FDA News: Academic Medical Centers and FDA

FDA BRIEF: Week of December 19, 2016

Voice


Academic Medical Centers and FDA – Working Together for the Future

By: Robert M. Califf, M.D., Commissioner

Robert Califf 

FDA and academic medical centers (AMCs) have a history of working together

  • basic science of medicine
  • fundamental concepts for medical tools
  • regulatory science programs

Focus to better understand and advance AMC interactions

  • Shared commitment to ameliorating and curing disease, promoting public health
  • Spinning off biotech startups
  • Working directly with private corporations, state and federal partners, entrepreneurs
  • Harnessing unprecedented amount of data on human genome, human behavior, how much people earn and spend, the environmental conditions  etc.

FDA role

  • Helping to maintain and hold everyone to a high standard while driving innovation forward.
  • Continue to communicate and engage with each other, collaborate to advance shared missions

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Reporting Product Problems and Complaints to the FDA

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FDA-regulated products account for about 20 cents/dollar by U.S. consumers – have /need to report

Which products: 

  • human prescription and over-the-counter (OTC) drugs
  • medical devices
  • foods, including dietary supplements, infant formulas, beverages, and ingredients added to foods
  • veterinary products, including foods and drugs for animals
  • electronic products that give off radiation
  • biologics, including vaccines, blood and blood components, and tissues for transplantation
  • cosmetics

Why: 

  • FDA assesses information on problems or unexpected reactions/unknown risk
  • Can lead to labeling update, safety messages or removal of product from market

What: 

  • Unexpected side effects or adverse events
  • Product quality problems
  • Potentially preventable mistakes
  • Therapeutic failures

How:  Online, phone, mail.

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FDA Approvals: RUBRACA & CDxBRCA test, DEXCOM G5, AEROFORM

FDA BRIEF: Week of December 19, 2016

FDA approved


RUBRACA (rucaparib) tablets, Clovis Oncology, Boulder, CO, USA

FoundationFocus CDxBRCA test, Foundation Medicine Inc. Cambridge, MA

Image result for Rucaparib

Image result for Foundation Focus CDx BRCA test

INDICATION: Monotherapy for patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies.

Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca

UNMET NEED:

  • 22,280 women diagnosed with ovarian cancer ; 15-20%  with BRCA gene mutation
  • Targeted agents to treat cancers caused by specific mutations patient’s genes
  • Additional treatment option for ovarian cancer patients with gene abnormalities

REG PATHWAY: NDA (drug) + approval of first next-generation sequencing (NGS)-based companion diagnostic

  • Accelerated Approval, Breakthrough Therapy designation, Priority Review status, Orphan Drug designation
  • Approved 2 mo. prior to PDUFA goal date
  • Accelerated approval based on objective response rate and duration of response – continued approval contingent upon verification and description of clinical benefit in confirmatory trials

MECHANISM OF ACTION:

Rucaparib

  • Poly (ADP-ribose) polymerase (PARP) enzyme inhibitor
  • Enzymes play a role in DNA repair
  • Increased rucaparib-induced cytotoxicity in tumor cell lines with BRCA1/2 deficiencies

CDxBRCA test : NGS based, detects alterations in BRCA1 and BRCA2 genes in the tumor tissue of ovarian cancer

EFFICACY:

  • 2 multicenter, single-arm, open-label clinical trials (n=106), patients with advanced BRCA-mutant ovarian cancer, RUBRACA  until disease progression or unacceptable toxicity
  • Endpoint:. Objective response rate (ORR), duration of response (DOR) – by investigator, independent radiology review according to RECIST
  • Objective Response Rate (95% CI) 54% (44, 64)
  • Complete Response 9%
  • Partial Response 45%
  • Median DOR in months (95% CI) 9.2 (6.6 ,11.6)

SAFETY:

  • Most common adverse reactions: Nausea, fatigue (including asthenia), vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea.
  • Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) reported

LABEL


DEXCOM G5 Mobile Continuous Glucose Monitoring System

Dexcom, Inc. San Diego, CA, USA

Image result for DEXCOM G5 Mobile Continuous Glucose Monitoring System

INDICATION FOR USE: Glucose monitoring system indicated for the management of diabetes in persons age 2 years and older. The Dexcom G5 is designed to replace fingerstick blood glucose testing for diabetes treatment decisions. Interpretation of the Dexcom G5 results should be based on the glucose trends and several sequential readings over time. The Dexcom G5 also aids in the detection of episodes of hyperglycemia and hypoglycemia, facilitating both acute and long-term therapy adjustments. The Dexcom G5 is intended for single patient use and requires a prescription.

REG PATHWAY: PMA Supplement

  • To expand Indication for Use (non-adjunctive use to make treatment decisions)

DESCRIPTION:

  • Sensor, transmitter, receiver, and mobile application
  • Sensor: Inserted into subcutaneous tissue to generate electrical current proportional to the local glucose concentration
  • Transmitter: Converts electrical current into glucose readings using algorithm; uses Bluetooth Low Energy (BLE) to communicate with Dexcom G5 receiver and  Apple iOS device- receives blood glucose calibration and other user inputs
  • Displays glucose reading and trends,  alerts for readings outside of a target zone etc.
  • Mobile application: User interface

EFFECTIVENESS & SAFETY:

  • Clinical studies + discussion/recommendations of Clinical Chemistry and Toxicology Devices Panel  + input provided by patients and caregivers on device experience
  • 2 PMA clinical studies established  trend accuracy, precision, calibration frequency , wear period, performance of alarms and alerts, number of readings displayed
  • Possible adverse device effects: local infection, inflammation, pain or discomfort, bleeding at the glucose insertion site, bruising, itching, scarring or skin discoloration, hematoma, tape irritation, sensor or needle fracture during insertion, wear or removal.

