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P T. 2018;43(5): 260-264, 308-309

Drug and Device News May 2018


Symfi for Once-Daily HIV-1 Treatment

The FDA has approved Symfi (efavirenz, lamivudine, and tenofovir disoproxil fumarate, Mylan) 600-mg/300-mg/300-mg tablets, a once-daily, single-tablet, complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 40 kg. This is Mylan’s third HIV combination drug to reach the U.S. market.

The introduction of Symfi comes after the FDA’s recent approval of two other Mylan combination antiretroviral (ARV) agents for the treatment of HIV-1: Cimduo (lamivudine and tenofovir disoproxil fumarate) 300-mg/300-mg tablets and Symfi Lo (efavirenz, lamivudine, and tenofovir disoproxil fumarate) 400-mg/300-mg/300-mg tablets. Following FDA approval, Mylan launched Symfi Lo in March 2018. It expects Cimduo and Symfi to launch in the second quarter of 2018.

Symfi and Symfi Lo feature the same triple combination of molecules; however, Symfi Lo features a reduced dose of efavirenz while Symfi uses a dosing similar to other efavirenz products already on the market. The combination represented by Symfi tablets is the most widely taken ARV regimen outside of the U.S., with more than seven million users worldwide in 2016, according to the company.

Source: Mylan, March 28, 2018

Ilumya for Plaque Psoriasis

Tildrakizumab-asmn (Ilumya, Sun Pharma) has received FDA approval for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This biologic selectively binds to the p19 subunit of interleukin (IL)-23 and inhibits its interaction with the IL-23 receptor leading to inhibition of the release of pro inflammatory cytokines and chemokines. Tildrakizumab-asmn is administered at a dose of 100 mg by subcutaneous injection every 12 weeks, after the completion of initial doses at weeks 0 and 4. It is contraindicated in patients with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients.

Source: Sun Pharma, March 21, 2018

Injectable Trogarzo for HIV

The FDA has approved ibalizumabuiyk (Trogarzo, TaiMed Biologics USA Corp.) for heavily treatment-experienced patients with multidrug-resistant human immunodeficiency virus (MDR HIV). It is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications.

Ibalizumab-uiyk is the first drug in a new class of antiretroviral medications that can benefit patients who have run out of HIV treatment options. Its safety and efficacy were evaluated in a clinical trial among 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of HIV RNA in their blood despite many having previously been treated with 10 or more antiretroviral drugs.

The majority of participants experienced a significant decrease in HIV RNA levels one week after ibalizumab-uiyk was added to their failing antiretroviral regimens. After 24 weeks of ibalizumabuiyk plus other antiretroviral drugs, 43% of trial participants achieved HIV RNA suppression.

Source: FDA, March 6, 2018

ZTlido Patch for PHN Pain

Sorrento Therapeutics, Inc., has received FDA approval for its lidocaine topical system (ZTlido), 1.8%, for the relief of pain associated with post-herpetic neuralgia (PHN).

ZTlido requires only 36 mg per topical system versus 700 mg per patch of Lidoderm (lidocaine patch 5%, Endo Pharmaceuticals) to achieve the same therapeutic dose. The safety and efficacy of ZTlido was bridged to Lidoderm in comparative pharmacokinetic studies that demonstrated bioequivalence between products.

ZTlido is comprised of a nonaqueous adhesive material that is applied to a non-woven polyester felt backing and covered with a polyethylene terephthalate film release liner. It is indicated for relief of pain associated with PHN and should be applied only to intact skin.

Source: Sorrento, February 28, 2018

Generic Approvals

Desflurane for General Anesthesia

Shanghai Hengrui Pharmaceutical has received approval to market the generic form of Baxter’s Suprane (desflurane liquid for inhalation), indicated for general anesthesia.

Source: FDA, February 26, 2018

Sumatriptan/Naproxen for Migraine

The FDA has granted marketing approval for the first generic version of Pernix Ireland’s Treximet (sumatriptan and naproxen, 85 mg/500 mg) tablets to Aurobindo Pharma Ltd. The drug is indicated for the acute treatment of migraine with or without aura in adults.

