Tag Archives: FDA alerts

Daratumumab injection

Daratumumab injection
The U.S. Food and Drug Administration granted accelerated approval to daratumumab injection (DARZALEX, Janssen Biotech, Inc.), administered as a single agent for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. November 16, 2015. More Information:
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm472904.htm

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U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves COTELLIC (Cobimetinib)

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves COTELLIC (Cobimetinib)

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*FDA Approves COTELLIC^® (Cobimetinib) for the Treatment of Patients with Unresectable or Metastatic Melanoma with a BRAF V600E or V600K Mutation, in Combination with Vemurafenib *

On November 10, 2015, the United States Food and Drug Administration (FDA) approved COTELLIC (Cobimetinib) in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K Mutation. The approved recommended dosage of COTELLIC tablets is 60 mg orally once daily with or without food for the first 21 days of each 28 day cycle until disease progression or unacceptable toxicity. The dosage of COTELLIC may be reduced to 40 mg or 20 mg once daily for adverse reactions. Clinically relevant QT prolongation has been reported with vemurafenib, further QTc prolongation was not observed when cobimetinib 60 mg daily was co-administered with vemurafenib. Monitor ECG and electrolytes before initiating treatment and routinely during treatment with cobimetinib, when administered with vemurafenib.

_Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Cobimetinib_

* /MOA:/ Cobimetinib reversibly inhibits mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. * /Dose proportionality:/ Exhibited dose-proportional increases in systemic exposure over the dose range of 3.5 to 100 mg (i.e., 0.06 to 1.7 times the approved recommended dosage).
* /Accumulation:/ Mean of 2.4-fold at the approved recommended dosage. * /Absorption:/ The absolute bioavailability of COTELLIC was 46% in healthy subjects. The Tmax was 2.4 hours (range:1 to 24 hours) in cancer patients.
* /Plasma protein binding:/ Approximately 95%.
* /Terminal half-life (mean):/ Approximately 44 hours (range: 23 to 70 hours) in cancer patients.
* /Metabolism:/ Primarily metabolized by CYP3A and glucuronidated by UGT2B7.
* /Excretion:/ Approximately 76% of the total recovered radio-labeled cobimetinib dose was eliminated in the feces (with 6.6% as unchanged drug) and 17.8% was eliminated in the urine (with 1.6% as unchanged drug).

_Drug Interaction Potential_

* Avoid strong or moderate CYP3A inhibitors. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors including certain antibiotics (e.g., erythromycin, ciprofloxacin) is unavoidable for patients who are taking COTELLIC 60 mg, reduce COTELLIC dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume COTELLIC at the previous dose. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of COTELLIC (40 or 20 mg daily). Coadministration of the strong CYP3A inhibitor itraconazole increased cobimetinib AUC by 6.7-fold and Cmax by 3.2-fold.
* Avoid strong or moderate CYP3A inducers. Cobimetinib exposures are estimated to decrease by 83% when coadministered with a strong CYP3A inducer and by 73% when coadministered with a moderate CYP3A inducer. * Cobimetinib is a substrate of efflux transporter P-glycoprotein (P-gp) in vitro. Drugs that inhibit P-gp may increase cobimetinib concentrations; however, the clinical relevance of this finding is unknown.
* Clinically relevant pharmacokinetic interactions were not observed following coadministration of COTELLIC with the following medications: vemurafenib, midazolam (sensitive CYP3A substrate), dextromethorphan (sensitive CYP2D6 substrate), or rabeprazole (proton pump inhibitor).

_Use in Specific Populations_

The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of cobimetinib: sex, age (19 to 88 years), race/ethnicity, mild to moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min), and mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > ULN but ≤ 1.5 × ULN and any AST). The effect of moderate to severe hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST), severe renal impairment or end-stage renal disease with or without hemodialysis (CLcr less than 29 mL/min) on cobimetinib exposure (i.e., AUC and Cmax) is unknown.

_Safety and Efficacy_

Clinical effectiveness and safety of cobimetinib were demonstrated at the approved recommended dosage in a multicenter, randomized (1:1), double-blinded, placebo-controlled trial in patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic, melanoma. The median progression-free survival (PFS) was 12.3 months in patients treated with cobimetinib and vemurafenib compared with 7.2 months in those receiving vemurafenib as a single agent [hazard ratio: 0.56 (0.45, 0.70, p < 0.001)].

