- Fasenra® (benralizumab) Approved to Treat Severe Eosinophilic Asthma
- Repatha® (evolucumab) Approved for the Prevention of Heart Attack and Stroke
- FDA Recommends Against Use of Opioid Cough Medications in Children Less than 18 Years of Age
- Generic Copaxone® (glatiramer acetate) 40 mg Three-Times-Weekly Approved
- Epidiolex® (cannabidiol) Receives Priority Review for Lennox-Gastaut and Dravet Syndrome
- Shortage of ADHD Medications Quillivant XR® and QuilliChew ER®
- Discontinuation of Aerospan® (flunisolide) Inhalation Aerosol
Specialty Drug Approvals
Fasenra® (benralizumab) Approved to Treat Severe Eosinophilic Asthma
In November 2017, AstraZeneca announced Fasenra® (benralizumab) had received FDA-approval as an add-on maintenance treatment for severe eosinophilic asthma in patients who are 12 years of age and older. Eosinophils are a type of white blood cell that can be elevated in patients with asthma resulting in inflammation and asthma exacerbations. Fasenra works to decrease the development, action, and survival of eosinophils. Up to 10% of asthma patients have severe asthma that is not adequately controlled despite receiving standard-of-care asthma controller medications and may require chronic oral corticosteroids. Patients with severe, uncontrolled asthma can experience frequent episodes of worsening control and limited lung function which can affect their quality of life. The use of oral steroids to treat severe episodes may lead to short- and long-term side effects.
The approval of benralizumab was based on results from the WINDWARD program. The program included the pivotal Phase III trials SIROCCO and CALIMA demonstrating the efficacy and safety of benralizumab as well as findings from the ZONDA trial demonstrating the corticosteroid-sparing ability of benralizumab. Patients treated with benralizumab demonstrated up to a 51% reduction in annual asthma exacerbation rate as well as significantly improved forced-expiratory volume in one second (FEV1), a measure of lung function, compared to patients who received placebo. Patients also exhibited a 75% median reduction in daily oral steroid use, and 52% of patients were able to discontinue oral steroid use entirely. The most common adverse effects observed in the trials were headache, fever, sore throat, and hypersensitivity reactions.
Fasenra is a monoclonal antibody that is supplied in a prefilled syringe. It is dosed as 30 mg via subcutaneous injection every 4 weeks for 3 doses followed by 30 mg every 8 weeks thereafter. It requires administration by a healthcare professional and carries an average wholesale price of $5,702.53 for a 30 mg dose. NPS is planning to review Fasenra for placement on the national formularies. For additional details on the approval of Fasenra, please view the manufacturer’s press release.
Repatha® (evolucumab) Approved for the Prevention of Heart Attack and Stroke
In December 2017, Repatha® (evolocumab) received FDA-approval to reduce the risk of heart attack, stroke, and coronary revascularizations in adults with established cardiovascular disease (CVD). With this new indication, Repatha is the first and only proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor indicated for this use. As a result of the new approval, healthcare providers now have another option to prevent cardiovascular (CV) events in patients with established CVD.
Evolocumab was initially approved in 2015 as an adjunct to diet and maximally-tolerated statin therapy in adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic CVD who required additional low-density lipoprotein-cholesterol (LDL-C) lowering. Evolocumab was also initially approved as an adjunct to diet and other LDL-C lowering therapies, such as statins or ezetimibe, for the treatment of individuals with homozygous familial hypercholesterolemia (HoFH) who also required additional LDL-C intervention.
Approval of evolocumab’s new indication was based on data from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study. This multinational, randomized, double-blind, placebo-controlled trial evaluated more than 27,000 patients with atherosclerotic CVD and LDL levels greater than 70 mg/dL. It assessed whether evolocumab + statin therapy resulted in a reduction in CV events compared to placebo + statin therapy. The primary composite endpoint was CV death, heart attack, stroke, hospitalization for unstable angina, or coronary revascularization. The secondary endpoint included a composite of time to first heart attack, stroke, or CV death. Patients were followed for a median duration of 2.2 years.
