FDA Approved Drugs: October 2019

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

FDA Approval for Orfadin Generic

Novitium Pharma was given FDA approval on Aug. 26, 2019, for nitisinone capsules, an AB-rated generic for Swedish Orphan Biovitrum’s (Sobi’s) Orfadin® (nitisinone) capsules. Used with dietary restrictions, nitisinone prevents the accumulation of tyrosine metabolites for individuals who have hereditary tyrosinemia type 1 (HT-1). Tyrosine is an amino acid that patients with HT-1 cannot break down adequately because they lack the necessary enzyme. Affecting only a few hundred patients – mainly children, HT-1 is a rare and progressive disease that results in potentially fatal kidney, liver and nerve complications if not treated. The generic will be distributed by Par Pharmaceutical, which plans to launch it in September. No generics are available for Orfadin Oral Suspension and NITYR (nitisinone – Cycle Pharmaceuticals) tablets. According to Sobi, global sales for Orfadin capsules amounted to about $85 million in the most recent four quarters.

New Dosage Form and Expanded Indication for Harvoni and Sovaldi

On Aug. 28, 2019, the FDA approved an oral pellet dosage form for two of Gilead’s hepatitis C (HCV) drugs – Sovaldi® (sofosbuvir) and Harvoni® (ledipasvir/sofosbuvir). The pediatric indications for both were extended to children as young as three years old, as well. For administration, the pellets are mixed with a small amount of a cool, soft, non-acid food, such as ice cream or pudding, and swallowed once a day within one-half hour of being added to the food. Dosing for either drug varies according to the child’s weight. Sovaldi is indicated for children who have genotype 2 or 3 HCV. Children taking Sovaldi also need to take ribavirin. Treatment with it lasts 12 weeks for children who have genotype 2 HCV, and 24 weeks for children who have type 3. Sovaldi pellets are available in packets of 150mg or 200mg. Harvoni also now comes in two strengths of pellets (ledipasvir 33.75mg/sofosbuvir 150mg and ledipasvir 45mg/sofosbuvir 200mg). It is used for 12 weeks to treat patients at least three years old who have HCV genotype 1, 4, 5, or 6. Some patients who have genotype 1 may need an additional 12 weeks of therapy and some patients may need ribavirin, too. Both drugs have boxed warnings to caution that taking either may worsen or reactivate hepatitis B (HBV), so all patients should have an HBV test before starting therapy and then regular monitoring should be performed during treatment for signs of HBV. Full prescribing information is here for Sovaldi and here for Harvoni.

Gvoke Receives FDA Approval

Xeris Pharmaceuticals’ Gvoke (glucagon) injection received approval on Sept. 10, 2019, from the FDA. It is indicated to treat severe hypoglycemia for patients at least two years old who have diabetes. It will be available in two single-dose subcutaneous (SC) dosage forms – prefilled syringes (Gvoke PFS) and auto-injectors (Gvoke HypoPen). Each will also be available in two strengths -- 0.5mg/0.1mL for children weighing less than 45Kg (about 100 pounds) and 1mg/0.2mL for heavier children and patients age 12 years and older. Recommended dosing is one injection into the upper arm, lower abdomen or outer thigh as soon as a hypoglycemic event is suspected. Emergency medical help should be called immediately and a second dose of Gvoke may be given if the patient hasn’t recovered within 15 minutes. A carbohydrate, such as chocolate or ice cream, should be given once the patient responds. Unlike other injectable glucagon products, Gvoke does not have to be mixed with sterile water or drawn into a syringe before use. Xeris plans to launch the prefilled syringes by the end of October and the auto-injectors in 2020. Both will be supplied in cartons of one device at a wholesale acquisition cost (WAC) of $280.80 -- or two devices (WAC $561.60). Prescribing information is here.

FDA Approves Ibsrela

Ibsrela® (tenapanor – Ardelyx) tablets was FDA approved on Sept. 12, 2019. Only slightly absorbed in the gastrointestinal (GI) tract, it blocks sodium/hydrogen exchanger 3 (NHE3) to reduce absorption of sodium and phosphorous in the small intestine and colon. The resulting increase in GI fluid loosens stools, speeds up transit time, promotes bowel movements and lessens abdominal pain for adults who have constipation-dominant irritable bowel syndrome (IBS-C). An estimated 11 million Americans have IBS-C, which causes significant discomfort and loss of productivity. To manage it, the recommended daily dose of Ibsrela is one tablet (50mg) right before breakfast and one tablet right before dinner. Since it may cause possibly severe diarrhea, Ibsrela carries a boxed warning that it should not be used for children. Ardelyx actively is seeking a partner to market it in the U.S. For Ibsrela’s full prescribing information, look here.