The most common adverse reactions were diarrhea, photosensitivity reaction, nausea, and vomiting. Advise patients to avoid sun exposure. Monitor for severe skin rashes and interrupt, reduce, or discontinue COTELLIC if required.

Medical Device Safety and Recalls: FDA Recommends Health Care Facilities Transition from Custom Ultrasonics Endoscope Washer/Disinfectors to Alternate Reprocessing Methods: FDA Safety Communication

Medical Device Safety and Recalls: FDA Recommends Health Care Facilities Transition from Custom Ultrasonics Endoscope Washer/Disinfectors to Alternate Reprocessing Methods: FDA Safety Communication

Today, the FDA issued the Safety Communication, “FDA Recommends Health Care Facilities Transition from Custom Ultrasonics Endoscope Washer/Disinfectors to Alternate Reprocessing Methods
to notify health care professionals about our concerns with the safety and effectiveness of all Custom Ultrasonics’ AER models. This communication provides recommended actions health care facilities should take if they use Custom Ultrasonics’ AERs because of the risk of transmission of infectious organisms to patients.

Drug Information Update- FDA approves new pill to treat certain patients with non-small cell lung cancer

Drug Information Update- FDA approves new pill to treat certain patients with non-small cell lung cancer
FDA Division of Drug Information: Know the Moment It Happens

The Division of Drug Information (DDI) is CDER’s focal point for public inquiries. We serve the public by providing information on human drug products and drug product regulation by FDA.

Today, the U.S. Food and Drug Administration granted accelerated approval for an oral medication to treat patients with advanced non-small cell lung cancer (NSCLC). Tagrisso (osimertinib) is now approved for patients whose tumors have a specific epidermal growth factor receptor (EGFR) mutation (T790M) and whose disease has gotten worse after treatment with other EGFR-blocking therapy.

Today, the FDA also approved the first companion diagnostic test (cobas EGFR Mutation Test v2) to detect the type of EGFR resistance mutation that Tagrisso is known to target. The newly approved version (v2) of the test adds the T790M mutation to the clinically relevant mutations detected by the original cobas EGFR Mutation Test (v1).

The most common side effects of Tagrisso are diarrhea, skin and nail conditions such as dry skin, rash and infection or redness around the fingernails. Tagrisso may cause serious side effects, including inflammation of the lungs and injury to the heart. It also may cause harm to a developing fetus.

The FDA granted Astra Zeneca breakthrough therapy designation, priority review and orphan drug designation for Tagrisso. Breakthrough therapy designation is granted for a drug that is intended to treat a serious condition when, at the time an application is submitted, preliminary clinical evidence indicates that a drug may demonstrate substantial improvement over available therapies. Priority review
designation is granted to drug applications that show a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation
provides incentives such as tax credits, user fee waivers, and eligibility for market exclusivity to assist and encourage the development of drugs for rare diseases.

Tagrisso was approved under the agency’s accelerated approval program which allows the approval of a drug to treat a serious or
life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials.

For more information please visit: Tagrisso

Drug Information Update- New FDA Drug Safety Communication on Plavix (clopidogrel)

Drug Information Update- New FDA Drug Safety Communication on Plavix (clopidogrel)
FDA Division of Drug Information: Know the Moment It Happens

The Division of Drug Information (DDI) is CDER’s focal point for public inquiries. We serve the public by providing information on human drug products and drug product regulation by FDA.

A U.S. Food and Drug Administration (FDA) review has determined that long-term use of the blood-thinning drug Plavix (clopidogrel) does not increase or decrease overall risk of death in patients with, or at risk for, heart disease. Our evaluation of the Dual Antiplatelet Therapy (DAPT)^1 trial and several other clinical trials also does not suggest that clopidogrel increases the risk of cancer or death from cancer.

Patients should not stop taking clopidogrel or other antiplatelet medicines because doing so may result in an increased risk of heart attacks and blood clots. Talk with your health care professional if you have any questions or concerns about clopidogrel. Health care professionals should consider the benefits and risks of available antiplatelet medicines before starting treatment.

Clopidogrel is an antiplatelet medicine used to prevent blood clots in patients who have had a heart attack, stroke, or problems with the circulation in the arms and legs. It works by helping to keep the platelets in the blood from sticking together and forming clots that can occur with certain medical conditions.

