Packaging and Storage Issues with Misoprostol Tablets

Misoprostol occurs as a light-yellow viscous oil with a musty odor that is stated to be soluble in water. The tablets must be stored in tight containers in a dry place at controlled room temperature; they should not be removed from original packaging. However, they are sometimes packaged as multiple tablets within an aluminum strip; each cavity holding multiple tablets. When this cavity is opened, tablets are exposed to atmospheric conditions.

Berard and colleagues* conducted a study to compare the pharmaceutical characteristics (weight, friability), water content, misoprostol content, and decomposition of misoprostol tablets (Cytotec, Pfizer) exposed to air (2�C/60% relative humidity) for periods of 1 to 720 hours (30 days), to those of identical non-exposed tablets.

By 48 hours, exposed tablets had increased in weight (+4.5%), friability, and water content (+80%) as compared to controls. There was a decrease in misoprostol content by 5.1% after 48 hours.

Misoprostol is known to be unstable and is stabilized in the form of a solid dispersion with HPMC to protect the misoprostol and decrease water penetration. The 48-hour increase in weight corresponds to the maximum penetration of water into the tablets; this initiates the degradation of misoprostol. This degradation reaches a 5% loss at 48 hours and a more than 10% loss after 7 days. Studies have shown that the first-order rate constants increased as the water content of misoprostol increased. Misoprostol tablets should be stored in original containers or in small, tight containers if repackaged.

Regarding compounding, studies of misoprostol suppositories in Suppocire base remained stable with a loss of 7% in 180 days refrigerated and about 9% in 120 days at room temperature. In Polybase, the suppositories were stable for up to 12 months refrigerated but only one week at room temperature.

*Berard V, Fiala C, Camerson S et al. Instability of misoprostol tablets stored outside the blister: A potential serious concern for clinical outcome in medical abortion. PLoS One 2014; (9(12): e112401.

Next week we will look at another example of "Clinical Pharmaceutics."

News

The FDA Considering Compounding Restrictions for Outsourcing Facilities
The FDA is considering adding the following drugs to its list of drugs unable to be compounded in bulk by outsourcing facilities:

• Acetaminophen (Tylenol)
• Aprotinin (Trasylol)
• Ondansetron hydrochloride (Zofran)
• Bromocriptine mesylate (Parlodel)

Under the DQSA, the FDA now regulates "outsourcing facilities" which may compound/manufacture products for unidentified patients. This permits them to compound bulk amounts and prevents them from compounding any drug withdrawn or removed from the market by the FDA for reasons of safety or efficacy. Other topics set to be discussed at the next PCAC meeting include the criteria for inclusion on the FDA's "demonstrably difficult to compound" list, and the inclusion of four other drug substances onto a banned list:

• Brilliant Blue G
• N-Acetyl-D-glucosamine
• Oxitriptan
• Tranilast

http://raps.org/Regulatory-Focus/News/2015/05/21/22228/FDA-Considers-Compounding-Restrictions-on-Four-Drugs-Including-Acetaminophen/#

Ceftolozane-Tazobactam Dosing Changing
The FDA has announced that pharmacy personnel have misinterpreted the phrase "1 g/0.5 g per vial" on the vial and carton labeling of ceftolozane-tazobactam for injection seven times, resulting in four patients receiving 50% more of the antibacterial treatment than had been prescribed. Because of those errors and their solution to prevent future ones, the FDA said the labeling for the combination product now states its strength as the sum of the two active ingredients: 1.5 g per vial. The FDA-approved labeling has always stated the dosages in terms of the total amount of ceftolozane and tazobactam. For example, the original labeling (PDF) recommended "1.5 g (1 g/0.5 g) administered every 8 hours by intravenous infusion over 1 hour." The FDA also said the medication-error reports on the four patients who received the excessive doses did not describe any adverse events.
http://www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=4214&utm_source=Real%20Magnet&utm_medium=Email&utm_campaign=75466645

(Editor's Note: Does this set a bad precedent for the many other combination products that are commercially marketed? Which combinations will be labeled individually and which ones as a total dose of constituents? How will one tell the difference? Is this a "knee-jerk" reaction with future unintended consequences resulting in additional confusion and errors?)

Failure to Heed Incompatibility Information
Reports about a drug-device incompatibility have focused attention again on the combination of hazardous-drug formulations and administration devices. In the current case, healthcare workers could have avoided the problem if they had adhered to the instructions for use of a particular closed-system drug-transfer device (CSTD). Drugs and CSTD systems recently involved in incidences include:

• Amsacrine
• Bendamustine hydrochloride
• Busulfan
• Paclitaxel injections

CSTDs include:

• ChemoLock
• Equashield
• PhaSeal
• Tevadaptor

http://www.ashp.org/menu/News/PharmacyNews/NewsArticle.aspx?id=4215&utm_source=Real%20Magnet&utm_medium=Email&utm_campaign=75466647

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