New Combination Approved for Metastatic Colorectal Cancer
On July 12, 2018, the Food and Drug Administration (FDA) approved Opdivo (nivolumab) in combination with Yervoy (ipilimumab) for the treatment of adult and pediatric patients ≥12 years old with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The combination of Opdivo, a programmed death receptor-1 (PD-1) blocking antibody, and Yervoy, a cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody is also approved for the treatment of patients with unresectable or metastatic melanoma and for those with intermediate or poor risk, previously untreated advanced renal cell carcinoma. Opdivo is also approved as a single agent for the treatment of MSI-H or dMMR metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Full prescribing information is at:
Kisqali Receives Additional Breast Cancer Information
On July 18, 2018, the FDA approved Kisqali (ribociclib) in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. Additionally, Kisqali has also been approved in combination with fulvestrant to treat postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine-based therapy or following disease progression on endocrine therapy. These approvals were the first to be granted as part of 2 new pilot programs (Real-Time Oncology Review, Assessment Aid) created to improve the development and review of cancer drugs. Revised prescribing information can be found at https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kisqali.pdf
New Drug for HIV-1 Infection
On July 18, 2018, the FDA approved Symtuza (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) for the treatment of HIV-1 infection in treatment-naive and in virologically suppressed adults (<50 copies/mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. Symtuza is the first complete darunavir-based single-tablet regimen to be approved. The drug combines darunavir, an HIV-1 protease inhibitor; cobicistat, a CYP3A inhibitor; and emtricitabine and tenofovir alafenamide, both HIV-1 nucleoside analog reverse transcriptase inhibitors. Symtuza carries a Boxed Warning describing the risk of post-treatment acute exacerbation of hepatitis B. Treatment is not recommended in patients with CrCl <30mL/min or in those with severe hepatic impairment. The product will be supplied as 800mg/150mg/200mg/10mg strength tablets in 30-count bottles. Full prescribing information is available at http://janssenlabels.com/package-insert/product-monograph/prescribing-information/SYMTUZA-pi.pdf
New Drug for Endometriosis
The U.S. Food and Drug Administration approved Orilissa™ (elagolix – AbbVie/Neurocrine Biosciences) tablets on July 24, 2018. It is an orally-administered gonadotropin-releasing hormone (GnRH) receptor antagonist indicated to relieve moderate to severe pain for women who have endometriosis. Recommended dosing is 150mg once a day for up to 24 months or 200mg twice a day for up to six months. AbbVie plans to launch Orilissa in early August 2018. Full prescribing information is available at: http://www.rxabbvie.com/pdf/orilissa_pi.pdf
Nivestym Gets FDA Approval
On July 23, 2018, the Food and Drug Administration (FDA) approved Nivestym (filgrastim-aafi), a biosimilar to Neupogen. The approval was based on data demonstrating that the biosimilar product and the reference product are highly similar, and that there are no clinically meaningful differences between the 2 agents. Nivestym, the second FDA-approved biosimilar to Neupogen, is approved for treating patients undergoing myelosuppressive chemotherapy (chemo) for cancer, patients receiving induction or consolidation chemo for acute myeloid leukemia (AML), patients having bone marrow transplantation to treat cancer, patients going through autologous peripheral blood progenitor cell collection/therapy and patients with severe chronic neutropenia. Complete prescribing information for Nivestym is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761080s000lbl.pdf
Perseris Approved for Schizophrenia
On July 30, 2018, the Food and Drug Administration (FDA) approved Perseris, a once-monthly subcutaneous (SC) risperidone-containing, long-acting injectable for the treatment of schizophrenia in adults. Perseris, an atypical antipsychotic, has an extended-release delivery system that releases sustained levels of risperidone over 1 month. Data showed clinically relevant levels of risperidone were achieved after the first injection without a loading dose or any supplemental oral risperidone doses. Prescribing information can be found at www.perseris.com.