For more information, please visit: Plavix

Drug Information Update- FDA approves new drug to treat severe asthma

Drug Information Update- FDA approves new drug to treat severe asthma FDA Division of Drug Information: Know the Moment It Happens

The Division of Drug Information (DDI) is CDER’s focal point for public inquiries. We serve the public by providing information on human drug products and drug product regulation by FDA.

The U.S. Food and Drug Administration today approved Nucala
(mepolizumab) for use with other asthma medicines for the maintenance treatment of asthma in patients age 12 years and older. Nucala is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.

The most common side effects of Nucala include headache, injection site reactions (pain, redness, swelling, itching, or a burning feeling at the injection site), back pain, and weakness (fatigue). Hypersensitivity reactions can occur within hours or days of being treated with Nucala, including swelling of the face, mouth, and tongue; fainting, dizziness, or lightheadedness; hives; breathing problems and rash. Herpes zoster infections have occurred in patients receiving Nucala. Herpes zoster is the virus that causes shingles.

To learn more, please visit: Nucala

This is an automated message delivery system. Replying to this message will not reach DDI staff. If you have comments or questions, please contact us at: 1-888-INFO FDA (1-888-463-6332) or (301) 796-3400 from 8:00 am – 4:30 pm ET Monday – Friday. You can also email us at druginfo@fda.hhs.gov .

FDA approved GENVOYA as a complete regimen for the treatment of HIV-1 infection

   

Today, November 5, 2015, FDA approved GENVOYA, a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.

GENVOYA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA.

GENVOYA contains a new form of tenofovir that has not been previously approved. This new form of tenofovir provides lower levels of drug in the bloodstream, but higher levels within the cells where HIV-1 replicates. It was developed to help reduce some drug side effects. GENVOYA appears to be associated with less kidney toxicity and decreases in bone density than previously approved tenofovir containing regimens based on laboratory measures. Patients receiving GENVOYA experienced greater increases in serum lipids (total cholesterol and low-density lipoprotein) than patients receiving other treatment regimens in the studies.

Dosage and Administration:

The recommended dosage of GENVOYA is one tablet taken orally once daily with food.

No dosage adjustment of GENVOYA is required in patients with estimated creatinine clearance greater than or equal to 30 mL per minute.

GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population is insufficient.

GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C)

Contraindications:

Coadministration of GENVOYA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of GENVOYA and possible resistance) are listed below.

Drug Class Drugs within Class that are Contraindicated with GENVOYA Clinical Comment
Alpha 1-Adrenoreceptor Antagonist Alfuzosin Potential for increased alfuzosin concentrations, which can result in hypotension.
Anticonvulsants Carbamazepine*

Phenobarbital

Phenytoin

Carbamazepine, phenobarbital, and phenytoin are potent inducers of CYP450 metabolism and may cause significant decrease in the plasma concentration of elvitegravir, cobicistat, and TAF. This may result in loss of therapeutic effect to GENVOYA.
Antimycobacterial Rifampin Rifampin is a potent inducer of CYP450 metabolism and may cause significant decrease in the plasma concentration of elvitegravir, cobicistat, and TAF. This may result in loss of therapeutic effect to GENVOYA.
Ergot Derivatives Dihydroergotamine

Ergotamine

Methylergonovine

Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent Cisapride Potential for serious and/or life-threatening events such as cardiac arrhythmias.
Herbal Products St. John’s wort (Hypericum perforatum) Coadministration of products containing St. John’s wort and GENVOYA may result in reduced plasma concentrations of elvitegravir, cobicistat, and TAF. This may result in loss of therapeutic effect and development of resistance.
HMG-CoA Reductase Inhibitors Lovastatin

Simvastatin

Potential for serious reactions such as myopathy, including rhabdomyolysis.
Neuroleptic Pimozide Potential for serious and/or life-threatening events such as cardiac arrhythmias.
Phosphodiesterase-5 (PDE5) Inhibitor Sildenafila when dosed as REVATIO for the treatment of pulmonary arterial hypertension There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).
Sedative/hypnotics Triazolam

Orally administered midazolamb

Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with GENVOYA may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.

