FDA Update: November 2019

The Express Scripts Office of Clinical Evaluation and Policy tracks some recent updates to the drug pipeline.
FDA Update

FDA Approves Pediatric Indication for Entresto

A Novartis combination drug, Entresto® (sacubitril/valsartan) tablets gained FDA approval on Oct. 1, 2019, for treating specific patients who are at least one year old. It contains a neprilysin inhibitor and an angiotensin receptor blocker (ARB) to treat children and teens who have symptomatic heart failure (HF) with systemic left ventricular systolic dysfunction. Its original approval, from July 2015, is for reducing the risk of CV death and hospitalization for HF in patients with chronic HF (NYHA Class II-IV) and reduced ejection fraction. Most often, it is used along with HF drugs from other therapeutic classes, but it should not be taken at the same time as an angiotensin-converting enzyme (ACE) inhibitor. Patients who also have diabetes should not take Entresto along with a drug that contains aliskiren. For children who cannot swallow Entresto tablets, a pharmacy can make a liquid form that can be stored at room temperature for a maximum of 15 days. Doses for patients who weigh less than 50Kg (110 pounds) are based on body weight, taken two times a day and increased, if needed, in two stages that are each two weeks apart. Entresto has a boxed warning that it can cause birth defects, so women and teenage girls should stop taking it if they become pregnant. For revised prescribing information, look here.

Descovy Receives New FDA Indication for Pre-Exposure Prophylaxis

As part of the government’s plan to decrease the number of new HIV-1 infections in the U.S., the FDA granted Descovy® (emtricitabine 200mg/tenofovir alafenamide 25mg - Gilead Sciences) tablets an additional approval on Oct. 3, 2019. It now is indicated as pre-exposure prophylaxis (PrEP) to prevent HIV-1 infection for certain adults and teens who weigh 35Kg (77 pounds) or more. In addition to following safe sex practices, such as using condoms, HIV-1 negative men and transgender women who are at high risk of getting HIV by having sex with men should take one Descovy tablet every day. However, it is not indicated for women who have receptive vaginal sex. Like Gilead’s Truvada® (emtricitabine 200mg/tenofovir disoproxil fumarate 300mg) tablets, the only other drug that is FDA approved for PrEP, Descovy contains two nucleoside analog reverse transcriptase inhibitors (NRTIs). Updated prescribing information for Descovy is posted here.

Bonsity Wins FDA Approval

Bonsity (teriparatide injection) for subcutaneous (SC) use was approved by the FDA on Oct. 4, 2019. It is indicated to be self-injected once-daily for up to two years as treatment for some patients who are at a high risk of bone fractures due to osteoporosis. Bonsity was approved through the FDA’s 505(b)(2) pathway, which allowed its developer, Pfenex, Inc., to use documentation from a similar drug that already is FDA approved rather than requiring a repeat of the clinical trials. Like its reference drug, Forteo® (teriparatide [rDNA origin]– Eli Lilly), Bonsity is a parathyroid hormone analog that regulates calcium and phosphate metabolism in bones and kidneys. Known as PF708 during its development, it will be marketed in the United States by Alvogen, a partner company to Pfenex. Launch depends on the results of an ongoing head-to-head comparison between Bonsity and Forteo, due later in 2019. If the two drugs produce similar enough results, Pfenex has requested an “A” equivalency rating from the FDA. If the A rating is granted, Bonsity could be interchanged with Forteo and substituted for it in states that allow automatic substitution. Because the use of teriparatide was associated with a higher rate of osteosarcoma in laboratory animals, Bonsity and Forteo have a boxed warning against their use by patients who have Paget’s disease of the bone or other conditions that may make osteosarcoma more likely. According to Eli Lilly’s 2018 annual report, U.S. sales of Forteo amounted to nearly $758 million last year. Here is prescribing information for Bonsity.

FDA Approves Aklief to Treat Acne

The FDA approved Galderma’s Aklief® (trifarotene) cream, 0.005% on Oct. 4, 2019, to treat acne for patients at least nine years old. A new retinoid that is comparable to several other topical products, which are available as both brands and generics, it is indicated for acne on the face, back, chest and shoulders. With a planned launch date before the end of November, it will be dispensed in 30Gm, 45Gm and 75Gm pump devices. Cost information is not yet available. Directions are to apply a thin layer of Aklief to clean, dry areas that are affected by acne once each evening. It should not be used in the eyes or on genital areas and mucous membranes. Patients using Aklief are cautioned either to avoid long exposure to natural and artificial sunlight or to use a strong sunscreen because retinoids increase the risk of sunburn. For its full prescribing information, look here.

