Proposed warnings on cigarettes would be first in 35 years

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

Recalls and warnings

A class I recall of certain Ellipse implantable cardioverter defibrillators by Abbott due to exposed aluminum wires that may prevent defibrillation therapy. The recall includes 108 devices distributed from May 6 to June 14, 2019.

A recall of two lots of eletriptan hydrobromide (Relpax) 40-mg tablets by Pfizer Inc. due to potential microbiological contamination. Affected products were distributed from June to July 2019.

A warning not to purchase or drink Miracle Mineral Solution, a product sold online as a medical treatment, and other similar products due to a recent rise in reported health issues. The products are marketed as a liquid that is 28% sodium chlorite in distilled water. While not FDA approved for any use, these products are promoted on social media as a remedy for treating autism, cancer, HIV/AIDS, hepatitis, flu, and other conditions. When mixed with citric acid as directed, the solution develops into a dangerous bleach that has caused serious and potentially life-threatening side effects. The FDA has recently received reports of people experiencing severe vomiting, severe diarrhea, life-threatening low blood pressure caused by dehydration, and acute liver failure after drinking these products.

An expanded recall of six lots of bulk losartan potassium USP tablets (two lots of 50-mg strength and four lots of 100-mg strength) by Teva Pharmaceuticals USA, Inc., due to the detection of an impurity. N-Nitroso-N-methyl-4-aminobutyric acid, a potential human carcinogen, was detected in one lot of the active pharmaceutical ingredient manufactured by Hetero Labs Limited, which was used in the manufacturing of the recalled products.

A recall of 32 lots of losartan potassium USP tablets (two lots of 50 mg) and losartan potassium/hydrochlorothiazide tablets (12 lots of 50 mg/12.5 mg; three lots of 100 mg/12.5 mg; and 15 lots of 100 mg/25 mg) to the patient level by Macleods Pharmaceuticals Limited due to the detection of an impurity. Trace amounts of N-Nitroso-N-methyl-4-aminobutyric acid, a potential human carcinogen, were found in the active pharmaceutical ingredient manufactured by Hetero Labs Limited.

A class I recall of enFlow Fluid Warming System disposable cartridges by Vyaire Medical due to potential risk of exposure to elevated levels of aluminum. The system is indicated for warming blood, blood products, and IV solutions prior to administration. Aluminum may elute from the warmer into the fluids, thereby exposing patients to unsafe levels of the metal. The recall includes about 2.9 million devices distributed from Jan. 4, 2016, to March 7, 2019.


A proposed rule to require new health warnings with color images on cigarette packages and in advertisements. The proposed warnings will feature photo-realistic color images depicting some of the lesser-known but serious health risks of cigarette smoking. Examples of warnings include that smoking causes head and neck cancer, fatal lung disease in nonsmokers, and bladder cancer, which can lead to bloody urine. Health warnings on cigarette packages were last updated in 1984.

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 (PAD) in the femoropopliteal artery. The agency has concluded that a late mortality signal was associated with the use of these devices to treat femoropopliteal PAD, although the magnitude of the signal should be interpreted with caution. Physicians should consider this risk when making treatment recommendations and continue diligent monitoring of patients who have been treated with paclitaxel-coated balloons and paclitaxel-eluting stents, the FDA recommended. The agency will continue to assess the long-term safety of these devices.

A safety announcement that an FDA review found no increased risk of prostate cancer with Parkinson's disease medicines containing entacapone (Comtan, Stalevo). The agency had alerted the public in March 2010 that a clinical trial had suggested a possible increased risk of prostate cancer with the entacapone component of Stalevo and asked the drug manufacturer to evaluate the potential risk in a study. The FDA also studied the issue independently using data from the Department of Veterans Affairs health care system. The additional studies concluded that entacapone use is not associated with an increased risk of prostate cancer.


