In this episode, I’ll discuss Paxlovid and other novel dosage forms that should not be crushed but look like they can be.
One of the worst phrases in a medication’s prescribing information is “do not do ___” without an explanation of why. This is because without a “why” clinicians will wonder if the warning is important or an unnecessary one that can be ignored.
Paxlovid’s FDA fact sheet says “The tablets should be swallowed whole and not chewed, broken, or crushed.” but does not provide a reason why. The likely reason is that Paxlovid uses nanoparticle or amorphous solid dispersion technology.
Two relatively new dosage form technologies are nanocrystals and amorphous solid dispersions. These technologies are meant to address the problems of oral absorption of certain medications that have poor aqueous solubility and slow dissolution rates.
Nanocrystals are extremely small-sized medication particles. This technology takes advantage of the fact that medication dissolution rates are directly proportional to the total surface area of the solid drug particles. With nano-sized drug particles, dissolution rates are greatly improved. Aprepitant, sirolimus, and certain forms of fenofibrate are examples of nanocrystal dosage forms.
Amorphous solid dispersions are crystalline medications that have been reduced from their crystalline lattice structure to an amorphous structure that dissolves more easily. Because the medication can easily revert back to its crystalline state, an inactive material is dispersed throughout the amorphous form to prevent re-crystalization. The amorphous solid dispersion technique is more common than nanocrystals. Tacrolimus, ritonavir, and itraconazole are examples of amorphous solid dispersions.
Both nanocrystal and amorphous solid dispersion formulations have a tendency to revert back to crystalline form and lose the benefit of improved medication dissolution. This process is hastened when the medications are crushed into a powder, exposed to water, or suspended in liquids for oral administration.
A non-inclusive list of nanocrystal and amorphous solid dispersions medications and manufacturers from a review article published in AJHP is below:
Emend (aprepitant) Merck
Rapamune (sirolimus) Pfizer
TriCor (fenofibrate) AbbVie
Triglide (fenofibrate) Sciele Pharma
Afinitor (everolimus) Novartis
Tablet for oral suspension
Astagraf XL (tacrolimus) Astella Pharma
Belsomra (suvorexant) Merck
Epclusa (sofosbuvir/velpatasvir) Gilead Sciences
Harvoni (ledipasvir/sofosbuvir) Gilead Sciences
Intelence (etravirine) Janssen
Isoptin SR (verapamil) Ranbaxy Laboratories
Kaletra (lopinavir/ritonavir) AbbVie
Kalydeco (ivacaftor) Vertex
Lynparza (olaparib) AstraZeneca
Mavyret (glecaprevir/pibrentasvir) AbbVie
Norvir tablet (ritonavir) AbbVie
Noxafil DR tablet (posaconazole) Merck
Onmel (itraconazole) Merz Pharma
Orkambi (lumacaftor/ivacaftor) Vertex
Prograf (tacrolimus) Astrellas Pharma
Sporanox (itraconazole) Janssen
Stivarga (regorafenib) Bayer
Symdeko (tezacaftor/ivacaftor) Vertex
Tibsovo (ivosedinib) Agios Pharmaceuticals
Trikafata (elexacaftor/tezacaftor/ ivacaftor) Vertex
Venclexta (venetoclax) AbbVie
Viekira XR (dasabuvir/ombitasvir/ paritaprevir/ritonavir) AbbVie
Zelboraf (vemurafenib) Roche
Zepatier (elbasvir/grazoprevir) Merck
Zortress (everolimus) Novartis
A major issue highlighted by the authors of the AJHP review article, is that some of these medications may appear as if they are a tablet that is meant to be crushed, and about two-thirds of these medications do not appear on ISMP’s do not crush list.
The absence of these medications from the ISMP list presents a particular challenge to practitioners, as this list often represents the “source of truth” in clinical practice. In a scenario where a medication’s prescribing information only contains a vague statement to not crush the tablet, and the ISMP list does not contain the medications, it is easy to envision a clinician deciding to crush one of these medications.
Until ISMP revises their list, institutions would be wise to add nanocrystal and amorphous solid dispersion medications forms to their internal do not crush lists.
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