (15-89 mL/min) do not have a clinically significant effect on the pharmacokinetics of inotuzumab ozogamicin. The pharmacokinetics in patients with end stage renal disease with or without hemodialysis is unknown.
Hepatic impairment:
No adjustment to the BESPONSA starting dose is required in patients with total bilirubin ≤ 1.5 × ULN and AST/ALT ≤ 2.5 × ULN. There is limited safety information available in patients with total bilirubin > 1.5 × ULN and/or AST/ALT > 2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to ≤ 1.5 × ULN and AST/ALT ≤ 2.5 × ULN prior to each dose unless due to Gilbert’s syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to ≤ 1.5 × ULN or AST/ALT does not recover to ≤ 2.5 × ULN.
Efficacy and Safety
The efficacy and safety of BESPONSA were demonstrated in a randomized, open label, international, multicenter study in patients with relapsed or refractory ALL. Efficacy of BESPONSA was established on the basis of achieving CR, the duration of CR, and attainment of minimal residual disease negativity. Additional information regarding the efficacy trial can be found in the full prescribing information linked below. The most common (≥ 20%) adverse reactions are thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia.

Full prescribing information is available at https://go.usa.gov/xRvhC.
Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
We always welcome your thoughts regarding the format, content, and utility of the communication. Comments may be sent via email to ocp@fda.hhs.gov.
This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Adult Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

SECTIONS

Changes to This Summary (08/11/2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Revised text to state that in previously treated patients, the B-cell receptor-inhibitor ibrutinib was given to 94 symptomatic patients in two trials, with a response rate of 90% and a progression-free survival of 69% to 86% in 18 to 24 months (cited Dimopoulos et al. as reference 51).
Revised text to state that a prospective, randomized trial of 401 patients with nongastric, extranodal mucosa-associated lymphatic tissue compared chlorambucil alone versus rituximab plus chlorambucil versus rituximab alone; added that with a median follow-up of 7.4 years, the event-free survival was better for the rituximab-plus-chlorambucil arm (cited Zucca et al. as reference 89).
Added text to state that in a retrospective review of 117 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who underwent autologous stem cell transplantation, the 4-year overall survival (OS) was 25% for double hit (rearrangement of bcl-2 and c-myc), 61% for double expressors (no rearrangement, but increased expression of bcl-2 and c-myc), and 70% for patients without these features (cited Herrera et al. as reference 17).
Revised text to state that therapy involves doxorubicin-based combination chemotherapy (such as CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] or CHOPE [CHOP + etoposide]), which is also used for DLBCL. Added text to state that for patients with early-stage disease, anecdotal retrospective series disagree on the value of consolidative radiation therapy after combination chemotherapy (cited Briski et al. as reference 92 and level of evidence 3iiiDiv).
Revised text to state that treatment of Burkitt lymphoma/diffuse small noncleaved-cell lymphoma involves aggressive multidrug regimens in combination with rituximab, similar to those used for the advanced-stage aggressive lymphomas (cited Ribrag et al. as reference 128). Also added that patients with HIV-associated Burkitt lymphoma also benefit from less-toxic modification of the aggressive multidrug regimens in combination with rituximab (cited Noy et al. as reference 134 and level of evidence 3iiiDiv).
Added text to state that in a multicenter phase II study of 26 relapsed patients, 42% responded to lenalidomide (including four complete responses) (cited Ishida et al. as reference 154 and level of evidence 3iiiDiv).
Added text to state that a prospective randomized trial of 497 patients younger than 65 years compared six cycles of R-CHOP (CHOP + rituximab) to six cycles of alternating R-CHOP and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin), with both groups then receiving autologous stem cell transplantation; with a median follow-up of 6.1 years, the time to treatment failure was longer in the cytarabine group; however, the OS was not different (cited Hermine et al. as reference 169 and level of evidence 1iiDiii).
Added Trappe et al. as reference 185.
Revised text to state that instances of Epstein-Barr virus‒negative posttransplantation lymphoproliferative disorder occur even later (median, 5 years posttransplant) and have a worse prognosis; R-CHOP chemotherapy should be applied directly in this circumstance.
Added Li et al. as reference 9.
Added obinutuzumab as a treatment option for indolent, recurrent adult NHL.
Revised the subsection on obinutuzumab.
Revised text to state that responses of 20% to 56% have been reported for lenalidomide, especially in patients with follicular lymphoma and small lymphocytic lymphoma, with even higher responses noted for the combination of lenalidomide and rituximab (cited Leonard et al as reference 25).
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
  • Updated: August 11, 2017