The Barostim Neo System to improve symptoms in patients with advanced heart failure who cannot be treated with other heart failure devices, such as cardiac resynchronization therapy. The device is indicated for patients who have a left ventricular ejection fraction of less than or equal to 35%. It includes a pulse generator that is implanted below the collarbone and is connected to a lead that attaches to the carotid artery in the neck. A physician tests and programs the implanted device, which delivers electrical impulses to baroreceptors that sense how blood is flowing through the carotid arteries and relay information to the brain. The brain then sends signals that relax the blood vessels and inhibit the production of stress-related hormones to reduce heart failure symptoms. In a trial of 408 patients, all receiving guideline-directed medical therapy, including medication, 125 received the implant and showed improvements in six-minute walk distance and the impact of symptoms on quality of life. Potential complications include infection, need for reoperation, low blood pressure, nerve damage, surgical or anesthetic complications, allergic reaction, arterial damage, exacerbation of heart failure, stroke, and death. A postapproval study will assess the device's potential to prolong life and reduce hospitalizations.

Lefamulin (Xenleta) to treat adults with community-acquired bacterial pneumonia. The drug, which is taken either orally or intravenously, was compared to moxifloxacin, with or without linezolid, in two clinical trials of 1,289 patients. Patients in both groups had similar rates of clinical success. The most common reactions were diarrhea, nausea, reactions at the injection site, elevated liver enzymes, and vomiting. Because the drug may cause prolonged QT interval, it is contraindicated in patients with arrhythmias and those taking antiarrhythmic agents or drugs that may cause prolonged QT interval. In addition, it should not be used in patients with known hypersensitivity to lefamulin or any other members of the pleuromutilin antibiotic class.

Pretomanid tablets, in combination with bedaquiline and linezolid, to treat a specific type of highly treatment-resistant tuberculosis (TB) of the lungs. The drug is indicated to treat adult patients with extensively drug-resistant, treatment-intolerant, or nonresponsive multidrug-resistant pulmonary TB. A study of 109 patients found a success rate of 89% six months after the end of therapy, which exceeded historical success rates for treatment of extensively drug-resistant TB. The most common adverse reactions were peripheral neuropathy, acne, anemia, nausea, vomiting, headache, increased liver enzymes, dyspepsia, rash, hyperamylasemia, visual impairment, hypoglycemia, and diarrhea.

Expanded indication for several transcatheter heart valves to include patients with severe aortic valve stenosis who are at low risk for death or major complications associated with open-heart surgery to replace the damaged valves. The Sapien 3, Sapien 3 Ultra, CoreValve Evolut R, and CoreValve Evolut PRO were previously indicated only for patients at intermediate or higher risk for death or major complications during open-heart surgery. The transcatheter heart valves should not be used in patients who cannot tolerate blood-thinning medications or have an active infection in the heart or elsewhere. The FDA is requiring device manufacturers to follow patients enrolled in their randomized studies for 10 years to monitor safety and effectiveness, including long-term valve durability.

Entrectinib (Rozlytrek) to treat adults and adolescents whose cancer has a specific genetic defect, neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and for whom there are no effective treatments. The orphan drug was also approved to treat adults with metastatic non-small-cell lung cancer whose tumors are ROS1-positive. This is the third cancer treatment approved by the FDA based on a common biomarker across different types of tumors, rather than the location of the tumor in the body. In four trials of 54 adults with NTRK fusion-positive tumors who received the drug, the proportion of patients with substantial tumor shrinkage was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had shrinkage persist for nine months or longer. In a study of 51 adults with ROS1-positive lung cancer, the overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had shrinkage persist for 12 months or longer. The most serious side effects include congestive heart failure, central nervous system effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and vision disorders.

Pexidartinib (Turalio) capsules to treat adults with symptomatic tenosynovial giant-cell tumor. The drug is indicated for patients with severe morbidity or functional limitations whose condition has not improved with surgery. Approval was based on a placebo-controlled trial of 120 patients. After 25 weeks of treatment, patients who received the drug had an overall response rate of 38%, compared to no response in patients who received placebo. The prescribing information contains a boxed warning about the risk of serious and potentially fatal liver injury. Common side effects include increases in lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and cholesterol levels and loss of hair color. The drug is available only through a Risk Evaluation and Mitigation Strategy program.

