Drug Update: October 2016 Issue 2

Specialty Update

FDA Reviewing New Biologic for Rheumatoid Arthritis: Sarilumab

The U.S. Food and Drug Administration (FDA) is currently in the process of reviewing a biologics license application (BLA) for a new monoclonal antibody, sarilumab. The new biologic is being reviewed for the treatment of adults with active, moderate-to-severe rheumatoid arthritis (RA) who have had an inadequate response to previous treatment regimens. The FDA is expected to make a decision regarding approval of sarilumab by October 30, 2016.

Read more

Drug Update: October 2016 Issue 1

New Drug Approvals

FDA Approves New Immune Globulin: Cuvitru®

Last month, the U.S. Food and Drug Administration (FDA) approved Cuvitru®, a subcutaneous immune globulin solution indicated as replacement therapy for primary humoral immunodeficiency in adults and pediatric patients two years of age and older. Cuvitru 200 mg/mL (20%) solution is infused subcutaneously at regular intervals from once daily to once every 2 weeks. Dose adjustments should be made based on the patient’s response. The manufacturer notes Cuvitru is the only 20% subcutaneous immune globulin product without proline and with the ability to infuse up to 60 mL per site and 60 mL per hour, as tolerated, resulting in fewer infusion sites and shorter infusion durations.

Primary immunodeficiency (PI) is a lifelong, genetic disorder found in up to six million worldwide. Individuals affected have absent or dysfunctional immune systems. Replacement therapies are used to prevent recurrent infections. Cuvitru does not require administration by a health care provider. However, patients must have proper instructions and training for self-administration.

Cuvitru was approved in June 2016 in 17 European countries prior to its approval in the United States. The safety and efficacy of Cuvitru was supported by a Phase II/III North American study evaluating a total of 74 patients with primary immunodeficiency over a median of 381 days. Cuvitru was shown to be safe and effective and was associated with a low incidence of local and systemic side effects. The most common side effects were local injection site reactions, headache, nausea, fatigue, diarrhea, and vomiting. As with other immune globulin products, Cuvitru carries a black box warning for blood clots. Therefore in patients at risk for blood clots, Cuvitru should be administered at the minimum dose and infusion rate with adequate hydration and monitoring for signs and symptoms of blood clots.

Cuvitru availability in the United States is expected in the coming weeks. NPS is planning to review Cuvitru for placement on the national formularies once it becomes commercially available. Other immune globulin products, such as Bivigam®, Carimune®, Gammagard®, Hizentra®, and HyQvia®, are specialty products on the standard NPS formulary. For additional information, please view the manufacturer’s press release.

FDA Approves First Drug to Treat Duchenne Muscular Dystrophy

Last month, the FDA approved the first drug to treat patients with Duchenne Muscular Dystrophy: Exondys® 51 (eteplirsen). Exondys 51 is indicated specifically for patients with a confirmed mutation in the DMD gene that is amenable to exon 51 skipping. This mutation affects about 13% of the population with DMD or an estimated 1,500 boys in the United States. DMD is characterized by progressive muscle deterioration and weakness. The severity of the disease and the life expectancy can vary, however DMD is universally fatal and patients usually only live into their 20s or 30s.

Exondys 51 is a once weekly weight-based intravenous infusion given over 35 to 60 minutes. The FDA granted Exondys 51 accelerated approval based on the surrogate endpoint of dystrophin increase in skeletal muscle. A clinical benefit of Exondys 51, such as improving motor function, has not yet been established. As a result, continued approval may require confirmatory trials demonstrating clinical benefit. The FDA is therefore requiring the manufacturer, Sarepta Therapeutics, to conduct a clinical trial to confirm whether Exondys 51 can improve motor function in DMD patients with the specific mutation.

