FDA Update: August 2019

Aug 16, 2019

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

New Pill Bottle

New Sodium Hyaluronate Product Launched

Teva Pharmaceutical Industries has introduced a new 1% Sodium Hyaluronate to the U.S. market. Also known as hylan, hyaluronan or hyaluronic acid, sodium hyaluronate is a major component of natural synovial fluid, which helps protect joints and keep them flexible. Synthesized sodium hyaluronate derivatives are used after non-drug treatments and pain relievers have failed to reduce pain and stiffness for patients who have osteoarthritis (OA) of the knee. Like similar products, Teva’s sodium hyaluronate is injected intra-articularly (directly into affected knee joints) to help restore lubrication and cushioning. Packaged as three single-use syringes per box, it is given in three weekly injections. Only one knee should be treated at a time. Teva’s product is not a generic, but its effectiveness was comparable to another product already in wide use. Please see here for prescribing information.

Generics to Uloric Approved

On July 1, 2019, the FDA approved generics for Uloric® (febuxostat – Takeda) from both Alembic Pharmaceuticals and Mylan. Febuxostat is a xanthine oxidase inhibitor that reduces the production of uric acid to help control gout. Available in 40mg and 80mg strength tablets, it is taken once a day. Earlier this year, the FDA required the addition of a boxed warning that patients taking febuxostat had a higher chance of dying from a cardiovascular (CV) problem, such as a heart attack or stroke, than patients taking a different xanthine oxidase inhibitor, 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 febuxostat, as well. Prescribers should consider it only for patients who are unable to use allopurinol. No launch or pricing information presently is available from either generic manufacturer. IQVIA estimated Uloric’s 2018 U.S. market at $578 million.

Xpovio Approved to Treat Relapsed Multiple Myeloma

The FDA approved Karyopharm Therapeutics’ Xpovio (selinexor) tablets on July 3, 2019. To be used in combination with dexamethasone, it is the first in a new class – nuclear export inhibitors. Xpovio works by keeping tumor suppressor proteins (TSP) inside cancer cell nuclei where they cause the cells to disintegrate. It is indicated for adults who have multiple myeloma that has returned despite four or more rounds of treatment with at least two proteasome inhibitors, at least two immunomodulatory agents and at least one anti-CD38 monoclonal antibody. Although several effective drugs are available to treat multiple myeloma, it develops resistance to many of them causing relapses. The recommended initial dose of Xpovio is 80mg (four tablets) taken with 20mg of dexamethasone on the first and third days of every week. Launch was in early July, at an approximate wholesale acquisition cost (WAC) of $22,000 per month. Complete prescribing information is available here.

Xembify Approved for Primary Immunodeficiency

Xembify(immune globulin subcutaneous, human- klhw) was approved by the FDA on July 3, 2019. It is a 20% immune globulin that is injected subcutaneously (SC) through an infusion pump to treat primary immunodeficiency (PI) disorders that include common variable immunodeficiency, congenital agammaglobulinemia, severe combined immunodeficiencies, Wiskott-Aldrich syndrome and several others. Patients who have a PI usually are at risk for repeated, serious infections. Dosing for Xembify, which may be given weekly or more frequently, depends on the patient’s response to treatment. Once a patient or caregiver is trained in its use, it may be administered at home for patients as young as two years old. Labeling for all immune globulin products includes warnings that they may cause blood clots and kidney damage that could lead to kidney failure. Grifols expects to launch single-dose vials containing 1Gm, 2Gm, 4Gm or 10Gm of Xembify in the fourth quarter of 2019. It will be added to Express Scripts’ specialty drug list. For its full prescribing information, please go here.

FDA Approves New Dosage Form for Amlodipine

The first commercially available oral liquid form of the calcium channel blocker, amlodipine, was FDA approved on July 8, 2019. Named Katerzia (amlodipine oral suspension - Azurity Pharmaceuticals), it is approved to manage hypertension for patients at least six years old. It has an additional indication for treating adults who have coronary artery disease (CAD), including vasoplastic angina. For pediatric patients and those who are elderly, frail or low weight; the recommended initial dose is 2.5mg (2.5mL) per day, increasing to a maximum of 5mg, if necessary. Most adults should start on 5mg daily, with an upper daily limit of 10mg. Katerzia will be dispensed in bottles containing 150mL of suspension, which should be stored in the refrigerator and shaken well before it is taken. Pricing and launch plans have not been announced. Check here for its prescribing information.