AEROFORM Tissue Expander

AirXpanders, Palo Alto, CA, USA

Image result for AeroForm device

INDICATION FOR USE: For soft tissue expansion in two-stage breast reconstruction following mastectomy and in the treatment of underdeveloped breasts and soft tissue deformities. A patient uses a dose controller to independently inflate the expander.

UNMET NEED:

  • Currently used saline-filled tissue expanders requiring needle to pierce skin and inject saline into the expander
  • Need for needlee-free option and for patients to have control over expansion, home use

REG PATHWAY: De Novo

DESCRIPTION:

  • 2 main components: Expander and Controller
  • Expander: Sterile implant with outer silicone shell; reservoir of compressed carbon dioxide
  • Controller: Hand-held remote dosage controller
  • Controller used to communicate to valve in reservoir to release carbon dioxide and gradually inflate the expander
  • Controller pre-programmed to limit releasing a small amount of carbon dioxide once every three hours, up to a maximum of three times per day.

EFFECTIVENESS & SAFETY:

  • Clinical trial, AeroForm expander (n=99) vs. saline expander (n=52)
  • Endpoint:  Breast tissue successfully expanded and exchanged to a breast implant
  • 96.1% (AeroForm) vs.  98.8% (saline)
  • Common adverse events: Necrosis, seroma, post-operative wound infection and procedural pain

 

Clin. Pharm. Card: SOLIQUA

SOLIQUA 100/33 (insulin glargine and lixisenatide injection), for subcutaneous use

 Sanofi-Aventis U.S. Bridgewater, NJ, USA

Image result for glp 1 receptor agonist

INDICATION:  Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) or lixisenatide


Mechanism of Action SOLIQUA 100/33 is a combination of insulin glargine, a basal insulin analog, and lixisenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist. The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis. Lixisenatide increases glucose-dependent insulin release, decreases glucagon secretion, and slows gastric emptying.
Pharmacodynamics (PD) No impact of combination on  on the pharmacodynamics of insulin glargine. Impact of combination on PD  of lixisenatide has not been studied.

In adults with type 2 diabetes mellitus, lixisenatide reduced fasting plasma glucose and postprandial blood glucose AUC0–300mim compared to placebo (-33.8 mg/dL and -387 mg.h/dL, respectively) following a standardized test meal. The effect on postprandial blood glucose AUC was most notable with the first meal, and the effect was attenuated with later meals in the day. Treatment with lixisenatide 20 mcg once daily reduced postprandial glucagon levels (AUC0–300min) compared to placebo by -15.6 h.pmol/L after a standardized test meal in patients with type 2 diabetes.

At a dose 1.5-times the recommended dose, lixisenatide does not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetics (PK) The insulin glargine/lixisenatide ratio has no relevant impact on the PK of insulin glargine in SOLIQUA 100/33.

Compared to administration of lixisenatide alone, the Cmax is lower whereas the AUC is generally comparable when administered as SOLIQUA 100/33. The insulin glargine/lixisenatide ratio has no impact on the PK of lixisenatide in SOLIQUA 100/33. The observed differences in the PK of lixisenatide when given as SOLIQUA 100/33 or alone are not considered to be clinically relevant.

 After subcutaneous administration of insulin glargine/lixisenatide combinations, insulin glargine showed no pronounced peak. Exposure to insulin glargine ranged from 86% to 101% compared to administration of insulin glargine alone.

After subcutaneous administration of insulin glargine/lixisenatide combinations, the median tmax of lixisenatide was in the range of 2.5 to 3.0 hours. There was a small decrease in Cmax of lixisenatide of 22–34% compared with separate simultaneous administration of insulin glargine and lixisenatide, which is not likely to be clinically significant. There are no clinically relevant differences in the rate.

 Protein binding of lixisenatide is 55%.

 Metabolism study in humans who received insulin glargine alone indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.

 Lixisenatide is presumed to be eliminated through glomerular filtration, and proteolytic degradation.

 After multiple dose administration in patients with type 2 diabetes, mean terminal half-life was approximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h.

PK-PD Analysis No reported.
Population PK Age, body weight, gender, and race were not observed to meaningfully affect the pharmacokinetics of lixisenatide in population PK analyses,
Special Populations Effect of age, race, and gender on the pharmacokinetics of insulin glargine has not been evaluated. In controlled clinical trials in adults with insulin glargine (100 units/mL), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy.

 Compared to healthy subjects (N=4), plasma Cmax of lixisenatide was increased by approximately 60%, 42%, and 83% in subjects with mild (CLcr 60–89 mL/min [N=9]), moderate (CLcr 30–59 mL/min [N=11]), and severe (CLcr 15–29 mL/min [N=8]) renal impairment. Plasma AUC was increased by approximately 34%, 69% and 124% with mild, moderate and severe renal impairment, respectively.

Drug Interactions Due to their peptidic nature, insulin glargine and lixisenatide have no relevant potential to induce or inhibit CYP isozymes and therefore, no direct drug interaction is expected.

 Interaction studies performed with the individual components. 

Lixisenatide did not change the overall exposure (AUC) of acetaminophen following administration of a single dose of acetaminophen 1000 mg, whether before or after lixisenatide. No effects on acetaminophen Cmax and tmax were observed when acetaminophen was administered 1 hour before lixisenatide. When administered 1 or 4 hours after 10 mcg lixisenatide, Cmax of acetaminophen was decreased by 29% and 31%, respectively, and median tmax was delayed by 2.0 and 1.75 hours, respectively.

 Administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour before or 11 hours after 10 mcg lixisenatide, did not change Cmax, AUC, t1/2 and tmax of ethinylestradiol and levonorgestrel. Administration of the oral contraceptive 1 hour or 4 hours after lixisenatide did not affect the AUC and mean terminal half-life (t1/2) of ethinylestradiol and levonorgestrel. However, Cmax of ethinylestradiol was decreased by 52% and 39%, respectively, and Cmax of levonorgestrel was decreased by 46% and 20%, respectively, and median tmax was delayed by 1 to 3 hours.

 When lixisenatide 20 mcg and atorvastatin 40 mg were coadministered in the morning for 6 days, the exposure of atorvastatin was not affected, while Cmax was decreased by 31% and tmax was delayed by 3.25 hours. No such increase for tmax was observed when atorvastatin was administered in the evening and lixisenatide in the morning but the AUC and Cmax of atorvastatin were increased by 27% and 66%, respectively.

 After concomitant administration of warfarin 25 mg with repeated dosing of lixisenatide 20 mcg, there were no effects on AUC or INR (International Normalized Ratio) while Cmax was reduced by 19% and tmax was delayed by 7 hours.

 After concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg at steady state, the AUC of digoxin was not affected. The tmax of digoxin was delayed by 1.5 hour and the Cmax was reduced by 26%.

 After concomitant administration of lixisenatide 20 mcg and ramipril 5 mg during 6 days, the AUC of ramipril was increased by 21% while the Cmax was decreased by 63%. The AUC and Cmax of the active metabolite (ramiprilat) were not affected. The tmax of Ramipril and ramiprilat were delayed by approximately 2.5 hours.

Source: http://products.sanofi.us/Soliqua100-33/Soliqua100-33.pdf

Guidances: OTC Hearing Aids, Emerging Device Signals, Electronic Informed Consent, Biomarker Qualification

FDA BRIEF: Week of Dec 5 and Dec 12, 2016

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Immediately in Effect Guidance Document:  Flexible and adaptive regulatory approach to the oversight of hearing aids to increase availability and accessibility

Applicability:

  • Class I air-conduction hearing aids – 21 CFR 874.3300(b)(1)
  • Class II wireless air-conduction hearing aids- 21 CFR 874.3305

Overview:

  • No enforcement of medical evaluation and recordkeeping requirements prior to the dispensing
  • Required to provide User Instructional Brochure containing specific labeling requirements prior to sale

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Emerging signal:

  • New information about a marketed medical device
  • New causal association , New aspect of known association
  • Information can impact patient management decisions, benefit-risk profile

Overview:

  • Signal and Signal Management
  • Considerations for FDA Public Notification
  • Content of Public Notification and Follow-up/Closure

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Use of electronic systems and processes to obtain informed consent (eIC)

  • Ensure protection of rights, safety, and welfare of human subjects
  • Facilitate comprehension of information presented
  • Ensure appropriate documentation of consent
  • Ensure the quality and integrity of eIC data

Instituting eIC

  • Information presentation
  • How/Where
  • Answering questions from subjects
  • Steps to facilitate understanding
  • Electronic signatures
  • Identity verification
  • Pediatric subjects
  • Information access
  • Steps for privacy, security, confidentiality
  • HIPAA authorization
  •  IRB communications
  • Archival & FDA inspection

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Aim: Create alignment among scientific stakeholders including FDA, NIH, industry, academia, patient groups and the non‐profit sector regarding a proposed framework for levels of evidence required to qualify biomarkers

Overview

  • Biomarker Categories & Milestones
  • Proposed Framework :  Assumptions, Components, Context of Use (COU)
  • Evidentiary Criteria (EC) Framework: COU, Benefits/Risks, EC data
  •  Evidentiary Criteria Level Assessment Map
  • Clinical Safety Module: Need Statement, COU, Benefit/Risk, Evidence Map , EC level assessment, References and related publications

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Clin. Pharm. Card: AMJEVITA

AMJEVITA (adalimumab-atto) injection for subcutaneous use

Biosimilar to HUMIRA (adalimumab

Image result for humira mechanism of action

INDICATIONS:

Rheumatoid Arthritis : Reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function

Juvenile Idiopathic Arthritis: Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis

Psoriatic Arthritis: Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis

Ankylosing Spondylitis : Reducing signs and symptoms in adult patients with active ankylosing spondylitis

Adult Crohn’s Disease: Reducing signs and symptoms and inducing and maintaining clinical remission

Ulcerative Colitis: Inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants

Plaque Psoriasis: Treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy


Mechanism of Action Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF (tumor necrosis factors) receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of patients with RA (Rheumatoid Arthritis), JIA (Juvenile Idiopathic Arthritis), PsA (Psoriatic Arthritis), and AS (Ankylosing Spondylitis) and play an important role in both the pathologic inflammation and the joint destruction. Increased levels of TNF are also found in psoriasis plaques (Ps). In Ps, treatment with AMJEVITA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown. Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X10-10 M).
Pharmacodynamics (PD) After treatment with adalimumab, a decrease in levels of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with RA. A decrease in CRP levels was also observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.
Pharmacokinetics (PK) The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) with adalimumab treatment were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects.

 The average absolute bioavailability of adalimumab estimated following a single 40 mg subcutaneous dose was 64%.

 The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. The single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg.

 The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies.

 Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.

In RA patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations of approximately 5 μg/mL and 8 to 9 μg/mL, were observed without and with methotrexate (MTX), respectively. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40, and 80 mg every other week and every week subcutaneous dosing. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time.

 Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg adalimumab every other week (6 to 10 μg/mL and 8.5 to 12 μg/mL,without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.

 The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.

In patients with CD, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 μg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 μg/mL were observed at Week 24 and Week 56 in CD patients after receiving a maintenance dose of 40 mg adalimumab every other week.