The safety and efficacy of Exondys 51 was evaluated in three small clinical trials. In the first study, 12 patients were randomized to receive Exondys 51 or placebo for 24 weeks, and the 6-minute walk test (6MWT) was used to assess clinical efficacy. At the end of the 24 weeks, there was no significant difference in the change in 6MWT between patients receiving placebo or Exondys 51. All 12 patients from this initial study were enrolled in an open-label extension study and continued treatment with Exondys 51 for another 4 years. These patients did not demonstrate evidence of a clinical benefit with Exondys 51 therapy when compared to an external control group. The third study was an open-label trial conducted in 13 patients treated with Exondys 51 weekly for 48 weeks. Patients received a muscle biopsy at baseline and after 48 weeks of treatment. At the end of treatment, dystrophin levels were found to have increased compared to baseline. The most common side effects observed were balance disorder and vomiting.

Following an intense lobbying campaign from patients and health care providers, Exondys 51 received accelerated approval from the FDA. The approval is considered to be controversial as FDA staffers felt there was little evidence demonstrating the efficacy of the drug, and the studies evaluated were generally considered to be flawed. However, the FDA did not only consider the scienctific data for Exondys 51 but also whether the drug may have a meaningful benefit to patients. The parents of the patients advocated that Exondys 51 showed promise and appeared to be safe. Exondys 51 was approved on the basis of an increase in the amount of dystrophin, demonstrating Exondys may provide some benefit.

NPS is planning to review Exondys 51 for placement on the national formularies. It is dosed as 30 mg per kilogram of body weight once weekly and is commercially available in 2 mL and 10 mL vials at a concentration of 50 mg/mL. The average wholesale price (AWP) for one mL (50 mg) is $960.00. For additional information on Exondys 51, please view the manufacturer’s press release.

New Indications

FDA Expands Indication for Biologic Drug: Stelara®

The FDA recently expanded the indication for the biologic drug Stelara® (ustekinumab) to include the treatment of adult patients with moderate to severe active Crohn’s disease. The new indication is specifically for Crohn’s disease patients who have 1) failed or were intolerant to immunomodulators* or corticosteroids, but never failed a tumor necrosis factor (TNF) blocker** or 2) who failed or were intolerant to treatment with one or more TNF blockers. Stelara is a monoclonal antibody that works by blocking the inflammatory substances, interleukin-12 and interleukin-23.

This new approval is Stelara’s third indication. It is also approved for 1) moderate to severe plaque psoriasis and 2) active psoriatic arthritis. Dosing of Stelara is dependent on the indication for use. For Crohn’s disease, Stelara is administered in two phases: an induction phase and a maintenance phase. The induction phase is a single, weight-based intravenous (IV) infusion, and the maintenance phase is a 90 mg subcutaneous dose administered 8 weeks after the initial IV dose, then every 8 weeks thereafter. The induction dose is administered under the supervision of a healthcare provider, and the maintenance doses can be administered either by a healthcare provider or via self-injection by the patient after sufficient training.

Stelara is a specialty product on the standard NPS formulary. The average wholesale price (AWP) for a 90 mg subcutaneous dose of Stelara is $21,216.53. NPS is planning to review Stelara’s new indication for Crohn’s disease. For additional information, please view the manufacturer’s press release.

*Examples of immunomodulators: Imuran®/Azasan® (azathioprine), Purinethol® (6-mercaptopurine, 6-MP), Sandimmune®/Neoral® (cyclosporine A), Prograf® (tacrolimus), Rheumatrex®/Mexate® (methotrexate)

**Examples of TNF Blockers: Humira® (adalimumab), Cimzia® (certolizumab pegol), Enbrel® (etanercept), Simponi® (golimumab), Remicade® (infliximab)

FDA Grants Tentative Approval to Trokendi® XR for Migraine Prevention

In August 2016, the FDA granted tentative approval to the epilepsy drug Trokendi® XR (topiramate extended-release) for prevention of migraine headache in adults. The new indication has been approved tentatively as the drug retains pediatric exclusivity until March 28, 2017. Final approval may not occur until after the exclusivity period ends.

Trokendi XR is a once-daily extended release formulation of topiramate and is indicated for 1) partial onset seizure and primary generalized tonic-clonic seizures as initial monotherapy in patients 10 years of age and older or adjunctive therapy in patients 6 years of age and older, and 2) Lennox-Gastaut Syndrome as adjunctive therapy in patients 6 years of age and older. It is available in the strengths of 25 mg, 50 mg, 100 mg and 200 mg capsules, which should be swallowed whole. Trokendi XR is contraindicated 1) with recent alcohol use (within 6 hours before and 6 hours after Trokendi XR use) and 2) in metabolic acidosis with concurrent metformin.