Ruzurgi Now Available

Ruzurgi (amifampridine Jacobus Pharmaceuticals), which was approved by the FDA on May 6, 2019, was launched recently. Designated as an Orphan Drug, Ruzurgi was approved through the FDA’s Fast Track and Priority Review procedures. It is indicated for the treatment of patients between the ages of six years and 17 years who have Lambert-Eaton myasthenic syndrome (LEMS). Diagnosed for only about 400 Americans, LEMS is an autoimmune condition. By damaging voltage-gated calcium channels, LEMS prevents nerves from communicating normally with muscles. It results in fatigue and weakened muscles especially in the legs. As a potassium channel blocker, Ruzurgi helps to increase calcium concentrations, which improves transmission of nerve signals to muscle cells. Recommended initial dosing for patients who weigh less than 100 pounds is 7.5mg to 15mg per day, gradually increased by 2.5mg to 5mg per day to a maximum daily dose of 50mg divided into up to five doses. For patients weighing 100 pounds or more dosing starts at 15mg to 30mg per day and increases by 5mg to 10mg daily to a maximum daily dose of 100mg divided into up to five doses. Tablets are scored for easy division. Children who have had seizures should not use Ruzurgi. Its complete prescribing information is here.

Symjepi Released to Retail Pharmacies

Adamis Pharmaceuticals’ Symjepi (epinephrine) injection was FDA approved in June 2017 for the emergency treatment of allergic reactions, including anaphylaxis. The distributor, Sandoz, started introducing it in the U.S. earlier in 2019, beginning with hospitals and clinics. Now, it is available in retail pharmacies. At a WAC of $250 for a package of two, Symjepi is dispensed as single-dose, pre-filled syringes for manual injection. Each syringe contains either 0.3mg/0.3mL of epinephrine (for patients weighing at least 66 pounds) or 0.15mg/0.3mL (for patients who weigh between 33 pounds and 66 pounds). Recommended dosing is one injection, administered intramuscularly (IM) or SC into the thigh. A second injection may be needed, but no more than two should be administered for a single reaction. The patient should receive emergency medical care, as well. Syringes should be stored in the original container away from light; used syringes should be discarded in a sharps container and any syringes that contain cloudy, brown or pinkish solution or that have particles in the solution should be returned to the pharmacy for replacement. Its complete prescribing information may be found here.

Recarbrio Receives FDA Approval

On July 16, 2019, the FDA granted approval for an injectable antibacterial combination drug that includes a new beta lactamase inhibitor. Merck’s Recarbrio (imipenem/cilastatin/relebactam) will be used to treat patients who are at least 18 years old and who have complicated infections of the urinary tract or abdomen that are caused by specific types of bacteria. Cilastatin and the new drug, relebactam, do not have antibacterial activity, but they prolong imipenem’s antibiotic effects by keeping it from being disintegrated by certain enzymes. Recommended dosing is one vial (imipenem 500mg/cilastatin 500mg/relebactam 250mg) given as a 30-minute intravenous (IV) infusion once every six hours for four days to 14 days. To limit possible drug resistance, Recarbrio will be reserved for use by patients who have not responded to or who cannot take other treatments. Merck plans to launch it later in 2019. The FDA approved Recarbrio under its Priority Review program. It also received a Qualified Infectious Disease Product (QIDP) designation, which facilitates approvals for antibacterial and antifungal drugs that treat serious or life-threatening infections. Full prescribing information for Recarbrio is here.

