Tuesday, 20 Mar 2018

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DSB – Safety Updates & Drug Shortages – March 2018

RheumNow will periodically compile a report on drug and health safety issues as the Drug Safety Bulletin (DSB). These updates will address medication safety issues, FDA label changes and reports of new, ongoing and resolved Drug Shortages that affect the practice of rheumatology. If you have suggestions or information about specific drug shortages or drug safety issues please email us at: info@rheumnow.com

Drug Safety News

  • WHO Estimates that 1/10 Hospitalizations are for Adverse Events. WHO Director General stated there are an estimated 421 million hospitalisations in the world every year, and on average, 1 in 10 of those results in adverse events. Adverse events are estimated to be the 14th leading cause of death and injury globally. That puts patient harm in the same league as tuberculosis and malaria.
  • Medical Errors Linked to Deaths in UK. UK National Health Service report shows over 230 million errors across the NHS last year and that these may be a contributing factor for up to 22,300 deaths across the health service. Main reasons for these errors outlined in the report include a lack of communication between GPs and hospitals, patients being given the wrong medication or doses and failure to monitor patients properly.  On average, over 700 deaths were linked to reactions to incorrect medication last year.  https://buff.ly/2FxQt05

FDA Updates – August 2017 to March 2018

  • FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older – FDA limits the use of these products to adults 18 years and older because the risks of these medicines outweigh their benefits in children younger than 18. We are also requiring the addition of safety information about the risks of misuse, abuse, addiction, overdose, death, and slowed or difficult breathing to the Boxed Warning, our most prominent warning, of the drug labels for prescription cough and cold medicines containing codeine or hydrocodone. Health care professionals should be aware that FDA is changing the age range for which prescription opioid cough and cold medicines are indicated.  These products will no longer be indicated for use in children, and their use in this age group is not recommended.  Health care professionals should reassure parents that cough due to a cold or upper respiratory infection is self-limited and generally does not need to be treated.  For those children in whom cough treatment is necessary, alternative medicines are available.  These include over-the-counter (OTC) products such as dextromethorphan, as well as prescription benzonatate products.  https://buff.ly/2HiNt4R
  • No Harmful Effects Identified with Gadolinium-based Contrast Agents for Magnetic Resonance Imaging (MRI) – The FDA has studied the safety of Gadolinium-based Contrast Agents (GBCAs) since 7/15 and now rewarns HCPs to limit GBCA to circumstances where a contrast agent is necessary & limit use of repetitive MRI with GBCAs https://t.co/ckEuDsJEUD
  • FDA issues a Safety Alert over Febuxostat – suggesting an increased risk of cardiac death (compared to allopurinol users). This is based on comparative 6000 pt safety trial wherein Febuxostat showed an increased risk of heart-related deaths and death from all causes. https://buff.ly/2zF1lWX
  • Recall of Methylprednisolone Sodium Succinate for Injection 40mg, 125mg, and 1g - Sagent Pharmaceuticals, Inc. announced the voluntary nationwide recall of ten lots of Methylprednisolone Sodium Succinate for Injection, USP, 40mg, 125mg, and 1g. A detailed listing of products and lots is listed in the recall notice. These products were manufactured by Gland Pharma Ltd. and distributed by Sagent Pharmaceuticals. Sagent has initiated this voluntary recall of Methylprednisolone Sodium Succinate for Injection, USP to the user level due to the discovery of high out of specification impurity results detected during routine quality testing of stability samples for two lots.  This impurity has not yet been identified.  (https://www.fda.gov/Safety/MedWatch/SafetyInformation)

FDA Safety Labeling Changes: drug label changes through 5 March 2018: 