Trokeni XR is currently a non-preferred brand medication on the standard NPS formulary and carries an average wholesale price (AWP) of $8.93 to $31.53 per capsule.

FDA Safety Update

Serious Risks of Combining Opioid Pain or Cough Meds with Benzodiazepines

The FDA has recently issued a black box warning be added to all prescription opioid analgesics, opioid-containing cough products, and benzodiazepines warning of the serious risks from combined use of these products. The warning will address the risk of concurrent use of opioids with benzodiazepines or other central nervous system (CNS) depressants as this combination can result in serious side effects including extreme sleepiness and slowed or trouble breathing, which can lead to coma or death. The labels and corresponding patient Medication Guides of almost 400 products will be updated.

Drug labels for these products have previously stated the risk of prescribing opioids in combination with benzodiazepines, but not as a black box warning. From 2002 to 2014, there was a 41% increase in the number of patients – about 2.5 million – receiving both opioids and benzodiazepines, and the rate of emergency department visits related to nonmedical use of opioids and benzodiazepines increased from 11 visits per 100,000 people to 34.2 visits from 2004 to 2011. The number of deaths related to overdoses from this combination of drugs has also tripled. As a result, the FDA is requiring revisions to the following sections of these drug labels: Warnings and Precautions, Drug Interactions, and Patient Counseling Information.

The FDA advises clinicians to only prescribe opioids and benzodiazepines together if alternative treatments are inadequate. If prescribed concurrently, clinicians should limit the dosages and duration of each drug to the minimum amount needed to treat the patient. Patients taking opioids and benzodiazepines or other CNS depressants should be counseled to seek medical attention immediately if they experience unusual lightheadedness, extreme sleepiness, or slowed or difficult breathing.

For additional information, including a list of prescription opioid pain/cough medicines and benzodiazepines/CNS depressants, please view the FDA’s safety announcement.

Drug Recalls

Recall of Hyoscyamine Tablets

On September 14, 2016, Virtus Pharmaceuticals voluntarily recalled 7 batches of hyoscyamine sulfate 0.125 mg tablets manufactured by Pharmatech, LLC. The recall was prompted due to failed potency tests, both superpotent and subpotent results were observed. As of the date the recall was issued, the manufacturer had received three adverse event reports. Patients had experienced hallucinations, stroke-like symptoms, confusion, dizziness, blurred vision, dry mouth, slurred speech, imbalance, and disorientation.

Formulations affected by the recall include tablets, orally disintegrating tablets, and sublingual tablets. These products were distributed across the United States and Puerto Rico starting on March 11, 2016. Additionally, a small number of bottles from one lot had an incorrect expiration date.

Please view the FDA Safety Alert for a complete listing of the lot numbers affected. For additional information, please view the company’s news release. NPS has notified patients and prescribers of affected patients of the recall by mail. Side effects or quality issues experienced with the use of these products or other drug products should be reported to the FDA MedWatch program.

Recall of GlucaGen® HypoKit®

On September 8, 2016, Novo Nordisk Inc., voluntarily recalled 6 batches of GlucaGen® HypoKit® in the United States due to two customer complaints from the UK and Portugal. Needles were reported to have detached from the syringe for sterile water for injection. If the needle becomes detached from the syringe, it cannot be used properly. GlucaGen HypoKit is indicated for the treatment of severe low blood sugar in patients with diabetes who are treated with insulin.

As of the date the recall was issued, Novo Nordisk was not aware of any adverse effects caused by use of the recalled pens. Novo Nordisk has determined there is a 0.006% chance that a needle could detach from the syringe in the affected batches which were distributed starting February 15, 2016. It is estimated that four pens out of the 71,215 pens recalled in the United States could be defective.