 In patients with UC, the loading dose of 160 mg adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves mean serum adalimumab trough levels of approximately 12 μg/mL at Week 2 and Week 4. Mean steady-state trough level of approximately 8 μg/mL was observed at Week 52 in UC patients after receiving a dose of 40 mg adalimumab every other week, and approximately 15 μg/mL at Week 52 in UC patients who increased to a dose of 40 mg adalimumab every week.

In patients with Ps, the mean steady-state trough concentration was approximately 5 to 6 μg/mL during adalimumab 40 mg every other week monotherapy treatment.

Minor increases in apparent clearance were also predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.

PK-PD Analysis                    No reported.
 Population PK Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to > 75 years.

 

Special Populations No gender-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.

 No pharmacokinetic data are available in patients with hepatic or renal impairment.

 In study with polyarticular JIA patients who were 4 to 17 years of age, the mean steady-state trough serum adalimumab concentrations for patients weighing < 30 kg receiving 20 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.8 μg/mL and 10.9 μg/mL, respectively. The mean steady-state trough serum adalimumab concentrations for patients weighing ≥30 kg receiving 40 mg adalimumab subcutaneously every other week as monotherapy or with concomitant MTX were 6.6 μg/mL and 8.1 μg/mL, respectively.

PD Interactions  In RA patients, increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit

Higher rate of serious infections RA patients treated with rituximab with subsequent treatment with a TNF blocker

The formation of CYP450 enzymes may be suppressed.

Source: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761024lbl.pdf

 

Clin. Pharm. Card: INTRAROSA

INTRAROSA (prasterone) vaginal inserts

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 INDICATION: Steroid indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. 


Mechanism of Action Prasterone is an inactive endogenous steroid and is converted into active androgens and/or estrogens. The mechanism of action of INTRAROSA in postmenopausal women with vulvar and vaginal atrophy is not fully established.
Pharmacodynamics (PD) Not reported.
Pharmacokinetics (PK) In a study conducted in postmenopausal women, administration of the INTRAROSA vaginal insert once daily for 7 days resulted in a mean prasterone Cmax and area under the curve from 0 to 24 hours (AUC0- 24) at Day 7 of 4.4 ng/mL and 56.2 ngh/mL, respectively, which were significantly higher than those in the group treated with placebo.

 The Cmax and AUC0- 24 on Day 7 of the testosterone metabolite (metabolite of prasterone) were 0.15 ng/mL and 2.79 ngh/mL, respectively which were slightly higher in women treated with the INTRAROSA vaginal insert compared to those receiving placebo, 0.12 ng/mL and 2.58 ngh/mL, respectively.

 The Cmax and AUC0- 24 on Day 7 of the estradiol metabolite (metabolite of prasterone) were 5.04 pg/mL and 96.93 pgh/mL, respectively which were also slightly higher in women treated with the INTRAROSA vaginal insert compared to those receiving placebo, 3.33 pg/mL and 66.49 pgh/mL, respectively.

 Exogenous prasterone is metabolized in the same manner as endogenous prasterone. Human steroidogenic enzymes such as hydroxysteroid dehydrogenases, 5α-reductases and aromatases transform prasterone into androgens and estrogens.

 In two primary efficacy trials, daily administration of INTRAROSA vaginal insert for 12 weeks increased mean serum Ctrough of prasterone and its metabolites testosterone and estradiol by 47%, 21% and 19% from baseline, respectively. This comparison based on Ctrough may underestimate the magnitude of increase in prasterone and metabolites’ exposure because it does not take into account the overall concentration-time profile following administration of INTRAROSA.

PK-PD Analysis                          Not reported.
Population PK Not reported.
 Special Populations  Not reported.
Drug Interactions Not reported.

Source: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208470s000lbl.pdf

Clin. Pharm. Card: EXONDYS 51

EXONDYS 51 (Eteplirsen) intravenous injection

Sarepta Therapeutics, Inc. Cambridge, MA, USA

Image result for EXONDYS 51 (Eteplirsen) image

INDICATION: Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51


Mechanism of Action Binds to exon 51 of dystrophin pre-mRNA (messenger ribonucleic acid), resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.
Pharmacodynamics (PD) All EXONDYS 51 treated patients evaluated (n=36) were found to produce mRNA for a truncated dystrophin protein by reverse transcription polymerase chain reaction.

 In Study 2, the average dystrophin protein level in muscle tissue after 180 weeks of treatment with EXONDYS 51 was 0.93% of normal (i.e., 0.93% of the dystrophin level in healthy subjects). Because of insufficient information on dystrophin protein levels before treatment with EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in response to EXONDYS 51 in Study 1.

 In Study 3, the average dystrophin protein level was 0.16% of normal before treatment and 0.44% of normal after 48 weeks of treatment with EXONDYS 51. The median increase in truncated dystrophin in Study 3 was 0.1%.           

Pharmacokinetics (PK) Single or multiple intravenous infusions lead to the peak plasma concentrations (Cmax) of eteplirsen occurring near the end of infusion (i.e., 1.1 to 1.2 hours across a dose range of 0.5 mg/kg/week to 50 mg/kg/week).

Following single or multiple intravenous infusions in male pediatric DMD patients, plasma concentration-time profiles of eteplirsen were generally similar and showed multi-phasic decline.

 The majority of drug elimination occurred within 24 hours.

 Approximate dose-proportionality and linearity in PK properties were observed following multiple-dose studies (0.5 mg/kg/week [0.017 times the recommended dosage] to 50 mg/kg/week [1.7 times the recommended dosage]). There was no significant drug accumulation following weekly dosing across this dose range. The inter-subject variability for Cmax and AUC range from 20 to 55%, respectively.

Plasma protein binding (in vitro) in human ranges between 6 to 17%. The mean apparent volume of distribution (Vss)  was 600 mL/kg following weekly intravenous infusion of EXONDYS 51 at 30 mg/kg.