New Dosage Form for Rosuvastatin

After receiving FDA approval on Dec, 18, 2018, Sun Pharmaceuticals released Ezallor Sprinkle (rosuvastatin) capsules to the U.S. market on July 15, 2019. It is an HMG-CoA reductase inhibitor that is indicated — along with dietary limitations — to treat primary dysbetalipoproteinemia (type III hyperlipoproteinemia) and hypertriglyceridemia. Either alone or in combination with other drugs that lower cholesterol, it also can be used to decrease LDL-C, total cholesterol and ApoB for patients who have homozygous familial hypercholesterolemia. Specifically formulated to treat adult patients who cannot swallow tablets, Ezallor Sprinkle capsules contain extended-release beads of rosuvastatin. Capsules can be swallowed whole or they can be opened, mixed into one teaspoonful of applesauce or another soft, cold food and consumed immediately. Alternately, it can be combined with 40mL of water in a catheter-tipped syringe and given through a nasogastric tube. Used once a day, it is available in 5mg, 10mg, 20mg and 40mg strengths. Full prescribing information can be found here.

First Avastin and Herceptin Biosimilars Launched in the U.S.

On July 18, 2019, Amgen and Allergan announced the introduction of two previously FDA-approved biosimilars. Each is the first biosimilar released in the U.S. for its originator brand, but neither is interchangeable with the brand or with any other biosimilars. Both are wholesale priced at 15% less than their corresponding brand products.

  • Mvasi (bevacizumab-awwb), a biosimilar to Genentech’s Avastin® (bevacizumab), was approved in September 2017 as combination treatment with chemotherapy (chemo) to treat metastatic colorectal cancer, non-squamous non-small cell lung cancer, glioblastoma and cervical cancer. Along with interferon-alfa, it is indicated for metastatic renal cell carcinoma. It is not approved for three Avastin indications (ovarian, fallopian tube, and primary peritoneal cancers) because they are still protected by Orphan Drug Exclusivity (ODE). Dosing, which varies depending on the indication, ranges from 5mg/kg once every two weeks to 15mg/kg once every three weeks by IV infusion. WAC for single-use vials of Mvasi are $677.40 for a 100mg vial and $2,709.60 for a 400mg vial. Find its full prescribing information here.
  • Kanjinti (trastuzumab-anns) is a biosimilar to Herceptin® (trastuzumab - Genentech). It was FDA approved on June 13, 2019, with the same indications as Herceptin — to treat breast cancer, metastatic gastric cancers and gastroesophageal junction adenocarcinomas that are positive for epidermal growth factor receptor-2 (HER2+). After a loading dose, it is given as an IV infusion at varying doses and on varying schedules according to the cancer being treated. All trastuzumab products have boxed warnings that they may cause birth defects, heart failure, respiratory distress or severe allergic reactions. WAC for Kanjinti is $3,697.26 per 420mg multi-use vial. Its prescribing information is here.

Generics to Lyrica Launched

The FDA approved the first AB-rated generics to Pfizer’s Lyrica® (pregabalin) on July 19, 2019. Multiple manufacturers received FDA approval to market all eight commercially available capsule strengths: 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 225mg and 300mg. No company was granted 180 days of generic exclusivity. They all are indicated for the same conditions that Lyrica treats — neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and neuropathic pain associated with spinal cord injury. They also are approved for use as adjunctive therapy for the treatment of partial-onset seizures in patients one month of age and older.

Expanded Indication for Otezla

Otezla® (apremilast - Celgene), an oral phosphodiesterase-4 (PDE-4) inhibitor that works inside cells to decrease inflammation, was given a third FDA indication on July 19, 2019. It originally received approvals for psoriatic arthritis and psoriasis in 2014. Now, it is the first drug to be FDA approved for the treatment of mouth sores that are caused by Behçet’s disease. Affecting only about 15,000 to 20,000 patients in the U.S, Behçet’s disease involves inflammation of blood vessels. Usually diagnosed in young adults, it causes recurring sores inside the cheeks and on the lips and tongue. Sores that can look like herpes virus infections or acne also may affect the genital area and the skin. Uveitis (pain and swelling of the eyes) may cause blindness for some patients who have severe forms of the disease. To limit possible diarrhea, nausea and vomiting that it may cause, dosing for Otezla begins at 10mg per day, increased daily to a maintenance dose of 30mg twice a day by the sixth day. For prescribing information, look here.