Source: FDA, February 15, 2018

Cinacalcet for Hyperparathyroidism

Two manufacturers—Cipla Ltd. and Aurobindo Pharma Ltd.—have received FDA approval to market cinacalcet hydrochloride. These will be the first generic versions of Sensipar tablets (Amgen). The drug is indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease on dialysis; hypercalcemia in adult patients with parathyroid carcinoma; and hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy.

Source: FDA, March 8, 2018


Adcetris for More Hodgkin’s Lymphoma

The FDA has approved brentuximab vedotin (Adcetris, Seattle Genetics, Inc.) in combination with chemotherapy in adult patients with previously untreated stage III or IV classical Hodgkin’s lymphoma. The approval is based on the successful outcome of the phase 3 ECHELON-1 clinical trial that compared brentuximab plus AVD (Adriamycin, vinblastine, and dacarbazine) with ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine). In addition, data from the ECHELON-1 trial converted the accelerated approval of brentuximab for the treatment of adults with systemic anaplastic large cell lymphoma after failure of at least one multiagent chemo therapy regimen to regular approval.

In October 2017, the FDA granted breakthrough therapy designation to brentuximab in combination with chemotherapy for the frontline treatment of patients with advanced classical Hodgkin’s lymphoma. The FDA also granted priority review for the supplemental biologics license application, and the Prescription Drug User Fee Act target action date was May 1, 2018.

This is the fifth FDA-approved indication for brentuximab.

Source: Seattle Genetics, March 20, 2018

Leukine for Acute Radiation Syndrome

The FDA has approved a new indication for sargramostim (Leukine, Partner Therapeutics, Inc.): to increase survival in adult and pediatric patients acutely exposed to myelosuppressive doses of radiation (hematopoietic syndrome of acute radiation syndrome, or H-ARS).

Sargramostim can help patients with H-ARS by facilitating recovery of bone marrow cells that develop into white blood cells that help fight off infections. The drug was shown to increase survival when administered up to 48 hours after total body irradiation exposure at doses expected to be fatal to 50% of those exposed subjects under conditions of minimal supportive care.

Sargramostim is the third FDA-approved medical countermeasure that is indicated to increase survival in patients exposed to myelosuppressive doses of radiation. It was approved based on efficacy studies in animals (under the “Animal Rule”), as efficacy studies in humans could not be ethically conducted. Sargramostim was originally approved in 1991 and was originally indicated to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections following induction chemotherapy in patients 55 years of age and older with acute myeloid leukemia and subsequently approved for several oncology-related indications.

The most commonly reported side effects associated with sargramostim injections are fever, injection-site reactions, and shortness of breath.

Other products from a similar pharmacological class and approved for the same indication are filgrastim (Neupogen, Amgen) and pegfilgrastim (Neulasta, Amgen).

Source: FDA, March 29, 2018

Blincyto for MRD-Positive ALL

The FDA has granted accelerated approval to blinatumomab (Blincyto, Amgen) to treat adults and children with B-cell precursor acute lympho blastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD). MRD refers to the presence of cancer cells below a level that can be seen under the microscope. In patients who have achieved remission after initial treatment for this type of ALL, the presence of MRD means they have an increased risk of relapse. This is the first FDA-approved treatment for patients with MRD-positive ALL. The agency previously granted this application priority review and orphan drug designation.

Blinatumomab works by attaching to CD19 protein on the leukemia cells and CD3 protein found on certain immune system cells. Bringing the immune cell close to the leukemia cell allows the immune cells to attack the leukemia cells better. The FDA first approved blinatumomab under accelerated approval in December 2014 for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive B-cell precursor ALL. Full approval for this indication was granted in July 2017, and at that time, the indication was also expanded to include patients with Ph-positive ALL.

The efficacy of blinatumomab in MRD-positive ALL was shown in a single-arm clinical trial that included 86 patients in first or second complete remission who had detectable MRD in at least one of 1,000 cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of blinatumomab treatment, in addition to the length of time that the patients remained alive and in remission (hematologic relapse-free survival). Overall, undetectable MRD was achieved by 70 patients. Over half of the patients remained alive and in remission for at least 22.3 months.