New ADHD Treatment Approved
On August 9, 2018, the Food and Drug Administration (FDA) approved Jornay PM (methylphenidate) extended-release capsules for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged ≥6 years. The drug has a unique delivery platform that consists of two functional film coatings the first layer delays the initial drug release for up to 10 hours and the second layer helps control the release rate of the active ingredient throughout the day. It is intended for dosing in the evening; timing of the dose may be adjusted between 6:30–9:30 PM to optimize efficacy and tolerability. For full prescribing information please visit http://ironshorepharma.com/labeling.pdf.
On August 10, 2018, the FDA approved Annovera™ (segesterone acetate/ethinyl estradiol vaginal system). It combines a new progestin (segesterone acetate) with a commonly used estrogen to provide hormonal contraception for one year. A ring-shaped vaginal insert, it is placed in the uterus by the user. It remains in place, releasing low levels of both hormones, for 21 days, then it is removed, washed and stored in a special case for one week. It can be used for up to 13 cycles (one year). Prescribing information is at: www.annovera.com/pi.pdf
New Approval for Treatment of Dry Eye Disease
On August 16, 2018, Sun Pharma announced that the FDA approved Cequa (cyclosporine ophthalmic solution) 0.09% for use in patients with keratoconjunctivitis sicca or dry eye disease. Cequa, a calcineurin inhibitor immunosuppressant, is the first cyclosporine A product to utilize nanomicellar technology. The unique formulation allows the drug molecule to overcome solubility difficulties, penetrate the eye’s aqueous layer, and prevent the release of active lipophilic molecule prior to penetration. Topical administration of cyclosporine is thought to act as a partial immunomodulator. Cequa will be available as 0.9mg/mL strength preservative-free solution in 0.25mL single-use vials. Each box contains 6 pouches containing 10 vials each. The entire contents of each box should be dispensed intact. Prescribing information can be found at: https://cequapro.com/pdf/CequaPI.pdf
Shire receives Approval for Takhzyro™ used to Treat Hereditary Angioedema (HAE)
Shire received U.S. Food and Drug Administration approval for Takhzyro™ (lanadelumab -flyo) on Aug. 23, 2018. Takhzyro is indicated to treat hereditary angioedema (HAE) for patients at least 12 years old. The first monoclonal antibody to be approved for HAE therapy, it blocks plasma kallikrein to prevent swelling caused by HAE. Recommended initial dosing is one 300mg subcutaneous (SC) self-injection every two weeks, which may be reduced to once every four weeks if the patient has no attacks for six months. Complete prescribing information is at:
New Topical Treatment for Acne
On August 24, 2018, the FDA approved Altreno (tretinoin) lotion for the topical treatment of acne vulgaris in patients ≥9 years of age. It is the first tretinoin product available in lotion form. Full prescribing information is available at https://www.bauschhealth.com/Portals/25/Pdf/PI/altreno-pi.pdf
Two New Oral Treatments Approved for HIV-1 Infection
On August 31, 2018, the Food and Drug Administration (FDA) approved approved Delstrigo (doravirine, lamivudine, tenofovir disoproxil fumarate) fixed-dose tablets and Pifeltro (doravirine) tablets for the treatment of HIV-1 infection in appropriate patients. Specifically, both Delstrigo and Pifeltro are indicated to treat HIV-1 infection in adults with no prior antiretroviral treatment experience. Delstrigo is approved as a complete regimen whereas Pifeltro is to be administered in combination with other antiretrovirals. Both medications are given once daily with or without food. Full prescribing information for Delstrigo is at: https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf
For Pifeltro at: https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_pi.pdf
Cassipa Approved for Opioid Dependence
On September 10, 2018, the Food and Drug Administration (FDA) approved Cassipa (buprenorphine and naloxone) sublingual film for the maintenance treatment of opioid dependence. Cassipa combines buprenorphine, an opioid (partial agonist-antagonist), and naloxone, an opioid antagonist. It is intended for use with a complete plan that includes counseling and psychosocial support. It should only be used after patient induction and stabilization up to a 16mg dose of buprenorphine using another marketed product. The approval of Cassipa was supported by the FDA’s finding of safety and efficacy for Suboxone sublingual film in addition to pharmacokinetic data specific to Cassipa. As with all opioids, Cassipa also can cause potentially severe breathing problems and it can be life-threatening if swallowed by children. It can be prescribed only by clinicians who are certified under the Drug Addiction Treatment Act (DATA). Prescribing information may be found at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208042s000lbl.pdf