Fedratinib (Inrebic) capsules to treat adult patients with certain types of myelofibrosis. The drug is indicated for patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. Approval was based on a trial where 289 patients were randomized to receive fedratinib (400 mg/d or 500 mg/d) or placebo. Of 96 patients treated with 400 mg/d (the dose recommended in the approved label), 35 experienced a significant therapeutic effect. A boxed warning advises clinicians about the risk of serious and fatal encephalopathy. Common side effects include diarrhea, nausea, vomiting, fatigue, and muscle spasms.

Bremelanotide (Vyleesi) to treat premenopausal women with acquired, generalized hypoactive sexual desire disorder. The disorder is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a coexisting medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. Patients inject the drug under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Dosing is limited to once within 24 hours and eight times per month. Patients should discontinue treatment if symptoms do not improve after eight weeks. Trials of 1,247 women found that a greater proportion of women who received the drug had an increase in sexual desire and a decrease in distress compared to those who received placebo. There was no difference between groups in change in the number of satisfying sexual events during the study period. The most common side effects are nausea and vomiting, flushing, injection-site reactions, and headache. About 40% of trial participants experienced nausea, most commonly with the first injection, and 13% needed medications for the treatment of nausea. About 1% reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away after stopping treatment in about half of the patients. The drug should not be used in patients with uncontrolled hypertension, known cardiovascular disease, or high risk for cardiovascular disease, as it increased blood pressure after dosing (which usually resolved within 12 hours).

Dupilumab (Dupixent) to treat adults with nasal polyps accompanied by chronic rhinosinusitis. Efficacy and safety were established in two studies of 724 adults with chronic rhinosinusitis and nasal polyps who were symptomatic despite taking intranasal corticosteroids. Patients who received the drug had significant reductions in nasal polyp size and nasal congestion compared to those who received placebo. They also reported an increased ability to smell and required a reduced amount of nasal polyp surgery and oral steroids. Dupilumab may cause serious allergic reactions and eye problems (e.g., conjunctivitis, keratitis), and the most common side effects were injection-site reactions and eye and eyelid inflammation. Patients who receive the drug should avoid receiving live vaccines. The injection is the first treatment to be approved for inadequately controlled chronic rhinosinusitis with nasal polyps. It was originally approved in 2017 to treat certain patients with eczema and in 2018 as an add-on maintenance treatment for moderate-to-severe eosinophilic asthma or oral corticosteroid-dependent asthma.

First-time generic approvals

Febuxostat tablets (40 mg and 80 mg) for the chronic management of hyperuricemia in adult patients with gout. (Brand name: Uloric)

Morphine sulfate tablets (15 mg and 30 mg) for the management of acute and chronic pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (No brand name provided)

Daptomycin for injection (350 mg/vial [50 mg/mL]) for the treatment of complicated skin and skin-structure infections and Staphylococcus aureus bacteremia in adult patients. (Brand name: Cubicin)

Icatibant injection (30 mg/3 mL [10 mg/mL]) to treat acute attacks of hereditary angioedema in adult patients. (Brand name: Firazyr)

Phenylephrine and ketorolac intraocular solution (1%/0.3%) for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain during cataract surgery or intraocular lens replacement. (Brand name: Omidria)

Carboprost tromethamine injection USP (250-µg/mL [1-mL] single-dose vial) for aborting pregnancy between the 13th and 20th weeks of gestation. (Brand name: Hemabate)

Kit for the preparation of technetium Tc 99m mertiatide (1 mg/vial) for use in the diagnosis of congenital and acquired abnormalities, renal failure, urinary tract obstruction, and calculi in adult and pediatric patients. (Brand name: Technescan MAG3)

Dapiprazole hydrochloride ophthalmic solution (0.5%) for the treatment of iatrogenically induced mydriasis produced by adrenergic (phenylephrine) or parasympatholytic (tropicamide) agents. (No brand name provided)

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