Error-Prone Concentrations of Ibuprofen Suspensions
Parents who are told to give their child or infant over-the-counter ibuprofen oral suspension may not be aware there are two different concentrations available. An infant's formulation (for infants 6-23 months or weighing 5.5-10.5 kg [12-23 lbs]) contains 50 mg/1.25 mL (40 mg/mL). This is twice as concentrated as the children's formulation (for children 2-11 years or weighing 10.9-43.1 kg [24-95 lbs]), which contains 100 mg/5 mL (20 mg/mL). Retail locations routinely stock both concentrations. The labeling and packaging of the two concentrations can sometimes look similar.
Staff at children's hospitals might be familiar with this issue and make it a point to educate parents. However, we have heard of mix-ups that sometimes occur after discharge. One reason is that some hospital computer systems sometimes convert oral liquid doses to a metric volume to help parents measure each dose using a dosing cup or oral syringe. However, the concentration parents might purchase or already have at home is often unknown.
One hospital reported a close call involving a child who was discharged from an ambulatory surgery unit. The mother was concerned because she was familiar with giving her 8.6 kg child less than 2 mL of ibuprofen, as per the manufacturer's label instructions. However, the discharge instructions said to give 4.3 mL, or 86 mg of the 100 mg/5 mL concentration. After confirming that the mother had the 50 mg/1.25 mL and not the 100 mg/5 mL concentration at home, the hospital was able to tell the mother the appropriate volume of ibuprofen to administer to her child.
In another case, a child was prescribed ibuprofen 70 mg. The child's mother was told to give 3.5 mL of the medication, with the expectation that the 100 mg/5 mL suspension would be used. However, the child's mother purchased ibuprofen suspension 50 mg/1.25 mL (200 mg/5 mL) and gave her child 3.5 mL per dose as instructed. So, instead of receiving 70 mg, the child received 140 mg per dose. Fortunately, we are not aware of any serious adverse outcome because of this twofold overdose. An overdose might lead to nausea, vomiting, diarrhea, headache, stomach bleeding, and kidney damage.
This situation is like an issue that has since been resolved with oral liquid acetaminophen (TYLENOL) products, which use to exist in two concentrations: a more concentrated liquid (100 mg/mL) for infants, and a less concentrated liquid (160 mg/5 mL) for children. When the 100 mg/mL concentrated product was accidentally administered to children in volumes appropriate for the 160 mg/5 mL product, there were accidental deaths and serious injuries to children. Manufacturers voluntarily withdrew the more concentrated infant's product and agreed to only provide the 160 mg/5 mL concentration that is available today (some manufacturers label their products as 500 mg/15 mL concentration).
Due to the potential for harm and the ongoing nature of these ibuprofen errors, we have interacted with the U.S. Food and Drug Administration (FDA) and asked them to determine if the more concentrated product is necessary. One of the children's hospital nurses who we spoke with queried colleagues about this, and the overwhelming response was, "Why isn't there just one concentration of liquid ibuprofen similar to acetaminophen?" Ideally, Johnson & Johnson Consumer Health, the sponsor of infant's and children's MOTRIN (ibuprofen), would modify the infant's concentration to match the children's concentration, as was done for acetaminophen, with other ibuprofen manufacturers to follow. Healthcare providers should counsel parents about the availability of the two liquid ibuprofen strengths, and that the 100 mg/5 mL strength includes "children's ibuprofen" in the name, whereas the more concentrated 200 mg/5 mL (50 mg/1.25 mL) strength is referred to as "concentrated infant drops." Ensure parents understand that the dose in mL (volume) must be based on which concentration they are using.
Dosing Error with Entresto
A dispensing error occurred when a pharmacist misinterpreted a prescription for ENTRESTO, a product used to treat heart failure that contains sacubitril and valsartan in different amounts (i.e., 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg). The prescription listed the strength as 100 mg, which the patient was supposed to take twice-daily. However, none of the three available strengths of Entresto includes a 100 mg strength. The pharmacist dispensed what he thought was closest to the strength prescribed, the 97 mg/103 mg product. A few months later, the patient's physician increased the dose to 200 mg twice-daily, and the pharmacist dispensed the 97 mg/103 mg strength with instructions to take two tablets twice-daily. However, that dose soon led to severe side effects, including lethargy and hypotension. At that point, the pharmacist discovered the patient had received twice the intended dose. The prescriber had added the dosage amounts of the two ingredients together in the original prescription, so Entresto 49 mg/51 mg (100 mg total) was the original intended dose (Figure 1). Even though the product label lists the ingredients separately, the package insert suggests that dosing in clinical trials was based on the total amount of both components of Entresto; sacubitril and valsartan 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively. Also, instructions for preparing a suspension from eight 49 mg/51 mg tablets indicate the final concentration in terms of the combined strengths of the ingredients, 800 mg/200 mL.
Such confusion by the pharmacist is easy to understand. A few combination products are labeled with the strength expressed as the total dose after combining the component drug doses together-ZOSYN (piperacillin and tazobactam) is one example (e.g., strength expressed as 4.5 g, which includes piperacillin 4 g and tazobactam 0.5 g). However, most combination tablets in the United States are prescribed according to the strengths of each respective drug, not the total strength of all active ingredients. For example, the anti-Parkinson's drug SINEMET (carbidopa and levodopa) lists the ingredients separately on the label and in the package insert, and the drug is prescribed according to the strengths of each respective drug (i.e., Sinemet 10 mg/100 mg, Sinemet 25 mg/100 mg). Entresto product labeling mentions dosing both in terms of individual ingredient strengths as well as the total mg dose of the two ingredients added together. Ideally, the way strengths are expressed for multi-ingredient products and how these drugs are prescribed should be standardized to prevent confusion.