Teva Received Approval for Migraine Prevention Drug, Ajovy™
Teva Pharmaceuticals received approval on Sept. 14, 2018, from the U.S. Food and Drug Administration (FDA) for its migraine prevention drug, Ajovy™ (fremanezumab-vfrm). It is the second drug to be approved in its class, calcitonin gene-related peptide (CGRP) inhibitors. CGRP is a protein produced by nerve cells and involved in constricting blood vessels. Baseline levels of CGRP may be unusually high for individuals who have migraines. By blocking it, Ajovy helps prevent or lessen the vasoconstriction that often triggers migraines. Recommended dosing is one self-administered, subcutaneous (SC) injection (225mg) once a month or three injections (675mg) given at the same time once every three months. Ajovy will be available through open distribution in approximately two weeks. It will be priced at about $575 per month — similarly to Aimovig™ (erenumab-aooe – Amgen/Novartis), the only other CGRP inhibitor currently available on the U.S. market. It is not approved for the acute treatment of migraine. Complete prescribing information is available at: https://www.ajovy.com/globalassets/ajovy/ajovy-pi.pdf
Eli Lily receives Approval for Emgality™ for the use of Migraine Treatment.
Eli Lilly’s Emgality™ (galcanezumab-gnlm) was approved by the U.S. Food and Drug Administration (FDA) on Sept. 27, 2018. The third calcitonin gene-related peptide (CGRP) inhibitor to enter the U.S. market, it is indicated to prevent migraine headaches for adults. Following a single loading dose of 240mg (two self-injections at the same time), one dose (120mg) will be self-injected subcutaneously (SC) each month. Emgality will be available through open distribution in the near future. Complete prescribing information is available at: http://pi.lilly.com/us/emgality-uspi.pdf
Pfizer receives Approval for Vizimpro® (dacomitinib)
On Sept. 27, 2018, the U.S. Food and Drug Administration (FDA) approved Pfizer’s Vizimpro® (dacomitinib) tablets as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as detected by an FDA-approved test. Recommended dosing is 45mg orally once daily, with or without food. Pfizer plans to launch Vizimpro within the next few weeks. Complete prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf
FDA Expands Approval
New Indication for Xtandi
On July 16, 2018, the Food and Drug Administration (FDA) approved an expanded indication for Xtandi (enzalutamide) to include the treatment of men with non-metastatic castration-resistant prostate cancer (CRPC), making it the first oral medication approved for both non-metastatic and metastatic CRPC. Xtandi, an androgen receptor inhibitor, is supplied as 40mg capsules in 120-count bottles. For more information please visit www.xtandi.com.
Actemra Receives New Approval
On September 13, 2018, the FDA approved Actemra SC (tocilizumab solution for subcutaneous injection) for the treatment of active systemic juvenile idiopathic arthritis (SJIA) alone or in combination with methotrexate in patients ≥2 years old. Previously, just the intravenous formulation of Actemra was FDA-approved for this indication. Full prescribing information is available at https://www.gene.com/download/pdf/actemra_prescribing.pdf
New Symjepi Dose Approved
On September 28, 2018, the Food and Drug Administration (FDA) approved a 0.15mg dose of Symjepi (epinephrine) to treat pediatric patients who weigh between 33 and 65 pounds. Symjepi is an emergency treatment for allergic reactions (Type 1) including anaphylaxis to stinging and biting insects, allergen immunotherapy, foods, drugs, diagnostic testing substances and other allergens, as well as idiopathic or exercise-induced anaphylaxis. The 0.3mg dosage strength of Symjepi was approved in June, 2018 for patients who weigh ≥30kg. Both doses will be supplied in single-dose, prefilled syringes for manual injection. Symjepi can be injected intramuscularly or subcutaneously, and through clothing if necessary. Full prescribing information can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207534lbl.pdf
FDA Extends Expiration Dates of Mylan’s EpiPen
The FDA took steps to lessen the shortage of EpiPens by extending the expiration date of specific lots of 0.3-mg products from Mylan by four months beyond the labeled expiration date. The FDA came to this decision after Mylan, the distributers of the EpiPen, requested the extension and provided data to show that it would be safe to use them past the listed, 20-month-long shelf life.
