Changes to FDA Pregnancy and Lactation Labeling

On December 3, 2014, the FDA issued a new rule revising the current regulations pertaining to the pregnancy, labor and delivery, and nursing mother sections of the prescribing information for prescription drugs and biologic products. Initiation of this amendment was prompted by the FDA’s goal to provide women and their healthcare providers with sufficient information when deciding which medications to prescribe in pregnant and breastfeeding patients.

^{Why the change?}

Recent data indicate that about 90% of pregnant women take at least one medication and 70% take one or more prescription drugs, potentially putting the fetus at high risk for drug-induced developmental abnormalities. Many pregnant women may also be on medications to control chronic disease states such as hypertension or to manage acute conditions developed during pregnancy such as gestational diabetes.  It is also necessary to consider that about half of all pregnancies are unexpected, leading to unintended drug exposure.

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.  

The questionable role of digoxin in atrial fibrillation

Let's start with a patient case.  An elderly patient is admitted to the hospital with complaints of intermittent shortness of breath and a fluttering feeling in his chest.  He has a past medical history of hypertension, atrial fibrillation, and heart failure (EF 6 months ago = 30%).  He is currently taking ramipril 10 mg daily, metoprolol succinate 50 mg daily, and warfarin 6 mg M/W/F and 3 mg the rest of the week.  Other findings include a BP of 106/56 mm Hg, a creatinine clearnace of 40 mL/minute, an INR of 1.28, and atrial fibrillation with a heart rate in the 80s but a rapid ventricular response intermittently into the 120s bpm.  What should be recommended at this time to control this patient's atrial fibrillation and what is the role of digoxin, if any?

Role for polyethylene glycol in treating hepatic encephalopathy?

Hepatic encephalopathy is a frequent and debilitating complication of liver disease.  The mainstay of treatment, lactulose, has been used since the 1960s, even without a strong evidence-base for efficacy.  Currently, in the AASLD guidelines for hepatic encephalopathy, updated in 2014, lactulose is recommended as first line therapy for the treatment of episodic overt hepatic encephalopathy (Grade II-1,B,1 which means controlled trials without randomization, moderate evidence strength, strong recommendation)1.  It's notable that there is a cost appeal of lactulose compared to alternative or add-on therapies such as rifaximin and this is considered in their recommendation.

Bridging anticoagulation when treating venous thromboemboli

Given the rising number of options for treating venous thromboemboli (VTE), questions occasionally arise on what is the standard for initiating and continuing anticoagulation.  Questions such as, "How long do we need to overlap parenteral anticoagulation for?" and "Can we begin monotherapy with a new oral anticoagulant?" will be discussed below.

Interpreting minimum inhibitory concentrations

Several previous discussions have dealt with the concept of the minimum inhibitory concentration (MIC) such as extended-infusion piperacillin/tazobactam (Zosyn) and vancomycin dosing in hemodialysis.  Though this concept was learned at some point, questions occasionally arise as to what these numbers represent and what to make of them when they show up on a culture and sensitivity result.  This post will discuss the MIC and hopefully address some common misconceptions.  For the take home points, skip down to the bullets at the end.

About becoming a clinical pharmacist

In this post we'll discuss some of the basic questions about clinical pharmacists including the steps in becoming a pharmacist, resident, and clinical pharmacist and what competencies a clinical pharmacist should have.  I'll also mention some statistics to give objectivity to the process.

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.

Doxycycline food and OTC interactions

Since it's the time of year again when Lyme disease is a concern for patients in many parts of the United States, I thought it would be good to discuss one issue concerning doxycycline.  Doxycycline is a preferred oral agent for Lyme disease and many of its complications.  It is recommended for a variety of situations when Lyme disease is suspected or confirmed such as1:

• Single dose prophylaxis after tick bite
• Erythema migrans
• Cranial nerve palsy
• Carditis
• Lyme arthritis
• Acrodermatitis chronica atrophicans
• Co-infection with human granulocytic anaplasmosis

When ordering or verifying the typical adult dose of 100 mg orally twice daily, an alert may pop up for an interaction with several drugs including iron, calcium, magnesium, aluminum, or bismuth subsalicylate.  The proposed mechanism for this interaction is chelation in the gastrointestinal tract, compounded by the enterohepatic circulation of doxycycline.  Let's look at some of the data regarding these interactions.

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).

Converting systemic corticosteroids

Let’s start with a patient case.  A patient is being treated with methylprednisolone 20 mg IV q6 hours for some inflammatory process and is clinically improving.  She can now tolerate oral medication and we would like to simplify her dosing regimen to transition to outpatient care. How can we manage her methylprednisolone dosing?

