Warning for tofacitinib; generic pregabalin approved

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

Recalls and warnings

A new boxed warning about an increased risk of blood clots and of death with the 10-mg twice-daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis. In addition, the approved use of tofacitinib for ulcerative colitis will be limited to certain patients who are not treated effectively or who experience severe side effects with certain other medicines. The changes follow the FDA's review of interim data from an ongoing safety clinical trial of tofacitinib in patients with rheumatoid arthritis that examined both this higher dose and a lower dose of the medicine. The 10-mg twice-daily dose is not approved to treat rheumatoid arthritis or psoriatic arthritis. Clinicians should discontinue the drug and promptly evaluate patients if they have symptoms of thrombosis and, when treating ulcerative colitis, use tofacitinib at the lowest effective dose while limiting use of the 10-mg twice-daily dosage to the shortest duration needed.

A warning that serious infections have occurred in adults who received investigational fecal microbiota transplantation (FMT) containing multidrug-resistant organisms. One immunocompromised patient died and another was infected after receiving preparations that used the same donor's stool, which contained extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. The donor stool and resulting FMT preparation were not tested for ESBL-producing gram-negative organisms prior to use. In response to the cases, the FDA proposed additional safety protections for the investigational use of FMT, including screening donors for risk factors for colonization with multidrug-resistant organisms and excluding individuals at increased risk of colonization. The FDA also recommended testing donor stool for multidrug-resistant organisms and excluding stool that tests positive.

A recall of BIOCELL textured breast implants and tissue expanders by Allergan due to the uncommon incidence of breast implant-associated anaplastic large-cell lymphoma recently reported by the FDA. The saline-filled and silicone-filled textured breast implants and tissue expanders will no longer be distributed or sold in any market where they are currently available. Effective immediately, surgeons should no longer implant the products. The global recall does not affect the manufacturer's NATRELLE smooth or MICROCELL breast implants and tissue expanders.

A recall of certain models of the MiniMed insulin pump by Medtronic due to potential cybersecurity risks. About 4,000 U.S. patients may be affected. The risks are related to the pumps' wireless communication with other devices, such as blood glucose meters and continuous glucose monitoring systems. Due to the identified vulnerabilities, an unauthorized individual could potentially connect wirelessly to a nearby insulin pump and change its settings. Because the manufacturer cannot update the MiniMed 508 and MiniMed Paradigm series insulin pump models, patients using them should switch to a model with more cybersecurity protection. After the recall, the manufacturer provided patients with alternative insulin pumps that have enhanced cybersecurity capabilities. While waiting for a replacement pump, patients should try to keep their pump and connected devices within their control at all times. To date, the FDA is not aware of reports of patient harm related to these cybersecurity risks.


Elimination of the Risk Evaluation and Mitigation Strategy (REMS) for emtricitabine/tenofovir disoproxil fumarate (Truvada) and its four approved generics. The drug was approved in 2004 to treat HIV-1 infection in combination with other antiretroviral drugs and in 2012 for HIV pre-exposure prophylaxis (PrEP). The REMS was established with the 2012 approval and required drug manufacturers to provide training materials for health care professionals and educational information for consumers due to the risk of developing resistant HIV-1 variants when HIV-1 infection is present. With the removal of the REMS, manufacturers are not required to provide educational materials, and prescribers should continue to follow the labeled directions for the initiation and proper use of the drug for the PrEP indication.

A labeling change for flibanserin (Addyi), which was approved in 2015 to treat acquired, generalized hypoactive sexual desire disorder in premenopausal women. The labeling currently includes a boxed warning and contraindication stating that women must avoid alcohol when taking the drug due to concerns of severe hypotension and syncope. Based on the results of postmarketing studies, the FDA determined that the updated drug labeling should convey that patients do not need to avoid alcohol completely. Women should either discontinue drinking alcohol at least two hours before taking the drug at bedtime or skip the dose that evening. The updated label will also state that women should not consume alcohol at least until the morning after taking the drug at bedtime. The FDA will not remove the boxed warning and contraindication completely from the product labeling.