The affected lots have current expiration dates between April 2018 and December 2018. The new expiration dates can be found on the FDA’s website. The extension of expiration dates does not apply to EpiPen Jr 0.15 mg auto-injectors or its authorized generic version of that strength.
There is currently a shortage of EpiPens due to supply disruptions and manufacturing issues. The FDA announced the shortage in May, and said that based on information from Mylan, they believed the shortage “to be short-term.” However, Mylan confirmed on August 8 that the shortage was still ongoing.
Pfizer, which makes the auto-injectors for Mylan, said in a statement that they are working with Mylan to improve “consistent availability” and that “Patients should have confidence in using the products from these particular lots as Pfizer works to stabilize supply, which is anticipated in the fourth quarter of 2018.”
“Many patients rely on self-injectable epinephrine products, such as EpiPen, to reverse life-threatening reactions to bee stings or other allergens for either themselves or for their children. We are doing everything we can to help mitigate shortages of these products, especially ahead of the back-to-school season,” Janet Woodcock, CDER director for the FDA, said in a statement.
The FDA also approved the first generic competitor to EpiPen but it’s not clear when the new device will be available.
Teva granted approval for generic versions of Mylan’s EpiPen®
Teva Pharmaceutical Industries was granted U.S. Food and Drug Administration (FDA) approval on Aug. 16, 2018, for its AB-rated generic versions of Mylan’s EpiPen® (epinephrine) Auto-Injector 0.3mg and EpiPen, Jr® (epinephrine) Auto-Injector 0.15mg. Used as emergency treatment for anaphylaxis (severe, systemic allergic reactions), they are indicated for adults and children who weigh at least 33 pounds. Recommended use is one auto-injection into the middle of the outer thigh (through clothing, if necessary) at the onset of the reaction. A second injection may be needed before emergency personnel arrive, but no more than two doses should be self-injected for one episode. Teva is expected to launch its generic epinephrine auto-injector in the coming months. Pricing information is not yet available. U.S. sales for EpiPen and EpiPen, Jr totaled approximately $763 million in 2017.
FDA Issues Alerts, Warnings and Recalls
FDA Issues Alert for SGLT2 Diabetes Drugs
The FDA stated that they had identified a dozen cases of a rare flesh-eating infection in patients taking SGLT2 diabetes drugs and are requiring SGLT2 drugmakers to add a warning about the risk to their labels.
The condition, called Fournier’s gangrene, or necrotizing fasciitis of the perineum, can be caused by diabetes itself, but the agency reported that in the dozen cases that they identified, the condition emerged, on average, approximately nine months after they started taking an SGLT2 inhibitor. All of the patients, seven men and five women, were hospitalized and one died, the agency said.
The warning will affect 13 products from Eli Lilly and Boehringer Ingelheim; Johnson & Johnson; AstraZeneca; Merck and Pfizer. All of the drugs have been linked to cases of Fournier’s except for Merck’s Steglatro, which was approved late last year. That product will still need to carry the warning label.
To determine whether the condition was linked to the drugs, the FDA searched its adverse event database going back to 1984. It found just six cases of Fournier’s gangrene, all in men.
“This contrasts with the findings for Fournier’s gangrene with the SGLT2 inhibitors where more cases were reported over a shorter timeframe, and cases involved both males and females,” the FDA’s document said.