New Ofev Indication

A new FDA indication as the first drug to treat systemic sclerosis (scleroderma) associated interstitial lung disease (SSc-ILD) was granted for Ofev® (nintedanib – Boehringer Ingelheim) capsules on Sept. 6, 2019. An autoimmune condition affecting about 100,000 Americans, SSc causes the buildup of fibers and scars in connective tissues. Around one-quarter of patients who have it develop ILD within a few years. As a result, lung function deteriorates, eventually failing completely. In the year-long, phase III SENSCIS® clinical trial of 576 patients who have SSc-ILD, loss of breathing capacity was slowed by 44% for actively treated patients as compared to those using a placebo. Ofev has a previous indication for treating idiopathic pulmonary fibrosis (IPF), another rare and progressive lung disease. For both conditions, the recommended dose is 150mg twice a day with food. Because Ofev may cause liver damage, liver function tests should be conducted prior to initiating treatment and during therapy. Check here for its complete prescribing information.

Expanded Pediatric Indication for Nucala

The approved age range for GlaxoSmithKline’s Nucala® (mepolizumab) was extended by the FDA on Sept. 12, 2019. Originally approved in November 2015 to be adjunct maintenance treatment of severe eosinophilic asthma for patients at least 12 years of age, it now can be used for children age six years and older. Nucala blocks the action of interleukin-5 (IL-5) to decrease eosinophils, which are white blood cells that contribute to increased sensitivity of the airways among asthma patients who have an eosinophilic phenotype. For patients between the ages of six years and 12 years, the recommended dose is 40mg once every four weeks. Although the adult dose of Nucala (100mg SC once every four weeks) is available in prefilled syringes and auto-injectors, the 40mg dose has to be administered by a health professional because it currently must be drawn from a 100mg vial. Here is updated prescribing information.

FDA Approves New Oncology Drug Regimen

On Sept. 17, 2019, the FDA approved the use of Keytruda® (pembrolizumab - Merck) and Lenvima® (lenvatinib - Eisai) together to treat endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). Eligible patients are not appropriate for treatment with radiation or surgery and they have cancer that has progressed despite previous systemic treatment. In a clinical trial of 94 patients, 10 of those treated with the Keytruda/Lenvima combination had complete clearing of their tumors and another 26 had at least some improvement. Responses lasted six months or longer for about 70% of patients who were helped by the drugs. For the new indication, the suggested dose of Keytruda is 200mg infused intravenously (IV) once every three weeks. Two 10mg capsules of Lenvima are taken once every day. Treatment lasts for two years, until the cancer begins to spread or until the patient can no longer tolerate the drugs’ side effects. Keytruda’s revised prescribing information is here; Lenvima’s here

The approval marks the first time that drugs have been reviewed and approved simultaneously in the U.S. and other countries. The Keytruda/Lenvima regimen also was approved in Canada and Australia. Under the FDA Oncology Center of Excellence’s Project Orbis initiative, drug regulatory bodies of each participating nation evaluate applications for the same oncology drugs at the same time – sharing information with the immediate goal to quickly approve therapies for cancer patients. Eventually, the project will include agencies from additional countries and it also aims to standardize conducting and reporting of clinical trials for cancer drugs. More information about Project Orbis may be found on the FDA’s website here.

Erleada Approved for Metastatic Castration-Sensitive Prostate Cancer

A second indication for Janssen’s Erleada® (apalutamide) was FDA approved on Sept. 17, 2019. Originally FDA approved in February 2018 to treat patients who have castration-resistant prostate cancer that has not spread, the androgen receptor inhibitor now can be taken for treating metastatic castration-sensitive prostate cancer, as well. The recommended dose for both conditions is 240mg (four tablets) taken once a day. For patients who have not had a bilateral orchiectomy (surgical castration), a gonadotropin-releasing hormone (GnRH) analog, such as Zoladex® (goserelin) implants, also should be used. Janssen estimates that the new indication extends the use of Erleada to as many as 40,000 additional patients annually in the U.S. For its full prescribing information, please look here

