Tag Archives: FDA approval

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.

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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

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update:FDA Approves LONSURF (trifluridine and tipiracil)

U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update:FDA Approves LONSURF (trifluridine and tipiracil)

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FDA Approves LONSURF^® (trifluridine and tipiracil) for the Treatment of Advanced Metastatic Colorectal Cancer

On September 22, 2015, the United States Food and Drug Administration (FDA) approved LONSURF (trifluridine and tipiracil) tablets for the treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and
irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. The approved recommended dosage is 35 mg/m^2 (based on the trifluridine component and rounded to the nearest 5 mg increment) orally twice daily within one hour of completion of morning and evening meals on Days 1 through 5 and Days 8 through 12 of each 28-day cycle until disease progression or unacceptable toxicity. Do not exceed 80 mg/dose.

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

* /MOA:/ Trifluridine is a thymidine-based nucleoside analogue and tipiracil is a thymidine phosphorylase inhibitor.
* /Dose proportionality:/ The AUC of trifluridine increased more than dose-proportionally over the dose range of 15 (0.43 times the recommended approved dosage) to 35 mg/m^2 . Tipiracil appeared to be dose proportional.
* /Accumulation:/ 3-fold for AUC_0-last and 2-fold for C_max at steady-state for trifluridine. No accumulation was observed for tipiracil.
* /Absorption (tablets):/ The mean relative bioavailability of LONSURF is 100% for trifluridine (T_max [mean]: 2 hours) and 96% for tipiracil (T_max [mean]: 3.5 hours) compared to oral solution. * /Food effect:/ An approximately 40% decrease in trifluridine C_max and tipiracil C_max and AUC was observed following the
administration of LONSURF with a high-fat meal to patients. * /Plasma protein binding:/ Greater than 96% for trifluridine and less than 8% for tipiracil.
* /Terminal half-life (mean):/ 2.1 hours for trifluridine and 2.4 hours for tipiracil at steady state.
* /Metabolism:/ Trifluridine and tipiracil are not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite 5-(trifluoromethyl) uracil (FTY).
* /Excretion:/ The mean 48-hour cumulative urinary excretion of unchanged trifluridine and tipiracil was 1.5% and 29.3%, respectively. * /Exposure-safety:/ LONSURF did not have a large effect (i.e. > 20 ms) on the mean QTc interval compared to placebo when administered to cancer patients at the approved recommended dosage.

_Drug Interaction Potential_

* The mean trifluridine AUC_0-last and C_max increased by 37-fold and C_max by 22-fold, respectively, following coadministration of tipiracil and trifluridine as LONSURF compared to trifluridine administered alone.
* Trifluridine, tipiracil, and FTY did not inhibit the CYP enzymes and had no inductive effect on CYP1A2, CYP2B6 or CYP3A4/5 in vitro. * Trifluridine was not an inhibitor of or substrate for human uptake and efflux transporter systems in vitro.

_Use in Specific Populations_

* No dose adjustment to the starting dose of LONSURF is recommended in patients with mild or moderate renal impairment (creatinine clearance (CLcr): 30 to 89 mL/min); however patients with moderate renal impairment may require dose modification for increased toxicity. The estimated mean AUC of trifluridine and tipiracil at steady state was 31% and 34% higher in patients with mild renal impairment (CLcr = 60-89 mL/min) and 43% and 65% higher in patients with moderate renal impairment (CLcr: 30 to 59 mL/min) based upon a pop-PK analysis of a Phase 3 trial. In addition, patients with moderate renal impairment had a higher incidence of Grade 3 or higher adverse events, serious adverse events, and dose delays and reductions compared to patients with normal renal function (CLcr greater than or equal to 90 mL/min) or patients with mild renal impairment (CLcr: 60 to 89 mL/min) in this trial. The effect of severe renal impairment or end-stage renal disease (CLcr less than 30 mL/min) on trifluridine and tipiracil exposure is unknown. * The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of
trifluridine or tipiracil: age, sex, race (White or Asian), or mild hepatic impairment. The effect of moderate to severe hepatic impairment on trifluridine and tipiracil exposure is unknown.

_Safety and Efficacy_

The clinical efficacy and safety of LONSURF were evaluated in an international, randomized, double-blind, placebo-controlled study conducted in patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS). A statistically significant median 1.8 month improvement in overall survival (Hazard ratio [95% CI]: 0.68 (0.58, 0.81) p <0.001) was demonstrated in patients in the LONSURF plus best supportive care (BSC) arm compared to those who received placebo plus BSC. The most common adverse reactions reported in this trial were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia.

Full prescribing information is available at http://go.usa.gov

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm
by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency’s Drugs@FDA website http://go.usa.gov

We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov .

/This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA./

Drug Information Update – FDA approves expanded use of drug to reduce the risk of melanoma returning after surgery

Drug Information Update – FDA approves expanded use of drug to reduce the risk of melanoma returning after surgery
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.

On October 28, 2015, the U.S. Food and Drug Administration expanded the approved use of Yervoy (ipilimumab) to include a new use as adjuvant therapy for patients with stage III melanoma, to lower the risk that the melanoma will return following surgery.

Yervoy, administered intravenously, was originally approved in 2011 to treat late-stage melanoma that cannot be removed by surgery. Yervoy is a monoclonal antibody that blocks a molecule known as CTLA-4 (cytotoxic T-lymphocyte antigen). CTLA-4 may play a role in slowing down or turning off the body’s immune system, and affects its ability to fight off cancerous cells. Yervoy may work by allowing the body’s immune system to recognize, target and attack cells in melanoma tumors.