Further study in randomized controlled trials is required to verify that achieving undetectable MRD with blinatumomab improves survival or disease-free survival in patients with ALL.

Source: FDA, March 29, 2018


Expanded Opdivo Dosing Options

The FDA has approved an updated dosing schedule for nivolumab (Opdivo, Bristol-Myers Squibb) to add a new option—480 mg infused every four weeks for most approved indications—to the previously available dose of 240 mg every two weeks. A 240-mg vial is now available. Nivolumab was also approved for a shorter 30-minute infusion across all approved indications.

The 480-mg, four-week dose is approved for metastatic melanoma (monotherapy or monotherapy phase after combination treatment with ipilimumab [Yervoy, Bristol-Myers Squibb]); previously treated metastatic non–small-cell lung cancer; advanced renal cell carcinoma following prior antiangiogenic therapy; previously treated locally advanced or metastatic urothelial carcinoma following disease progression during or after platinum-based chemotherapy; classical Hodgkin’s lymphoma following relapse/progression after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin (Adcetris, Seattle Genetics) or three or more lines of systemic therapy that includes autologous HSCT; recurrent/metastatic squamous cell carcinoma of the head and neck following platinum-based therapy; hepatocellular carcinoma after prior sorafenib (Nexavar, Bayer Healthcare) therapy; and adjuvant therapy for patients with completely resected melanoma with lymph node involvement or metastatic disease.

Source: Bristol-Myers Squibb, March 6, 2018

New Data for Tresiba Label

The FDA has approved updates to the prescribing information for insulin degludec injection (Tresiba, Novo Nordisk), 100 U/mL and 200 U/mL, to include data from the DEVOTE safety outcomes trial.

The following data from DEVOTE in patients with type-2 diabetes and atherosclerotic cardiovascular disease are now included in the label:

  • Primary composite endpoint: Insulin degludec U-100 demonstrated no increased risk of major adverse cardiovascular events (MACE) with a hazard ratio of 0.91 compared with insulin glargine U-100 (95% confidence interval [CI], 0.78–1.06; P < 0.001). MACE in the DEVOTE trial was defined as the first occurrence of cardiovascular death, nonfatal heart attack, or nonfatal stroke.
  • Secondary confirmatory end point: Insulin degludec U-100 demonstrated 40% significantly lower rates of severe hypoglycemia compared with insulin glargine U-100 (95% CI, 0.48–0.76; P < 0.001).

Blood sugar control between the two groups was similar at baseline and throughout the trial. In DEVOTE, severe hypoglycemia was defined as having a low blood sugar level that required assistance from another person to treat.

Source: Novo Nordisk, March 26, 2018


Breakthrough Therapy Designation

Enfortumab for Urothelial Cancer

The FDA has granted a breakthrough therapy designation to enfortumab vedotin (Seattle Genetics and Astellas), an antibody–drug conjugate, for patients with locally advanced or metastatic urothelial cancer who were previously treated with checkpoint inhibitors (CPIs).

The designation was granted based on interim results from a phase 1 study examining enfortumab vedotin as monotherapy for patients with metastatic urothelial cancer previously treated with CPIs. Enfortumab vedotin is also being studied as monotherapy in this patient setting and in combination with CPI therapy.

Enfortumab vedotin is an investigational agent that targets Nectin-4, a cell-adhesion molecule expressed on many solid tumors.

Source: Seattle Genetics and Astellas, March 26, 2018

Priority Review Designations

Xtandi for Prostate Cancer

Pfizer and Astellas have announced that a supplemental new drug application (sNDA) for enzalutamide (Xtandi) has been accepted for filing and was granted a priority review designation. If approved, the sNDA would expand enzalutamide’s indication to include men with nonmetastatic castration-resistant prostate cancer (NM-CRPC). Enzalutamide, an androgen receptor inhibitor, is currently indicated for the treatment of patients with metastatic CRPC.