New Indication for Pifeltro and Delstrigo

Two Merck HIV drugs, Pifeltro™ (doravirine) tablets and Delstrigo™ (doravirine/lamivudine/tenofovir disoproxil fumarate) tablets were approved by the FDA on Sept. 19, 2019, for treating certain adults who have HIV-1 that is suppressed by other drug therapy to a viral load of less than 50 copies of HIV-1 RNA per mL. Patients also must have been on a stable regimen of antiretroviral therapy, have had no failures during treatment and have no substitutions that relate to resistance to the ingredients in either drug. Previously, they were approved only for patients new to HIV treatment. Pifeltro is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that must be used along with other HIV drugs, but Delstrigo is a complete therapy that is taken alone. Both are taken once daily. In the clinical trials that led to the approvals, the effectiveness and safety of treatment with Delstrigo or Pifeltro plus other antiretroviral drugs was comparable to that of other antiretroviral regimens after patients switched. Delstrigo’s labeling includes a boxed warning that discontinuing the use of lamivudine or tenofovir disoproxil fumarate can activate hepatitis B virus (HBV) for patients who have or who have had HBV. Patients should be monitored for signs of HBV before, during and for several months after treatment with Delstrigo. Check here for Pifeltro’s revised prescribing information, and here for Delstrigo’s.

MedWatch Update

CDK 4/6 Inhibitors

The FDA issued a safety communication for cyclin-dependent kinase (CDK) 4/6 inhibitors on Sept. 13, 2019. It is warning that the drugs – Ibrance® (palbociclib - Pfizer), Kisqali® (ribociclib - Novartis), Kisqali®/Femara® Co-Pack (ribociclib/letrozole - Novartis) and Verzenio® (abemaciclib – Lilly USA) – may cause rare but severe inflammation in the lungs of patients using them. All are taken orally, along with a hormone, to treat some forms of advanced breast cancer. Patients should not stop taking their drugs, however, unless they have been prescribed alternative treatments. Patients who continue using CDK4/6 inhibitors should let their doctors know right away if they have trouble breathing, especially while they are resting. Prescribers should watch patients carefully for any signs of respiratory distress. More information is in patient Medication Guides that are included with each fill of the drugs and also in the FDA’s notice found here.

MedWatch Update


In a separate alert that also was released on Sept. 13, 2019, the FDA announced that slight amounts of a contaminant, N-nitrosodimethylamine (NDMA), have been detected in samples of ranitidine. NDMA and similar chemicals can cause cancer if consumed in large quantities. An oral histamine-2 (H2) blocker, ranitidine is available both with and without a prescription. Sold under the brand-name, Zantac® (Chattem, a subsidiary of Sanofi-Aventis), and numerous generics, it is widely used to treat gastroesophageal reflux disease (GERD), heartburn and stomach ulcers. Over the last year, several angiotensin receptor blocking (ARB) drugs have been recalled because they contain unacceptably higher amounts of NDMA and chemicals like it than those that have been found in ranitidine, so far. While the FDA continues to investigate, several companies that make them, have recalled ranitidine and Zantac. The FDA emphasizes that trace amounts of NDMA naturally are present in foods, tap water and other everyday exposures. Patients who have concerns should discuss changing to another drug in the same class or to a different type of medication with their doctors or pharmacists. Look here for more information about the issue.

Rybelsus Approved to Treat Type 2 Diabetes

On Sept. 20, 20109, Novo Nordisk announced FDA approval for Rybelsus® (semaglutide) oral tablets. It is the first orally-administered glucagon-like peptide (GLP-1) receptor agonist protein approved along with diet and exercise for treating adults who have type 2 diabetes. The recommended starting dose is 3 mg/day taken at least 30 minutes before the first food, beverage or other oral medications of the day and with no more than four ounces of plain water. After 30 days, the dose can be increased to 7 mg once daily. The daily dose may be further increased to the 14 mg tablet if additional glycemic control is needed, but only after at least 30 days on the 7mg daily dose. Rybelsus is a GLP-1 agonist that moderates blood glucose levels through several pathways, which include slowing glucose absorption from the intestines after meals, decreasing glucagon production and promoting insulin secretion from the pancreas. Similar to other GLP-1 agonists, the labeling for Rybelsus contains a boxed warning about tumors of the thyroid gland (thyroid C-cell tumors) that have occurred among  laboratory rodents treated with some GLP-1 receptor agonists in preclinical studies. However, whether or not Rybelsus causes humans to develop thyroid C-cell tumors, such as medullary thyroid carcinoma (MTC), is not yet known. Patients with MCT, individuals with close family members who have thyroid C-cell tumors and patients with Multiple Endocrine Neoplasia syndrome type 2 (tumors in more than one gland) should not use Rybelsus. Launch is planned for early in the fourth quarter of 2019. Complete prescribing information can be found here.

