FDA analyzing mortality risk with paclitaxel-coated balloons

This column reviews details on recent recalls, warnings, and approvals.


A recall of four lots of drospirenone and ethinyl estradiol tablets USP (3 mg/0.03 mg) by Apotex Corp. due to the possibility of defective blisters with incorrect tablet arrangements and/or an empty blister pocket. Patients who have received affected products should contact their pharmacy and should use a nonhormonal method of birth control.

A recall of two lots of levoleucovorin injection (250 mg/25 mL) by Mylan Institutional LLC due to the presence of particulate matter identified as copper salts. Affected products were distributed in the U.S. between August 2017 and July 2018.

A class I recall of all lots of the Raindrop Near Vision Inlay by Optics Medical due to postapproval study data showing an increased risk of corneal haze associated with the device. The recall includes 2,869 units distributed from Aug. 1, 2016, to March 7, 2018.

A class I recall of transseptal needles by Cook Medical Inc. due to the risk of detached plastic fragments. The recall includes 97 devices distributed from May 30 to Nov. 5, 2018.

A recall of 60 lots of losartan potassium tablets USP and 54 lots of losartan potassium/hydrochlorothiazide tablets USP by Torrent Pharmaceuticals Limited due to the detection of an impurity. Trace amounts of N-nitroso-N-methyl-4-aminobutyric acid (NMBA) were found.

A recall of one lot of valsartan tablets USP by American Health Packaging due to the detection of an impurity. Trace amounts of N-nitrosodiethylamine (NDEA), a probable human carcinogen, were found.


Esketamine (Spravato) nasal spray, in conjunction with an oral antidepressant, to treat depression in adults with treatment-resistant depression. The drug, a chemical mirror image of ketamine, is only available through a restricted distribution system under a Risk Evaluation and Mitigation Strategy (REMS) because of the risk of serious adverse outcomes resulting from sedation and dissociation, as well as the potential for misuse. The drug must be self-administered in a certified medical office under the supervision of a clinician, who monitors the patient for at least two hours after administration. The spray may not be taken home, and patients should not drive or operate machinery until the next day. In one short-term study, the spray plus an oral antidepressant improved depressive symptoms significantly more than the oral antidepressant plus placebo, but two other short-term studies did not demonstrate effectiveness. In a longer-term trial, stable patients who continued treatment with the drug plus an oral antidepressant had a significantly longer time to relapse of depressive symptoms than those on a placebo plus an antidepressant. The most common side effects were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk. The drug labeling contains a boxed warning about the serious risks of sedation, dissociation, misuse, and suicidal thoughts and behaviors.

Brexanolone (Zulresso) injection to treat women with postpartum depression. This is the first drug to be approved by the FDA specifically to treat postpartum depression. It will be available only through a REMS program that requires the drug to be administered by a clinician in a certified health care facility. The continuous IV infusion is administered over a total of 60 hours, and patients must have continuous pulse oximetry monitoring and must also be monitored for excessive sedation and sudden loss of consciousness. Patients must be accompanied during interactions with their child or children while receiving the infusion, and the need for these steps is addressed in a boxed warning. In two studies of patients with moderate or severe postpartum depression who received the treatment or placebo and were followed for four weeks, the drug was superior to placebo in improving depressive symptoms at the end of the first infusion, and this improvement was also found at the end of 30-day follow-up. The most common adverse reactions were sleepiness, dry mouth, loss of consciousness, and flushing.

Testosterone undecanoate (Jatenzo) capsules to treat men with certain forms of hypogonadism. The drug is indicated for men with low testosterone levels due to specific medical conditions, such as genetic disorders like Klinefelter syndrome or tumors that have damaged the pituitary gland. It should not be used to treat those with “age-related hypogonadism” because its benefits do not outweigh its risks for that indication. A trial of 166 men found that 87% of treated patients achieved an average testosterone level within the normal range. A boxed warning states that the drug can cause blood pressure to rise, increasing the risk of heart attack, stroke, and cardiovascular death. Common side effects are headache, an increase in hematocrit, a decrease in HDL cholesterol, high blood pressure, and nausea. An increase in prostate-specific antigen levels was also observed.

Cladribine (Mavenclad) tablets to treat relapsing forms of multiple sclerosis (MS), including relapsing-remitting disease and active secondary progressive disease. The drug is generally indicated for patients who have had an inadequate response to, or are unable to tolerate, another MS drug. It is not recommended for patients who have clinically isolated syndrome. A trial of 1,326 patients found a fewer relapses in those who received the drug compared to placebo. The drug also reduced the progression of disability compared to placebo. The most common adverse reactions include upper respiratory tract infections, headache, and decreased lymphocyte counts. The drug has a boxed warning for an increased risk of malignancy and fetal harm.

Siponimod (Mayzent) tablets to treat relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. A trial of 1,651 patients found a significantly lower proportion with confirmed progression of disability in three months in the treatment group versus a placebo group. The drug also decreased the number of relapses. The most common adverse reactions were headache, high blood pressure, and changes in liver function. Because the drug may increase the risk of infections, patients should have a complete blood count taken before initiating treatment.

A new generic of valsartan (Diovan), an angiotensin II receptor blocker (ARB). The approval is meant to help relieve the recent shortage of the medication as a result of multiple recalls of generic valsartan products due to the detection of nitrosamine impurities. The FDA evaluated the company's manufacturing processes and also made sure it used appropriate testing methods to demonstrate that the product does not contain the impurities.