 Total clearance is 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week. Renal clearance accounts for approximately two-thirds of the administered dose within 24 hours of intravenous administration.

 Elimination half-life (t1/2) is 3 to 4 hours. 

PK-PD Analysis Not reported.
Population PK Not reported.
 Specific Populations  Effect of age (65 years or older), sex, race or renal/hepatic Impairment was not reported.
 Drug Interactions  In vitro studies showed that eteplirsen did not significantly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Eteplirsen did not induce CYP2B6 or CYP3A4, and induction of CYP1A2 was substantially less than the prototypical inducer, omeprazole. Eteplirsen was not a substrate nor did it have any major inhibitory potential for any of the key human transporters tested (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, P-gp, BCRP, MRP2 and BSEP). Based on in vitro data on plasma protein binding, CYP or drug transporter interactions, and microsomal metabolism, eteplirsen is expected to have a low potential for drug-drug interactions in humans.
 Source   http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206488lbl.pdf

 

 

 

 

 

FDA News: 21st Century Cures Act, CDER and CDRH Performances, Drug Safety Information, Mutual Reliance Initiative

FDA News: Week of December 5 and 12, 2016Voice


21st Century Cures Act: Making Progress on Shared Goals for Patients

By: Robert M. Califf, M.D., FDA Commissioner 

Robert Califf

President Obama signed into law the 21st Century Cures Act, on Dec 13th

  • Builds on FDA’s ongoing efforts to advance medical product innovation, quick patient access, assurance of high quality evidence of safety and effectiveness
  • Improves FDA’s ability to hire and retain scientific experts

Focus on:

  • Incorporation of patient’s voice into FDA’s decision-making
  • Modernizing and improving efficiency in clinical trial design
  • Effective FDA engagement for expediting product development and application reviews
  • New pathways for  antibacterials/antifungals, regenerative medicine products
  • Real world post market data for conducting more efficient research
  • Healthcare economic information to payers and formulary committees

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CDER PERFORMANCE

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Novel New Drug Approvals

  • Received 36 NME applications
  • Approved 19 NMEs*, including 7 Orphan Drugs

Reasons for fewer NMEs compared to CY15

  • Approval of 5 NMEs in CY15 with CY16 due dates
  • Fewer NME actions in CY16
  • Increased number of CR letters in CY16

Expedited Review

  • Priority Review : 68%
  • Breakthrough Therapy designation : 32%
  • Fast Track designation : 37%

Drug Innovation

  • Rare diseases : 37%
  • First in class : 37%
  • First approved in US : 84%

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CDRH PERFORMANCE

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  • Guidance Documents: 58
  • PMA: 89% approved
  • 510(k): 83% Substantially Equivalent
  • Direct De Novo: 30%
  • Pre-Submission Meetings: 939

Includes Division Level Data : DAGRID, DCD, DNPMD, DOD, DOED, DRGUD, DSD, DCTD, DIHD, DMD, DMGP, DRH

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Faster Information from FDA Means Improved Drug Safety for Patients

Mary E. Kremzner, PharmD, MPH, CAPT, U.S. Public Health Service, Director, Division of Drug Information, CDER

Mary KremznerEasy, FAST, Up-to-Date drug safety information for health care professionals and patients


The Mutual Reliance Initiative: A New Path for Pharmaceutical Inspections in Europe and Beyond

Dara Corrigan, J.D., Associate Commissioner for Global Regulatory Policy

Dara Corrigan

  • Concern: Rapid increase in imported drugs from nations with limited inspection resources e.g. China and India
  • Solution: FDA partnering with EU to rely on each other’s inspections, avoid duplication, conduct more inspections

Initiative: Mutual Reliance Initiative (MRI)

  • Launched in May 2014 -mutual recognition agreement
  • “Brexit” has no impact on FDA’s relationship with UK counterparts at this time
  • Key component covered in Transatlantic Trade and Investment Partnerships (T-TIP)

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FDA Approval : MACI, EUCRISA

FDA BRIEF: Week of December 5 and 12, 2016

FDA approved


MACI  (autologous cultured chondrocytes on porcine collagen membrane)

Vericel Corporation, Cambridge, MA, USA

Image result for Maci AND vericel

INDICATION: Repair of single or multiple symptomatic, full thickness cartilage defects of the knee with or without bone involvement in adults.

UNMET NEED:

  • Knee problems common in all ages
  • Knee cartilage defects due injury, straining, overuse, muscle weakness, general wear and tear
  • Tailored therapy required; need to additional treatment option

REG. PATHWAY: BLA

  • First approval for process of tissue engineering to grow cells on scaffolds using healthy cartilage tissue from the patient’s own knee.

DESCRIPTION:

  • Autologous cultured chondrocytes on porcine Type I/III collagen
  • Autologous chondrocytes propagated in cell culture and seeded on collagen
  • MACI implant contains at least 500,000 cells per cm 2 and does not contain any preservative

EFFICACY:

  •   2-year prospective, multicenter, randomized, open-label, parallel-group study, MACI vs. Microfracture Treatment., patients with symptomatic articular cartilage defects in the knee, n=144, 104 weeks
  • Co-primary efficacy endpoint:  Change in Knee injury and Osteoarthritis Outcome Score (KOOS) in two subscales: Pain and Function (Sports and Recreational Activities [SRA]), week 104
  • Statististically significant improvement in KOOS pain and function (SRA) p = 0.001

SAFETY: Most common side effects:  joint pain, common cold-like symptoms, headache and back pain.

LABEL


EUCRISA (crisaborole) ointment 

Anacor Pharmaceuticals (Pfizer), Palo Alto, CA, USA

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INDICATION:  Topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.