The study found a statistically significant reduction in the risk of the primary composite endpoint by 15% in the patients who received evolocumab compared to placebo. Major adverse cardiovascular events (MACE), as assessed by the secondary endpoint, were also significantly reduced by 20% in the patients who received evolocumab compared to placebo. Patients treated with evolocumab had a 27% reduced risk of heart attack, 21% reduced risk of stroke, and 22% reduced risk of coronary revascularization. However, there was no effect on cardiovascular mortality observed. The safety findings of evolocumab were similar to those observed in other clinical trials evaluating patients with primary hyperlipidemia. Common adverse events included diabetes mellitus, nasopharyngitis, and upper-respiratory tract infections.
Repatha is given as a subcutaneous injection with dosing dependent on the indication. For patients with established CVD or heterozygous familial hypercholesteromia, it is dosed as 140 mg every 2 weeks or 420 mg once monthly injected into the abdomen, thigh, or upper arm. For patients with HoFH, the dosing is 420 mg once monthly. It is supplied in a 140 mg/mL single-use prefilled syringe and SureClick® autoinjector as well as in a 420 mg/3.5 mL single-use Pushtronex® system. The average wholesale price for a 140 mg dose is $670.30, and the AWP for the 420 mg dose provided by the Pushtronex system is $1,452.30.
FDA Safety Update
FDA Recommends Against Use of Opioid Cough Medications in Children Less than 18 Years of Age
Following an extensive review and meeting with a panel of outside experts, the FDA is requiring safety labeling changes on prescription cough and cold medications containing codeine or hydrocodone. The changes will limit the use of these drugs to patients 18 years and older and add information concerning the risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing to the Boxed Warning of the drug labels. The Boxed Warning is the FDA’s most prominent warning included on drug labels.
Prescription cough and cold products that contain codeine or hydrocodone are available in combination with antihistamines or decongestants and are used to treat coughs and other symptoms associated with a cold or allergies. The FDA has determined the risks of these products outweigh the benefits when used in children ages 18 years and younger.
Cough due to the common cold usually does not require treatment. The FDA advises parents to discuss with their child’s healthcare prescriber or pharmacist to determine if a prescribed cough medication contains codeine or hydrocodone and to always read labels on prescription bottles. It is also recommended to discuss non-opioid alternatives with the child’s healthcare professional. Healthcare professionals are advised to be aware that prescription cough and cold products containing codeine or hydrocodone are no longer indicated for children 18 years and younger. These products are not recommended for use in this age group, and parents should be counseled that coughs due to the common cold or upper respiratory infection are usually self-limiting and do not require treatment. However, if treatment of the cough is necessary, acceptable non-opioid options include over-the-counter (OTC) dextromethorphan or prescription benzonatate.
A Boxed Warning and Warning and Precautions section will also be added to the label of cough and cold medications containing codeine or hydrocodone. These additions will align with the warnings included in the labeling of prescription opioid medications. There are currently cough medications containing codeine available OTC in certain states and FDA regulatory action on these products is being considered. The FDA encourages healthcare professionals and patients to report adverse events or side effects related to opioid cough medications to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program. This can be done online at www.fda.gov/MedWatch/report or by calling 1-800-332-1088 to request a reporting form to be filled out and faxed to 1-800-332-0178. For a complete listing of products affected by the labeling changes, please view the FDA’s Drug Safety Communication.
Generic Copaxone® (glatiramer acetate) 40 mg Three-Times-Weekly Approved
In October of 2017, the FDA approved Mylan’s Abbreviated New Drug Application (ANDA) for glatiramer acetate injection 40 mg/mL. Approval marked the first generic version of Copaxone® (glatiramer acetate injection) 40 mg/mL. This strength is given as a three-times-weekly injection and is able to be substituted for the brand-name Copaxone 40 mg/mL product.
The generic glatiramer injectable medication is indicated to treat patients with relapsing forms of multiple sclerosis (MS). MS is a chronic inflammatory disease affecting the central nervous system. The indication also includes patients who have experienced a first MS episode and have magnetic resonance imaging (MRI) characteristic of MS. There are approximately 400,000 people in the U.S. who have multiple sclerosis with 85% of initial cases defined as relapsing MS.