One issue that comes up frequently on the internal medicine service is the potency of different corticosteroids relative to each other and the correct way to convert the doses. Below is the chart that shows the equivalent dose of the various agents we commonly use.

Piperacillin-tazobactam (Zosyn) extended-infusion dosing

Let's start with a patient case.  A 70 year old male patient is admitted to the hospital for a diabetic foot infection.  He has a past medical history of HTN, hyperlipidemia, CKD, gout, and obesity.  He weighs 100 kg and has a Scr of 2.8 mg/dL.  You recall that piperacillin-tazobactam is indicated for diabetic foot infections and are deciding what dosing regimen should be started.  Upon consulting Lexicomp or Micromedex, you will find that piperacillin-tazobactam has a wide dosing range depending on the type of infection being treated in addition to the extent of renal impairment.  Recommended doses range from 2.25 g to 4.5 g intravenously every 6 to 12 hours depending on these factors, leaving much room for uncertainty in many cases.

The following will briefly discuss piperacillin-tazobactam, its pharmacokinetics and pharmacodynamics, and how computer modeling has generated new dosing strategies.  If you just want a simplified way of dosing this medication, feel free to skip down to the 'Take home pearls' at the bottom of the article.

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?

4 Tips for new medical residents

Since July is here and the academic calendar is starting over, it is time for new medical residents to be arriving to the hospital floors.  With this in mind, here are a few tips to help in the transition from student to physician.

Argatroban and warfarin dosing in heparin-induced thrombocytopenia

Let’s start with a patient case.  A 45 year old woman is referred to the hospital after seeing her primary care physician for unusual bruising.  She was discharged four days ago after a two day hospitalization for an asthma exacerbation.  Her PMH includes HTN and asthma.  Her CBC reveals platelets of 73 (baseline 190) and the comprehensive metabolic panel and CBC are otherwise within normal limits.  The diagnosis of heparin-induced thrombocytopenia (HIT) is suspected since she received heparin for DVT prophylaxis during her recent hospitalization.

To see another post on how to determine the probability of HIT by using the 4 T's score, click here.

If the diagnosis of HIT is confirmed, discontinuation of all forms of heparin is paramount.  This includes unfractionated heparin and low molecular weight heparins (including flushes and heparin-coated catheters).

After diagnosis, the decision needs to be made whether to institute a non-heparin anticoagulant, a vitamin K antagonist, and/or simply discontinue all heparins.

Update to anticoagulation in atrial fibrillation

Let’s start with a patient case. A 72 year old female presents to the hospital with fatigue, palpitations, and shortness of breath that has occurred intermittently over the last two weeks.  Her PMH is significant for anxiety, seasonal allergies, and PAD which is rarely symptomatic and not lifestyle-limiting.  She is admitted to the hospital with the diagnosis new-onset atrial fibrillation.  What anticoagulation strategy is recommended for someone like this?

This pharmacy pearl highlights just a few of the key points regarding anticoagulation from the 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation which was just published in April of this year.¹  There are several differences between this newest guideline and the most recent version of the Chest guidelines from 2012 (which only addressed warfarin and dabigatran since it was the only new oral anticoagulant approved at the time).  Note that this entire summary will be referring to nonvalvular atrial fibrillation.

False-positives in urine drug screening caused by medications

Testing urine for the presence of drugs has a variety of uses including assessing poisoning or overdose, pre-employment testing, substance abuse treatment monitoring, or other medicolegal purposes.  There are a number of common medications that can cause false-positive screening of these tests which can lead to a variety of ramifications.

Initial tests are usually performed with an immunoassay.  These can generally be done quickly (an hour or two) and inexpensively and vary in their sensitivity.  They may miss particular substances (for opioids in particular – synthetic or semisynthetic opioids such as hydrocodone, oxycodone, fentanyl, or methadone may not test positive on the initial immunoassay) so if you’re suspicious/concerned about a certain agent, let the lab know so the correct test is performed.  Following the immunoassay, positive results can be confirmed with a more specific technique such as gas chromatography or mass spectrometry but these tests are more costly and time consuming so results may not be available for hours to days. 

Here is a table of medications that can cause false-positives on the urine immunoassay and some comments about the caveats of each category.