Spokespeople for Merck, Johnson & Johnson, Boehringer Ingelheim, Eli Lilly and AstraZeneca said in emailed statements that the companies are discussing the labeling update with the FDA.
Stronger Warnings for Fluoroquinolone Antibiotics
On July 10, 2018, the FDA approved class-wide labeling changes for all fluoroquinolone antibiotics to strengthen the warnings related to mental health side effects and the risk for severe low blood sugar, including hypoglycemic coma. Fluoroquinolone antibiotics include moxifloxacin (Avelox), delafloxacin (Baxdela), ciprofloxacin (Cipro), gemifloxacin (Factive), levofloxacin (Levaquin), and ofloxacin. The labeling changes are based on a review of post marketing adverse event reports found in the FDA Adverse Event Reporting System (FAERS) database and published medical literature. Fifty-six reports of hypoglycemic coma associated with fluoroquinolones use were identified in the database from October 1987 to April 2017; most of these patients had risk factors for hypoglycemia. As for psychiatric events, the FDA is requiring that all fluoroquinolone antibiotics include the following 6 adverse reactions: disturbance in attention, memory impairment, delirium, nervousness, agitation, and disorientation. To read the full report, please visit www.fda.gov.
On July 16, 2018, the FDA announced that drugs containing the active ingredient valsartan are being recalled due to the fact that these drugs contain N-nitrosodimethylamine (NDMA), an impurity classified as a probable human carcinogen. he recalled medications include Valsartan Tablets manufactured by Major Pharmaceuticals, Solco Healthcare, and Teva Pharmaceuticals, as well as Valsartan/Hydrochlorothiazide Tablets from Solco Healthcare and Teva Pharmaceuticals. “We have carefully assessed the valsartan-containing medications sold in the United States, and we’ve found that the valsartan sold by these specific companies does not meet our safety standards,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research. “This is why we’ve asked these companies to take immediate action to protect patients.” For more information on the recall, please see the FDA notice at: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm614030.htm
FDA Panel Votes Against GlaxoSmithKline’s Nucala for COPD
The FDA outlined their issues with GlaxoSmithKline application to gain an approval for Nucala (mepolizumab) as a therapy for COPD. The panel voted 16-3 against a COPD approval.
The panel found that the drug, which is already approved for treating severe asthma patients, was safe but that it did not demonstrate efficacy for a new indication. FDA staff reviewers earlier raised doubts as to whether the data GSK submitted provided evidence of the drug’s efficacy.
The FDA noted that “investigations of a subset of COPD patients who experience airway inflammation with a measurable eosinophilic component led to efforts to characterize ‘eosinophilic COPD’ as a distinct, clinically meaningful phenotype. Despite research, uncertainty still exists regarding accurate defining criteria of the phenotype, the importance of sputum eosinophils versus peripheral blood eosinophils (PB-Eos) as biomarkers, and the clinical impact of the eosinophilic COPD phenotype in patient care and drug development.”
The committee also noted that GSK was not able to replicate efficacy when mepolizumab was given at 100 mg and also at 300 mg. The committee also raised concerns about the fact that the company did not collect data on patient asthma history nor use of chronic maintenance oral corticosteroids for COPD, which could have affected the results.
“In particular, any observed benefit of mepolizumab on exacerbations could be driven primarily or entirely by an effect in patients with concomitant asthma, given that asthma exacerbations and COPD exacerbations are not well differentiated clinically. Asthma-related adverse events appear in the safety database, suggesting subjects with active asthma were present in the trials,” the committee said.
Dave Allen, GlaxoSmithKline SVP of R&D in respiratory, stated “We remain confident our data supports (Nucala) as a targeted treatment for patients continuing to experience COPD exacerbations guided by blood eosinophil count,” and that the company would continue to work with the regulator to “address outstanding questions.”
The FDA is not required to take the advice of its advisory committees, but usually does.