FDA Approves Jynneos to Prevent Smallpox and Monkeypox

Bavarian Nordic’s Jynneos (smallpox and monkeypox vaccine, live, non-replicating) suspension for injection was approved by the FDA on Sept. 24, 2019. Both smallpox and monkeypox are viral diseases that produce body aches, fever and large blistery rashes. Highly contagious, smallpox spreads from person-to-person, but monkeypox is carried by rodents and other animals. Jynneos is indicated to prevent either disease for patients age 18 years and older who are immunocompromised or who have other conditions that could make them particularly vulnerable to getting one of the diseases. Healthcare providers who have been exposed to either virus, and military personnel stationed in areas where the viruses are prevalent, should be vaccinated, as well. The recommended dosing is two subcutaneous (SC) injections given one month apart. Although other smallpox vaccines may be available, Jynneos is the first to use live viruses that are not able to produce additional viral particles, which makes it less likely to cause adverse reactions. It also is the only vaccine against monkeypox -- a less common and usually milder illness than smallpox -- that is found mainly in Central and Western Africa. In 2003, however, nearly 50 monkeypox cases were confirmed or suspected in six states of the midwestern United States. The outbreak was traced to imported animals, which had infected prairie dogs that were being kept as pets. Because naturally-occurring smallpox was essentially eliminated by 1980, widespread vaccination is no longer suggested for entire populations. Global researchers and government agencies maintain samples of the virus, though, and accidental releases are possible. The use of smallpox as a biological weapon also is a real potential threat. As a precaution, the U.S. Strategic National Stockpile will store enough frozen doses of Jynneos to assure adequate coverage for general emergencies. In addition to FDA’s Priority Review, Jynneos received a Material Threat Medical Countermeasure (MCM) Priority Review Voucher, which Bavarian Nordic has indicated it plans to sell to another pharmaceutical company. Here is full prescribing information.

New Dysport Indication

Ipsen Biopharmaceuticals received FDA approval for an additional Dysport® (abobotulinumtoxinA) indication on Sept. 25, 2019. It already was approved for several adult conditions, including cervical dystonia and upper limb spasticity (inflexibility, spasms or stiffness in the muscles) and to treat lower limb spasticity for children as young as two years old. Now, it also is indicated for children, except those whose arm and hand spasticity is caused by cerebral palsy, who are at least two years old and who have spasticity in their upper limbs. Spasticity is fairly common for children who have had head injuries, multiple sclerosis (MS), spinal cord injuries or strokes. Recommended total pediatric dosing for each treatment depends on the weight of the patient, the number of affected muscles and the severity of spasticity. The range is 8 units to 16 units per Kg of body weight injected intramuscularly (IM) into affected muscles of each arm or hand. Dosing should not exceed 16 units/Kg or 640 units per treatment and treatments should be separated by at least 16 weeks. All botulinum toxin products, including Dysport, carry a boxed warning that they may migrate away from the areas where they are injected and may possibly cause widespread side effects that rarely may include serious breathing or swallowing problems. Migration and side effects can happen even several months after the product has been injected. Children may be especially prone to having adverse effects. Complete prescribing information for Dysport is here.

Mavyret Approval Extended

The shortest dosing regimen of AbbVie’s Mavyret® (glecaprevir 300mg/pibrentasvir 120mg) now can be used for additional hepatitis C patients. On Sept. 26, 2019, the FDA approved an eight-week course of Mavyret treatment for newly diagnosed patients age 12 years and older who weigh at least 45 Kg (about 100 pounds), who have any of the six known types of hepatitis C and who also have compensated cirrhosis. Previously, only patients who do not have cirrhosis were eligible for the shorter treatment. Some patients still will need 12 weeks or 16 weeks of therapy, however. The recommended dose is three tablets taken together once every day. Labeling includes a boxed warning that taking Mavyret can activate hepatitis B virus (HBV) for patients who have or who have had HBV. Patients should be tested for HBV before treatment begins, and then monitored for signs of infection with it during and for several months after treatment ends. For Mavyret’s full prescribing information, look here.

Expanded Indication for Darzalex

Also on Sept. 26, 2019, the FDA approved an addition to the indications for Darzalex® (daratumumab – Genmab/Janssen) solution for injection. Used together with three drugs known as VTd, which include Velcade® (bortezomib – Millennium), Thalomid® (thalidomide – Celgene) and dexamethasone, it can be used as first-line treatment of adults who are candidates for autologous stem-cell transplants to treat multiple myeloma. In the clinical trial of over one thousand patients, some are receiving VTd while others also get Darzalex. For patients on the four drug regimen, the chance of progression free survival (PFS) increased by 53% compared to those on VTd. The dose for Darzalex is an intravenous (IV) infusion of 16mg/Kg once a week for eight weeks, then once every two weeks for four more doses as induction therapy. At least one month after the patient receives high doses of chemotherapy (chemo) and the stem-cell transplant, the consolidation phase of treatment includes four Darzalex infusions given at two-week intervals. Darzalex also can be used in several other combinations and alone to treat different stages of multiple myeloma. To see its complete prescribing information, check here.

