FDA Update: August 2018

Aug 20, 2018

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

New Pill Bottle 

Express Scripts’ Emerging Therapeutics team features several of the important actions taken by the U.S. Food and Drug Administration (FDA):

Generic Launched for Makena

American Regent launched hydroxyprogesterone caproate injection 250mg/mL on June 25, 2018. It is the first preservative-free AP-rated (interchangeable) generic for Makena® (AMAG Pharma USA), a drug indicated to reduce the risk of preterm birth for women who are pregnant with one baby and who previously delivered one preterm baby spontaneously. Intramuscular (IM) injections must be given once a week by a healthcare provider. At a recommended dose of 250mg, the injections begin between weeks 16 and 21 of the pregnancy, and then continue until week 37 or the birth of the child. The generic is available in single-dose vials, but pricing information is not available. According to the AMAG annual report, worldwide net sales for Makena were approximately $387 million in 2017.

Sialorrhea Indication for Xeomin

Xeomin® (incobotulinumtoxinA) was granted a new indication on July 3, 2018, for treating adults who experience sialorrhea (excessive drooling). Xeomin is a nerve toxin with previous approvals to treat upper limb spasticity (ULS), muscle spasms associated with cervical (neck muscle) blepharospasm (involuntary closing of the eyelids) and dystonia. It also has a cosmetic indication for temporarily improving glabellar lines (frown lines between the eyebrows). Although other botulinum toxins have similar indications, Xeomin is the first one approved for sialorrhea. Associated with strokes and conditions such as Parkinson’s disease, excess drooling can cause skin and tooth problems, as well as embarrassment for the patient. To reduce drooling, Xeomin will be injected by a health professional into two sets of the patient’s salivary glands (four injections per treatment). Treatments must be separated by 16 weeks or longer. Updated prescribing information is available here.

Opdivo/Yervoy Combination Approved to Treat a Rare Cancer Type

Bristol-Myers Squibb received approval from the FDA on July 11, 2018, to use Opdivo® (nivolumab) and Yervoy® (ipilimumab) for approximately 5% of patients who have colorectal cancer. Specifically, the two drugs will be used together to treat patients who are at least 12 years old and whose metastatic or inoperable colorectal cancer (mCRC) is microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR). Additionally, the cancer must have advanced despite prior treatment with a chemotherapy (chemo) regimen containing fluoropyrimidine, irinotecan or oxaliplatin. For the new indication, the recommended doses are given on one day --  3mg/kg of Opdivo infused intravenously (IV) over one-half hour followed by 1mg/kg of Yervoy over one-half hour -- once every three weeks for four cycles. Yervoy then is discontinued and Opdivo is given IV once every two weeks at a dose of 240mg for as long as the patient can tolerate taking it or until the cancer worsens. Product labeling for Yervoy carries a boxed warning that it can cause immune-mediated adverse reactions potentially involving any organ system and possibly life-threatening. Patients should be tested for adrenal, hormone, liver and thyroid functions before Yervoy is initiated and before each dose. Full prescribing information can be found here (Opdivo) and here (Yervoy).

Symtuza Approved to Treat HIV-1

Janssen’s Symtuza was approved by the FDA on July 17, 2018. It combines 800mg of darunavir (a protease inhibitor), 150mg of cobicistat (a CYP3 inhibitor), 200mg of emtricitabine and 10mg of tenofovir alafenamide (both are nucleoside analog reverse transcriptase inhibitors) to treat adults who have HIV-1. It can be used for initial treatment and also for certain patients who have maintained an HIV-1 RNA viral load of less than 50 copies per mL for at least six months on a stable antiretroviral regimen. Recommended dosing is one tablet daily. The labeling for Symtuza includes a boxed warning that discontinuing the use of emtricitabine or tenofovir disoproxil fumarate (a drug similar to tenofovir alafenamide) 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 Symtuza. Full prescribing information is available here.