FDA Approval for Second Rituxan Biosimilar

Ruxience (rituximab-pvvr), Pfizer’s biosimilar to Rituxan® (rituximab – Celgene), was approved by the FDA on July 23, 2019. It is indicated to treat adults who have non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL) or granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). A monoclonal antibody, it causes B cells to disintegrate by binding to CD20 proteins on their cell surfaces. Administered as IV infusions, it has to be given by a health professional in a facility equipped to handle emergency treatment of serious side effects that it may cause. A boxed warning lists its potentially fatal adverse effects, including infusion-related reactions, mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML) and reactivation of hepatitis B. Doses vary according to the condition under treatment. Ruxience is not interchangeable with Rituxan or with Rituxan’s other biosimilar, Truxima® (rituximab-abbs – Celltrion/Teva), which was FDA approved in November 2018. Launch and pricing information is not yet available for Ruxience, but its full prescribing information is here.

Hadlima, a Biosimilar to Humira, Approved

On July 23, 2019, the FDA approved Hadlima (adalimumab-bwwd – Samsung Bioepis), a biosimilar to AbbVie’s Humira® (adalimumab). It is a monoclonal antibody that inhibits tumor necrosis factor (TNF) to reduce inflammation. Its indications are to treat adults who have ankylosing spondylitis (AS), Crohn’s disease, plaque psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA) or ulcerative colitis (UC). Additionally, it is approved for treating children at least four years of age who have polyarticular juvenile idiopathic arthritis (JIA). For most indications, it is given by SC injections at maintenance doses of 40mg once every two weeks, after loading doses. A boxed warning on the labels of all TNF blockers outlines the increased risks of cancer and serious infections that may be associated with their use. Prospective patients should be screened for tuberculosis (TB) before starting treatment and periodically while therapy continues. Hadlima is not interchangeable with Humira or with the other Humira biosimilars already FDA approved — Boehringer Ingelheim’s Cyltezo (adalimumab – adbm) and Amgen’s Amjevita (adalimumab – atto). Under the terms of an agreement with AbbVie, Merck will distribute Hadlima in the U.S., but not until after the end of the second quarter in 2023. Check here for its complete prescribing information.

Inhaled Glucagon Approved

Eli Lilly’s new dosage form of glucagon, Baqsimi (glucagon) Nasal Powder, 3mg, was FDA approved on July 24, 2019. It will be used to raise dangerously low blood sugar levels (hypoglycemia) for patients four years old and older who have diabetes. Usually considered to be an emergency, hypoglycemia can cause unconsciousness, seizures, coma and death. Although glucagon has been used for decades to treat hypoglycemia, it previously was available only in a powdered form that has to be mixed with sterile water and injected. Expected to be launched within the month, Baqsimi will be dispensed in single-dose inhalation devices. One dose should be given immediately when a hypoglycemic event is suspected. Emergency help should be called and the patient should be given a high sugar drink as soon as possible, followed by a protein-containing food. If the patient is still unconscious 15 minutes after the first dose of Baqsimi, a second one may be used. One device has a WAC of $280.80; a carton of two devices is $561.60. Devices should be kept in their shrink-wrapped tubes until needed. Here is full prescribing information.

New Drug Approved to Treat Iron Deficiency

The FDA has approved a new oral treatment for adults who have iron deficiency. On July 25, 2019, Shield Therapeutics was granted approval for Accrufer (ferric maltol), which is branded as Feraccru® in Europe. Presently, oral iron products available in the U.S. are derived from iron salts that break apart in the gastrointestinal (GI) system to release the iron. They cause significant side effects such as constipation and nausea for many patients, however. The alternative, IV iron infusions, must be given in a healthcare facility, making them inconvenient and expensive. Because Accrufer is a non-salt form of iron, it does not cause as much GI disturbance. It is taken as one 30mg capsule twice a day at least one hour before or two hours after eating. Treatment lasts until blood levels of iron are within normal ranges – usually three months or longer. No information about pricing or launch have been made available. Look here for Accrufer’s prescribing information.

