- New Drug Approved for Prostate Cancer: Erleada® (apalutamide)
- New Drug Approved for Cystic Fibrosis: Symdeko® (tezacaftor/ivacaftor and ivacaftor)
- New Fast-Acting Insulin “Follow-on” Product Available: Admelog® (insulin lispro injection)
- Imfinzi® (durvalumab) Receives Approval for Use in Certain Lung Cancer Patients
- New Safety Warning Regarding Use of Clarithromycin in Patients with Heart Disease
- PCSK9 Inhibitor, Praluent® (alirocumab), Demonstrates Reduction in Cardiovascular Events
- Multiple Sclerosis Drug, Zinbryta® (daclizumab), Voluntarily Withdrawn from U.S. Market
Specialty Drug Approvals
New Drug Approved for Prostate Cancer: Erleada® (apalutamide)
In February 2018, the U.S. Food and Drug Administration (FDA) approved Erleada® (apalutamide) for the treatment of patients with prostate cancer that has not spread to other areas (non-metastatic) and does not respond to other therapies used to lower testosterone (castration-resistant). Approval marks the first FDA-approved therapy for patients with this specific form of prostate cancer: non-metastatic, castration-resistant prostate cancer (NM-CRPC). Apalutamide is considered a next-generation androgen receptor (AR) inhibitor and in animal models has demonstrated a reduction in tumor volume through decreasing tumor cell growth and increasing cell death. The majority of patients with CRPC over time experience spread of the prostate cancer to the bone which can result in pain, fractures, and other complications. Therefore, delaying the onset of cancer spread in these patients is of considerable importance.
The safety and efficacy of apalutamide was evaluated in the Phase III, randomized, double-blind, placebo-controlled SPARTAN trial which evaluated 1,207 patients with NM-CRPC. Patients enrolled had exhibited a rapid increase in prostate specific antigen (PSA) during ongoing androgen deprivation therapy (ADT). Patients concurrently received a gonadotropin-releasing hormone (GnRH) analog during the study or had previously received surgical castration. The risk for cancer spread to distant sites or death was reduced by 72% in the patients who received apalutamide compared to placebo. Additionally, the median metastasis-free survival (MFS) was prolonged by more than two years in patients who received apalutamide compared to placebo. At the time of analysis, overall survival data had not yet matured.
The most common side effects occurring in patients treated with apalutamide included: fatigue, high blood pressure, rash, diarrhea, nausea, decreased weight, joint pain, falls, hot flush, reduced appetite, fracture, and fluid accumulating in the extremities. Apalutamide also carries warnings/precautions for falls and fractures as well as seizures. Male patients receiving apalutamide with female partners of reproductive potential should be advised to use effective contraception during treatment and for 3 months after the last dose.
Apalutamide is supplied as a 60 mg oral tablet and is taken as four 60 mg tablets once daily with or without food. The average wholesale price (AWP) for a 60 mg tablet is $109.20. Dose reductions may be required due to side effects or toxicity. Patients are required to simultaneously receive a GnRH analog or should have received surgical castration. NPS is planning to review Erleada for placement on the national formularies. For additional details on the approval, view the FDA’s press release or the manufacturer’s press release.
New Drug Approved for Cystic Fibrosis: Symdeko® (tezacaftor/ivacaftor and ivacaftor)
In February 2018, the U.S. FDA approved a new combination drug therapy to treat cystic fibrosis (CF) in patients aged 12 years and older. The new product, Symdeko® (tezacaftor/ivacaftor and ivacaftor), is indicated specifically for patients who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that has demonstrated responsive to tezacaftor/ivacaftor. Vertex, the manufacturer of Symdeko, has announced the approval marks their third disease-modifying CF agent.