Xtandi Indication Expanded

The indication for Xtandi® (enzalutamide - Astellas Pharma/Pfizer) was extended by the FDA on July 13, 2018. Xtandi is an androgen receptor inhibitor that originally was approved in 2012 to treat men who have metastatic castration-resistant prostate cancer (CRPC) that previously was treated with docetaxel. Its new approval, which was granted under a Priority Review, allows its use to treat patients whose cancer has not yet metastasized. Xtandi is used along with an androgen-deprivation therapy (ADT), such as Eligard® (leuprolide – Tolmar Pharmaceuticals) or Zoladex® (goserelin – TerSera Therapeutics). In the clinical trials leading to the approval, participants who took Xtandi in addition to receiving ADT survived without developing metastases for an average of 36.6 months compared to 14.7 months for participants on ADT alone. Prescribing information for Xtandi can be found here.

Kisqali Label Expanded under FDA’s First Real-Time Oncology Review Program

The FDA has approved the first expanded indication under its pilot Real-Time Oncology Review program. Novartis’ Kisqali® (ribociclib) also was given Breakthrough and Priority designations for the two new indications it received on July 18, 2018. Real-Time Oncology Review speeds up the approval process by allowing manufacturers to submit data from cancer clinical trials to the FDA for evaluation before filing a complete application. Originally approved by the FDA on March 13, 2017, Kisqali already was indicated as first-line treatment for postmenopausal women who have metastatic or advanced hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) breast cancer. Kisqali is now approved for use in combination with any aromatase inhibitor for initial endocrine-based treatment of pre-, peri- or postmenopausal women who have advanced or metastatic HR+/HER2- breast cancer and in combination with fulvestrant to treat patients with postmenopausal HR+/HER2- breast cancer following disease progression on endocrine therapy. Kisqali is taken on 28-day cycles with one 600mg dose (three 200mg tablets) every day for 21 consecutive days and then no treatment for the remaining seven days. It selectively inhibits cyclin-dependent kinase (CDK) 4 and 6 (CDK4/6), enzymes that promote the growth and spread of cancer cells. Revised prescribing information is available here.

Valsartan Recall

On July 13, 2018, the FDA announced that several generic companies voluntarily had recalled multiple lots of valsartan and valsartan with hydrochlorothiazide – drugs widely used to treat high blood pressure and heart failure. Later, additional companies recalled their valsartan products, as well. Trace amounts of an impurity, N-nitrosodimethylamine (NDMA), which is a probable cancer-causing agent, were detected in samples of the recalled products. Although the potential harm to patients is low, some manufacturers are recalling drug at the patient level. Patients who have recalled valsartan or valsartan with hydrochlorothiazide should continue taking it. They should call their doctors or pharmacies to see if they can switch to a valsartan product that was not recalled or if they need a prescription for a different drug. For more information on the recall, including a list of affected companies and phone numbers for them, please see the FDA notices here and here.

Tibsovo Approved to Treat Acute Myeloid Leukemia

The FDA announced on July 20, 2018, that it had approved Agios Pharmaceuticals’ Tibsovo® (ivosidenib) oral tablets. Tibsovo is indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation, as determined by an FDA-approved test. According to the American Cancer Society (ACS), approximately 21,000 patients – mostly adults over 45 years of age – are diagnosed with AML in the United States each year. Between 6% and 10% of patients with AML have IDH1 mutations. Recommended dosing for Tibsovo is 500mg (two tablets) orally once daily until the patient can no longer tolerate the drug or the cancer spreads. A boxed warning cautions that differentiation syndrome, which can be life-threatening, may be associated with taking Tibsovo. Full prescribing information can be found here.

