Goodbye to Andexanet Alfa (AndexxaⓇ)

Andexanet alfa (Andexxa) made its quiet exit from the U.S. market just a few weeks ago.  It's an interesting story so in case you missed it, I'll recap what andexanet alfa is, or rather was, and what happened that led to its removal.  Being pulled from the U.S. market may have come to a surprise for some considering its main study (ANNEXA-I) was stopped early for successfully meeting its main efficacy outcome. While having a trial stopped early for superior efficacy results sounds good on the surface, it can have negative ramifications on other aspects of the clinical inquiry (explained below).

Thiamine deficiency and supplementation in heart failure

Thiamine is a water-soluble vitamin that is an important coenzyme for various metabolic processes in the body.  These include the regulation of glucose metabolism, the Krebs cycle (generates ATP), the pentose shunt (generates NADPH), and maintenance of sodium/potassium gradients in the brain (necessary for conducting nerve impulses).  Thiamine is mostly obtained from dietary intake with absorption occurring in the jejunum and ileum. After traveling to the liver, thiamine spends a relatively short amount of time in the blood before distributing to tissues throughout

Sulfamethoxazole/trimethoprim and increase in serum creatinine: When to be concerned

A 65 year old male is being treated for an infection on his forearm that developed purulent drainage within the last few days.  He denies experiencing any penetrating trauma to his arm and denies any other complaints at this time.  He weighs 70 kg, His WBC count is 14.7 x 109/L, serum creatinine is 1.3 mg/dL, and his vital signs are within normal limits.  His past medical history includes hypertension and an MRSA infection last year.  He is currently taking valsartan 160 mg daily and chlorthalidone

Linezolid-induced thrombocytopenia

Thrombocytopenia is a notable adverse effect of linezolid.  Some of the evidence behind the onset, duration, and the extent of platelet decrease will briefly be described here and summarized in bullets at the bottom of the discussion.  For a discussion of linezolid's mechanism of action and some other notable features, see a prior post here.

Dabigatran reversal with idarucizumab (Praxbind)

A 77 year old black patient is admitted to the hospital for a gastrointestinal bleed.  He has a past medical history of CAD (MI 15 years ago), CKD (stage 4), atrial fibrillation, PUD, and hyperlipidemia for which he is taking ASA 81 mg daily, metoprolol tartrate 50 mg twice a day, atorvastatin 20 mg daily, lisinopril 20 mg daily, omeprazole 20 mg daily, and dabigatran 75 mg orally twice a day.  Initial labs indicate an aPTT of 95 seconds, hemoglobin of 6.8 g/dL, and serum creatinine 2.3 mg/dL.

Risk of hyperglycemia from glucocorticoids

A 65 year old patient with COPD sees his primary care provider for worsening shortness of breath over the past week.  His current medications include tiotropium and albuterol.  He has no other significant past medical history but has a family history of diabetes.  His current labs include a fasting plasma glucose of 96 mg/dL, HbA1c of 6.1%, Scr = 0.8 mg/dL.  His primary care provider determines that the patient is having a COPD exacerbation and is opting to initiate a 5 day course of prednisone 40 mg orally daily (click here for more on a 5 days course versus longer steroid courses for COPD exacerbations).  What are some of the risk factors, the time-course, and the mechanism for developing hyperglycemia in a situation like this?

Heparin-induced hyperkalemia

Heparin and low molecular weight heparins (LMWH) are some of the many medications that have been identified to cause hyperkalemia.  When looking for more information about this in the prescribing information, Lexicomp, and Micromedex, there is a paucity of information.  

The prescribing information does not mention potassium at all, merely stating that suppression of aldosterone synthesis has been reported, whereas the other sources give rates from <1% to 8%.  The following will discuss the typical time course and extent of changes in potassium identified in some studies, the proposed mechanism for these effects, and risk factors.

