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Boxed warning about neuropsychiatric events

The FDA is requiring a boxed warning for montelukast, a leukotriene receptor antagonist sold as a generic drug and under the brand name Singulair. Montelukast is labeled for treatment of asthma, exercise-induced bronchoconstriction, and allergic rhinitis. The new warning strengthens the drug's existing warning about the risk of adverse neuropsychiatric reactions such as agitation, depression, sleeping problems, and suicidal thoughts and actions.


The boxed warning advises healthcare providers to avoid prescribing montelukast for patients with mild symptoms, particularly those with allergic rhinitis. "Although the incidence of neuropsychiatric adverse reactions is unknown, some reports are serious, and many patients and healthcare professionals are not fully aware of these risks," says Sally Seymour, MD, director of the FDA's Division of Pulmonary, Allergy and Rheumatology Products. She notes that many other medications that have been proven safe and effective for treating allergic rhinitis are available by prescription and over the counter.


Source: US Food and Drug Administration. FDA requires stronger warning about risk of neuropsychiatric events associated with asthma and allergy medication Singulair and generic montelukast. News release. March 4, 2020.



Metformin reduces adverse metabolic effects

Adults with inflammatory diseases who are treated with continuous glucocorticoid therapy may experience serious metabolic disorders related to glucocorticoid overexposure, such as Cushing syndrome. Researchers conducted a randomized, double-blind study to evaluate whether adding metformin to the glucocorticoid regimen would reverse adverse metabolic effects without impairing the anti-inflammatory benefits of glucocorticoids. Study participants were patients without diabetes ages 18 to 75 being treated with continuous prednisolone for an inflammatory condition.


Fifty-three eligible patients were randomly assigned to either the metformin or placebo group. Metformin and placebo were administered orally for 12 weeks in escalating doses. Patients in both groups received an equivalent cumulative dose of glucocorticoids. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by computed tomography. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks.


The findings revealed no change in the visceral-to-subcutaneous fat area ratio between the treatment groups, but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group. These patients also experienced improvements in markers of carbohydrate, lipid, liver, and bone metabolism, as well as improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. In addition, patients in the metformin group experienced lower rates of pneumonia, moderate-to-severe infections, and hospitalization. The researchers concluded that "metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation."


Source: Pernicova I, Kelly S, Ajodha S, et al. Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial. Lancet Diabetes Endocrinol. [e-pub Feb. 25, 2020]



Warn patients about EpiPen malfunctions

The FDA warns healthcare professionals and consumers that EpiPen 0.3 mg and EpiPen Jr 0.15 mg epinephrine autoinjectors and authorized generic versions may be prone to administration errors due to delayed or improper injection. These devices are indicated for emergency treatment of allergic reactions, including anaphylaxis. Possible reasons for administration errors include:


* device failure from spontaneous activation caused by using sideways force to remove the blue safety release. For example, while holding the device in one hand, a patient may try to push the safety release sideways with the thumb on the same hand. The correct technique is to grasp the autoinjector in one hand with the needle end pointing downward, then use the other hand to remove the blue safety release by pulling it straight up without bending or twisting it.


* device failure from inadvertent or spontaneous activation due to a raised blue safety release, which is a product defect affecting a few EpiPens. The safety release should not be raised and/or removed until immediately before use.


* difficulty removing the device from the carrier tube due to a slight deformation on the rim of the carrier tube.


* user error, such as failing to remove the blue safety release and failing to keep the needle end of the device in contact with the outer thigh before and during activation.



Teach patients correct injection technique and review the "Patient Information and Instructions for Use" in the package insert. Patients and healthcare professionals should periodically review the user instructions and practice their injection technique using an EpiPen training device to ensure proper utilization of the autoinjector in an emergency.


In addition, tell patients to inspect their autoinjectors before use to ensure the blue safety release is not raised and that they can easily remove the device from the carrier tube. If a device is defective, they can obtain a replacement at no cost by contacting Mylan Customer Relations at 800-796-9526.


Remind patients to always seek emergency medical help immediately after using an epinephrine autoinjector.


Source: US Food and Drug Administration. FDA alerts patients and health care professionals of EpiPen auto-injector errors related to device malfunctions and user administration. News release. March 24, 2020.



Contamination concerns trigger recall

In April, the FDA asked manufacturers to withdraw both prescription and over-the-counter (OTC) ranitidine, a histamine H2-receptor antagonist commonly used to treat gastroesophageal reflux disease among other indications. The request was prompted by an ongoing investigation of a contaminant known as N-Nitrosodimethylamine (NDMA) found in ranitidine medications. The FDA determined that the impurity in some ranitidine products increases over time and when the drug is stored at higher than room temperatures. Consequently, patients may be exposed to unacceptable levels of NDMA, a probable carcinogen.


The FDA advises patients taking OTC ranitidine to stop taking any tablets or liquid they currently have, dispose of them properly, and not buy more. Patients taking prescription ranitidine should speak with their healthcare provider about other treatment options before stopping the medication. Many prescription and OTC drugs have been approved for the same or similar uses as ranitidine without the same risk of NDMA contamination.


Source: US Food and Drug Administration. FDA requests removal of all ranitidine products (Zantac) from the market. News release. April 1, 2020.