New Dosage Form for Cetirizine

The first injectable cetirizine product was FDA approved on Oct. 4, 2019. Quzyttir (cetirizine) injection is indicated to treat acute urticaria (hives) for patients who are at least six months old. Usually in response to an allergen, urticaria causes itchy skin bumps, which typically last no more than a day or two. Quzyttir blocks histamine-1 (H-1) receptors to relieve itching. It will be administered as an intravenous (IV) push injection of 2.5mg for patients between six months and six years old, 5mg or 10mg for those between six years and 12 years, and 10mg for patients over the age of 12 years. If subsequent doses are needed, they will be given once daily. In clinical studies, Quzyttir was about as effective as the current standard of care, diphenhydramine injection, when itching was rated at two hours after the drug was given. Fewer patients treated with it had to have further treatment after using it, however; and the average time to treatment effectiveness was about one-half hour shorter (1.7 hours for Quzyttir compared to 2.1 hours for diphenhydramine). The manufacturer, JDP Therapeutics, has not yet disclosed launch or pricing plans. Prescribing information can be found here

Beovu Approved for Wet Age-Related Macular Degeneration

On Oct. 7, 2019, Novartis received approval from the FDA for Beovu® (brolucizumab-dbll) injection for the treatment of wet age-related macular degeneration (AMD). Affecting approximately 1.75 million Americans, wet AMD is the leading cause of blindness in people over the age of 65 years in the United States. Beovu is a biologic drug known as a vascular endothelial growth factor (VEGF) inhibitor that works by blocking angiogenesis (the formation of new blood vessels) in the back of the eye. It is administered as an injection into the back of the eye by a healthcare professional. The recommended dose for Beovu is 6mg once monthly for three months followed by 6mg every eight to 12 weeks. Novartis plans to launch Beovu within the next two weeks. Full prescribing information can be found here.

Scenesse Approved to Treat Erythropoietic Protoporphyria

Under its Priority Review program, the FDA approved Clinuvel’s Scenesse® (afamelanotide) on Oct. 8, 2019. Also an orphan drug, it is the first drug approved to increase pain-free light exposure in patients who have a rare condition known as erythropoietic protoporphyria (EPP). The drug, a melanocortin-1 receptor agonist, increases the production of eumelanin which offers some protection from light. EPP is a rare genetic disorder that results in the accumulation of a chemical compound called protoporphyrin in the blood, liver and skin. In the skin, protoporphyrin can absorb energy from sunlight, setting off a chemical reaction that can damage the surrounding tissue leading to itching, pain, redness and swelling.  EPP is estimated to affect about 1:75,000 to 1:200,000 patients worldwide. The number of patients in the U.S. is not known. Recommended dosing for Scenesse is one implant placed SC by a trained healthcare professional once every two months. Scenesse may cause the skin to darken, and a full body skin examination is recommended for patients twice each year. In addition, patients are encouraged to maintain sun protection measures during treatment to prevent phototoxic reactions related to EPP. Clinuvel has not yet released pricing information. The company plans to distribute the drug directly to hospitals within the next 12 months. Complete prescribing information can be found here.

New Indications for Wilate

Wilate® (von Willebrand factor/coagulation factor VIII complex [human]) now has an FDA-approved indication for patients who have hemophilia A. It was first approved in 2009 to treat bleeding episodes and control bleeds associated with surgery for adult and pediatric patients who have von Willebrand disease (VWD). A bleeding disorder caused by deficiencies in von Willebrand clotting factor, VWD affects approximately 1% of the U.S. population – both males and females about equally. On Oct. 8, 2019, the manufacturer, Octapharma, announced that the FDA also has approved Wilate to prevent bleeding episodes and to manage bleeds for teens and adults who have hemophilia A. Affecting males almost exclusively, hemophilia A is a different type of bleeding disorder that results from the lack of coagulation factor VIII (factor VIII). Around 20,000 patients in the U.S. have it. Wilate’s dosing for hemophilia A is based on the patient’s weight. To prevent excessive bleeding, it is given by IV infusion at between 20 international units (IU) and 40 IU per kilogram once every two or three days. Once a bleed starts, the severity of the bleeding, the patient’s blood levels of factor VIII and other aspects of the episode also are considered to determine the dose, the timing of infusions and the length of treatment. Go here for updated prescribing information.