Use of sodium polystyrene sulfonate for hyperkalemia

Let's start with a patient case.  A 58 year old male is sent to the hospital from his PMD for hyperkalemia.  He has a past medical history of diabetes mellitus type 2, hypertension, osteoarthritis, and obesity for which he is taking sitagliptin 100 mg daily, lisinopril 20 mg daily, atorvastatin 80 mg daily, and aspirin 81 mg daily.  Pertinent findings on arrival to the emergency department are SCr = 1.2 mg/dL (at his baseline), K+ = 5.9 mEq/L (previously 4.2), blood pressure = 152/96 mm Hg, Hb A1c = 10.8%, and a normal EKG.  Upon further questioning about his medication and supplement use, he admits to occasional ibuprofen and oxycodone use this past month for his osteoarthritis and is newly using Morton's Salt Substitute (as he's trying to avoid salt because of his uncontrolled hypertension).  What is the role of sodium polystyrene sulfonate (SPS) in this situation?

Risk of peripheral neuropathy with fluoroquinolones

Last year, the FDA issued a drug safety communication, warning about the risk of nerve damage from fluoroquinolone antibiotics.  You can read last year's post about the warning and other information on fluoroquinolones here: Serious peripheral neuropathy and fluoroquinolones.  

4 T's - Determining the probability of HIT

An earlier post discussed how to bridge argatroban to warfarin in patients with HIT but didn't cover how to determine the likelihood of HIT when it is suspected.  This post will cover the 4 T's that are used to quantify this probability and guide clinical decision-making.

Risk of serotonin toxicity with procarbazine

A question recently came up regarding the risk of serotonin toxicity from a drug interaction between procarbazine and a number of different serotonergic agents.  When checking for an interaction between procarbazine and medications like sertraline, duloxetine, nortriptyline, and tramadol on resources such as Lexicomp and Micromedex, the interactions are listed inconsistently, from no interaction to contraindicated, with varying degrees of evidence, from theoretical to established.

Update on niacin - Results from the HPS2-THRIVE study

In a previous blog post, niacin for dyslipidemia, we discussed the concerns regarding niacin's lack of improvement of clinically meaningful endpoints in addition to some of its adverse effects and how to deal with them.  Recently, final results of the HPS2-THRIVE study have been published.  Here are a few highlights of the results of this study.

More cardiovascular safety data for azithromycin

There has been concern in recent years regarding cardiovascular risk in patients using azithromycin which I discussed in an earlier post found here.

A recent study in JAMA further examined cardiovascular risk and mortality in a retrospective review of more than 60,000 patients in the VA Health System.  This study specifically identified patients with a diagnosis of pneumonia who were treated with antibiotics including azithromycin compared to other guideline-concordant antibiotics.  Their outcomes of measure were 30-day mortality, 90-day mortality, any cardiovascular event, myocardial infarction, heart failure, or cardiac arrhythmias.  The mean patient age was 78 years old and comorbid conditions were fairly common (35% with diabetes, 52% with COPD, 26% with heart failure).

Dealing with statin-induced myopathy

Let’s start with a patient case.  An 82 year old female patient presents to clinic with complaints of weakness in her lower extremities. She describes her weakness as symmetrical heaviness and identifies some stiffness and cramping. Other causes of her complaints are ruled out except for her medications. Her hyperlipidemia is currently being managed with simvastatin 40 mg orally daily and niacin ER 1 g orally daily. What are our options for dealing with suspected statin-induced myopathy?

Drug interaction between warfarin and acetaminophen?

The management of anticoagulant therapy is an important component of the treatment of various disease states. Maintaining the narrow therapeutic range required for the safe and effective use of warfarin is essential to avoid suboptimal dosing and adverse events. Numerous drug interactions with warfarin are present due to alterations in absorption, distribution, and metabolism.  The severity of interactions with warfarin varies greatly and dictates very different recommendations for management and monitoring. In the most insignificant interactions, no change in dosage or monitoring is necessary, whereas some interactions require a significant empiric reduction in warfarin dosage and close monitoring of INR.

