FDA Update: March 2019

Mar 15, 2019

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

New Pill Bottle

First True Generic Launched for Advair Diskus

Mylan’s Wixela Inhub, the first interchangeable generics for all three strengths of GlaxoSmithKline’s Advair Diskus® (fluticasone propionate/salmeterol inhalation powder) were FDA approved on Jan. 30, 2019 and launched about two weeks later. Inhaled twice daily, it treats asthma for patients age four years and older. It also is used as maintenance treatment for chronic obstructive pulmonary disease (COPD). Wixela Inhub was released at wholesale acquisition costs (WAC) approximately 70% below the brand and 67% below the authorized generic, which was introduced on Feb 8, 2019. U.S. sales for Advair Diskus amounted to about $4.2 billion in 2017, as reported by IQVIA.

Tremfya Self-Injector Approved

The FDA has approved Tremfya® (guselkumab - Janssen) One-Press injector. Tremfya is a monoclonal antibody that inhibits the action of interleukin 23 (IL-23) for treating adults who have moderate to severe plaque psoriasis and who are candidates for systemic treatment or phototherapy. Previously available only in prefilled syringes, it is given SC in doses of 100mg once every eight weeks after two initial doses four weeks apart. The new injector was easier to use for most patients in a clinical trial that lead to its approval. Disposal was less complicated, as well, since the self-injector needle retracts into the unit after use. Tremfya’s prescribing information is here.

New Formulation Approved for Colchicine

ROMEG Therapeutics revealed that Gloperba® Oral Solution, its liquid form of colchicine, was FDA approved on Jan. 30, 2019. Colchicine, which has been used for centuries, treats gout and prevents gout flare-ups. It already is available in oral capsules and tablets and as a topical gel. Gloperba is indicated to be taken twice every day in doses of 0.6mg (5mL) each to keep adults who have gout from experiencing attacks. Although the daily dose should not be increased to more than 1.2mg, decreasing the dose for patients who have kidney or liver conditions will be easier with the liquid form than with other marketed forms of the drug. Gloperba has not been studied for treating acute flares and it does not relieve pain associated with gout. ROMEG plans to launch it this summer in bottles containing 150mL of solution. Full prescribing information is here.

Jeuveau, New Cosmetic Injection Approved

Evolus, Inc. received approval from the FDA on Feb. 1, 2019, for Jeuveau (prabotulinumtoxinA-xvfs). A neuromuscular blocker, it temporarily improves the appearance of moderate to severe glabellar (frown) lines between the eyebrows in adults. Currently, Jeuveau is approved only for cosmetic use; it has no other indications. It will be injected by a healthcare professional intramuscularly (IM) into five separate sites on the forehead no more than once every 90 days. Even though the total recommended dose for each treatment is 20 Units, it will be supplied only in 100 Unit single-use vials. In its clinical trials, results, duration of effectiveness and side effects were comparable to other cosmetic botulinum products available on the U.S. market. None of the products is interchangeable, however. Evolus will release Jeuveau nationwide to physician offices and clinics this spring. Its initial list price is expected to be approximately 70% to 80% of the cost for Botox® Cosmetic (onabotulinumtoxinA - Allergan). All botulinum products carry boxed warnings that their effects may spread to areas far from the injection sites, potentially causing adverse reactions that potentially could include serious breathing and/or swallowing problems. Both mild and severe side effects may occur immediately or be delayed until long after the injections have been administered. Full prescribing information is here.

FDA Approves Generic for Zovirax Cream

On Feb. 4, 2019, the FDA gave final approval to Perrigo for its AB-rated generic of Zovirax® Cream (acyclovir cream, 5% - Valeant). It is a topical treatment for patients age 12 and older who have cold sores that are caused by herpes simplex virus. Therapy is started as soon as cold sores appear and the recommended dosing is applications to the affected areas of the lips and face five times a day for four days. Perrigo planned to launch acyclovir cream, 5% in February. Acyclovir ointment, 5% has been available from several generic companies since 2013. Sales for Zovirax Cream, 5% reached about $92 million in 2018, as reported by IQVIA.