  • Ambien (zolpidem; Mar 2017): Warnings added - Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem and is not recommended.  Use of St. John’s wort, a CYP3A4 inducer, in combination with zolpidem may decrease blood levels of zolpidem and is not recommended.
  • CAMPATH (alemtuzumab; Dec 2017): Warning added - Listeria monocytogenes infections (e.g., meningitis, encephalitis, sepsis, and gastroenteritis), including fatal cases of Listeria meningoencephalitis, have occurred in LEMTRADA-treated patients. Listeria infections have occurred as early as 3 days after treatment and up to 8 months after the last LEMTRADA dose. The duration of increased risk for Listeria infection after LEMTRADA treatment is unknown. Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes (e.g., deli meat, dairy products, etc)
  • Cosentyx (secukinumab; Jan 2018): Pregnancy info added - Limited available human data with COSENTYX use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In an embryo-fetal development study, no adverse developmental effects were observed in infants born to pregnant monkeys after subcutaneous administration of secukinumab during organogenesis at doses up to 30 times the maximum recommended human dose (MRHD). The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. It is not known whether secukinumab is excreted in human milk or absorbed systemically after ingestion. There are no data on the effects of COSENTYX on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COSENTYX and any potential adverse effects on the breastfed child from COSENTYX or from the underlying maternal condition.
  • Humira (adalimumab; Dec 2017): under adverse reactions - Anti-adalimumab antibodies were measured in clinical trials of subjects with moderate to severe HS with two assays (an original assay capable of detecting antibodies when serum adalimumab concentrations declined to < 2 mcg/mL and a new assay that is capable of detecting anti- adalimumab antibody titers in all subjects, independent of adalimumab concentration). Using the original assay, the rate of anti-adalimumab antibody development in subjects treated with HUMIRA was 6.5%. Among subjects who stopped HUMIRA treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to < 2 mcg/mL (approximately 22% of total subjects studied), the immunogenicity rate was 28%. Using the new titer-based assay, anti- adalimumab antibody titers were measurable in 61% of HS subjects treated with HUMIRA. Antibodies to adalimumab were associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum adalimumab concentrations is greater with increasing titers of antibodies to adalimumab. No apparent association between antibody development and safety was observed.
  • Simponi (golimumab; Feb 2018): Under warnings - There have been reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, aplastic anemia, and thrombocytopenia in patients receiving golimumab. Caution should be exercised.   Under adverse reactions -  increased LFTs (ALT, AST) have been noted in clinical trials of PsA and AS.
  • Stelara (Ustekinumab; Feb 2018): Under adverse reactions - Approximately 6-12.4% of subjects treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. In Crohn’s disease clinical studies, less than 3% of patients treated with STELARA® developed antibodies to ustekinumab. In psoriasis clinical studies, antibodies to ustekinumab were associated with reduced or undetectable serum ustekinumab concentrations and reduced efficacy. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.  Under warnings - STELARA may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA. Serious infections requiring hospitalization occurred in patients with psoriasis, psoriatic arthritis and Crohn’s disease in clinical studies. In patients with psoriasis, serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. In patients with psoriatic arthritis, serious infections included cholecystitis. In patients with Crohn’s disease, serious or other clinically significant infections included anal abscess, gastroenteritis, ophthalmic herpes, pneumonia, and listeria meningitis.  Reversible Posterior Leukoencephalopathy Syndrome has been reported - One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in clinical studies of psoriasis and psoriatic arthritis. The subject, who had received 12 doses of STELARA over approximately two years, presented with headache, seizures and confusion. No additional STELARA injections were administered and the subject fully recovered with appropriate treatment. No cases of RPLS were observed in clinical studies of Crohn’s disease.
  • Xeljanz (tofacitinib; Dec 2017): Boxed warning includes - Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ/XELJANZ XR use. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.  Under adverse reactions: No dose adjustment is needed with mild renal impairment. Drug has not been studied in RA patients with baseline creatinine clearance < 40 mL/ min (nor in psoriatic arthritis patients with baseline creatinine clearance < 50 mL/ min).

Reported Drug Shortages as of March 2, 2018



Drug Shortage

Reason for shortage

Estimated Availability


(25, 50, 100 mg tabs)

Shortage of active ingredient; increased demand

Back order or Limited supply.


(4 mg/ml) vials

Fewer manufacturers; manufacturing delays; intermittent back order

intermittent back order; some companies releasing product with limited expiration dates; 1ml vial release date of mid-May 2018

Folic acid injectable

(50 mg per 10 mL)

Active ingredient delay

Now available

Lidocaine injection, 1%, 2% (2 ml, 5 ml, 10 ml vials)

Fewer manufacturers; increased demand; supply interruptions

On Back order; Intermittent availability; Additional quantities expected by early March 2018

Methotrexate injection (25mg/ml) 2 ml, 4 ml, 10 ml preservative free vials

Manufacturing delays

Now available


250 mg tablets


Unknown. Mylan tablets available with an expiration date of September 2018.

Source: https://www.ashp.org/Drug-Shortages/Current-Shortages





The author has no conflicts of interest to disclose related to this subject

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