Warnings and Precautions:

The GENVOYA product labeling includes several Warnings and Precautions and are similar to those included in the tenofovir (VIREAD) or STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) labels. The label also includes statements specific to new onset or worsending of renal impairment as follows:

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of GENVOYA, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of GENVOYA in treatment naïve subjects and in virally suppressed subjects switched to GENVOYA with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA. In a study of virally suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with GENVOYA for a median duration of 43 weeks, GENVOYA was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute [see Adverse Reactions
(6.1)]. GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Clinical Trials Experience

Genvoya’s safety and efficacy in adults were evaluated in 3,171 participants enrolled in four clinical trials. Depending on the trial, participants were randomly assigned to receive Genvoya or another FDA approved HIV treatment. Results showed Genvoya was effective in reducing viral loads and comparable to the other treatment regimens.

Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea. The safety profile was similar for treatment-naïve and virologically suppressed adults. The safety profile in adolescent subjects was similar to adults. Additionally the safety profile of GENVOYA in subjects with renal impairment was similar to that of subjects with normal renal function. In an open-label trial (Study 112), 248 HIV-1 infected subjects with eGFR of 30 to 69 mL per minute (by Cockcroft-Gault method) were treated with GENVOYA for a median duration of 43 weeks. Of these subjects, 64% had previously been on a stable TDF-containing regimen. Among the 80 subjects with baseline eGFR less than 50 mL per minute receiving GENVOYA, two subjects developed worsening renal impairment and discontinued treatment. One subject with an eGFR over 50 mL per minute developed transient acute renal failure.

Serum Lipids:

Subjects receiving GENVOYA experienced greater increases in serum lipids compared to those receiving STRIBILD.

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio are presented in Table 4.

Table 4 Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving GENVOYA or STRIBILD in Studies 104 and 111a

GENVOYA

N=866

STRIBILD

N=867

Baseline Week 48 Baseline Week 48
mg/dL Changeb mg/dL Changeb
Total Cholesterol (fasted) 162

[N=757]

+30

[N=757]

166

[N=742]

+13

[N=742]

HDL-cholesterol (fasted) 46

[N=757]

+7

[N=757]

45

[N=742]

+4

[N=742]

LDL-cholesterol (fasted) 104

[N=753]

+15

[N=753]

107

[N=744]

+3

[N=744]

Triglycerides (fasted) 113

[N=757]

+29

[N=757]

119

[N=742]

+10

[N=742]

Total Cholesterol to HDL ratio 3.7

[N=757]

0.2

[N=757]

3.9

[N=742]

0

[N=742]

a. Excludes subjects who received lipid lowering agents during the treatment period.

b.The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values.

Description of Clinical Trials

The efficacy and safety of GENVOYA were evaluated in the studies summarized in the table below

Trials Conducted with GENVOYA in Subjects with HIV-1 Infection

Trial Population Study Arms (N) Timepoint (Week)
Study 104a

Study 111a

Treatment-naïve adults GENVOYA (866)

STRIBILD (867)

48
Study 109b Virologically-suppressedd adults GENVOYA (799)

ATRIPLA® or TRUVADA®+atazanavir+cobicistat or ritonavir or STRIBILD (397)

48
Study 112c Virologically-suppressedd adults with renal impairmente GENVOYA (242) 24
Study 106c Treatment-naïve adolescents between the ages of 12 to less than 18 years GENVOYA (23) 24

a. Randomized, double blind, active controlled trial.
b. Randomized, open label, active controlled trial.
c. Open label trial.
d. HIV-1 RNA less than 50 copies per mL.
e. eGFR of 30 to 69 mL per minute by Cockcroft-Gault method.

Clinical Trial Results in HIV-1 Treatment-Naïve Subjects

In both Study 104 and Study 111, subjects were randomized in a 1:1 ratio to receive either GENVOYA (N=866) once daily or STRIBILD (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TDF 300 mg) (N=867) once daily. The mean age was 36 years (range 18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies per mL (range 1.3–7.0) and 23% of subjects had baseline viral loads greater than 100,000 copies per mL. The mean baseline CD4+ cell count was 427 cells per mm3 (range 0-1360) and 13% had CD4+ cell counts less than 200 cells per mm3.

Pooled treatment outcomes of Studies 104 and 111 through 48 weeks are presented in Table 13.