Cablivi Approved to Treat Acquired Thrombotic Thrombocytopenic Purpura

Sanofi announced on Feb. 6, 2019, that the FDA had approved Cablivi® (caplacizumab-yhdp). The first drug that the FDA specifically has approved to treat acquired thrombotic thrombocytopenic purpura (aTTP), it is indicated for use along with both an immunosuppressant and plasma exchange (plasmapheresis). Affecting fewer than 4,500 patients in the United States, aTTP causes blood clots in small blood vessels. The first Cablivi treatment is given by a healthcare provider as a single intravenous (IV) injection 15 minutes or more before plasma exchange. A second dose is administered subcutaneously (SC) after the exchange is finished. Then, Cablivi is used as a once-a-day, SC injection that may be administered by the provider, the patient or a caregiver for 30 days beyond the last plasma exchange. If signs of persistent underlying disease remain after this course of therapy, treatment may be extended for a maximum of an additional 28 days. Launch is planned for late in the first quarter of 2019. Complete prescribing information is here.

New Dosing for Darzalex

A new dosing regimen for Darzalex® (daratumumab – Janssen) was granted FDA approval on Feb. 8, 2019. A CD38-directed antibody, it is indicated alone or combined with other drugs on three-week or four-week cycles to treat multiple myeloma. It is administered as a dose of 16mg/kg in 1,000mL of sodium chloride by intravenous (IV) infusion. Because doses are started at the slowest rate, the recommended infusion rate of 50mL to 200mL per hour can result in infusions lasting up to 20 hours on the first day of treatment. The rate is gradually increased if the patient can tolerate side effects. Now the first dose can be divided into two with 8mg/kg given in 500mL of sodium chloride on each of two consecutive days, making the first treatment less stressful for new patients. Subsequent infusions will be at full strength, but they may be able to be given at a faster rate. In a clinical trial comparing the two regimens, no significant differences were found in effectiveness and side effects between the full dose and the divided dose for the first infusion. Complete prescribing information for Darzalex is available here.

Mayne Pharma Launches Lexette

Lexette (halobetasol) foam, 0.05% was introduced in the U.S. the week of Feb. 10, 2019. It is the first topical foam formulation of the high strength corticosteroid, which is used to treat adults who have plaque psoriasis. Recommended dosing is a thin layer rubbed lightly into affected areas twice a day for no longer than two weeks. It should not be used in the eyes or on the face, genital area, mucous membranes or underarms. Pricing information is not yet available, but it will be dispensed in 50Gm canisters, either singly or in boxes containing two cans. Mayne will have marketing exclusivity until May 2021. Prescribing information is available here.

FDA Approves Egaten to Treat Fascioliasis

The FDA approved Egaten® (triclabendazole) tablets on Feb. 13, 2019. An antiparisitic, Egaten is indicated to treat fascioliasis (liver flukes), a disease caused by flatworms that infect humans and animals through contaminated water or food. In the United States, it is carried mainly by a species of snails. Fascioliasis is rare in the US – with only a few locally acquired human cases reported in California, Florida and Hawaii. Globally, however, it affects over 2 million patients, primarily in tropical areas of Africa, Asia and South America. Residents of the U.S. who travel in areas where it is common may become infected. Acute fascioliasis infection results in abdominal pain, fever, nausea, rash and vomiting. If untreated, the parasites concentrate in the liver, gallbladder and bile ducts; where they produce chronic pain, inflammation and blockages. Indicated for patients as young as six years old, Egaten is taken as two 10mg/kg doses given 12 hours apart to eradicate the flukes. Novartis, which has been supplying it to the World Health Organization (WHO) for about 15 years, has promised to keep contributing an average of 600,000 doses annually at least through 2022. U.S. distribution and pricing plans have not yet been announced. Because fascioliasis is classified as a neglected tropical disease, Egaten qualifies for a Tropical Disease Priority Review Voucher, which Novartis can use to accelerate a future FDA review or sell to another company. Prescribing information is here.

Additional Indication Approved for Keytruda

The FDA granted a new indication for Merck’s Keytruda® (pembrolizumab) on Feb. 15, 2019. Keytruda now is approved as adjuvant therapy for patients who have a significant chance of relapse after surgery to remove stage III melanoma that has spread to the lymph nodes. In the clinical trial that supported the new indication, 71.4% of patients who were treated with Keytruda remained recurrence free for at least 18 months, compared to 61% of participants who received a placebo. Following resection of the melanoma, 200mg of Keytruda is infused over a 30-minute period once every three weeks until 18 cycles have been finished, until the cancer recurs or until the drug’s side effects become too severe. Keytruda's label now has indications in multiple cancers including classical Hodgkin's lymphoma, non-small cell lung cancer (NSCLC) and squamous cell cancer of the head and neck. It also is FDA approved for treating solid tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) regardless of the tumors’ primary site of origin. Its revised prescribing information is available here.

