Alex Evans, PharmD, CGP
Alex Evans, PharmD, CGP
Alex Evans, PharmD, CGP, works in community pharmacy in Jacksonville, Florida, and is preceptor at the University of Florida and Florida AM University. He graduated from the University of North Carolina-Greensboro with a BS in Biology and graduated from the University of North Carolina-Chapel Hill with a Doctor of Pharmacy degree. He has worked in both the community and long-term care settings. He can be reached at alex.evans.pharmd@gmail.com

Top 5 Drugs With Confusing Formulations

JANUARY 05, 2017
The following list are medications that in practice I see most often confused often by prescribers, nurses, and (yes, even) pharmacists. I would like to provide some depth into their formulation differences and hopefully prevent errors. Here, in my opinion, are the top 5:

Nitrofurantoin
Nitrofurantoin, an antibiotic used to treat urinary tract infections, is available under 2 brand names – Macrobid and Macrodantin. As the name suggests, Macrobid is dosed twice-daily while Macrodantin is dosed 4 times daily. Macrodantin is also sometimes used to prevent UTIs and in this case is typically dosed once daily.1,2 Keep in mind, though, that nitrofurantoin is on the Beer’s list for long-term use because of the risk of pulmonary fibrosis, hepatotoxicity, and peripheral neuropathy, so using it long-term to prevent UTIs is generally not recommended, especially in the elderly. These reactions can occur in anyone using nitrofurantoin.2,3 When I was working in nursing home pharmacy, we actually had to remove nitrofurantoin from the emergency kit after multiple errors where someone pulled the wrong product from the kit.
Macrobid consists of 2 formulations of nitrofurantoin – nitrofurantoin macrocrystals and nitrofurantoin monohydrate. After ingesting, the nitrofurantoin macrocrystals are absorbed while the nitrofurantoin monohydrate mixes with gastric juices, forming a gel-like matrix. By forming the matrix, the nitrofurantoin monohydrate gets released slowly over time, resulting in the ability to dose twice-daily. Macrodantin, on the other hand, only contains nitrofurantoin macrocrystals, and so compared to Macrobid has a shorter duration of action.1
A common error to look out for is prescribers electronically prescribing Macrodantin but prescribing it twice daily. I have seen this quite often, and typically the prescriber intended to prescribe Macrobid but chose the wrong product.

Diltiazem
Diltiazem, a calcium-channel blocker used to treat hypertension, is available in immediate release, 12-hour extended release, and 3 different types of 24-hour extended release formulations: 1) a single-microbead system, 2) a dual-microbead system, and 3) a geomatrix system.4
The tricky part is that the different types of 24-hour extended release formulations are not AB rated because they do not share the same pharmacokinetics. With the single-microbead system, the medication is released slowly over a 24-hour time period in only 1 phase. The dual-microbead system, on the other hand, contains 2 layers that create a 2- phase system of 12 hours each. The geomatrix system releases medication in different phases by being hydrated at different rates.4
A best practice would be to obtain the brand name (and thus the formulation) from the prescriber each time when receiving a prescription and to obtain either the brand name or the NDC from the transferring pharmacist when transferring a prescription. Be sure not to attempt override the computerized substitution limitations that are letting you know that the products are not AB-rated. Of note, improper substitution of these products has been reported to have led to harm.4

Nifedipine
Nifedipine, also a calcium-channel blocker used for hypertension, is available as immediate-release as well as 2 different 24-hour extended release formulations. These extended release formulations are termed ‘GITS’ (gastrointestinal therapeutic system) and ‘CC’ (coat core). Procardia XL and Nifedical XL are 2 example brand names for the GITS formulation, while Adalat CC and Nifediac CC are 2 example brand names for the CC formulation.5,6 While both formulations yield similar pharmacokinetics, because they are not considered AB-rated they should not be interchanged.6 As with diltiazem products, best practice is to obtain either a brand name or an NDC to prevent errors.

Bupropion
Bupropion, a dopamine norepinephrine reuptake inhibitor (DNRI), is used most commonly for depression and smoking cessation and is available as immediate release, 12-hour extended release (termed ‘sustained release’ with bupropion), and 24-hour (termed ‘extended release’ with bupropion).  Sometimes I have seen confusion as to which formulation the patient is taking, especially in light of the fact that, as we have seen from the above examples, there is no standardized system for using the terms ‘sustained release’ and ‘extended release’. It is best practice to make sure the prescriber writes on the prescription ’24 hour’ or ’12 hour’ to clarify and not assume that the patient is on the 24-hour just because they are taking it once daily. For example, I have seen that some patients take a 12-hour tablet in the morning so that it wears off before bedtime (the norepinephrine reuptake inhibition can lead to insomnia in many patients).7
In addition, the 12-hour formulation is the only one approved for smoking cessation and is available under the brand names Zyban and Buproban. Be sure if the patient is taking it for this indication that the prescription is written for the 12-hour formulation.7

Divalproex Sodium, Sodium Valproate, and Valproic Acid
Divalproex sodium (Depakote), sodium valproate, and valproic acid are often confused. Valproic acid is the protonated form – in case that term doesn’t bring back memories from biochemistry, that means that the compound is bonded to a proton (H+). Sodium valproate, on the other hand, is the sodium salt of valproic acid. Divalproex is a compound containing sodium valproate and valproic acid that are bonded together with the sodium atom and is formed by partially neutralizing valproic acid with sodium hydroxide. Fortunately for us, all formulations’ dosages are expressed in terms of valproic acid activity, so when converting patients from one formulation to the other we can convert dosages on a 1:1 basis. The different formulations, however, are not AB-rated and thus not interchangeable. Depakote is available in both a delayed release and extended release formulation among others and, just as with bupropion, it is best not to assume that all patients follow the typical dosing (ie once daily for extended release and twice daily for delayed release).6,8,9 

References:
1.       Macrobid [package insert]. Procter and Gamble Pharmaceuticals Inc., Cincinnati, OH; 2009.
2.       Macrodantin [package insert]. Procter and Gamble Pharmaceuticals Inc., Cincinnati, OH; 2009.
3.       American Geriatrics Society. American geriatrics society 2015 updated beer’s criteria for potentially inappropriate medication use in older adults. JAGS. 2015; 63:2227-2246. Accessed online January 4, 2017 at http://onlinelibrary.wiley.com/doi/10.1111/jgs.13702/pdf.
4.       Piepho R. Therapeutic interchange and equivalence: focus on antihypertensive agents. Medscape. 2000; Accessed online January 2, 2017 at http://www.medscape.org/viewarticle/416390
5.       Procardia XL [package insert]. Pfizer Laboratories Div Pfizer Inc., New York, NY; 7/2016.
6.       Generic substitution for common drugs. Pharmacists Letter Jul 2013; Document#290707.
7.       Wellbutrin XL. Daily Med. Accessed online January 4, 2017 at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c7b80939-0b2d-4dbc-b921-2081cfd5ae3e.
8.       Depakene [package insert]. AbbVie Inc., North Chicago, IL; 11/2016.
9.       Depakote [package insert]. Abbott Laboratories, North Chicago, IL; 1/2009.



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