The Optimizer Smart System to restore a normal timing pattern of the heartbeat in patients with chronic, moderate-to-severe heart failure. The device is indicated for patients who have a marked limitation in physical activity, remain symptomatic despite optimal medical therapy, and are not suited for treatment with other heart failure devices (e.g., cardiac resynchronization therapy). The system includes an implantable pulse generator, battery charger, programmer, and software. After the device is implanted under the skin of the chest, a physician tests and programs the device, which delivers electrical impulses to the heart during regular heartbeats to help improve the heart's squeezing capability. In two randomized, multicenter trials of 389 patients with moderate-to-severe heart failure who all received medical therapy, patients who also received the implant showed improvements in six-minute walking distance, quality of life, and functional status compared to those who received medical therapy alone. Potential complications of the device include infection, bleeding, worsened heart failure, and problems with the device itself (e.g., dislodgement or fracture of the leads implanted in the heart).

A new indication for certolizumab pegol (Cimzia) injection to treat adults with nonradiographic axial spondyloarthritis and objective signs of inflammation. Initially approved in 2008 to treat moderate-to-severe Crohn's disease, the tumor necrosis factor inhibitor is the first FDA-approved treatment for this type of inflammatory arthritis. A trial of 317 adults showed greater improvement in disease activity with the drug than with placebo. The drug's safety profile for this indication was consistent with its known safety profile. A boxed warning advises about the increased risk of serious infections leading to hospitalization or death, including tuberculosis, sepsis, and invasive fungal infections.

A new indication for the MitraClip Clip Delivery System to reduce moderate-to-severe or severe mitral regurgitation. The heart valve repair device, first approved in 2013, is now indicated for patients with normal mitral valves who develop heart failure symptoms and moderate-to-severe or severe mitral regurgitation because of diminished left heart function despite optimal medical therapy. The device is contraindicated in patients who cannot tolerate blood thinners during or after the procedure and those who have active mitral valve endocarditis, rheumatic mitral valve disease, or evidence of blood clots in the heart or veins leading to the heart.

Trastuzumab-qyyp (Trazimera), a biosimilar to trastuzumab (Herceptin). The drug is approved to treat patients with HER2-overexpressing breast cancer and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. The labeling contains a boxed warning alerting clinicians about increased risks of cardiomyopathy, infusion reactions, pulmonary toxicity, and embryo-fetal toxicity. Common side effects include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, insomnia, cough, and rash. Serious side effects include worsening of chemotherapy-induced neutropenia.

Marketing of a new device intended to be used in the ED to help treat patients with carbon monoxide poisoning. The ClearMate device delivers a mixture of oxygen and carbon dioxide in addition to 100% oxygen, which increases the patient's rate of breathing. In multiple studies that tested the device's effectiveness at eliminating carbon monoxide in 100 patients, the device led to faster elimination of carbon monoxide than treatment with 100% oxygen alone but was not faster than hyperbaric oxygen therapy. Patients did not experience any device-related complications.


An updated letter to clinicians about the potential for increased long-term mortality after use of paclitaxel-coated balloons and paclitaxel-eluting stents to treat peripheral arterial disease in the femoropopliteal artery. A preliminary analysis of long-term follow-up data has identified about 50% increased long-term mortality in study participants treated with paclitaxel-coated products compared to patients treated with uncoated devices, the FDA said. The agency will hold an advisory committee meeting about the issue and provide updates as further information becomes available.

A letter to clinicians about an increasing number of adverse events associated with surgical staplers and staples for internal use. From Jan. 1, 2011, to March 31, 2018, the FDA received more than 41,000 related medical device reports, including 366 deaths, more than 9,000 serious injuries, and more than 32,000 malfunctions. The agency recommends following stapler manufacturers' instructions for use, having a range of staple sizes available, and selecting the appropriate size cartridge for the tissue type and thickness.

To ensure continued access to losartan, the FDA will not object to certain manufacturers temporarily distributing products containing NMBA above the interim acceptable intake limit of 0.96 parts per million (ppm) but below 9.82 ppm until the impurity is eliminated. The agency expects that many companies will be able to manufacture the drug without nitrosamine impurities and replenish the country's supply later this year.

First-time generic approvals

Ambrisentan tablets (5 mg, 10 mg) to treat pulmonary arterial hypertension. (Brand name: Letairis)

Sevelamer hydrochloride tablets (400 mg, 800 mg) for the control of serum phosphorus in patients with chronic kidney disease on dialysis. (Brand name: Renagel)

Levofloxacin ophthalmic solution (1.5%) to treat corneal ulcer caused by susceptible strains of bacteria. (Brand name: Iquix)

Levomilnacipran extended-release capsules (20 mg, 40 mg, 80 mg, 120 mg) to treat major depressive disorder. (Brand name: Fetzima)

Acyclovir cream (5%) to treat recurrent herpes labialis in immunocompetent adults and adolescents ages 12 years and older. (Brand name: Zovirax)

Pyridostigmine bromide syrup (60 mg/5 mL) to improve muscle strength in patients with myasthenia gravis. (Brand name: Mestinon)

Deferiprone tablets (500 mg) to treat patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. (Brand name: Ferriprox)

Note: The FDA states that drugs are not always commercially available immediately after approval.