Please view the FDA Safety Alert for a complete listing of the lot numbers affected. For additional information, please view the company’s news release. NPS has notified patients and prescribers of affected patients of the recall by mail. Side effects or quality issues experienced with the use of these products or other drug products should be reported to the FDA MedWatch program.

Drug Shortages

Scopolamine Patch

As of September 15th, all formulations of Transderm Scop® (scopolamine transdermal system patch) are on a shortage. Transderm Scop is indicated for adults for the prevention of nausea and vomiting associated with motion sickness as well as the prevention of post-operative nausea and vomiting. There are two manufacturers of transdermal scopolamine patches, Sandoz and Baxter.

Affected Sandoz products include Transderm Scop 1.5 mg patch, 4 count. Sandoz has stated the shortage is due to a delay in shipping of the drug and the product will be on intermittent backorder until early December 2016. Affected Baxter products include Transderm Scop 1.5 mg Patch, 10 count and 24 count. Baxter has stated the 10 count package size is on a shortage due to an increase in demand for the drug and the product is currently on intermittent backorder until early December 2016. The 24 count package size is on shortage due to issues related to complying with good manufacturing practices. This package size is currently unavailable with availability expected to resume around mid-October 2016, limited availability is anticipated until early December 2016.

Sumatriptan Nasal Spray

There has been an ongoing shortage of sumatriptan (Imitrex®) nasal spray since November 2015. The generic sumatriptan nasal spray in the concentration of 20 mg currently has limited availability caused by a shortage of the active ingredient. The shortage is expected to resolve in January 2017.

Both the 5 mg and 20 mg strengths of the brand name product Imitrex, distributed by GlaxoSmithKline, are currently available. The generic product in the 5 mg strength distributed by Sandoz Inc. is also available. Sumatriptan nasal spray is indicated for the acute treatment of migraine with or without aura in adults.

For the most up-to-date information on drug shortages, please visit the ASHP Drug Shortage Resource Center or the FDA Drug Shortage Website.