CF is a rare genetic disease caused by a defect or absent CFTR protein due to a mutation in the CFTR gene. Defects or absent CFTR proteins lead to impaired water and salt flow into cells, affecting various organs and tissues. In the lungs, this impairment leads to chronic lung infections and lung damage which can become life-threatening. It is estimated approximately 75,000 individuals in the North America, Europe, and Australia are affected by CF. These individuals have a shortened life span with a median age of death before age 30.
Two Phase III studies enrolling 750 patients with CF demonstrated patients who received Symdeko had significant improvements in measures of lung function and other disease outcomes. The safety profile was also determined to be acceptable. The most common side effects observed were lung infection exacerbations and cough. Early data from the long-term extension study had also demonstrated the safety and efficacy of Symdeko for up to 48 weeks of therapy. Warnings and precautions for Symdeko include: the potential for elevated liver enzymes, use with CYP3A inducing medications or supplements, and the development of cataracts in pediatric patients.
Symdeko is supplied as a fixed-dose combination tablet of tezacaftor 100 mg/ivacaftor 150 mg co-packaged with 150 mg ivacaftor tablets. It is dosed as one tablet of tezacaftor/ivacaftor in the morning and one tablet of ivacaftor in the evening with a fat-containing food. The average wholesale price (AWP) per tablet of Symdeko is $480.00. NPS is planning to review Symdeko for placement on the national formularies. For additional details, view the manufacturer’s press release.
New Drug Launch
New Fast-Acting Insulin “Follow-on” Product Available: Admelog® (insulin lispro injection)
The first follow-on insulin lispro product, Admelog® (insulin lispro injection), recently became commercially available in the U.S. Admelog was granted tentative approval from the FDA in September of 2017 and received final approval in December 2017. As a follow-on product to Humalog® (insulin lispro injection) approval of Admelog was granted through an abbreviated approval pathway that allowed data from Humalog to provide support for the safety and efficacy.
Admelog is indicated for use in adult and pediatric patients 3 years and older with type 1 diabetes and adults with type 2 diabetes to improve blood glucose control. It is supplied as 100 units of rapid-acting insulin lispro per milliliter (mL) and is available in a 10 mL multi-dose vial as well as the 3 mL single-patient use SoloStar® prefilled pen. Approval marks the first short-acting insulin product to be granted approval as a follow-on product.
Admelog is considered to be highly similar to the mealtime insulin product Humalog. In addition to the Humalog safety and efficacy data used for approval of Admelog, the manufacturer also submitted findings from two Phase III clinical trials, each evaluating approximately 500 patients. Based on the regulatory review pathway used for approval, Admelog is considered to be a follow-on product rather than a biosimilar. The first follow-on insulin product to receive FDA approval was Basaglar® (insulin glargine injection). Basaglar became commercially available in December of 2016, one year after receiving FDA approval. The primary objective of the FDA’s abbreviated approval pathways is to lower the development costs of products highly similar to existing products, in order to increase competition and reduce drug costs.
The average wholesale price (AWP) for a 3 mL Admelog SoloStar pen is $108.20. In comparison, the Humalog KwikPen® (100 units/mL) carries an AWP of $127.30 per 3 mL pen. NPS is planning to review the new insulin lispro product, Admelog, for placement on the national formularies. For additional details, please view the FDA’s press release or manufacturer’s press release.
Imfinzi® (durvalumab) Receives Approval for Use in Certain Lung Cancer Patients
In February 2018, Imfinzi® (durvalumab) received FDA approval for the treatment of patients with Stage III non-small cell lung cancer (NSCLC) that cannot be removed surgically and has not progressed after concomitant platinum-based chemotherapy and radiation therapy. In 2017, it was estimated more than 220,000 individuals were diagnosed with lung cancer with NSCLC being the most common form of lung cancer. Durvalumab is indicated for patients with Stage III NSCLC which is considered to be cancer that has advanced locally but has not spread to other organs. Most patients who are diagnosed with this stage of lung cancer have tumors that cannot be removed with surgery. For these patients, chemotherapy and radiation therapy have been utilized followed by monitoring for further disease progression. As a result, the prognosis for these patients has been unfavorable.