Update on steroid recommendations for COPD exacerbations

Let’s start with a patient case.  An elderly patient is admitted through the emergency department with markedly worsening dyspnea and purulent sputum production over the last three days.  When reviewing his history, you find that he has GOLD grade 4 (very severe) COPD and experiences roughly one exacerbation per year that requires hospitalization.  His home medications for COPD include tiotropium (Spiriva) 18 mcg/inhalation once daily, albuterol MDI (Proventil HFA, ProAir HFA, or Ventolin HFA) 90 mcg/inhalation 2 inhalations every 4-6 hours as needed for dyspnea, and fluticasone/salmeterol (Advair Diskus) 250/50 mcg inhaled twice daily.  You are now deciding what steroid regimen should be initiated to manage this exacerbation.

Risk factors for stress ulcers and stress ulcer prophylaxis

Stress ulcer prophylaxis is a topic that comes up frequently on the internal medicine service but is not frequently given more than a moment of consideration.  Numerous studies have identified how acid-suppressive therapies (eg. namely proton pump inhibitors and histamine-2 receptor antagonists) are widely prescribed and often lacking an indication.  Studies of various designs have revealed that 46-73% of patients who receive acid-suppressive therapy while hospitalized do not have an indication.^1-3 

The most robust guideline to date for the use of acid-suppressive therapy for stress ulcer prophylaxis was published in 1999 and was comprised of data almost entirely from patients in the intensive care unit (ICU).⁴  At that time, there was only one randomized control trial addressing stress ulcer prophylaxis in the non-ICU setting.  These guidelines identified and determined the weight of various risk factors for the development of stress ulcers and these values are continued to be used today.  The presence or absence or risk factors should be used to determine the need for stress ulcer prophylaxis, not just admission to the ICU.  The summary of recommendations follows below.

Statins in liver disease?

A middle-aged patient arrives to his regularly scheduled clinic appointment looking for refills of his medication. His PMH includes HTN, hyperlipidemia, diabetes mellitus, obesity, and cirrhosis secondary to nonalcoholic fatty liver disease. His medications include antihypertensive and antihyperglycemic drugs in addition to atorvastatin 80 mg by mouth daily. At this time, you recall that statins have a risk for hepatotoxicity and are concerned whether it should be refilled at this time. What are the considerations for continuing statin therapy in this patient with known liver disease?

Elevation of liver enzymes is a well-known risk of statin therapy. Since the first statin was approved by the FDA in 1987, regular monitoring of liver enzymes to screen for elevations was routine practice. However, in 2012, the FDA revised the prescribing information for all statins to recommend serum aminotransferases be measured at baseline and then only thereafter if clinically indicated. There were primarily two reasons for this change:

“Sulfa” allergy cross-reactivity

Let’s start with a patient scenario.  A patient presents to the emergency room experiencing a heart failure exacerbation.  When entering the order for intravenous diuretics, you note that a cross-reactivity warning has popped up for a “sulfa” allergy.  What evidence is there for cross-reactivity between Loop diuretics and “sulfa” allergy and how should this affect your decision?

Vancomycin dosing and monitoring in hemodialysis

Let's start with a patient case.  A patient on hemodialysis (M/W/F) is admitted to the hospital with cellulitis who also meets sepsis criteria.  He has a history of an MRSA infection during a previous admission so you want to initiate vancomycin at this time.  The patient is 76 kg and still makes some urine.  What dosing strategy should you choose and when/should vancomycin concentrations be monitored?

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.

Prevention of postherpetic neuralgia

An elderly patient is admitted to the internal medicine service with a diagnosis of herpes zoster infection in the typical dermatomal distribution.  The patient’s rash is currently not very painful (2/10) but she is concerned about long-lasting pain as her friend had pain from zoster that lasted for months.  What can we use to prevent the development of postherpetic neuralgia?

Postherpetic neuralgia is a common complication of herpes zoster infection and can be challenging to treat.  Drugs approved by the FDA to treat postherpetic neuralgia include pregabalin (Lyrica), gabapentin (Neurontin), and capsaicin patch (high-concentration patch - Qutenza).  Other medications that have been shown in randomized controlled trials to also reduce pain from postherpetic neuralgia include topical lidocaine, tricyclic antidepressants (eg. nortriptyline), opioids, and tramadol¹. 

No medication has been approved for the prevention of postherpetic neuralgia but here is the data on several agents that have been studied:

Is levalbuterol (Xopenex) more effective than albuterol?

The choice between levalbuterol and albuterol continues to be an area of contention for outpatients, in the emergency department, and those admitted into the hospital. Here is a brief explanation of the difference between the two products.