Esperoct, a New Agent to Treat Hemophilia A, Approved

Novo Nordisk’s Esperoct® (turoctocog alfa pegol) received approval from the FDA on Feb. 19, 2019. It is indicated to replace blood clotting factor VIII for patients who have hemophilia A. With an extended half-life, it is approved for regular injections every four days for older patients and every three or four days for children to reduce the occurrence of bleeding episodes. Also indicated on an as-needed basis, it manages both bleeds and bleeding due to dental or surgical procedures. As a result of patent agreements, Esperoct will not be available in the U.S. until 2020. No pricing or prescribing information is available, yet.

Generics Available for Suboxone Film

After U.S District Court rulings that invalidated prior legal actions and the U.S. Supreme Court’s refusal to hear a patent case, both Alvogen and Dr. Reddy’s Laboratories released generics to Suboxone® (buprenorphine/naloxone) sublingual film on Feb. 20, 2019. Both companies are marketing generics for all four strengths (2mg buprenorphine/0.5mg naloxone, 4mg/1mg, 8mg/2mg and 12mg/3mg). Mylan followed with its generics for the two higher strengths a few days later. A schedule III controlled substance that combines an opioid blocker and a partial opioid agonist, it is used once daily to treat opioid dependence as part of a program that also includes counseling and psychosocial support. Dr. Reddy’s had marketed generics in June 2018, but they quickly were forced off the market by litigation. Some of the current generic launches also may be at risk while additional patent infringement lawsuits continue. To help preserve market share for Indivior, the brand manufacturer, Sandoz introduced authorized generics on Feb. 19, 2019. They are priced at wholesale acquisition costs (WAC) 14% less than those for the brand. Pricing for the true generics has not yet been announced. Prescribing any buprenorphine/naloxone product is restricted to physicians who have qualified under terms of the Drug Addiction Treatment Act. A specific identification number unique to each prescriber who meets certification requirements must be included on each prescription. IQVIA estimates that U.S. sales for Suboxone film neared $1.9 billion in 2018.

Uloric Boxed Warning

Strengthening previous safety communications, the FDA announced on Feb. 21, 2019, that it is requiring a boxed warning and a patient Medication Guide for Uloric® (febuxostat – Takeda) tablets, which are used to treat gout. Additionally, use of the drug is being limited to patients who cannot take an alternative gout treatment, allopurinol, due to adverse events, lack of effectiveness or both. In a post-marketing clinical study that involved more than 6,000 participants, those taking Uloric had a higher chance of dying from a cardiovascular (CV) problem, such as a heart attack or stroke, than patients taking allopurinol. Although the relative numbers of non-fatal CV events did not differ significantly between the two groups, the overall risk of death from any reason was increased among those taking Uloric, as well. Prescribers should consider it only for patients who are unable to use allopurinol. Patients who do take Uloric are advised to seek immediate medical attention for chest pain, dizziness, irregular heartbeat, sudden headaches or other signs of possible CV events. For the full FDA notice, click here.

FDA Approves Lonsurf to Treat Gastric Cancers

Taiho Oncology’s Lonsurf® (trifluridine/tipiracil) tablets received FDA approval for a second indication on Feb. 22, 2019. Originally approved in 2015 as second- or third-line treatment for adults who have metastatic colorectal cancer, it now also is indicated to treat metastatic adenocarcinomas of the stomach or gastroesophageal junction for adults who have had two or more courses of therapy. It combines trifluridine, a nucleoside metabolic inhibitor that interrupts DNA production and cell multiplication, with tipiracil, a thymidine phosphorylase inhibitor that limits the breakdown of trifluridine. Lonsurf is taken along with food twice a day on days one through five and eight through 12 on 28-day cycles. Its recommended dosing is 35mg/m2/dose with an upper limit of 80mg per dose. The American Cancer Society estimates that about 27,500 new cases of gastric cancers will be discovered in the United States in 2019. Almost all are adenocarcinomas, most are in patients age 50 years and older and they are more common for men than women. Because they develop slowly with very few symptoms, many cases are in advanced stages before being diagnosed. Lonsurf’s prescribing information is here.