Approval of durvalumab for NSCLC was based on results from the Phase III, randomized, double-blind, placebo-controlled PACIFIC study. Patients enrolled had Stage III NSCLC without progression after two or more cycles of platinum-based chemoradiotherapy. Patients who received durvalumab as consolidation therapy exhibited a significantly longer median progression-free survival (PFS) by 11.2 months compared to those who received placebo (median of 16.8 months vs. 5.6 months). In addition, the risk for disease progression or death was reduced by 48% in patients receiving durvalumab compared to placebo. Common adverse reactions, occurring in 20% or more of patients receiving durvalumab, included: cough, fatigue, lung inflammation, upper respiratory tract infections, shortness of breath, and rash. More patients in the durvalumab group discontinued treatment than patients receiving placebo (15% vs. 10%, respectively).
Imfinzi received accelerated approval from the FDA in 2017 for certain patients with locally advanced or metastatic bladder cancer. It is available as a solution for intravenous infusion with weight-based dosing of 10 mg per kilogram (kg) every 2 weeks for both lung cancer and bladder cancer. For patients with NSCLC, therapy is continued until disease progression, unacceptable toxicity, or up to a maximum of 12 months. The average wholesale price (AWP) for one dose for a 70 kg patient is $5,844.40.
FDA Safety Update
New Safety Warning Regarding Use of Clarithromycin in Patients with Heart Disease
In February 2018, the FDA released a Drug Safety Communication regarding the potential for increased long-term risks following use of the antibiotic clarithromycin in patients with heart disease. Based on an evaluation of a 10-year follow-up study in patients with coronary heart disease, the FDA has added a warning to the drug regarding the increased risk for death in patients with heart disease. As a result, prescribers are recommended to consider alternative antibiotics in these patients. The FDA has stated they will continue to monitor the safety of clarithromycin (Biaxin®).
The new warning is based on data from the prospective, placebo-controlled clinical CLARICOR trial. The study demonstrated an unanticipated increase in death for patients with coronary heart disease who received a 14-day course of clarithromycin. The increased risk was observed when patients were followed for one year or more. Findings from observational studies evaluating these safety concerns have been inconsistent. At this time, the FDA has not determined how clarithromycin would increase the potential for death, compared to placebo, or an explanation as to why the risk of death appears to be higher for patients with heart disease.
Health care providers should use caution prior to prescribing clarithromycin to patients with coronary heart disease based on the likelihood of increased heart problems or death years after the treatment course. These risks should be considered in all patients, especially those with preexisting heart disease, regardless of the duration of the treatment course. Alternative antibiotics should be considered, and patients with heart disease who receive clarithromycin should be counseled on the signs of cardiovascular issues.
Patients are instructed to communicate with their health care provider if they have underlying heart disease, particularly if an antibiotic is to be prescribed for treating an infection. Patients should not discontinue their heart medication or antibiotic without first consulting a health care professional. Signs of a heart attack or stroke include: shortness of breath, difficulty breathing, pain or weakness in one side or area of the body, or slurred speech. If any of these symptoms occur, seek immediate medical help.
For additional details, please view the FDA’s Safety Announcement.
PCSK9 Inhibitor, Praluent® (alirocumab), Demonstrates Reduction in Cardiovascular Events
Recently released findings from the ODYSSEY outcomes study have demonstrated Praluent® (alirocumab) significantly reduced the risk of major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome events, such as a heart attack. Alirocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor currently FDA-approved as an add-on to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-cholesterol. The other FDA-approved PCSK9 inhibitor, Repatha® (evolocumab), received an expanded indication in December of 2017 to reduce the risk of heart attack, stroke, and coronary revascularization in adults with established cardiovascular disease.