MedWatch Update

Xeljanz/Xeljanz XR

On July 26, 2019, the FDA expanded a Safety Communication it had released in February for Pfizer’s Xeljanz® (tofacitinib) and Xeljanz® XR (tofacitinib extended-release) tablets. Labeling for both drugs now must include a boxed warning that taking 10mg twice a day significantly raises the chance of pulmonary embolisms (blood clots in the lungs) and death. 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 TB. In preliminary results from a continuing safety study of patients who have RA, those taking 10mg of Xeljanz or Xeljanz XR two times a day had more pulmonary embolisms, and more of them died for various reasons compared to patients who took two 5mg doses per day. All study participants were switched to the lower dose. Although the twice-daily 10mg dose has been approved to treat ulcerative colitis (UC), it is not FDA approved for RA or psoriasis. Patients taking the higher dose should get immediate medical help if they suddenly become short of breath, cough up blood, sweat excessively or have other symptoms that might result from pulmonary blood clots. Patients are advised not to stop their Xeljanz or Xeljanz XR, but to talk with their doctors about dose or drug changes. Physicians should be sure that patients are aware of the risks. The twice-daily 10mg dose should be prescribed only for patients who have UC that does not respond to other treatment options and only for as long as needed to resolve the UC episode. For additional information, please see the FDA notice here.

New Indication for Keytruda

On July 30, 2019, Merck’s Keytruda® (pembrolizumab) received an additional indication from the FDA. Following at least one round of another systemic treatment, it now can be used as a single agent to treat recurrent, locally advanced or metastatic squamous cell esophageal tumors that express human programmed death receptor-1 ligand (PD-L1) and that have progressed. Before Keytruda treatment begins, PD-L1 status will be verified as a combined positive score of 10 or more by an FDA-approved test. Keytruda, a PD-1-blocking antibody that helps the body’s immune system attack cancer cells, has numerous previous FDA approvals for treating various other kinds of cancer. For its new indication, it will be administered as a 200mg IV infusion once every three weeks for 24 weeks, if the tumors do not progress. Treatment will be stopped earlier if the patient can no longer tolerate the drug or the tumors begin to worsen. Check here for Keytruda’s complete revised prescribing information.

Extended Approvals for Two Psoriasis Medications

Two topical products made by Leo Pharma have been granted new pediatric indications by the FDA. On July 25, 2019, Taclonex® (calcipotriene/betamethasone dipropionate) Topical Suspension got approval for the treatment of plaque psoriasis of the scalp for patients 12 to 17 years old. A second product, Enstilar® (calcipotriene/betamethasone dipropionate) Foam, received a new indication on July 30, 2019, for the treatment of plaque psoriasis for patients at least 12 years old. Previously, both products were approved only for adults age 18 and older. Both, which each contain a vitamin D analog and a corticosteroid, can be used for psoriasis of the scalp as well as on other areas of the skin. For patients between the ages of 12 years and 17 years, dosing for Taclonex is once daily until psoriasis improves or for up to eight weeks with a limit of 60 grams per week. Enstilar can be applied once a day for four weeks or less, but patients in the 12 to 17 age group should use no more than 60 grams in any four-day period. Neither product should be applied to the face, eyes or mucous membranes, such as the mouth. Here is prescribing information on Taclonex, and here is Enstilar’s.

Nubeqa Approved for Prostate Cancer

Under its Priority Review program, the FDA approved Bayer’s Nubeqa® (darolutamide) tablets on July 30, 2019. It is an androgen receptor inhibitor indicated for the treatment of non-metastatic castration-resistant prostate cancer. The recommended dose for Nubeqa is 600mg (two tablets) twice a day. A gonadotropin-releasing hormone (GnRH) analog, such as leuprolide, also should be used for patients who have not had a bilateral orchiectomy (surgical castration). According to the American Cancer Society (ACS), around 175,000 cases of prostate cancer are diagnosed in the U.S., annually. Approximately 40% of the estimated 73,000 cases that are castration-resistant have not yet metastasized when they are discovered. In the phase III ARAMIS study, patients taking Nubeqa and using a GnRH analog averaged 40.4 months before the cancer metastasized or the patient died, compared to 18.4 months for patients taking a placebo along with a GnRH analog. Nubeqa will be the third androgen receptor inhibitor approved for this indication. Janssen’s Erleada (apalutamide) was the first drug approved in the non-metastatic setting in February 2018. In July of the same year, Astellas/Pfizer’s Xtandi® (enzalutamide) received an expanded indication for patients with non-metastatic castration-resistant prostate cancer. Bayer has not yet announced a launch date. Prescribing information for Nubeqa is available here.

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