Table 13 Pooled Virologic Outcomes of Randomized Treatment in Studies 104 and 111 at Week 48a in Treatment-Naïve Subjects

GENVOYA (N=866) STRIBILD (N=867)
HIV-1 RNA < 50 copies/mL 92% 90%
Treatment Difference 2.0% (95% CI: -0.7% to 4.7%)
HIV-1 RNA ≥ 50 copies/mLb 4% 4%
No Virologic Data at Week 48 Window 4% 6%
Discontinued Study Drug Due to AE or Deathc 1% 2%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd 2% 4%
Missing Data During Window but on Study Drug 1% <1%

a.Week 48 window was between Day 294 and 377 (inclusive).

b.Included subjects who had ≥ 50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

c.Includes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.

d.Includes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

Treatment outcomes were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.

In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 48 was 230 cells per mm3 in GENVOYA-treated subjects and 211 cells per mm3 in STRIBILD-treated subjects.

Clinical Trial Results in HIV-1 Virologically-Suppressed Subjects Who Switched to GENVOYA

In Study 109, the efficacy and safety of switching from either ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD to GENVOYA once daily were evaluated in a randomized, open-label trial of virologically-suppressed (HIV-1 RNA less than 50 copies per mL) HIV-1 infected adults (1196 of 1436 enrolled and treated were evaluable for efficacy). Subjects must have been suppressed (HIV-1 RNA less than 50 copies per mL) on their baseline regimen for at least 6 months and had no known resistance-associated substitutions to any of the components of GENVOYA prior to study entry. Subjects were randomized in a 2:1 ratio to either switch to GENVOYA at baseline (N=799), or stay on their baseline antiretroviral regimen (N=397). Subjects had a mean age of 41 years (range 21-72), 90% were male, 67% were White, and 21% were Black. The mean baseline CD4+ cell count was 705 cells per mm3 (range 79-1951).

Subjects were stratified by prior treatment regimen. At screening, 42% of subjects were receiving TRUVADA plus atazanavir (given with either cobicistat or ritonavir), 32% were receiving STRIBILD, and 26% were receiving ATRIPLA.

Treatment outcomes of Study 109 through 48 weeks are presented in Table 14.

Table 14 Virologic Outcomes of Study 109 at Week 48a in Virologically-Suppressed Subjects who Switched to GENVOYA

GENVOYA (N=799) ATRIPLA or TRUVADA+atazanavir+cobicistat or ritonavir or STRIBILD (N=397)
HIV-1 RNA < 50 copies/mL 96% 93%
HIV-1 RNA ≥ 50 copies/mLb 1% 1%
No Virologic Data at Week 48 Window 3% 6%
Discontinued Study Drug Due to AE or Deathc 1% 1%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd 1% 4%
Missing Data During Window but on Study Drug 2% 1%

a. Week 48 window was between Day 294 and 377 (inclusive).

b. Included subjects who had ≥ 50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

c. Includes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.

d. Includes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

Treatment outcomes were similar across subgroups receiving ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD prior to randomization. In Study 109, the mean increase from baseline in CD4+ cell count at Week 48 was 33 cells per mm3 in GENVOYA-treated subjects and 27 cells per mm3 in subjects who stayed on their baseline regimen.

Clinical Trial Results in HIV-1 Infected Subjects with Renal Impairment

In Study 112, the efficacy and safety of GENVOYA once daily were evaluated in an open-label clinical trial of 248 HIV-1 infected subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method). Of the 248 enrolled, 6 were treatment naïve and 242 were virologically suppressed (HIV-1 RNA less than 50 copies per mL) for at least 6 months before switching to GENVOYA.

The mean age was 58 years (range 24-82), with 63 subjects (26%) who were 65 years of age or older. Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were Asian. Thirteen percent of subjects identified as Hispanic/Latino. The mean baseline CD4+ cell count was 664 cells per mm3 (range 126-1813). At Week 24, 95% (230/242 virologically suppressed subjects) maintained HIV-1 RNA less than 50 copies per mL after switching to GENVOYA. Three subjects had virologic failure at Week 24.