The ODYSSEY study evaluated more than 18,000 patients who had recently experienced an acute coronary event in the one to 12 months prior to enrollment. Patients were also required to have been receiving maximally-tolerated statin therapy with atorvastatin or rosuvastatin. Following randomization to either alirocumab or placebo, the time to coronary heart disease death, nonfatal heart attack, stroke, or unstable chest pain leading to hospitalization (primary composite endpoint) was assessed. Following a median treatment duration of 2.8 years, the primary composite endpoint was found to be reduced by 15% with alirocumab compared to placebo. Additionally, the patients receiving alirocumab also exhibited a 15% reduction in all-causes of death. The greatest benefit was observed in patients with baseline LDL-cholesterol levels of 100 mg/dL or more; the primary endpoint was reduced by 24% and all-cause mortality was reduced by 29% in these patients who received alirocumab compared to placebo. Although there were fewer coronary heart disease deaths in the patients who received alirocumab compared to placebo, this endpoint did not reach statistical significance (p=0.38). No unexpected safety concerns were observed in the trial.
Praluent is supplied in a single-dose prefilled pen in the strengths of 75 mg/mL or 150 mg/mL of solution. It is dosed as 75 mg once every 2 weeks given subcutaneously. For patients with an insufficient LDL-cholesterol reduction, the dose can be increased to a maximum of 150 mg every 2 weeks. Praluent can also be administered as 300 mg every 4 weeks. The AWP for a 75 mg or 150 mg dose is $672.00. The manufacturers of alirocumab have stated plans to submit a supplemental Biologics License Application (BLA) to the FDA for inclusion of the ODYSSEY trial data in the drug’s label in the second quarter of 2018. For additional details on the findings from the ODYSSEY study, please view the manufacturer’s press release.
Drug Shortages and Discontinuations
Multiple Sclerosis Drug, Zinbryta® (daclizumab), Voluntarily Withdrawn from U.S. Market
In March 2018, the manufacturers of multiple sclerosis drug Zinbryta® (daclizumab) announced the product would be voluntarily withdrawn from commercialization in the United States. The decision was based on emerging safety concerns for the medication. The FDA is collaborating with the product manufacturers to help inform health care professionals of the product removal and assist with transitioning patients who are currently receiving Zinbryta to an alternative therapy. Health care providers and patients are being notified by the manufacturer of the product withdrawal, and no new patients are to be initiated on the therapy. The existing supplies of Zinbryta are expected to be depleted by April 30, 2018.
Zinbryta received FDA approval in 2016 as a monoclonal antibody indicated for adult patients with relapsing forms of multiple sclerosis (MS). Due to safety concerns, the use of daclizumab was reserved for patients who had not achieved an adequate response with two or more other therapies for MS. Zinbryta was also approved with a black box warning regarding the risk of liver injury and other immune-mediated disorders, such as skin reactions. Due to these risks, Zinbryta was only available through a Risk Evaluation and Mitigation Strategy (REMS) program requiring prescribers, patients, and pharmacies to be enrolled and complete additional training or certification prior to prescribing, receiving, or dispensing daclizumab.
Patients currently receiving daclizumab are recommended to consult with their health care provider as soon as possible to determine a new treatment plan, and health care providers are instructed to initiate conversations with their patients regarding other treatment options. The product is being withdrawn due to cases of brain inflammation. For patients who are currently receiving Zinbryta, if it is determined by the patient and healthcare provider to continue use during the transition period, the patient can receive a maximum of one additional dose prior to April 30, 2018. Patients should continue to receive monthly liver assessments during therapy and monthly for 6 months after the last dose of daclizumab. Patients are also instructed to contact their health care provider immediately if they experience any new or unexpected symptoms during therapy and for 6 months following the last dose.
Zinbryta is given as subcutaneous injection of 150 mg once per month and is supplied in a single-dose prefilled autoinjector and syringe. For additional details on the voluntary market withdrawal of Zinbryta, please view the FDA’s press release or the manufacturer’s letter to health care prescribers or patients. For the most up-to-date information on drug shortages and product discontinuations, please visit the ASHP Current Shortages Database or the FDA Drug Shortages Database.