Treatment options have been limited for men with NM-CRPC, in whom the only evidence of progressive disease is a rapidly rising prostate-specific antigen level. Many of those men develop metastatic CRPC.

The sNDA is based on data from the phase 3 PROSPER trial, which evaluated enzalutamide plus androgen deprivation therapy (ADT) versus ADT alone in 1,401 patients with NM-CRPC. Enzalutamide plus ADT significantly reduced the risk of metastasis or death, compared with ADT alone. Adverse events were higher in the enzalutamide plus ADT arm (87% versus 77%) and were generally consistent with those reported in prior enzalutamide clinical trials in patients with metastatic CRPC.

The FDA assigned a Prescription Drug User Fee Act goal date for July 2018.

Source: Pfizer and Astellas, March 19, 2018

Keytruda for Advanced Cervical Cancer

The FDA has accepted a new supplemental biologics license application and granted priority review for Keytruda (pembrolizumab), Merck’s anti-programmed death-1 (PD-1) therapy. The company is seeking approval for Keytruda as a treatment for patients with advanced cervical cancer with disease progression on or after chemotherapy. This is the first filing acceptance and priority review granted for an anti-PD-1 therapy in cervical cancer.

The application is based in part on data from the phase 2 KEYNOTE-158 trial, which evaluated Keytruda in patients with multiple types of advanced solid tumors— including cervical cancer—that have progressed on standard-of-care therapy.

The FDA has set a target action date of June 28, 2018.

Keytruda, a monoclonal antibody, increases the immune system’s ability to detect and fight tumor cells. It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes that may affect both tumor cells and healthy cells.

Source: Merck, March 13, 2018

Lusutrombopag for Thrombocytopenia in CLD

The FDA has granted priority review for lusutrombopag (S-888711, Shionogi), an investigational, once-daily, oral, small-molecule thrombopoietin (TPO) receptor agonist. Lusutrombopag is intended for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) at risk for bleeding associated with invasive procedures.

The new drug application is based on two phase 3 clinical trials in which lusutrombopag showed statistically significant results.

The Prescription Drug User Fee Act date is set for August 26, 2018.

Source: Shionogi, February 26, 2018

Fast-Track Designation

Nintedanib for Systemic Sclerosis

Boehringer Ingelheim has been granted a fast-track designation for nintedanib for the treatment of systemic sclerosis with associated interstitial lung disease (SSc-ILD).

Nintedanib, which is marketed as OFEV, is approved for a rare lung disease called idiopathic pulmonary fibrosis (IPF) and has been shown to slow disease. Because SSc-ILD and IPF share similarities in how the underlying lung scarring forms, Boehringer Ingelheim is evaluating the impact of nintedanib on SSc-ILD.

This designation is based on data from a phase 3 trial that has enrolled more than 520 patients from 32 countries.

Source: Boehringer Ingelheim, March 19, 2018


Febuxostat, Gout, and Heart Deaths

A large study of cardiovascular events in gout patients found that febuxostat (Uloric, Takeda) increased the risk of death for those with heart disease compared with allopurinol. Yet the two drugs, which prevent excess build-up of uric acid, were comparable with respect to a combination of nonfatal heart attack, nonfatal stroke, urgent surgery to treat angina, and death due to cardiovascular causes.

The febuxostat mortality findings in the CARES trial were “entirely unexpected,” says University of Connecticut Professor William B. White, MD, principal investigator and lead author of the study published in the New England Journal of Medicine. The results were consistent across subgroups with no evidence of a relationship with age, gender, race, ethnicity, history of cardiovascular disease, gout duration, or gout severity.

The excess in sudden cardiac deaths with febuxostat remains unexplained, and there was no difference between patients taking febuxostat or allopurinol with regard to nonfatal hospitalizations for heart failure, arrhythmias, pulmonary embolism, myocardial infarction, or stroke.

Source: University of Connecticut, March 12, 2018

Zinbryta Market Withdrawal

The multiple sclerosis medication daclizumab (Zinbryta, Biogen/AbbVie) is being withdrawn from the market voluntarily following reports that it has been associated with inflammatory encephalitis and meningoencephalitis.