The most common side effects of glatiramer acetate injection are injection-site reactions, such as redness, pain, swelling, itching, or a lump at the site of injection, and systemic side effects, such as flushing, rash, shortness of breath, and chest pain. Some patients may experience a short-term reaction immediately following a glatiramer injection; this reaction can include flushing, chest tightness or pain with heart palpitations, anxiety, and/or trouble breathing. The reaction usually resolves within 15 minutes and does not generally require treatment. However, development of severe symptoms requires emergency medical care. A permanent indentation under the skin where glatiramer is injected may also occur. Patients are advised to follow proper injection technique as well as discuss skin changes with their healthcare provider.
Upon approval of the generic, shipments began immediately. The manufacturer has also launched a patient support service, Mylan MS Advocate, to assist patients in starting and maintaining treatment plans. All patients who are prescribed Mylan’s glatiramer injection are eligible for the program which includes a mobile app, in-home injection training, a 24/7 support center, copay assistance, and support from a multiple sclerosis-experienced nurse.
Epidiolex® (cannabidiol) Receives Priority Review for Lennox-Gastaut and Dravet Syndrome
In December 2017, the FDA accepted GW Pharmaceuticals’ New Drug Application (NDA) for Epidiolex® (cannabidiol or CBD). Epidiolex is an investigational treatment for two rare, childhood-onset epilepsy disorders: Lennox-Gastaut syndrome (LGS) and Dravet syndrome.
The onset of LGS usually occurs between the ages of 3 to 5 years and can be caused by several different conditions, including brain malformations, severe head injuries, or genetic conditions. It is associated with multiple seizure types which can lead to injuries. Patients with LGS frequently do not respond to anti-epileptic drugs. Dravet syndrome usually develops in the first year of life and is also extremely treatment-resistant. It commonly occurs in patients with a SCN1A sodium channel genetic mutation. Early in the disease, severe seizures related to body temperature elevation occur. As the disease progresses, patients experience multiple types of seizures, some of which may be life-threatening. Currently, there are no FDA-approved therapies for patients with Dravet syndrome.
Epidiolex is a pharmaceutical formulation of purified CBD and is being reviewed as adjunctive treatment for seizures associated with LGS and Dravet syndrome. The product NDA has received Priority Review status. This designation is granted to drugs developed to treat conditions without adequate therapies currently available or for promising therapies that may provide a significant advancement in treatment. The FDA has indicated plans to hold an advisory committee meeting to discuss the application and is expected to make a decision regarding approval by June 27, 2018. For additional details, please view the manufacturer’s press release.
Drug Shortages and Discontinuations
Shortage of ADHD Medications Quillivant XR® and QuilliChew ER®
On January 22, 2018, the FDA reported both Quillivant XR® and QuilliChew ER® as being on shortage. Quillivant XR is a methylphenidate extended-release (ER) oral suspension and QuilliChew ER is a methylphenidate ER chewable tablet. These central nervous system (CNS) stimulants are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and older.
All product sizes of Quillivant XR are on shortage; this includes the 300 mg/60 mL, 600 mg/120 mL, 750 mg/150 mL, and 900 mg/180 mL bottles of suspension. Additionally, all three strengths of QuilliChew ER are on shortage. The current shortage is reported to be related to manufacturing delays. At this time, there are no estimated release dates on when either product will become available. QulliChew ER and Quillivant XR are currently Preferred Brands on the standard NPS formulary.
Discontinuation of Aerospan® (flunisolide) Inhalation Aerosol
On January 26, 2018, the U.S. FDA posted the discontinuation notice for Aerospan® (flunisolide) metered-dose inhaler (MDI). The manufacturer, Mylan Specialty, has stated product discontinuation is not due to safety or efficacy concerns. The discontinuation will affect both the 60- and 120-actuation sizes and is due to a business decision.
Aerospan is an orally inhaled corticosteroid supplied in a pressurized MDI with a built-in spacer delivering 80 mcg of flunisolide per dose. It is indicated for the maintenance treatment of asthma as preventive therapy in adult and pediatric patients 6 years of age and older. It is also indicated for asthma patients who require oral corticosteroid therapy, when addition of Aerospan may decrease or eliminate the requirement for oral corticosteroids.
- AstraZeneca. Fasenra® (benralizumab) receives U.S. FDA approval for severe eosinophilic asthma. AstraZeneca Press Release. https://www.astrazeneca.com/media-centre/press-releases/2017/fasenra-benralizumab-receives-us-fda-approval-for-severe-uncontrolled-eosinophilic-asthma-14112017.html. Published November 14, 2017. Accessed January 23, 2018.