UNMET NEED:

  • Atopic dermatitis (Eczema) , a chronic inflammatory skin disease
  • Caused by combination of genetic, immune and environmental factors
  • Skin develops red, scaly and crusted bumps, itchy and  “weeping” clear fluid
  • Need to another treatment option

REG. PATHWAY: NDA

MECHANISM OF ACTION: Phosphodiesterase 4 (PDE-4) inhibitor; results in increased intracellular cyclic adenosine monophosphate (cAMP) levels; specific therapeutic mechanism(s)  not well defined

EFFICACY:

  • 2 multicenter, randomized, double-blind, parallel-group, vehicle-controlled trials , n=1522, EUCRISA vs. vehicle, twice daily for 28 days
  • Primary efficacy endpoint: Proportion of subjects with ISGA grade of Clear (score of 0) or Almost Clear (score of 1) with a 2-grade or greater improvement from baseline
  • Greater ‘success’ with EUCRISA
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SAFETY:

  • Serious side effect: Hypersensitivity reactions
  • Most common side effect: Site pain, including burning or stinging

LABEL


 

Patient-Reported Outcomes with LASIK (PROWL)

Patient-Reported Outcomes with LASIK (PROWL)

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WHAT:  Patient experiences, not health care provider, to measure impact symptoms directly had on performing usual activities.

HOW: Pilot, PROWL-1 and PROWL-2 studies

  • Evaluate new scales to measure visual symptoms, patient satisfaction, and expectations for and following LASIK surgery

RESULTS:

  • Difficulty driving at night, severely impacted a patient’s daily living
  • Debilitating vision symptoms and severe dry eye
  • <1% experienced difficulty performing their usual activities following LASIK surgery

LEARN

Webinar – Final Guidance on Medical Device Reporting for Manufacturers

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SUMMARY

Reporting requirements for:

  • Manufacturer
  • Device user facilities
  • Importers

Reporting of:

  • Death
  • Serious injury
  • Malfunctions

Reporting Followups:

  • Complete investigation of each event
  • Develop & Implement reporting procedures
  • Establish & Maintain reporting files
  • Create system for expedited information access for follow-up/FDA inspection

SUMMARY SLIDE

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SLIDES

Guidances : Bladder Cancer, Pediatric Drug Development, Drug Metabolite Safety, Contract Manufacturing, Clinical Pharmacology Labeling

FDA BRIEF: Week of Nov. 21, 2016

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PURPOSE:  Assist in clinical development of drugs, biologics, for the treatment of patients who have bacillus Calmette-Guerin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC

DEVELOPMENT PROGRAM

  • Early Phase
  • Late Phase

GENERAL CONSIDERATIONS

  • Trial Population and Entry Criteria
  • Randomization, Stratification, and Blinding
  • Dose Selection
  • Single-Arm vs. Randomized, Controlled Trial Design
  • Efficacy Endpoints
  • Trial Procedures and Timing of Assessments
  • Endpoint Adjudication
  • Statistical Considerations
  • Accelerated Approval (Subpart H and Subpart E) Considerations
  • Risk-Benefit Considerations

OTHER CONSIDERATONS

  • Risk Management Considerations
  • Nonclinical Safety Considerations

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PURPOSE: Current regulatory perspective on topics in pediatric drug development

ETHICAL CONSIDERATIONS & SCIENTIFIC APPROACH

AGE CLASSIFICATION

  • Subgorups
  • Neonates

OPTIMIZATION

  • Use of Existing Knowledge in Pediatric Drug Development
  • Use of Extrapolation in Pediatric Drug Development
  • Use of Modelling and Simulation in Pediatric Drug Development

PRACTICALITIES

  • Feasibility
  • Outcome Assessments.
  • Long-term Clinical Aspects, including safety

PEDIATRIC FORMULATIONS

  • Dosage and Administration
  • Excipients.
  • Palatability and Acceptability
  • Neonates

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PURPOSE: When and how to identify and characterize drug metabolites whose nonclinical toxicity needs to be evaluated

GENERAL CONCEPTS

  • Approaches for Assessing Metabolite Safety
  • Identification of Metabolites
  • General Considerations for Nonclinical Study Design

RECOMMENDED STUDIES

  • General Toxicity Studies
  • Genotoxicity Studies
  • Embryo-Fetal Development Toxicity Studies
  • Carcinogenicity Studies

TIMING
DECISION TREE FLOW DIAGRAM
CASE EXAMPLES

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PURPOSE: Defining, establishing, and documenting manufacturing activities  for  contract drug manufacturing  and Current Good Manufacturing Practice (CGMP) requirements

DEFINING : Who, What

RESPONSIBILITIES

DOCUMENTING CGMP ACTIVITIES

  • Quality Agreemen
  • Manufacturing Activities.
  • Change Control

ILLUSTRATIVE SCENARIOS

  • Owners and Contract Facilities Are Both Responsible for CGMP
  • CGMPs Apply to all Contract Facilities, Including Analytical Testing Laboratories
  • Owners and Contract Facilities Perform Change Control Activities

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cp-label

SCOPE: Assist applicants in preparing CLINICAL PHARMACOLOGY section of prescription drug labeling

  • to meet regulatory requirements
  • ensure appropriate consistency in the format and content

GENERAL PRINCIPLES

  • Content and Organization
  • Cross-Referencing

SUBSECTIONS

  • Mechanism of Action
  • Pharmacodynamics
  • Pharmacokinetics: Absorption, Distribution, Elimination, Specific Populations, Drug Interaction, Microbiology, Pharmacogenomics

PRESENTATION

  • Central Tendency and Variation
  • Presentation Format

PROCEDURAL

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FDA Approvals/Classification Order: JARDIANCE, BRAINPULSE100