Characterizing the drug’s complex risk–benefit profile won’t be possible given the limited number of patients being treated, the companies said.

Daclizumab is used to treat adults with relapsing forms of multiple sclerosis. Because of the risk profile, it is generally used in people who have tried two or more medicines that have not worked well enough.

Source: Biogen/AbbVie, March 2, 2018


Interoperable Continuous Glucose Monitoring System

The FDA has permitted marketing of the Dexcom G6 integrated continuous glucose monitoring (iCGM) system (Dexcom, Inc.) for determining blood glucose levels in patients 2 years of age and older with diabetes. This is the first type of CGM system permitted by the agency to be used as part of an integrated system with other compatible medical devices and electronic interfaces, which may include automated insulin dosing systems, insulin pumps, blood glucose meters, or other electronic devices used for diabetes management. The authorization also classifies this new type of device in class II and subjects it to certain criteria called special controls. This enables developers of future iCGM systems to bring their products to market in the least burdensome manner possible.

Continuous glucose monitoring systems that were first marketed had a different intended use and were evaluated through the FDA’s premarket approval pathway, the most rigorous review designed for the “highest risk” class III medical devices. However, the Dexcom G6 system is intended for a more seamless integration with other diabetes devices, and the FDA recognized this as an opportunity to reduce the regulatory burden for this type of device by establishing criteria that would classify these as “moderate risk” class II medical devices with special controls. With the authorization of the Dexcom G6, future iCGMs that meet the special controls criteria can go through a more streamlined premarket review known as 510(k) clearance.

The Dexcom G6 is a patch device, about the size of a quarter, that is applied to the skin of the abdomen and contains a small sensor that continuously measures the amount of glucose in body fluid. The device transmits real-time glucose readings every five minutes to a compatible display device such as a mobile medical app on a cell phone and will trigger an alarm when a patient’s blood sugar enters a danger zone soaring too high or dropping too low. If it is integrated with an automated insulin dosing system, a rise in blood sugar would trigger the release of insulin from the pump.

Source: FDA, March 27, 2018

15-mm Mechanical Heart Valve

The FDA has approved the world’s smallest mechanical heart valve to aid in the treatment of newborns and infants. The 15-mm valve size was added to the existing line of Masters Series Mechanical Heart Valves with Hemodynamic Plus Sewing Cuff (St. Jude Medical).

In pediatric patients, a malfunctioning heart valve is often the result of a congenital heart defect. Some patients will require heart valve surgery and, potentially, replacement heart valve surgery, but limited replacement options have been available because of the patients’ size.

The Master Series Mechanical Heart Valve is a rotatable, bileaflet valve designed for implantation in the aortic or mitral position. It consists of two semicircular discs that open and close in response to blood pressure changes during the heartbeat, similar to a patient’s own valve. The Masters Series Mechanical Heart Valve was first approved in 1995; the new approval expands the range of sizes available.

The FDA evaluated data from a single-arm study of 20 pediatric patients with serious heart failure ranging from 1.5 weeks to 27 months of age at the time of mitral valve implant. One year after the implant procedure, the probability of survival was 69.3%, and the probability of not experiencing a valve-related adverse event was 66.8%. Serious valve-related adverse events observed through one-year follow-up included blood clots in the device and bleeding in the brain. Anticoagulation therapy may be necessary after the procedure to prevent clotting on the device.

Source: FDA, March 6, 2018

Test Finds Rare BRCA Mutations

The FDA has approved the first direct-to-consumer test that can warn users of their increased risk of breast, ovarian, or prostate cancer, but only a small percentage of Americans can reap a benefit.

The Personal Genome Service Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants), marketed by 23 and Me, targets specific BRCA1/BRCA2 gene mutations that are most common in people of Ashkenazi (Eastern European) Jewish descent. These three mutations, however, are not the most common BRCA1/BRCA2 mutations in the general population. They are present in about 2% of Ashkenazi Jewish women and in 0% to 0.1% of other ethnic populations.

