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./

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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

Quest Medical, Inc. Issues Recall of MPS® Delivery Set

Quest Medical, Inc. Issues Recall of MPS® Delivery Set

You are subscribed to Recalls, Market Withdrawals and Safety Alerts for U.S. Food & Drug Administration (FDA).

This information has recently been updated and is now available.

Quest Medical, Inc. Issues Recall of MPS® Delivery Set
10/29/2015 12:45 PM EDT

On October 28, 2015, Quest Medical, Inc. initiated a nationwide recall of Myocardial Protection System (MPS) Delivery Sets, Models 5001102, 5001102-AS, and 7001102 of specified lots. The product(s) have been found to intermittently exhibit a seal failure during use, which potentially could result in patient blood loss.

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

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

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

You are subscribed to Recalls, Market Withdrawals and Safety Alerts for U.S. Food & Drug Administration (FDA).

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.

Drug Information Update- FDA approves new treatment for advanced pancreatic cancer

Drug Information Update- FDA approves new treatment for advanced pancreatic 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 approved Onivyde (irinotecan liposome injection), in combination with fluorouracil and leucovorin, to treat patients with advanced (metastatic) pancreatic cancer who have been previously treated with gemcitabine-based chemotherapy.

According to the National Cancer Institute, there will be 48,960 new cases of pancreatic cancer diagnosed in the U.S. in 2015, and nearly the same number of deaths caused by the disease (40,560). Pancreatic cancer can be difficult to diagnose early and treatment options are limited, especially when the disease has spread to other parts of the body (metastatic disease) and surgery to remove the tumor is not possible.

The safety of Onivyde was evaluated in 398 patients who received either Onivyde with fluorouracil/leucovorin, Onivyde alone or
fluorouracil/leucovorin. The most common side effects of treatment with Onivyde included diarrhea, fatigue, vomiting, nausea, decreased appetite, inflammation in the mouth (stomatitis) and fever (pyrexia). Onivyde was also found to result in low counts of infection-fighting cells (lymphopenia and neutropenia). Death due to sepsis following neutropenia has been reported in patients treated with Onivyde.

The labeling for Onivyde includes a boxed warning to alert health care professionals about the risks of severe neutropenia and diarrhea. Onivyde is not approved for use as a single agent for the treatment of patients with metastatic pancreatic cancer.

For more information, please visit: Onivyde
.

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
.

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

Idarucizumab

Idarucizumab

U. S. Food and Drug Administration granted accelerated approval to idarucizumab (Praxbind Injection, Boehringer Ingelheim Pharmaceuticals, Inc.) for the treatment of patients treated with dabigatran (Pradaxa) when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. October 16, 2015. More Information:
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm467396.htm

Drug Information Update- FDA approves new drug to reverse effects of neuromuscular blocking drugs used during surgery

Drug Information Update- FDA approves new drug to reverse effects of neuromuscular blocking drugs used during 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.

The U.S. Food and Drug Administration today approved Bridion (sugammadex) injection to reverse the effects of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide, which are used during certain types of surgery in adults.

Rocuronium bromide and vecuronium bromide are neuromuscular blocking drugs that cause temporary paralysis by interfering with the transmission of nerve impulses to the muscle and are used to paralyze the vocal cords when patients require an artificial airway or breathing tube for surgery, a process called tracheal intubation. They can also be used to prevent patients from moving during surgery while they are receiving general anesthesia. Neuromuscular blocking drugs are also sometimes used to prevent the body from breathing automatically when a patient has to be placed on a ventilator.

Due to concerns about the nature and frequency of anaphylaxis (severe, potentially life-threatening allergic reaction) and hypersensitivity reactions reported in the clinical trials, Bridion was further evaluated in a randomized, double-blind, parallel-group, repeat-dose trial. Of the 299 participants treated with Bridion, one person had an anaphylactic reaction. Clinicians should be aware of the possibility of a hypersensitivity reaction or anaphylaxis and should intervene as appropriate.

Cases of marked bradycardia (abnormally slow heart action), some of which have resulted in cardiac arrest, have been observed within minutes after the administration of Bridion/. /Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade, and treatment with anticholinergic agents, such as atropine, should be administered if clinically significant bradycardia is observed.

The most common adverse reactions reported in clinical trials included vomiting, low blood pressure (hypotension), pain, headache and nausea. Doctors should also advise women using hormonal contraceptives that Bridion may temporarily reduce the contraceptive effect so they must use an alternate method of birth control for a period of time.

For more information please visit: Bridion