Clinical Trial Results in HIV-1 Treatment-Naïve Adolescent Subjects Aged 12 to Less than 18

In Study 106, the efficacy, safety, and pharmacokinetics of GENVOYA were evaluated in an open-label trial in HIV-1-infected treatment-naïve adolescents aged 12 to less than 18 years. Twenty-three subjects treated with GENVOYA once daily for 24 weeks had a mean age of 14 years; 52% were male, 17% were Asian, and 83% were black. At baseline, mean plasma HIV-1 RNA was 4.8 log10 copies per mL (35% had baseline plasma HIV-1 RNA greater than 100,000 copies per mL), median CD4+ cell count was 456 cells per mm3 (range: 104 to 748), and median CD4+ percentage was 23% (range: 7% to 41%).

At 24 weeks, the virologic response rate to GENVOYA in treatment naïve HIV-1 infected adolescents was similar to response rates in trials of treatment naïve HIV-1 infected adults; 91% achieved HIV-1 RNA less than 50 copies per mL. The mean increase from baseline in CD4+ cell count at Week 24 was 212 cells per mm3. Two subjects had virologic failure at Week 24; neither subject had evidence of resistance to GENVOYA.

You can view the complete label at drugs@fda or dailymed.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

For more information about the HIV Liaison Program visit the FDA Patient Network

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves YONDELIS (trabectedin)

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves YONDELIS (trabectedin)

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*FDA Approves YONDELIS^® (trabectedin) for Advanced Soft Tissue Sarcoma Subtypes, Liposarcoma, and Leiomyosarcoma, With Prior Chemotherapy*

On October 23, 2015, the United States Food and Drug Administration (FDA) approved YONDELIS (trabectedin) for the treatment of patients with advanced soft tissue sarcoma (STS), liposarcoma, and leiomyosarcoma subtypes (L-type sarcoma), who have received prior chemotherapy, including an anthracycline regimen. The approved recommended dosage of YONDELIS lyophilized powder for injection is 1.5 mg/m2 administered as a 24-hour intravenous (IV) infusion once every three weeks (Q3W). Patients receiving YONDELIS will be premedicated with dexamethasone 20 mg IV or an equivalent dose of an IV corticosteroid on day 1 of each treatment cycle, 30 minutes before the infusion.

_Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Trabectedin_

* /MOA:/ Trabectedin disrupts the cell cycle and inhibits cell proliferation.
* /Dose proportionality:/ Exhibited dose-proportional increases in systemic exposure over the dose range of 0.024 mg/m2 to 1.8 mg/m2 (i.e., 0.016 times to 1.2 times the approved recommended dosage). * /Accumulation:/ No accumulation was observed at the approved recommended dosage.
* /Plasma protein binding:/ Approximately 97%.
* /Terminal half-life (mean):/ Approximately 175 hours in patients. * /Metabolism:/ Extensive. Primarily metabolized by CYP3A.
* /Excretion:/ Approximately 58% of the total recovered radio-labeled trabectedin dose was eliminated in the feces and 6% was eliminated in the urine. Unchanged trabectedin recovery was negligible. * /Exposure-safety:/ Adverse reactions (ARs), mainly neutropenia and elevation in transaminases, led to dose reductions in 35% of patients receiving trabectedin in the registration trial. The proposed dose adjustment from 1.5 mg/m2 to 1.2 mg/m2 and then to 1 mg/m2 due to toxicity was used in the registration trial. Exposure-response (E-R) relationships were identified for the common ARs in the registration trial, including neutropenia, elevation in transaminases, and hyperbilirubinemia, using data from Phase 1 and 2 studies. The proposed dose adjustments are likely to decrease toxicity based on the exposure-toxicity relationships.

_Drug Interaction Potential_

* Avoid strong CYP3A inhibitors (e.g., oral ketoconazole,
itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS. Avoid taking grapefruit or grapefruit juice during YONDELIS treatment. Administer the strong CYP3A inhibitor 1 week after the YONDELIS infusion, and discontinue it the day prior to the next YONDELIS infusion if short term strong CYP3A inhibitor use (i.e., less than 14 days) must be used.
Coadministration of a strong CYP3A4 inhibitor (i.e., ketoconazole) increased the trabectedin dose normalized AUC by 66% and Cmax by 22%. * Avoid strong CYP3A inducers. Coadministration of a strong CYP3A4 inducer (i.e.., rifampicin) decreased trabectedin dose normalized AUC by 31% and Cmax by 21%.