The test analyzes DNA collected from a self-collected saliva sample. The report describes if a woman is at increased risk for breast and ovarian cancer or if a man is at increased risk for breast and prostate cancer. There are more than 1,000 known BRCA mutations, so a negative result does not rule out the possibility that an individual carries other BRCA mutations that increase cancer risk. In addition, most cancer is caused not by hereditary gene mutations but by a wide variety of factors, including smoking, obesity, hormone use, and other lifestyle issues.

The FDA determined that the company provided sufficient data to show that the test is accurate (i.e., can correctly identify the three genetic variants in saliva samples) and can provide reproducible results. The company submitted data on user comprehension studies, using representative genetic health risk test reports, that showed instructions and reports were generally easy to follow and understood by the consumer. The test report provides information describing what the results might mean, how to interpret results, and where additional information about the results may be found.

Source: FDA, March 6, 2018

Babesia microti Blood Screening

The FDA has approved the Imugen Babesia microti Arrayed Fluorescent Immunoassay for the detection of antibodies to B. microti in human plasma samples and the Imugen Babesia microti Nucleic Acid Test for the detection of B. microti DNA in human whole blood samples. These screening tests from Oxford Immunotec, Inc., are the first approved to detect Babesia in donations of whole blood and blood components, and in other living donors.

About 1,000 to 2,000 cases of babesiosis are reported in the U.S. each year. The vast majority of people infected with B. microti do not have symptoms and are never diagnosed, but for certain people, especially those with a weak immune system, it can be a severe, life-threatening disease.

Source: FDA, March 6, 2018


FDA Demands Completion Of Duodenoscope Studies

The FDA has issued warning letters to three duodenoscope manufacturers for failing to complete required post-market surveillance studies to assess the effectiveness of reprocessing the devices.

In an effort to prevent transmission of bacterial infections from contaminated duodenoscopes, the FDA in 2015 ordered Olympus, Fujifilm, and Pentax to study whether health care facilities were able to properly clean and disinfect the devices, but progress has been spotty, the agency said.

For the sampling and culturing study, the FDA expects 50% of samples collected in the study to be processed by August 31, 2018, and 100% by the end of 2018. For the Olympus and Pentax human factors studies (the Fujifilm study is on track), the agency expects 50% of testing to be completed by May 31, 2018, and 100% by June 30, 2018.

Source: FDA, March 9, 2018

Class I Recall of Neuro Probe

The FDA has provided preliminary information about the potential for unintended heating and patient injury with use of the Monteris Medical NeuroBlate probe to bring attention a class I recall for the device. Monteris issued three product advisories between October and December 2017, which were part of the class I recall; however, the FDA has concerns that the information provided by Monteris has not sufficiently mitigated the risk of unintended probe tip heating.

The NeuroBlate system is indicated to ablate, necrotize, or coagulate soft tissue in the brain through interstitial irradiation or thermal therapy in neurosurgical procedures with 1,064-nm lasers. It is intended for planning and monitoring thermal therapies under magnetic resonance imaging (MRI) visualization and provides MRI-based trajectory planning assistance for the stereotaxic placement of MRI compatible (conditional) Neuro-Blate laser delivery probes. It also provides real-time thermographic analysis of selected MRI images.

The device is currently the subject of a voluntary recall initiated by the firm and classified as class I by the FDA due to several instances of unintended heating and damage to the probe, which may have resulted in unintended damage to surrounding brain tissue. The damage to the probe appears to have been caused by an interaction between the thermocouple in the probe and the MRI environment. These events occurred independent of laser energy delivery and have been associated with damage to the tip of the probe implanted within the brain (e.g., charring, release of carbon dioxide). The FDA has received reports related to overheating of the probe, including one report of a patient who experienced an intracranial hemorrhage and died, although causality with the device malfunction cannot be concluded with certainty.

Until appropriate mitigation strategies have been identified by the manufacturer and evaluated by the FDA, health care providers should strongly consider treating patients using alternative procedures if available. The benefits and risks of the device, as well as the availability and benefits and risks of alternative treatment modalities, should be considered on an individual patient basis. Health care providers who do not believe there is a viable alternative should use the device with extreme caution.

Source: FDA, March 22, 2018