FDA BRIEF: Week of Nov. 28, 2016

FDA approved


JARDIANCE (empagliflozin) tablets

Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA

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NEW INDICATION: Reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease

UNMET NEED:

  • 70% higher cardiovascular deaths in diabetics
  • Need for treatment option to reduce deaths

REG PATHWAY:

  • sNDA
  • First approval in 2014 for improvement in  glycemic control in type 2 diabetes mellitus

EFFICACY:

  • Postmarketing study – part of post approval requirement
  • n=7000, patients with type 2 diabetes and cardiovascular disease, JARDIANCE vs placebo, followed for  3.1 years
  • Primary Endpoint: Major adverse cardiovascular event (MACE)
  • Significant reduction in the time to first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke
  • Significant reduction in the risk of cardiovascular death; no change in non-fatal myocardial infarction or non-fatal stroke

SAFETY:

  • Dehydration and hypotension, ketoacidosis, serious urinary tract infection, acute kidney injury and impairment in renal function, hypoglycemia,  vaginal yeast infections, genital mycotic infections, and increased cholesterol.

LABEL


BRAINPULSE 100

Jan Medical, Mountain View, CA, USA

INDICATION FOR USE:  For use on a patient’s head to non-invasively detect, amplify and capture the skull motion caused by pulsatile flow from the cardiac cycle. The BrainPulse is not indicated to aid in the diagnosis of neurological conditions, diseases, or disorders.

REG PATHWAY: De Novo

  • Regulation Number: 21 CFR 882.1630
  • Regulation Name: Cranial Motion Measurement Device:  Prescription device; utilizes accelerometers to measure motion or acceleration of skull; not for diagnostic purposes.
  • Regulatory Classification: Class II
  • Product Code: POP

DEVICE DESCRIPTION:

  • 3 main components: a headset, data collector, and computer
  • Headset: Forehead photoplethysmograph (PPG) sensor (pulse rate), Sound Pressure Level (SPL) sensor (ambient environment noise), six accelerometers (skull acceleration at six selected locations)
  • Data collector: Converts analog signals to digital data stream via Ethernet cable to  computer
  • Computer: Software to initiate/end recordings, save data
  • Not capable of displaying recorded data

SAFETY & EFFECTIVENESS:

  • 6 clinical studies
  • 616 successful recordings evaluated from 273 patients across studies
  • Demonstration of correlation of measured skull motion to regular pulse related to cardiac cycle
  • No major variations in within-patient recordings
  • Discomfort (n=2) when wearing the headset – no other adverse events, complaints, device issues or malfunctions

CLASSIFICATION ORDER


 

FDA News: Trade Alert, Bipolar Disorder, Pathogens, Combination Products

FDA BRIEF: Week of November 28, 2016

Voice


Trade Alert: FDA Issues New Import Data Requirements

By: Howard Sklamberg, J.D., Deputy Commissioner for Global Regulatory Operations and Policy

Howard SklambergIncreasing volume of imports: six million (2002) – 35 million (2015)

FDA reviews imported products to determine admissibility.

To facilitate:

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Bipolar Disorder and FDA-Approved Treatments

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Symptoms

  • Bipolar I disorder (also known as manic-depressive illness): Unusual shifts in mood, energy, activity levels,manic episodes .
  • Bipolar II disorder: less severe manic episodes, can switch to major depressive episodes.

FDA Approved Bipolar Drug Treatments (Division of Psychiatry Products)

  • mood stabilizers: balance brain chemicals to prevent mania, hypomania, or depressive episodes
  • antipsychotic drugs: new atypical antipsychotics- safer that older antipsychotic drugs

Bottom Line

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How Pathogens cause DiseaseCDERConversations 715pxPhoto of Daniela I. Verhelyi, Office of Biotechnology Products, Studying How Pathogens Cause Disease

Daniela Verthelyi, Chief, Laboratory of Immunology, Office of Biotechnology Products, Office of Pharmaceutical Quality, CDER

Scientists in CDER and CBER advancing regulatory science and research on pathogens

Examples of important discoveries from CDER’s research

  • Dr. David Frucht : Mouse models with the anthrax infection
  •  Dr. Kathleen Clouse : Study Ebola virus by using non-infectious components
  • Dr. Daniela Verthely: New model of infection with Zika virus
  • Other : Bacillus anthracis, Epstein-Barr virus,  HIV, Sindbis and Tacaribe viruses, Ebola, Junin, and Machupo viruses, vesicular stomatitis virus

Address public health issues in the US and abroad.

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Combination Products Review Program: Progress and Potential

By:

Nina L. Hunter, Ph.D., Associate Director for Science Policy,

Robert M. Califf, M.D., Commissioner 

Nina HunterRobert Califf

Combination products account for a growing proportion of products for FDA review

FDA addressing issues identified in Intercenter Consult Process Study Report

Great progress over the past year summarized below

Combination Products Review Table

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Clinical Pharmacology Cards: EXONDYS 51, DARZALEX

EXONDYS 51 (Eteplirsen) intravenous injection

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INDICATION Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. 

Mechanism of Action Eteplirsen is designed to bind to exon 51 of dystrophin pre-mRNA (messenger ribonucleic acid), resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.
Pharmacodynamics (PD) All EXONDYS 51 treated patients evaluated (n=36) were found to produce mRNA for a truncated dystrophin protein by reverse transcription polymerase chain reaction.

 In Study 2, the average dystrophin protein level in muscle tissue after 180 weeks of treatment with EXONDYS 51 was 0.93% of normal (i.e., 0.93% of the dystrophin level in healthy subjects). Because of insufficient information on dystrophin protein levels before treatment with EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in response to EXONDYS 51 in Study 1.