- Erleada (apalutamide), a next-generation androgen receptor inhibitor, granted U.S. FDA approval for the treatment of patients with non-metastatic castration-resistant prostate cancer. Johnson & Johnson Press Release. https://www.jnj.com/media-center/press-releases/erleada-apalutamide-a-next-generation-androgen-receptor-inhibitor-granted-us-fda-approval-for-the-treatment-of-patients-with-non-metastatic-castration-resistant-prostate-cancer. Updated February 14, 2018. Accessed March 23, 2018.
- Erleada (apalutamide) 60 mg tablets. Janssen Oncology. https://www.erleada.com/. February 2018. Accessed March 23, 2018.
- Erleada [package insert]. Horsham, PA: Janssen Products, LP; February 2018. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/ERLEADA-pi.pdf. Accessed March 23, 2018.
- Symdeko [package insert]. Boston, MA: Vertex Pharmaceuticals, Inc.; February 2018. https://pi.vrtx.com/files/uspi_tezacaftor_ivacaftor.pdf. Accessed March 2018.
- Cystic fibrosis combo treatment Symdeko gets FDA approval. EMPR.com. https://www.empr.com/news/symdeko-approved-vertex-tezacaftor-ivacaftor-cystic-fibrosis/article/743944/. Updated February 13, 2018. Accessed March 20, 2018.
- FDA approves Symdeko (tezacaftor/ivacaftor and ivacaftor) to treat the underlying cause of cystic fibrosis in people ages 12 and older with certain mutations in the CFTR gene. Vertex News Releases. http://investors.vrtx.com/releasedetail.cfm?ReleaseID=1057241. Updated February 12, 2018. Accessed March 22, 2018.
- FDA approves Admelog, the first short-acting ‘follow-on’ insulin product to treat diabetes. FDA News Release. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm588466.htm. Updated December 11, 2017. Accessed March 22, 2018.
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- FDA expands approval of Imfinzi to reduce the risk of non-small cell lung cancer progressing. FDA Press Releases. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm597217.htm. Updated February 16, 2018. Accessed March 23, 2018.
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- Imfinzi (durvalumab) [prescribing information]. Cambridge, England: AstraZeneca UK; February 2018.
- US FDA approves Imfinzi for unresectable Stage III non-small cell lung cancer. AstraZeneca Press Release. https://www.astrazeneca.com/media-centre/press-releases/2018/us-fda-approves-imfinzi-for-unresectable-stage-iii-non-small-cell-lung-cancer-180202018.html. Published February 19, 2018. Accessed March 23, 2018.
- FDA Drug Safety Communication: FDA review finds additional data supports the potential for increased long-term risks with antibiotic clarithromycin (Biaxin) in patients with heart disease. FDA.gov. https://www.fda.gov/Drugs/DrugSafety/ucm597289.htm. Updated February 22, 2018. Accessed March 19, 2018.
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- Praluent (alirocumab) injection significantly reduced risk of cardiovascular events in high-risk patients, and was associated with lower death rate. Cision PR Newswire. https://www.prnewswire.com/news-releases/praluent-alirocumab-injection-significantly-reduced-risk-of-cardiovascular-events-in-high-risk-patients-and-was-associated-with-lower-death-rate-300611896.html. Updated March 10, 2018. Accessed March 22, 2018.
- Regeneron-Sanofi cholesterol drug cuts heart risk in major study. BioPharmaDive. https://www.biopharmadive.com/news/regeneron-sanofi-praluent-cut-cardiovascular-heart-risk-odyssey-study/518854/. Updated March 10, 2018. Accessed March 22, 2018.
- Praluent [prescribing information]. Bridgewater, NJ: Sanofi-Aventis, LLC; January 2018. http://products.sanofi.us/praluent/praluent.pdf. Accessed March 23, 2018.
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