3. Does the drug product or category of drug products involve a complex dosage form that presents a demonstrable difficulty for compounding that is reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug product?

RESPONSE

As previously mentioned, the dosage forms that are compounded for bHRT are not complex but are straightforward and have been successfully compounded on physicians' prescriptions and orders for over 70 years to meet the needs of millions of patients. In fact, if one looks at the commercially manufactured dosage forms that are similar to what is compounded, their formulations are also straightforward and involve tablets, capsules, creams, ointments, gels, injections, pellets, suppositories/inserts, topical and oral solutions, suspensions and emulsions, as well as sprays and drops. Most of these dosage forms have been compounded routinely by pharmacists for centuries.

4. Does the drug product or category of drug products involve complexities in achieving and/or assessing bioavailability that present a demonstrable difficulty for compounding that is reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug product?

RESPONSE

Bioavailability issues utilizing bHRT have not really been significant over the long history of bHRT use, whether in manufacturing or compounding. bHRT active pharmaceutical ingredients (APIs) are apparently in the BCS classification 2 (Low Solubility and High Permeability). Approaches to formulating for compounded or manufactured products include numerous methods that have been used in manufacturing and compounding for years. One of the most common approaches for manufacturing and compounding of BCS Class 2 compounds is the use of micronized APIs. (See the Volume 14(32) August 11, 2017 issue of this newsletter for more details and additional approaches.)

A commercial estradiol tablet (Estrace [FDA approved]) uses typical ingredients including micronized estradiol along with colloidal silicon dioxide, cornstarch, dibasic calcium phosphate, lactose monohydrate, magnesium stearate, and sodium starch glycolate, in addition to coloring agents. One can see that the ingredients are common and that the use of micronized estradiol is appropriate for a BCS Class 2 API; the same is used in compounding. Other bHRT formulations for various dosage forms mentioned last week also utilize common pharmaceutical methods and techniques for both compounded and manufactured products.

Progesterone capsules (Prometrium [FDA approved]) contain micronized progesterone along with peanut oil, gelatin, glycerin, lecithin, and coloring agents. As is evident, the API is in micronized form, the same as that used in compounding. The other ingredients are common and are used in oil-filled capsules.

Testosterone 75-mg pellets (Testopel [FDA approved]) for subcutaneous implantation contain testosterone 75 mg, stearic acid 0.97 mg, and polyvinylpyrrolidone 2 mg as a compressed pellet.

BCS Class 2 products also include the following, many of which are commonly compounded and have been for decades.

One distinct advantage to compounded bHRT preparations is that the physician and pharmacist are both intimately involved in monitoring the patient. Clinical response is the key to dosing and the triad of patient-physician-pharmacist has supported successful bHRT compounding for over 70 years.

SUMMARY FOR QUESTIONS 3 AND 4

Compounding bHRT preparations does NOT involve complex dosage forms nor does it involve complexities in achieving and/or assessing bioavailability that present a demonstrable difficulty for compounding that is reasonably likely to lead to an adverse effect on the safety or effectiveness of the drug product.