Niacin for dyslipidemia

Niacin is one of our options for managing cholesterol in patients with dyslipidemia.  The benefits of high doses of niacin are well established in reducing triglycerides by 20-50%, reducing LDL by 10-25%, and increasing HDL by 10-30%.  What is not well established, however, are the clinically beneficial endpoints of niacin. 

Does enteric coating aspirin change efficacy or adverse effects?

Bleeding risk with anticoagulant and antiplatelet medications is something that we struggle with on a regular basis.  Should we fully anticoagulate a patient with atrial fibrillation who is falling?  Should we continue the aspirin and clopidogrel even though it’s X number of months since their stents? 

Azithromycin and cardiovascular risk

Since 2012, the FDA has made two statements regarding the safety of azithromycin related to cardiovascular risk.  These warnings were largely in response to an observational cohort study that found a small absolute increase in cardiovascular deaths in patients receiving azithromycin versus those receiving amoxicillin or no antibiotic in a Tennessee Medicaid population¹.  This excess risk varied based on patients’ baseline cardiovascular risk and was found to be highest in the highest decile of cardiovascular risk.  While a warning from the FDA does seem concerning, it is important to examine some of the details of the data.

• Of the 347,795 azithromycin prescriptions in the study cohort, there were 29 cardiovascular deaths (absolute risk = 0.008%)
• Of the 1,391,180 matched controls, there were 41 cardiovascular deaths (absolute risk = 0.003%)
• These above cardiovascular deaths occurred during the five day treatment course, whereas the analysis that also included the following five days had no difference in death from any cause
• 4,082 prescriptions would have to be used in patients at the highest cardiovascular risk decile to cause one additional cardiovascular death

Serious peripheral neuropathy and fluoroquinolones

This week’s pharmacy pearl describes a recent alert from the FDA that you might have heard about regarding fluoroquinolones.  Fluoroquinolones are a diverse group of antibiotics used to treat various types of infections including pulmonary, genitourinary, skin, gastrointestinal, and bone infections. 

A recent warning from the FDA announced the potential for all systemic (IV or po) fluoroquinolones to cause serious peripheral neuropathy.  While peripheral neuropathy has been a known side effect of fluoroquinolones for nearly a decade, the FDA felt that the nature of this reaction was not sufficiently described.   They state that a large review has shown a continued association between fluoroquinolones and “disabling” peripheral neuropathy.  Peripheral neuropathy may occur rapidly, within a few days, and has persisted for longer than a year, even when the medication was discontinued.  No risk factors were identified, including age and duration of therapy.  The specific incidence or prevalence was not listed and it is likely underreported since the review was done through the FDA’s Adverse Events Reporting System.  Events occurred with all systemic drugs in this class.

Interaction between linezolid (Zyvox®) and SSRIs

Linezolid is an oxazolidinone antibiotic (see more about its mechanism here) that is active against many gram-positive organisms including those that are resistant to multiple other agents such as methicillin-resistant staphylococci, penicillin-resistant streptococci, and vancomycin-resistant enterococci.  Linezolid is also a weak, reversible, inhibitor of monoamine oxidase (MAO), predominantly MAO-A, which is responsible for the metabolism of neurotransmitters such as serotonin, in the brain.  This effect has led to an increased risk of serotonin syndrome in patients taking other medications that increase serotonergic tone.  SSRIs fall in this category as they increase synaptic serotonin concentrations by preventing transport into the presynaptic neuron.  They are commonly prescribed for numerous psychiatric conditions. Due to the high prevalence of both depressive disorders and nosocomial infections in patients with chronic medical illnesses, this medication combination may be encountered in the hospital setting.  Though case reports are few, deaths have been reported due to serotonin syndrome and a Food and Drug Administration Safety Alert was issued in 2011 specifically warning about the linezolid-SSRI interaction.