The safety and effectiveness of Yervoy for this new use were studied in 951 patients who received Yervoy or a placebo as adjuvant therapy following complete surgical removal of melanoma. The study measured the amount of time after treatment it took for the cancer to come back (“recurrence-free survival”) and overall survival. Forty-nine percent of participants taking Yervoy had their cancer return after an average of 26 months, compared to 62 percent of those receiving a placebo, whose cancer returned after an average of 17 months. The analysis of overall survival data has not yet occurred.

The most common side effects of Yervoy in this study were rash, diarrhea, fatigue, itching, headache, weight loss and nausea. Yervoy can also cause autoimmune disease in the digestive system, liver, skin, nervous system (which would each require treatment with
corticosteroids), as well as in the hormone-producing glands (which requires life-long hormone replacement therapy). Women who are pregnant should not take Yervoy because it may cause harm to a developing fetus.

Due to the potential for fatal immune-mediated adverse reactions and unusual severe side effects with Yervoy, the label includes a Boxed Warning. A Medication Guide will also be provided to patients to inform them about the therapy’s potential side effects.

For more information, please visit: Yervoy

Ipilimumab (Yervoy)

Ipilimumab (Yervoy)

FDA approved ipilimumab (Yervoy Injection), for the additional indication of adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy. October 28, 2015. More Information:
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm470061.htm

Source: FDA.GOV

Drug Information Update – FDA approves new treatment for rare metabolic disorder

Drug Information Update – FDA approves new treatment for rare metabolic disorder
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.

On October 23, 2015, the U.S. Food and Drug Administration approved Strensiq (asfotase alfa) as the first approved treatment for perinatal, infantile and juvenile-onset hypophosphatasia (HPP).

Strensiq is administered via injection three or six times per week. Strensiq works by replacing the enzyme (known as tissue-nonspecific alkaline phosphatase) responsible for formation of an essential mineral in normal bone, which has been shown to improve patient outcomes.

The safety and efficacy of Strensiq were established in 99 patients with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that patients with perinatal- and infantile-onset HPP treated with Strensiq had improved overall survival and survival without the need for a ventilator (ventilator-free survival). Ninety-seven percent of treated patients were alive at one year of age compared to 42 percent of control patients selected from a natural history study group. Similarly, the
ventilator-free survival rate at one year of age was 85 percent for treated patients compared to less than 50 percent for the natural history control patients.

Patients with juvenile-onset HPP treated with Strensiq showed improvements in growth and bone health compared to control patients selected from a natural history database. All treated patients had improvement in low weight or short stature or maintained normal height and weight. In comparison, approximately 20 percent of control patients had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. Juvenile-onset patients also showed improvements in bone mineralization, as measured on a scale that evaluates the severity of rickets and other HPP-related skeletal abnormalities based on x-ray images. All treated patients demonstrated substantial healing of rickets on x-rays while some natural history control patients showed increasing signs of rickets over time.

The most common side effects in patients treated with Strensiq include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney.

For more information, please visit: Strensiq

Drug Information Update- FDA grants accelerated approval for drug that treats non-small cell lung cancer

Drug Information Update- FDA grants accelerated approval for drug that treats 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.

The U.S. Food and Drug Administration today granted accelerated approval for Keytruda (pembrolizumab) to treat patients with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments and with tumors that express a protein called PD-L1. Keytruda is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 expression in non-small cell lung tumors.

The safety of Keytruda was studied in 550 patients with advanced NSCLC. The most common side effects of Keytruda included fatigue, decreased appetite, shortness of breath or impaired breathing (dyspnea) and cough. Keytruda also has the potential to cause severe side effects that result from the immune system effect of Keytruda (known as “immune-mediated side effects”).

To learn more, please visit: Keytruda
.

Drug Information Update- FDA approves new drug for advanced colorectal cancer

Drug Information Update- FDA approves new drug for advanced colorectal 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.

Drug Information Update- New FDA Drug Safety Communication on tramadol

Drug Information Update- New FDA Drug Safety Communication on tramadol 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 (FDA) is investigating the use of the pain medicine tramadol in children aged 17 years and younger, because of the rare but serious risk of slowed or difficult breathing. This risk may be increased in children treated with tramadol for pain after surgery to remove their tonsils and/or adenoids. We are evaluating all available information and will communicate our final conclusions and recommendations to the public when our review is complete.

Tramadol is not FDA-approved for use in children; however, data show it is being used “off-label” in the pediatric population. Health care professionals should be aware of this and consider prescribing alternative FDA-approved pain medicines for children.

Parents and caregivers of children taking tramadol who notice any signs of slow or shallow breathing, difficult or noisy breathing, confusion, or unusual sleepiness should stop tramadol and seek medical attention immediately by taking their child to the emergency room or calling 911. Parents and caregivers should talk with their child’s health care professional if they have any questions or concerns about tramadol or other pain medicines their child is taking.

For more information, please visit: tramadol
.

Drug Information Update- FDA approves new drug to treat schizophrenia and bipolar disorder

Drug Information Update- FDA approves new drug to treat schizophrenia and bipolar disorder
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 Vraylar (cariprazine) capsules to treat schizophrenia and bipolar disorder in adults.

Vraylar and all other FDA-approved drugs used to treat schizophrenia and bipolar disorder have a Boxed Warning alerting health care professionals about an increased risk of death associated with the use of these drugs in older people with dementia-related psychosis. Neither Vraylar nor any other drug in this class is approved to treat such patients.

The most common side effects reported by participants receiving Vraylar in the clinical trials for schizophrenia were extrapyramidal symptoms, such as tremor, slurred speech, and involuntary muscle movements. The most common side effects reported by trial participants receiving Vraylar for bipolar disorder were extrapyramidal symptoms, the urge to move (akathisia), indigestion (dyspepsia), vomiting, drowsiness (somnolence) and restlessness.

For more information, please visit: Vraylar
.