Nivestym, Second Neupogen Biosimilar, Approved

On July 20, 2018, the FDA approved Nivestym™ (filgrastim-aafi - Pfizer) injection. It is the second FDA-approved biosimilar to Neupogen® (filgrastim – Amgen), and it has the same FDA approved indications as Neupogen and Zarxio (filgrastim-sndz – Sandoz), the first biosimilar to Neupogen which was introduced to the U.S. market in the fall of 2015. All three are indicated 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. Doses, which differ according to the condition being treated, may be injected IV or given subcutaneously (SC). A launch date and pricing are still uncertain. Complete prescribing information for Nivestym is available here.

Orilissa Approved to Treat Endometriosis

The FDA approved Orilissa (elagolix – AbbVie/Neurocrine Biosciences) tablets on July 24, 2018. Indicated to relieve moderate to severe pain for women who have endometriosis, it is a gonadotropin-releasing hormone (GnRH) receptor antagonist that is taken orally. Endometriosis results when small fragments of the endometrium (the lining of the uterus) dislocate outside the uterus. This tissue responds to menstrual cycles in the same way that the uterus does -- filling with blood and then bleeding each month.  Affecting 11% or more of women during their child-bearing years, endometriosis causes pain, inflammation and swelling – usually in the abdomen. Recommended dosing for Azedra 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 here.

Azedra Approved to Treat Adrenal Tumors

On July 30, 2018, the FDA approved Azedra® (iobenguane I 131 – Progenics Pharmaceuticals, Inc.) under its Breakthrough, Fast-Track, Orphan and Priority Review. Azedra, a radiopharmaceutical, is the first drug to be FDA approved for treating patients who have rare neuroendocrine cancers – either a pheochromocytoma (tumor of the adrenal gland) or a paraganglioma (tumor in similar tissue outside the adrenals). Additionally, patients must be at least 12 years old and they must need systemic therapy for inoperable tumors that have spread. Radiopharmaceuticals emit low levels of radiation to diagnose or treat diseases. Recommended dosing for Azedra is based on the patient’s weight, with one dose given by IV infusion to determine the required level likely to produce results. Two therapeutic doses then are infused at least 90 days apart. It will be administered by physicians who are trained to give radiopharmaceuticals and in facilities that are equipped to minimize exposure to radiation. Prescribing information can be found here.

New Delivery System for Remodulin

On July 30, 2018, United Therapeutics and Medtronics received FDA approvals for a new dosage form and delivery device for Remodulin® (treprostinil). A prostacyclin vasodilator, Remodulin relaxes blood vessels to relieve blood pressure for adult patients who have Class I, II or III pulmonary arterial hypertension (PAH). Presently, it is given either SC or IV through a surgically implanted catheter. Both use an external device similar to an insulin pump to provide continuous dosing. Since the IV route is more prone to infections, most patients and prescribers choose the SC route. The new delivery system uses Medtronic’s SynchroMed II pump, which is implanted under the skin, and a specially adapted catheter that remains within a blood vessel. In clinical studies, patients used the implant for four years or longer with only 10% having pump failures or other device-related problems. Filling the pump’s drug reservoir will be done through injections given by healthcare providers. Refills may last as long as four months -- depending on the patient’s dose. Launch for the Implantable System for Remodulin is expected in the first quarter of 2019. It will be excluded at launch on the Express Scripts National Preferred Formulary (NPF) until our formulary development process is complete. The manual for the pump is not yet available, but Remodulin’s prescribing information is available here.

Mulpleta Approved for Pre-Procedure Thrombocytopenia

On July 31, 2018, the U.S. Food and Drug Administration (FDA) approved Mulpleta® (lusutrombopag) for the treatment of thrombocytopenia (platelet counts lower than 50,000mcg/L) in adult patients who have chronic liver disease (CLD) and who are scheduled to undergo a medical or dental procedure. The recommended dose is one 3mg tablet orally once daily for seven consecutive days. Dosing should begin eight to 14 days prior to the procedure and the procedure should be two to eight days after the last dose. Shionogi plans to launch Mulpleta in early September. Full prescribing information can be found here.

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Lab Staff
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