Dosage Forms and Dosing Considerations. Jerra Banwarth, RPh, FIACP

Transcription

1 Dosage Forms and Dosing Considerations Jerra Banwarth, RPh, FIACP

2 Disclosure Jerra Banwarth, RPh, FIACP, is employed by PCCA. Conflict of interest was resolved through peer review of slide content. Professional Education Services Group staff have no financial interest or relationships to disclose. Disclosure This continuing education activity is managed and accredited by Professional Education Services Group. Neither PESG nor any accrediting organization supports or endorses any product or service mentioned in this activity. Educational Grant Support This continuing education activity is supported by an educational grant from PCCA All Rights Reserved 1

3 Learning Objectives At the conclusion of this activity, the participant will be able to: Discuss the different dosage forms used in BHRT; their applications, advantages and disadvantages. Discuss considerations in changing BHRT therapy from one route of administration to another. Discuss basic dosing guidelines for oral and topical BHRT and compare oral and topical routes of administration. Topical Transdermal Vaginal Buccal/Sublingual Oral Dosage Form Dosage forms: Suppositories Creams Gels Vaginal Administration All Rights Reserved 2

4 Vaginal Administration Good absorption systemically Documented effectiveness for Progesterone in luteal phase defect Commercial products for Estrogens Used for systemic and local effects Plasma Levels of Progesterone after Vaginal and Oral Administration of Progesterone Progesterone (ng / ml) Vaginal Oral Hours * Nahoul et al. Profiles of plasma estrogens, progesterone, and their metabolites after oral or vaginal administration of estradiol and progesterone. Maturitas 16: , 1993 Vaginal Considerations Mucoadhesion Retention of API to the mucosa Allergies Preservatives Petrolatum free Hypoallergenic Wetting agents ph All Rights Reserved 3

5 Vaginal Considerations (cont d) Volume/Size Melting point Suppositories Fatty Acid Base Melts at body temperature Non irritating Rapid release of API Polyethylene glycol 1450 base Allows for a slower release of API Must wet the suppository prior to insertion Combine suppository bases to obtain better mucoadhesion Vaginal Gels Hydroxypropylcellulose (HPC) 1 3 % Hydroxyethylcellulose (HEC) 1 3 % Premade versatile gels Poloxamer: Thermo reversable gel All Rights Reserved 4

6 Vaginal Creams Appropriate vaginal creams include: Emollient cream base Vanishing cream base Cream base with natural oils Hypoallergenic cream base Poloxamer Bio adhesive Acts as a depot/reservoir for APIs Thermo reversable Promotes Microcirculation Healing properties Can use vaginally and other routes 30% gel for vaginal use Transdermal and Topical Administration of BHRT What is transdermal? Conventional medical use of term Drug delivered through the skin Delivered by patch or any base Compounding pharmacy use of term Drug driven across the skin Implies the use of a base designed with penetration enhancement All Rights Reserved 5

7 Transdermal and Topical Administration of BHRT (cont d) What is topical? Applied to the skin API Considerations Permeability (Scheuplein Units cm/hr) Aldosterone 3.0 x 10 6 Hydrocortisone 3.0 x 10 6 Estriol 4.0 x 10 5 Estradiol 3.0 x 10 4 Increasing Testosterone 4.0 x 10 4 Permeability Pregnenolone 1.5 x 10 3 Progesterone 1.5 x 10 3 Estrone 3.6 x 10 3 * Johnson ME, et al. J Pharm Sci 84: , 1995 Permeation of Steroids through Human Skin Topical Administration Skin cement and adipose tissue may act as natural reservoir for hormones Drained by the lymphatic system All Rights Reserved 6

8 Topical Administration Method of application can vary degree of depot effect Concentration Volume (area covered) Penetration properties of base Solubility of drug Topical Base Considerations Transdermal delivery??? Creams: (remember topical) Hypoallergenic Cream Base A HRT cream base with natural oils (no parabens) Emollient creams, Vanishing cream bases Topical Base Considerations Gels: Pre made Gel base Carbopol, HEC, HPC Usually contain alcohol Solutions: Alcohol 65%/Propylene Glycol 35% All Rights Reserved 7

9 Do you mill? Do you mix? Topical Administration Application considerations Site of application Common: inside of arm, back of upper arm, upper thigh, lower abdomen Avoid transference: back of knee, buttocks, covered site Rotation of application site Specific site based on application Topical Administration Packaging considerations Accurate measurement of dosage (1mL vs 1gm) Ability to adjust dosage Prevent contamination All Rights Reserved 8

10 Consultation Considerations Compliance most important Do not adjust dosage without supervision Accurate measurement Rub in well for at least one minute Caution on possible transfer of hormone to others Have patient promptly contact RPh or MD when symptoms reoccur Sublingual / Buccal Administration Advantages Avoid upper GI tract destruction Avoid first pass effect Fast dissolution Quick onset Buccal Administration Disadvantages May not get true sublingual absorption regularly May have to dose more often Taste may not be acceptable May not be convenient to patient Saliva testing considerations All Rights Reserved 9