Reyvow Approved for Acute Migraine Treatment

Eli Lilly received approval from the FDA on Oct. 11, 2019, for Reyvow (lasmiditan) tablets. It is the first in a novel class of oral drugs, serotonin (5-HT) 1F receptor agonists (ditans) that are indicated for acute, but not preventive, treatment of adults who have migraine headaches. Recommended dosing for Reyvow is 50mg, 100mg or 200mg taken once a migraine has started. No more than one dose should be taken per day and no safety information is available for using more than four doses in a one-month period. Because it may cause sleepiness, patients are advised to wait at least eight hours after taking it to drive or do other tasks that require mental alertness. The Migraine Research Foundation (MRF) estimates that in the United States, around 18% of women and 6% of men have migraines – mostly averaging one or two per month. During their headaches, about 90% of migraine sufferers cannot participate normally in regular activities, such as school or work. Direct and indirect costs of migraines may be as high as $36 billion per year, according to the MRF. Reyvow’s launch date depends on an evaluation of its potential for abuse. The U.S. Drug Enforcement Agency (DEA) is expected to take about three months to decide on a controlled substance schedule for it. Pricing information currently is unavailable, but Reyvow’s prescribing information is here.

Secuado Receives FDA Approval

On Oct. 11, 2019, the FDA approved a new topical dosage form for an atypical antipsychotic drug that also is available from a different manufacturer as sublingual (SL) tablets. Secuado® (asenapine) transdermal system is indicated to treat adult patients who have schizophrenia. It will be marketed in three strengths – 3.8mg/24 hours, which roughly parallels an SL dose of 5mg twice a day; 5.7mg/24 hours (similar to twice daily 10mg SL doses) and 7.6mg/24 hours. One patch at a time is applied to clean, dry, intact skin on the patient’s abdomen, hip, upper arm or upper back, and worn for 24 hours. Secuado’s manufacturer, Noven Pharmaceuticals, has not announced a definite launch date, but it intends to introduce Secuado as soon as possible in the U.S. A boxed warning cautions that, like all atypical antipsychotic drugs, Secuado should not be used by elderly patients who have psychoses due to dementia because it increases their chance of dying. Prescribing information is here.

Expanded Indication for Xofluza

The FDA broadened its approval for Genentech’s Xofluza® (baloxavir marboxil) tablets on Oct. 16, 2019. It originally was approved last October to treat acute uncomplicated influenza (flu) for otherwise healthy patients at least 12 years old who have had flu symptoms for no more than 48 hours. Based on results from a clinical trial, its indication now includes patients with underlying conditions, such as asthma, diabetes and heart disease, which make them more likely to experience complications from having the flu. In the study, symptoms began to resolve slightly more than one day sooner for patients taking Xofluza compared to patients who took a placebo (an average of 73 hours vs 102 hours, respectively). Xofluza works differently than other antiviral drugs that treat flu. It blocks the activity of an enzyme that helps flu viruses replicate. Recommended dosing is 40mg (two 20mg tablets) for those who weigh between 40kg (about 88 pounds) and 80kg (about 175 pounds). Patients weighing 80kg or more should receive a single dose of 80mg (two 40mg tablets). Xofluza is not approved for patients weighing less than 40kg. Taking it should be separated by several hours from eating or drinking dairy foods, using antacids and taking mineral supplements. It may be used in addition to other flu treatment drugs, such as oseltamivir. Here is updated prescribing information for Xofluza.

Amzeeq Approved to Treat Acne

Amzeeq (minocycline) topical foam, 4% was approved by the FDA on Oct. 18, 2019. It is indicated for treating patients at least nine years old who have moderate to severe non-nodular acne. The first commercial topical formulation of an antibiotic used orally to treat acne, it uses “Molecule Stabilizing Technology” patented by its manufacturer, Foamix. The planned launch date is in January 2020; pricing information is not yet known. It will be available in 30 Gm canisters. Recommended dosing is a once daily application patted lightly onto affected areas, avoiding the eyes and mucous membranes. Amzeeq should not be used around open flames or people who are smoking because its propellant is flammable. A patient Medication Guide will accompany each prescription that is filled. Check here for its prescribing information.

Farxiga Granted New Indication

AstraZeneca’s sodium-glucose cotransporter 2 (SGLT2) inhibitor, Farxiga® (dapagliflozin) tablets has received FDA approval for a cardiovascular (CV) indication. Based on data from the 17,000-patient DECLARE-TIMI 58 clinical trial, it was approved on Oct. 18, 2019, to decrease the risk of HF-related hospitalizations for adult patients who have type 2 diabetes and who also have CV disease or several risk factors for CV disease. Its original indication is in combination with dietary restrictions and exercise to manage glycemic control for adults who have type 2 diabetes. Farxiga’s recommended dose for its CV indication is 10mg once a day. Because SGLT2 inhibitors decrease glucose reabsorption in the kidneys causing more glucose to be excreted in urine, kidney function should be checked before patients start treatment and periodically during therapy with any SGLT2 inhibitor. Here is updated prescribing information for Farxiga.