  1. FDA Letter of Drug Approval. U.S. Food and Drug Administration. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/. Updated September 13, 2016. Accessed September 26, 2016.
  2. Cuvitru [package insert]. Westlake Village, CA: Baxalta; 2016. http://www.shirecontent.com/PI/PDFS/Cuvitru_USA_ENG.pdf.
  3. Brooks M. FDA OKs immune globulin Cuvitru for primary immunodeficiency. Medscape Medical News. http://www.medscape.com/viewarticle/868845. Updated September 15, 2016. Accessed September 26, 2016.
  4. Suez D, Stein M, Gupta S, et al. Efficacy, safety, and pharmacokinetics of a novel human immune globulin subcutaneous, 20% in patients with primary immunodeficiency diseases in North America. J Clin Immunol. 2016;36(7):700-12. http://rd.springer.com/article/10.1007/s10875-016-0327-9. Accessed September 26, 2016.
  5. Shire announces U.S. FDA approval of Cuvitru [immune globulin subcutaneous (human), 20% solution] treatment for Primary Immunodeficiency. Shire Newsroom. https://www.shire.com/newsroom/2016/september/frj956. Updated September 14, 2016. Accessed September 28, 2016.
  6. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. FDA News Release. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm. Published September 19, 2016. Accessed September 26, 2016.
  7. Sarepta Therapeutic announces FDA accelerated approval of Exondys 51 (eteplirsen) injection, an exon skipping therapy to treat Duchenne Muscular Dystrophy (DMD) patients amenable to skipping exon 51. Sarepta Therapeutics. http://investorrelations.sarepta.com/phoenix.zhtml?c=64231&p=irol-newsArticle&ID=2204492. Published September 19, 2016. Accessed September 26, 2016.
  8. Exondys 51 [package insert]. Cambridge, MA: Sarepta Therapeutics; 2016.
  9. Harris, R. Controversy continues over muscular dystrophy drug, despite FDA approval. NPRhttp://www.npr.org/sections/health-shots/2016/09/24/495174472/controversy-continues-over-muscular-dystrophy-drug-despite-fda-approval. Updated September 24, 2016.Accessed September 26, 2016.
  10. Perrone M. FDA Oks 1st muscular dystrophy drug; awaits proof it works. Associated Press. http://hosted2.ap.org/APDEFAULT/. Updated September 19, 2016. Accessed September 29, 2016.
  11. Brooks M. FDA clears ustekinumab (Stelara) for Crohn’s disease. Medscape Medical News. http://www.medscape.com/viewarticle/869259. Updated September 26, 2016. Accessed September 28, 2016.
  12. Stelara [package insert]. Horsham, PA: Janssen Biotech, Inc; September 2016. https://www.stelarainfo.com/pdf/prescribinginformation.pdf.
  13. Crohn’s & Colitis Foundation of America. http://www.ccfa.org/resources/immunomodulators.html. Updated January 16, 2009. Accessed September 28, 2016.
  14. FDA approves Stelara (ustekinumab) for treatment of adults with moderately to severely active Crohn’s disease. PR Newswire. http://www.prnewswire.com/news-releases/fda-approves-stelara-ustekinumab-for-treatment-of-adults-with-moderately-to-severely-active-crohns-disease-300333868.html?tc=eml_cleartime. Updated September 26, 2016. Accessed September 28, 2016.
  15. ‘Tentative’ FDA nod to Trokendi XR for migraine prevention. Medscape Medical News. http://www.medscape.com/viewarticle/867721. Updated August 22, 2016. Accessed September 26, 2016.
  16. Trokendi XR [package insert]. Winchester, KY: Catalent Pharma Solutions; 2016.
  17. Supernus receives FDA tentative approval for expanded label of Trokendi XR to include migraine prophylaxis in adults. Supernus Pharmaceuticals. http://ir.supernus.com/releasedetail.cfm?ReleaseID=985010. Updated August 19, 2016. Accessed September 26, 2016.
  18. Robert L. Limit prescribing opioids, benzos together, FDA warns. Medscape Medical News. http://www.medscape.com/viewarticle/868217. Updated August 31, 2016. September 28, 2016.
  19. FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. FDA News Release. http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm. Published August 31, 2016. Updated September 16, 2016. Accessed September 26, 2016.
  20. Fox M. Mixing opioids and tranquilizers can be deadly, FDA warns. NBC News. http://www.nbcnews.com/health/health-news/mixing-opioids-tranquilizers-can-be-deadly-fda-warns-n640851. Updated August 31, 2016. Accessed September 26, 2016.
  21. FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use. FDA News Release. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/. Updated August 31, 2016. Accessed September 28, 2016.
  22. PharmaTech drug recalled after reports of hallucinations. Fierce Pharma. http://www.fiercepharma.com/manufacturing/pharmatech-drug-tied-to-hallucinations-recalled. September 15, 2016. Accessed September 26, 2016.
  23. Virtus Pharmaceuticals Opco II, LLC issues voluntary nationwide recall of hyoscyamine sulfate due to superpotent and subpotent results. FDA.gov. http://www.fda.gov/Safety/Recalls/ucm520847.htm. Updated September 14, 2016. Accessed September 26, 2016.
  24. PharmaTech drug recalled after reports of hallucinations. FiercePharma. http://www.fiercepharma.com/manufacturing/pharmatech-drug-tied-to-hallucinations-recalled. September 15, 2016. Accessed September 26, 2016.
  25. Novo Nordisk Inc. issues voluntary nationwide recall of six batches of GlucaGen HypoKit (glucagon for [rDNA origin] for injection) due to detached needles on the syringe in the kit. FDA.gov. http://www.fda.gov/Safety/Recalls/ucm519872.htm. Updated September 8, 2016. Accessed September 29, 2016.
  26. FDA Drug Shortages. FDA News. http://www.accessdata.fda.gov/scripts/drugshortages/dsp. Published September 15, 2016. Accessed September 26, 2016.
  27. Transderm Scop [package insert]. Parsippany, NJ: Novartis; December 2014.
  28. Sumatriptan (Imitrex) Nasal Spray. FDA Drug Shortages. http://www.accessdata.fda.gov/scripts/drugshortages/dsp. Updated September 21, 2016. Accessed September 22, 2016.