 In Study 3, the average dystrophin protein level was 0.16% of normal before treatment and 0.44% of normal after 48 weeks of treatment with EXONDYS 51. The median increase in truncated dystrophin in Study 3 was 0.1%.           

Pharmacokinetics (PK) Single or multiple intravenous infusions leads to the peak plasma concentrations (Cmax) of eteplirsen occurred near the end of infusion (i.e., 1.1 to 1.2 hours across a dose range of 0.5 mg/kg/week to 50 mg/kg/week).

 Following single or multiple intravenous infusions of EXONDYS 51 in male pediatric Duchenne muscular dystrophy (DMD) patients, plasma concentration-time profiles of eteplirsen were generally similar and showed multi-phasic decline.

 The majority of drug elimination occurred within 24 hours.

 Approximate dose-proportionality and linearity in PK properties were observed following multiple-dose studies (0.5 mg/kg/week [0.017 times the recommended dosage] to 50 mg/kg/week [1.7 times the recommended dosage]). There was no significant drug accumulation following weekly dosing across this dose range. The inter-subject variability for eteplirsen Cmax and AUC range from 20 to 55%, respectively.

 Plasma protein binding (in vitro) of eteplirsen in human ranges between 6 to 17%. The mean apparent volume of distribution (Vss) of eteplirsen was 600 mL/kg following weekly intravenous infusion of EXONDYS 51 at 30 mg/kg.

 The total clearance of eteplirsen was 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week. Renal clearance of eteplirsen accounts for approximately two-thirds of the administered dose within 24 hours of intravenous administration.

 Elimination half-life (t1/2) of eteplirsen was 3 to 4 hours. 

PK-PD Analysis Not reported.
Population PK Not reported.
Specific Populations  Effect of age (65 years or older), sex, race or renal/hepatic Impairment was not reported.
 Drug Interactions  In vitro studies showed that eteplirsen did not significantly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Eteplirsen did not induce CYP2B6 or CYP3A4, and induction of CYP1A2 was substantially less than the prototypical inducer, omeprazole. Eteplirsen was not a substrate nor did it have any major inhibitory potential for any of the key human transporters tested (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, P-gp, BCRP, MRP2 and BSEP).

 Based on in vitro data on plasma protein binding, CYP or drug transporter interactions, and microsomal metabolism, eteplirsen is expected to have a low potential for drug-drug interactions in humans.

Source: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206488lbl.pdf

 


DARZALEX (daratumumab) injection, for intravenous use

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 INDICATION: Treatment of patients with multiple myeloma

Mechanism of Action CD38 (cluster of differentiation 38) is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including multiple myeloma and other cell types, and tissues and has multiple functions, such as receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1k human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Myeloid derived suppressor cells (MDSCs) and a subset of regulatory T cells (CD38+Tregs) express CD38 and are susceptible to daratumumab mediated cell lysis.
Pharmacodynamics (PD) NK (Natural killer) cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated

(CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX treatment. CD4+ and CD8+ T cell absolute counts, as well as their percentage of total lymphocytes, increased with DARZALEX treatment in both the peripheral blood and bone marrow.

 DARZALEX as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX has the potential to delay ventricular repolarization.

Pharmacokinetics (PK) The PK of daratumumab following intravenous administration were evaluated in patients with relapsed and refractory multiple myeloma at dose levels from 0.1 mg/kg to 24 mg/kg, and included the recommended 16 mg/kg dose and regimen.

 Over the dose range from 1 to 24 mg/kg, increases in area under the concentration-time curve (AUC) were more than dose proportional. Clearance decreased with increasing dose and repeated dosing, indicating target-mediated pharmacokinetics.

 Following the recommended schedule and dose of 16 mg/kg, the mean [standard deviation (SD)] serum Cmax value was 915 (410) μg/mL at the end of weekly dosing, approximately 2.9-fold higher than following the first infusion. The mean (SD) predose (trough) serum concentration at the end of weekly dosing was 573 (332) μg/mL.

PK-PD Analysis  Not reported.
Population PK Based on the population PK analysis, daratumumab steady state is achieved approximately 5 months into the every 4-week dosing period (by the 21st infusion), and the mean (SD) ratio of Cmax at steady-state to Cmax after the first dose was 1.6 (0.5). The mean (SD) linear clearance and mean (SD) central volume of distribution are estimated to be 171.4 (95.3) mL/day and 4.7 (1.3 L), respectively. The mean (SD) estimated terminal half-life associated with linear clearance was approximately 18 (9) days.

Population PK analyses indicated that the central volume of distribution and clearance of daratumumab increase with increasing body weight, supporting the body weight-based dosing regimen. Population PK analyses also showed that age (31 to 84 years) and gender do not have clinically important effects on the pharmacokinetics of daratumumab.

Special Populations The population PK analysis included 71 patients with normal renal function (creatinine clearance [CrCL] ≥ 90 mL/min), 78 patients with mild renal impairment (CrCL <90 and ≥ 60 mL/min), 68 patients with moderate renal impairment (CrCL <60 and ≥ 30 mL/min) and 6 patients with severe renal impairment or end stage renal disease (CrCL <30 mL/min). No clinical differences in exposure to daratumumab were observed between patients with renal impairment and those with normal renal function.

 The population PK analysis included 189 patients with normal hepatic function (TB and AST≤ULN and 34 with mild hepatic impairment (TB 1.0x to 1.5x ULN or AST>ULN) patients. No clinical differences in the exposure to daratumumab were observed between patients with mild hepatic impairment and those with normal hepatic function. Daratumumab has not been studied in patients with moderate (TB>1.5x to 3× ULN and any AST) or severe (TB>3× ULN and any AST) hepatic impairment.

Drug Interactions None 

Source: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761036s004lbl.pdf