_Use in Specific Populations_

The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of trabectedin: sex, age (19 to 83 years), body weight (36 to 148 kg), BSA (0.9 to 2.8 m2), mild to moderate (creatinine clearance (CLcr) 30 to 89 mL/min) renal impairment. The effect of any degree of hepatic impairment, severe renal impairment (CLcr 15 to 29 mL/min), or end stage renal disease (CLcr less than 15 mL/min) with or without hemodialysis on trabectedin exposure is unknown.

_Safety and Efficacy_

Clinical effectiveness and safety of trabectedin were demonstrated at the recommended dose in a multicenter, randomized, open-label, active-controlled trial that enrolled 518 patients with L-type sarcoma who received prior chemotherapy, including an anthracycline regimen. The median progression-free survival was 4.2 months in trabectedin-treated patients compared to 1.5 months in those receiving dacarbazine [hazard ratio: 0.55 (0.4, 0.7, p < 0.0001)]. The most common ARs were nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, dyspnea, headache, fever, cough, increases in AST or ALT, neutropenia, and anemia.

Source: FDA.GOV

Sanofi US Issues Voluntary Nationwide Recall of Auvi-Q® Due to Potential Inaccurate Dosage Delivery

Sanofi US Issues Voluntary Nationwide Recall of Auvi-Q® Due to Potential Inaccurate Dosage Delivery

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This information has recently been updated and is now available.

Sanofi US Issues Voluntary Nationwide Recall of Auvi-Q® Due to Potential Inaccurate Dosage Delivery
10/28/2015 09:38 PM EDT

Sanofi US is voluntarily recalling all Auvi-Q (epinephrine injection, USP). The recall involves all Auvi-Q currently on the market and includes both the 0.15 mg and 0.3 mg strengths for hospitals, retailers and consumers. This includes lot number 2299596 through 3037230, which expire March 2016 through December 2016. The products have been found to potentially have inaccurate dosage delivery.

For detailed information pertaining to this Recalls, Market Withdrawals and Safety Alerts message, please click the link at the beginning of this bulletin.

FDA Drug Safety Communication: FDA review found no increased cardiovascular risks with Parkinson’s disease drug en tacapone

FDA Drug Safety Communication: FDA review found no increased cardiovascular risks with Parkinson’s disease drug entacapone FDA Division of Drug Information: Know the Moment It Happens

The Division of Drug Information (DDI) is CDER’s focal point for public inquiries. We serve the public by providing information on human drug products and drug product regulation by FDA.

This is an update to the FDA Drug Safety Communication: Ongoing Safety Review of Stalevo and Possible Increased Cardiovascular Risk issued on August 20, 2010.

A FDA safety review has found no clear evidence of an increased risk of heart attacks, stroke, or other cardiovascular events associated with the use of entacapone for the treatment of Parkinson’s disease. As a result, our recommendations for using Comtan (entacapone) and Stalevo (a combination of entacapone, carbidopa, and levodopa) will remain the same in the drug labels. Patients should discuss any questions they have with their health care professionals.

We alerted patients and health care professionals about a possible increased risk for cardiovascular events and death with Stalevo in an August 2010 Drug Safety Communication. This possible safety issue was observed in a clinical trial called the Stalevo Reduction in Dyskinesia Evaluation in Parkinson’s Disease (STRIDE-PD) and in a meta-analysis that combined the cardiovascular-related findings from 15 clinical trials comparing Stalevo to carbidopa/levodopa. Carbidopa and levodopa have been used extensively and have not been shown to have an increased cardiovascular risk. We were concerned that the entacapone in Stalevo was responsible for these cardiovascular risks because the comparison drugs do not contain this ingredient.

To better understand the significance of these findings, we required the Stalevo manufacturer, Novartis, to study the potential for
cardiovascular risk with the entacapone component of the drug. We examined the results from this required study and from one additional study and concluded they do not show an increased risk of cardiovascular adverse events with entacapone. The results observed in the original meta-analysis were driven by results of a single study (STRIDE-PD), which was not designed to assess cardiovascular risks. We believe that the meta-analysis and STRIDE-PD results are chance findings and do not represent a true increase in risk due to entacapone.

In light of the results from these two additional studies, FDA finds no evidence of an increased risk of myocardial infarction, stroke, or other cardiovascular events associated with the use of entacapone, Comtan or Stalevo. As a result, the drug labels will remain unchanged.

We urge patients and health care professionals to report side effects involving entacapone, Comtan, or Stalevo to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page.

To learn more, please visit: entacapone
.