- Fasenra® [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; November 2017. https://www.azpicentral.com/fasenra/fasenra_pi.pdf#page=1. Accessed December 1, 2017.
- Brooks M. FDA approves evolocumab (Repatha®) to prevent CV events. Medscape Medical News. https://www.medscape.com/viewarticle/889513. Updated December 1, 2017. Accessed January 3, 2018.
- Sabatine M, Giugliano R, Keech A, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1615664. Accessed January 3, 2018.
- Amgen. FDA approves Amgens Repatha® (evolocumab) to prevent heart attack and stroke. Amgen.com. http://www.amgen.com/media/news-releases/2017/12/fda-approves-amgens-repatha-evolocumab-to-prevent-heart-attack-and-stroke/. Updated December 1, 2017. Accessed January 3, 2018.
- U.S. Food and Drug Administration (FDA). Prescription opioid cough and cold medicines: Drug safety communication – FDA requires labeling changes. FDA.gov. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm592053.htm. Published January 11, 2018. Accessed January 24, 2018.
- U.S. Food and Drug Administration (FDA). FDA drug safety communication: FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older. FDA.gov. https://www.fda.gov/Drugs/DrugSafety/ucm590435.htm. Published January 11, 2018. Accessed January 24, 2018.
- Mylan N.V. Mylan Announces U.S. FDA approval of first generic for Copaxone 40 mg/mL 3-times-a-week and may be eligible for 180-day exclusivity. PRNewswire.com. https://www.prnewswire.com/news-releases/mylan-announces-us-fda-approval-of-first-generic-for-copaxone-40-mgml-3-times-a-week-and-may-be-eligible-for-180-day-exclusivity-300530551.html. Published October 3, 2018. Accessed January 24, 2018.
- U.S. Food and Drug Administration (FDA). First generic drug approvals. FDA.gov. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ANDAGenericDrugApprovals/default.htm. Updated January 11, 2018. Accessed January 24, 2018.
- GW Pharmaceuticals announces acceptance of NDA filing for Epidiolex (cannabidiol) in the treatment of Lennox-Gastaut syndrome and Dravet syndrome. GW Pharmaceuticals. http://ir.gwpharm.com/releasedetail.cfm?releaseid=1052733. Published December 28, 2017. Accessed January 16, 2018.
- U.S. Food and Drug Administration. Current and Resolved Drug Shortages and Discontinuations Reported to FDA: Methylphenidate hydrochloride (QuilliChew ER®) extended-release chewable tablets. FDA.gov. https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Methylphenidate%20Hydrochloride%20(QUILLICHEW%20ER)%20Extended-Release%20Chewable%20Tablets&st=c&tab=tabs-1. Updated January 22, 2018. Accessed January 24, 2018.
- U.S. Food and Drug Administration. Current and Resolved Drug Shortages and Discontinuations Reported to FDA: methylphenidate hydrochloride (Quillivant XR®) for extended-release oral suspension. FDA.gov. https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Methylphenidate%20Hydrochloride%20(QUILLIVANT%20XR)%20for%20Extended-Release%20Oral%20Suspension&st=c&tab=tabs-1. Updated January 22, 2018. Accessed January 24, 2018.
- Hee Han D. Shortage of two ADHD medications due to manufacturing delays. EMPR.com. Available at: https://www.empr.com/news/quillivant-xr-quillichew-er-drug-shortage-attention-deficit-hyperactivity-disorder/article/738438/. Updated January 22, 2018. Accessed January 30, 2018.
- U.S. Food and Drug Administration. Current and Resolved Drug Shortages and Discontinuations Reported to FDA: Flunisolide (Aerospan) inhalation aerosol. FDA.gov. https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Flunisolide&st=d. Updated January 26, 2018. Accessed January 30, 2018.
- Hee Han D. Asthma treatment Aerospan has been discontinued. EMPR.com. https://www.empr.com/safety-alerts-and-recalls/aerospan-asthma-discontinued-inhaler/article/740214/. Updated January 29, 2018.
- U.S. National Library of Medicine. DailyMed. https://dailymed.nlm.nih.gov/dailymed/. Accessed January 2018.