Romosozumab-aqqg (Evenity) to treat osteoporosis in postmenopausal women at high risk of fracture. These are women with a history of osteoporotic fracture or multiple risk factors for fracture, or those who are intolerant to other osteoporosis therapies or in whom such therapies have failed. One dose of the drug, a monoclonal antibody, consists of two injections, one immediately following the other, given once a month by a health care professional. More than 12 doses should not be used, as the drug's bone-forming effect wanes after 12 doses. In two trials of more than 11,000 women, one year of treatment with the drug (followed by one year of denosumab) lowered the risk of a new vertebral fracture by 73% compared to placebo followed by denosumab, and one year of treatment with romosozumab-aqqg (followed by one year of alendronate) reduced the risk of a new vertebral fracture by 50% compared to two years of alendronate alone. Common side effects include joint pain, headache, and injection-site reactions. A boxed warning states that the drug may increase the risk of heart attack, stroke, and cardiovascular death and should not be used in patients who have had a heart attack or stroke within the previous year.

Dolutegravir and lamivudine (Dovato) as a complete regimen for the treatment of HIV-1 infection. The drug, taken as one daily tablet, is indicated for adults with no antiretroviral treatment history and with no known or suspected substitutions associated with resistance to its individual components. It is the first FDA-approved two-drug, fixed-dose, complete regimen for HIV-infected adults who have never received treatment for HIV. In two trials of 1,433 patients, the drug regimen had a similar effect of reducing the amount of HIV in the blood compared to a regimen of dolutegravir, emtricitabine, and tenofovir. The most common adverse reactions were headache, diarrhea, nausea, insomnia, and fatigue. A boxed warning cautions that patients co-infected with hepatitis B should add additional treatment for their hepatitis B or consider a different drug regimen.

Marketing of four existing tests to aid in the diagnosis of Lyme disease. The tests are the first to follow a new testing paradigm in which two enzyme immunoassays are run concurrently or sequentially versus the current two-step process of running a western blot after the initial enzyme immunoassay. Studies have shown the ZEUS ELISA enzyme immunoassay tests Borrelia VlsE1/pepC10 IgG/IgM, Borrelia burgdorferi IgG/IgM, Borrelia burgdorferi IgM, and Borrelia burgdorferi IgG to be as accurate as current methods for detecting antibodies to assess exposure to Borrelia burgdorferi, the causative agent of Lyme disease.

First-time generic approvals

Pregabalin capsules and oral solution (25, 50, 75, 100, 150, 200, 225, 300 mg, and 20 mg/mL) for the management of postherpetic neuralgia, fibromyalgia, and neuropathic pain associated with diabetic peripheral neuropathy or with spinal cord injury, as well as for the adjunctive treatment of partial-onset seizures in patients ages 17 years and older. (Brand name: Lyrica)

Mesalamine delayed-release capsules (400 mg) for the treatment of patients ages 5 years and older with mildly to moderately active ulcerative colitis and for maintenance of remission of ulcerative colitis in adults. (Brand name: Delzicol)

Tramadol hydrochloride tablets USP (100 mg) for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (Brand name: Ultram)

Diclofenac sodium injection (37.5 mg/mL single-dose vials) for the management of mild to moderate pain or the management of moderate to severe pain, alone or in combination with opioid analgesics. (Brand name: Dyloject)

Sildenafil for oral suspension (10 mg/mL) to improve exercise ability and delay clinical worsening in adults with WHO Group I pulmonary arterial hypertension (Brand name: Revatio)

Dapsone gel (7.5%) for the topical treatment of acne vulgaris in patients ages 12 years and older. (Brand name: Aczone)

Micafungin for injection (50 mg/vial and 100 mg/vial single-dose vials) for the treatment of candidemia, acute disseminated candidiasis, candida peritonitis, and abscesses; also for the treatment of esophageal candidiasis and prophylaxis of Candida infections in patients undergoing hematopoietic stem-cell transplantation. (Brand name: Mycamine)

Tobramycin inhalation solution USP (300 mg/4 mL) for the management of cystic fibrosis patients with Pseudomonas aeruginosa. (Brand name: Bethkis)

Penicillamine capsules USP (250 mg) to treat patients with Wilson's disease or cystinuria, as well as those with severe, active rheumatoid arthritis who have not responded to an adequate trial of conventional therapy. (Brand name: Cuprimine)

Sapropterin dihydrochloride tablets (100 mg) for the reduction of blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin-responsive phenylketonuria. (Brand name: Kuvan)

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