Second Indication for Ultomiris 

Ultomiris (ravulizumab-cwvz - Alexion) injection was approved by the FDA on Oct. 18, 2019, to treat atypical hemolytic uremic syndrome (aHUS) for patients as young as one month old. A rare, life-threatening hereditary disease, aHUS affects only about two individuals per million. It causes clots in small blood vessels throughout the body, so it can lead to end-stage renal disease, heart attacks and death, if it is not treated. The only presently marketed long-acting C5 complement inhibitor, Ultomiris is administered by IV infusion. Recommended dosing depends on the patient’s weight with a minimum weight of 5 Kg (about 10 pounds). Two weeks after a loading dose, it is given once every four weeks for patients weighing less than 20 Kg (44 pounds) or once every eight weeks for patients whose weight is 20 Kg or more. The labeling for Ultomiris contains a boxed warning that highlights an increased risk of serious meningococcal infections. Patents should be vaccinated with a meningococcal vaccine at least two weeks prior to receiving their first dose. During therapy, patients also should be monitored for early signs of meningococcal infections. Ultomiris is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS). Prescribers must enroll in the program and patients are required to receive a Medication Guide that describes the risks associated with the use of Ultomiris. The previous Ultomiris indication, from December 2018, is for the treatment of adults who have another rare condition, paroxysmal nocturnal hemoglobinuria (PNH). Complete prescribing information for Ultomiris may be found here.

New Stelara Indication

On Oct. 18, 2019, the FDA granted Janssen’s Stelara® (ustekinumab) a new indication to treat adults who have active cases of ulcerative colitis (UC) that are moderate to severe. UC, progressing chronic inflammation of the large intestines, is believed to affect about 900,000 American adults. Stelara reduces inflammation by blocking two interleukins – IL-12 and IL-23. For UC, it will be given in two phases. First is one IV infusion of 260mg, 390mg or 520mg — based on the patients weight and delivered in a healthcare facility by a health professional. Beginning eight weeks after the IV dose, 90mg will be given by SC injection once every eight weeks. A patient or caregiver should be able to give the SC doses using prefilled syringes. A Medication Guide warns patients that using Stelara may raise the risk of having some kinds of cancer, serious infections (including tuberculosis) or a rare brain condition known as reversible posterior leukoencephalopathy syndrome (RPLS). For its full prescribing information, look here.

New Pediatric Indication for Botox

Allergan’s Botox® (onabotulinumtoxinA) was approved by the FDA on Oct. 18, 2019, to treat lower limb spasticity (muscle contractions, inflexibility or stiffness in the legs) for children two years old and older, with the exception of children and adolescents whose spasticity is due to cerebral palsy. Children who have head injuries, multiple sclerosis (MS), spinal cord injuries or strokes also may have problems with spasticity. To treat it in the legs, the recommended Botox dose is between four units/Kg and eight units/Kg administered intramuscularly (IM) by a healthcare provider and divided among the affected muscles. For one affected leg, each treatment should be limited to the lower of eight units/Kg or 300 units. If two limbs (both arms, both legs or one arm and one leg) are being treated at the same time, the limits increase to the lesser of 10 units/Kg or 340 total units. Treatments should be given at least three months apart. All botulinum toxin products have Medication Guides and boxed warnings that they may migrate away from the areas where they are injected -- possibly causing widespread side effects, such as muscle weakness and vision changes. Rarely, serious breathing or swallowing problems can occur. Migration and side effects can happen even several months after the product has been injected. Children may be especially prone to having adverse effects. Botox has multiple other medical and cosmetic indications for both adult and pediatric patients. Its complete prescribing information is here.

Trikafta Approved for Cystic Fibrosis

The FDA approved Trikafta (elexacaftor 100mg/tezacaftor 50mg/ivacaftor 75mg and ivacaftor 150mg - Vertex) as a Breakthrough Therapy on Oct. 21, 2019. The combination of two already approved drugs (tezacaftor and ivacaftor) with a next-generation CFTR corrector, it is indicated for treating cystic fibrosis (CF) for patients 12 years of age and older who have at least one F508del mutation (the absence of protein F508) on the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The Cystic Fibrosis Foundation estimates that about 30,000 Americans currently have CF and that about 1,000 new patients, mostly young children, are diagnosed with it annually. Many more CF patients are surviving into adulthood, with about one-half of CF patients in the U.S. now over the age of 18 years. By far, the most common genetic mutation in CF is F508del -- about 45% of patients have CF caused by two F508dels and approximately 45% more patients have CF that results from one F508del and another mutation associated with the condition. Trikafta will be dispensed as cartons of four one-week blister card “wallets” containing 14 combination tablets that are to be taken as two tablets together once each morning and seven tablets of ivacaftor 150mg that is taken as one each evening – about 12 hours after the morning dose. All the tablets should be taken with food that contains fat. The wholesale acquisition cost (WAC) is $23,896 for each 28-day carton. It was launched upon approval. Complete prescribing information is available here.

