Question: Why were the four drugs, Oxitriptan, Piracetam, Silver Protein Mild, and Tranilast, not approved for inclusion in the Bulks List for compounding?

Answer:
Note: As a follow up to the past several week's Newsletters, this is the final installment regarding the four drugs listed above. We will look at the reasons as provided by the FDA why "Tranilast" was not included on the Bulks List.

TRANILAST

Tranilast, an antiallergenic agent, was evaluated for the treatment of allergic disorders, arthritis, dry-eye syndrome, keloids, and hypertrophic scars. It is approved in South Korea and Japan for the treatment of asthma, keloids, and hypertrophic scarring, and as an ophthalmic solution for allergic conjunctivitis. It is well characterized physically and chemically. However, there are significant safety concerns associated with its systemic administration. In a well-controlled clinical trial with nearly 12,000 participants (the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial) (Ref. 10), tranilast was associated with significantly elevated liver enzymes (three times the upper limit of normal) in 11 percent of patients within 1 to 3 months of drug initiation, as well as anemia, renal failure, rash, and dysuria. Liver toxicity is of particular concern because many of the conditions for which tranilast was nominated are chronic conditions. While there is some evidence that tranilast may be effective for allergic disorders, evidence of effectiveness for other uses is either not available or inconclusive. For allergy, arthritis, and ophthalmic indications, there are numerous FDA-approved and OTC monograph products. The length of time tranilast has been used in compounding is uncertain, although it has been discussed in scientific journals dating back approximately 40 years.

On balance, the physiochemical characteristics, safety concerns, lack of evidence of effectiveness, and historical use of tranilast weigh against inclusion of this substance on the 503A Bulks List, particularly given the seriousness of the safety concerns related to hepatotoxicity of tranilast and contraindications in pregnant and breastfeeding women, the availability of approved products for most of the proposed uses, and the lack of evidence that tranilast is effective. The FDA proposed to the PCAC that this substance not be included on the 503A Bulks List (Ref. 7). However, at its meeting on June 17, 2015, the PCAC voted to include tranilast on the list for topical use only (Ref. 4).

Subsequent to that meeting, the FDA reviewed the topical use of tranilast further. It obtained the label of the Japanese tranilast product, RIZABEN, but found no information on the transdermal absorption or other pharmacokinetics of tranilast when applied topically to healthy or diseased human skin (Ref. 11). The labeling of the Japanese product identifies a number of safety concerns, including a contraindication in pregnant women, especially during the first trimester of pregnancy, and in those who might be pregnant, due to evidence of teratogenicity in animal studies (id.). The labeling also states that tranilast is detected in breast milk and should be avoided by breastfeeding women. In addition, the RIZABEN label lists a drug interaction with warfarin and identifies a number of serious adverse events, particularly those that are hematologic in nature (leukopenia, thrombocytopenia, anemia, hemolytic anemia), associated with the oral use of tranilast. Safety information regarding other routes of administration is limited.

The FDA also noted evidence that some increases in some liver function tests (bilirubin) are explained by tranilast inhibition of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) especially in patients with a genotype for Gilbert's Disease. Increases in liver transaminases observed with tranilast are not typically seen with inhibition of UGT1A1. It is speculated that tranilast impairs the metabolism of drugs that are metabolized by UGT1A1. If these drugs are associated with transaminase elevations, inhibiting the drug's metabolism may lead to liver transaminitis.

As was found in the Agency's initial review and presented to the PCAC, there is no persuasive information available regarding the safety or effectiveness of topical tranilast. The FDA has identified only two reports in the literature describing the efficacy and safety of tranilast administered topically for the treatment of keloids and hypertrophic scars (Refs. 12 and 13). One of those studies was an open-label trial, and the other was a case series. Between the two studies, only five patients were exposed to topical tranilast.

As stated previously, the FDA has serious concerns about the safety of tranilast when administered orally. The Agency has insufficient information about the systemic absorption of topical tranilast formulations to determine whether topical administration of the drug product would present the same safety concerns. Given the lack of information available about the safety and efficacy of topical tranilast, and safety concerns related to the oral use of this product, the proposed rule would not place tranilast on the 503A Bulks List.

Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition

News

Questions of Effectiveness of Makena to Prevent Preterm Birth
For over a decade, the recommended treatment for most pregnant women who previously had given birth prematurely was a weekly injection of progesterone. Progesterone injection was formerly a compounded preparation; then KV Pharmaceuticals obtained approval for Makena Injection (Progesterone). KV Pharmaceuticals eventually filed bankruptcy and now the product is sold by AMAG Pharmaceuticals. The company recently announced the results of a new study that the drug wasn't effective. Most experts and medical groups say it's too early to make a call on Makena.
https://www.wsj.com/articles/new-doubt-on-treatment-to-prevent-preterm-birth-11552922786

FDA Approves Testosterone Undecanoate for Hypogonadism
The FDA has approved orally administered testosterone undecanoate (Jatenzo) for the treatment of men with hypogonadism. The capsule therapy is designated for men with low testosterone levels due to specific genetic disorders or pituitary gland-damaging tumors. This approval does not extend to age-related hypogonadism because the therapy's benefits do not outweigh its risks in that use.
https://www.mdmag.com/medical-news/fda-approves-testosterone-undecanoate-for-hypogonadism

Report: FDA to Tighten Regulations Amid Recalls
The FDA plans to introduce stricter rules for drug manufacturers in light of a series of recalls of contaminated imports from China and India. "We've seen a lot of instances of adulterated products-contamination, impurities-recently," said outgoing FDA Commissioner Scott Gottlieb, who plans to leave his post in April. “The underlying causes have been traced back to manufacturing, inadequate quality controls, and generally poor management oversight,� he said. The proposed rule changes will primarily affect active pharmaceutical ingredients (APIs). Gottlieb noted that the proposed reforms may take several years to implement.
https://thehill.com/homenews/news/436112-report-fda-to-tighten-pill-manufacturing-regs-amid-recalls

Vertex Destroys Nearly 8,000 Orkambi 28-day Packs, A Cystic Fibrosis Drug, Amid U.K. Pricing Standoff
Vertex won European approval for Orkambi in 2015 but hasn't launched the drug in England, as it hasn't agreed on a price with government officials. While patients are pleading for access to the drug, the company instead destroys thousands of months' worth of supply; it appears to be a pricing standoff. Off-and-on negotiations between Vertex and U.K. health officials over Orkambi pricing have lasted so long that Vertex trashed almost 8,000 packs that expired last year. Vertex disclosed the info after its executives headed to U.K. Parliament this month to face questions over the pricing standoff.
https://www.fiercepharma.com/pharma/vertex-destroys-nearly-8-000-orkambi-packs-amid-u-k-pricing-standoff

Did You Know ...

…that Thomas Jefferson (1743-1826) said the following?

“The moment a person forms a theory, his imagination sees, in every object, only the traits which favor that theory.�

Tip of the Week

In today’s world, one can probably extend the beginning of that statement to “The moment a person hears a theory….� How often do we hear or see some new “theory� or just a “statement� and suddenly start “seeing� around us events/circumstances that we interpret as being related to what we have heard or seen? And, it may or may not be true.

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Looking Back

Soap’s that irritate
Their mugs,
Turn jolly gents
To jitterbugs!
     Burma-Shave