Rituxan Approved to Treat Rare Conditions for Children

The first pediatric indications for Rituxan® (rituximab – Genentech) were granted by the FDA on Sept. 27, 2019. For children as young as two years old, it can be used to treat granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Two severe forms of a rare autoimmune vasculitis, they cause inflammation and damage in the small blood vessels of the kidneys, lungs and other organs. Rituxan is an infused monoclonal antibody that targets CD20 receptors on B-cells. Since it originally was FDA approved in November 1997 to treat Non-Hodgkin’s Lymphoma (NHL), it has received new indications for treating adults who have acute and chronic lymphocytic leukemias (ALL and CLL) mantle cell and small lymphocytic leukemias (MCL and SLL), GPA, MPA, macroglobulinemia and rheumatoid arthritis (RA). For its new pediatric indications, it will be administered along with a glucocorticoid, such as methylprednisolone, and given as an intravenous (IV) infusion of 375mg/m2 once each week for four weeks. If the patient responds to treatment, recommended maintenance dosing is one 250mg/m2 infusion followed by a second one after two weeks, then one every six months. Boxed warnings on the label advise that some patients using Rituxan may experience infusion-related or severe mucocutaneous (skin and mucous membrane) reactions, reactivation of hepatitis B virus or progressive multifocal leukoencephalopathy (PML). Revised prescribing information may be found here.

Expanded Indication for Invokana

On Sept. 27, 2019, the FDA approved a new indication for Janssen’s sodium-glucose co-transporter 2 (SGLT2) inhibitor, Invokana® (canagliflozin). It is the first diabetes drug to be approved for decreasing the chance of end-stage kidney disease (ESKD), kidney function decline, cardiovascular (CV)-related death and hospitalization due to heart failure for adults who have type 2 diabetes, diabetic nephropathy and more than 300mg/day of protein in their urine. The CREDENCE clinical trial of 4,400 patients who have type 2 diabetes and moderate or severe chronic kidney disease was ended early because patients taking Invokana along with standards of care for renin-angiotensin blockade were around 30% less likely to have any of the primary adverse outcomes. Recommended dosing is one 100mg tablet taken daily before the first food of the day. Diet limitations and exercise should be used, as well. Doses can be increased up to a maximum of 300mg/day if blood sugar is not controlled adequately with a lower dose. A boxed warning and a patient Medication Guide caution patients who have or who are at risk of having CV disease, that taking Invokana may be associated with amputations of the lower leg, feet or toes. Patients using it should report infections or sores on their feet or legs to their doctors as soon as they are seen. Here is prescribing information that includes the new indication.

Expanded Crysvita Indication and Label Information

Ultragenyx Pharmaceutical Inc. received FDA approval on Sept. 27, 2019, for Crysvita® (burosumab - twza) to treat patients as young as six months old. Crysvita is a monoclonal antibody that blocks the activity of fibroblast growth factor 23 (FGF23). It was approved in April 2018 to restore more normal phosphate reabsorption and increase blood levels of vitamin D for patients age one year and older who have X-linked hypophosphatemia (XLH). A rare, hereditary bone disease, XLH is believed to affect between 12,000 and 16,000 patients in the U.S. For patients who have XLH, overproduction of FGF23, a hormone that controls phosphate elimination and vitamin D production in the kidneys, causes too much phosphate to be lost in the urine. Not enough minerals deposit in bones and teeth, which can cause rickets (weak bones), bone and tooth pain, increased fracture risk, shortness and hearing loss. The FDA also is allowing labeling revisions that state Crysvita produced better outcomes and improved symptoms better for clinical trial patients than standard treatment with oral phosphate and vitamin D supplements. For adults, recommended Crysvita dosing is 1mg/Kg rounded to the nearest 10mg injected SC once every four weeks. For children, the dose is 1mg/Kg (rounded to the closest 1mg) for patients who weigh less than 10Kg (about 20 pounds) and 0.8mg/Kg (rounded to the nearest 10mg) for those heavier than 10Kg. Children receive injections once every two weeks. The maximum single dose for patients of any age and weight is 90mg. Check here for Crysvita’s updated prescribing information.

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