New Indication for Zejula

Tesaro, the oncology business unit of GlaxoSmithKline, got a new indication from the FDA for the use of Zejula® (niraparib) capsules as late-stage therapy for certain cancer patients. Specifically, the new indication, granted on Oct. 23, 2019, is for treating women whose ovarian, fallopian tube or primary peritoneal cancer has advanced more than six months following the last of at least three rounds of chemotherapy (chemo). The cancer also must be positive for a homologous recombination deficiency (HRD) as indicated by either a deleterious/suspected deleterious BRCA mutation or a genomic instability. Zejula is a poly (ADP-ribose) polymerase (PARP) inhibitor that initially was FDA approved early in 2017 as maintenance treatment for women who have a recurrence of one of the same three cancers and who are in complete or partial response to platinum-based chemo. The recommended dose for both indications is 300mg (three capsules) taken together once every day. For its revised prescribing information, go here.

Vumerity Approved to Treat Multiple Sclerosis

Biogen and Alkermes received approval from the FDA on Oct. 29, 2019, for Vumerity (diroximel fumarate) delayed-release capsules, a new oral drug to treat multiple sclerosis (MS). It is indicated to treat adult patients who have relapsing forms of MS, including clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS). For initial treatment, patients will take one 231mg capsule twice a day. After one week, the dose increases to two capsules (462mg) twice daily. Vumerity is a successor to Biogen’s Tecfidera® (dimethyl fumarate) capsules. The EVOLVE-MS series of clinical trials comprises patients who are new to therapy for MS and some who have had prior treatment with an interferon or glatiramer. One group of study patients taking Vumerity had 72% fewer relapses and 64% fewer lesions after about one year, compared to their status before starting the drug. In another part of the study, Vumerity produced fewer and milder gastrointestinal (GI) side effects than Tecfidera did. Biogen will market Vumerity in the near future, but a target date and pricing are not yet available. Complete prescribing information is here.

Expanded Indication for Baxdela

Baxdela® (delafloxacin), a fluoroquinolone antibiotic first FDA approved in June 2017 to treat acute bacterial skin and skin structure infections (ABSSSI), now has an additional indication. It was approved on Oct. 24, 2019, to treat adults who have community-acquired bacterial pneumonia (CABP). Results of its use in a key clinical trial were comparable to those from a similar antibiotic, moxifloxacin. Both drugs are available in IV and oral forms, meaning that either can be started as an infusion in the hospital and then continued in more convenient oral form once the patient is discharged. In either form, Baxdela is given once every 12 hours, at 300mg IV or 450mg orally, for five to 10 days to treat CABP. Like all fluoroquinolone antibiotics, Baxdela has a boxed warning about its potential to worsen myasthenia gravis (MG) and to cause peripheral neuropathy, central nervous system (CNS) effects and inflammation or tears in tendons. A Medication Guide explaining its risks is dispensed with each Baxdela prescription. Its manufacturer, Melinta Therapeutics, will delay promoting the new indication until some financial issues are resolved. Here is updated prescribing information.

MedWatch Update

Ranitidine

Following the FDA’s first alert in September, several more manufacturers and distributors of ranitidine and the branded product, Zantac®, have recalled both their prescription and over-the-counter versions of the drug. Ranitidine is a histamine-2 (H2) blocker taken to treat gastroesophageal reflux disease (GERD), heartburn or stomach ulcers. Small amounts of a suspected cancer-causing substance, N-nitrosodimethylamine (NDMA), have been detected in samples of ranitidine. However, the FDA still is investigating the potential severity of the contamination. Currently, the FDA is not recommending that patients stop taking ranitidine, but it did comment that no NDMA had been found in preliminary analyses of other H2 blockers, such as cimetidine and famotidine; or in proton pump inhibitors (PPI), such as esomeprazole and lansoprazole. Patients who want to stop taking ranitidine should discuss changing to another drug with their doctors or pharmacists. Additional information is in the FDA’s links to notices here and its Question and Answer page here.


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