Approval Expanded for Soliqua

On Feb. 27, 2019, the FDA extended the indications for Sanofi’s Soliqua® 100/33 (insulin glargine 100 Units/lixisenatide 33mcg/mL) injection. It originally was approved in July 2016 for adult patients who have type 2 diabetes that is not well controlled by diet, exercise and treatment with Adlyxin (lixisenatide - Sanofi) or a long-acting insulin, such as Lantus (insulin glargine - Sanofi). Soliqua 100/33 now can be used, along with diet and exercise, by patients whose type 2 diabetes is not managed by oral antidiabetic medications. Soliqua 100/33 is injected SC once daily one hour or less before the patient’s first meal. Recommended dosing depends on multiple factors that include the patient’s blood sugar monitoring results, physical activity and concurrent medical conditions. No more than 60 Units/20mcg should be used in any one day, however. Soliqua 100/33 is dispensed in disposable pen injectors containing 3mL of drug. Prescribing information is at here.

Generic Launched for Ranexa

Under a settlement agreement, Lupin Pharmaceuticals released AB-rated generics to Ranexa® (ranolazine extended-release - Gilead) tablets in both strengths – 500mg and 1,000mg – on Feb. 27, 2019. Lupin says it will have exclusivity for the generic, which is used to treat chronic angina. No cost information is available. For 2018, U.S. sales of Ranexa were about $945 million, according to IQVIA.

FDA Approval for Herceptin Hylecta

The FA approved Genentech’s Herceptin Hylecta (trastuzumab/hyaluronidase-oysk) on Feb. 28, 2019. Herceptin is a monoclonal antibody that has been available in the U.S. as an intravenous (IV) form since 1998. This new subcutaneous (SC) formulation is indicated for certain types of HER-2 positive breast cancer. As monotherapy, it will treat patients who have metastatic HER-2 positive breast cancer that has been treated with chemotherapy (chemo) at least twice. In combinations with chemo and other drugs, it can be used first-line or in early-stages as treatment for HER-2 positive breast cancers that have other specific genetic characteristics. It can be given over two to five minutes as compared to the 30 to 90 minutes needed for an IV infusion. All trastuzumab products have boxed warnings that they may cause birth defects, heart failure, respiratory collapse or severe allergic reactions. An April launch date is anticipated for Herceptin Hylecta, but its pricing is not yet public. Prescribing information is here.

Changes for Chantix

The labeling for Chantix® (varenicline – Pfizer) has been revised to show that it is not recommended for use by patients who are 16 years old or younger. Chantix, which is approved to help adult smokers quit, is taken once a day for 12 weeks or 24 weeks as the smoker gradually cuts down on the number of cigarettes. A study that included smokers between the ages of 12 years and 16 years found no benefit for Chantix in helping adolescents stop, however. Whether it helped participants in their later teens and early 20s was not determined. Although the FDA is committed to helping teens and children stop using nicotine products, including e-cigarettes, it does not believe that Chantix offers a good pathway for younger smokers.  More information is here.

Higher Doses of Xeljanz Not Recommended for Rheumatoid Arthritis

In the interim results from a safety study, the FDA found a serious risk for patients who have rheumatoid arthritis (RA) and who take 10mg of Pfizer’s Xeljanz® (tofacitinib) or Xeljanz® XR (tofacitinib extended-release) tablets two times a day. Compared to patients who take two 5mg doses per day, patients on the higher dose had more pulmonary embolisms (blood clots in the lungs) and more of them died for various reasons. Although the twice-daily 10mg dose has been approved to treat ulcerative colitis, it is not FDA approved for RA. All patients in the trial are being transitioned to the lower dose. Final results should be reported by the end of the year. In the meantime, patients are advised not to stop their Xeljanz or Xeljanz XR, to talk with their about a possible dose change and to seek emergency help if they suddenly become short of breath, cough up blood, sweat excessively or have other symptoms that might be from pulmonary blood clots. Both drugs already have a boxed warning that taking them can cause lymphoma or other cancers, and that their use has been associated with serious bacterial, fungal and viral infections, including tuberculosis. For additional information, please click here.

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