11 Sublingual Drops Drops Vehicle choices Fixed oils Aqueous suspensions or emulsions Alcohol / Glycerin mixtures Sublingual Drops (cont d) Drops (cont d) Concentration Flavor vs. convenience Should use small volume, ml max Concentrated taste harder to mask Wettable Progesterone more palatable Rapid Dissolve Tablet More rapid absorption too rapid? Good flavor choices Melting point of actives Concentration of hormone: E2, E1, P4, Testosterone??? All Rights Reserved 10

12 Oral (PO) IR SR Oil filled capsules Capsules that bypass stomach dissolution Quickly dissolving tablets Oral Dosage Form Considerations Micronized vs. non micronized Use source of chemical with consistent quality Size & percentage of micronization is critical Higher risk of toxic metabolites with oral dosing of estrogens Ingredient content Hypoallergenic: fillers Consistency Oil Filled Capsules (IR) Approximately 90 percent of oral progesterone is metabolized by the "first pass effect (caused by shunting through the entero hepatic circulation), leading to difficulties in dosing as well as an abrupt increase in 5 alpha progesterone metabolites 2 Half life is 3 4 hours = frequent dosing Bioavailability of oral progesterone is unknown 1 * 1 ip.com/ * 2 Warren MP, Shantha S. Uses of progesterone in clinical practice. Int J Fertil Womens Med1999;44: All Rights Reserved 11

13 SR: Slow Release Capsules HPMC Provides good level response Less Sedation that IR form Easier to titrate dosage to an individual Most women can dose once or twice a day IJCP article validates use of Hydroxypropyl methylcellulose CR grade in compounded capsules to provide sustained release * Methocel Premium cellulose ethers, Dow Chemical Company, Midland, MI Dosing Considerations Dosing Considerations in ERT Determine the true need Measure Estrogen not FSH Correct Cortisol, Thyroid and Progesterone first Never give unopposed estrogen Start at low dose and use lowest dose necessary Monitor levels and outcomes Slower conversion from synthetics All Rights Reserved 12

14 Synthetic to BHRT Conversion Considerations in conversion from synthetics to bio identical hormones Length of time on synthetics Addition of progesterone Effects on estrogen receptors, SHBG, thyroid Add progesterone first before converting estrogen therapy Synthetic to BHRT Conversion (cont d) Considerations in conversion from synthetics to bio identical hormones Estrogen may not be needed If needed taper off synthetic while initiating BERT Metabolites of synthetic estrogens Indol 3 carbinol or DIM to clear liver metabolism Suggested Taper Protocol Week 1: Start topical progesterone 20 40mg qd while on synthetic dose. Week 2: Dose Synthetic qod and initiate BERT on the other days. Week 3: Synthetic 3 days BERT the other 4 days Week 4: Synthetic 2 days BERT the rest Week 5: May need to repeat week 4 dependent on symptoms Week 6: Progesterone and BERT Every day! All Rights Reserved 13

15 Things to Keep in Mind If patient has a headache it may be due to estrogen dominance, thus drop the synthetic dose more quickly Housekeeping menses It takes a long time for the synthetic hormone to wash out of the system Bi est BHRT nomenclature Bi est = Estriol/Estradiol Tri est = Estriol/Estradiol/Estrone Bi est (cont d) Ratios of Estrogens written Bi est: 80/20 50/50 70/30 40/ All Rights Reserved 14

16 Bi est (cont d) Concentrations of Bi est 1mg/ml 0.25mg/ml 0.5mg/ml Possible Peri menopause Dosing Symptoms will help decide dosage form and dose Birth control considerations??? Progesterone USP MICRONIZED Topical 20 40mg qd May need to cycle if menstruating on a regular basis Oral = sedative metabolite Sleep issues: IR or SR Can be used hs and topical dose in am Possible Peri menopause Dosing (cont d) Bi est Typically not necessary once progesterone is initiated Address cortisol issues first Start low and go SLOW All Rights Reserved 15

17 Possible Topical Menopausal Dosing Progesterone USP Micronized mg daily, usually mg daily QD to BID Hormone holiday? Bi est 50:50, 80:20 or other ratios mg daily Hormone holiday recommended if tolerated Possible Oral Menopausal Dosing Progesterone USP Micronized: SR IR = Symptoms? 50 to 200 mg, dosed once or twice daily (SR) Bi Est 80:20, 50:50 or other ratios 0.1 to 0.5 mg daily, dosed once or twice daily Hormone holiday? Other Hormones Dehydroepiandrosterone (DHEA) 5 10 mg PO daily gradual release mg daily, immediate release May also be given vaginally, sublingually, topically Testosterone Micronized 0.25 mg 4 mg topically daily Not bio available when given orally Sublingual drops Quickly dissolving tablets All Rights Reserved 16

18 References * The Bioidentical Hormone Debate: Are Bioidentical Hormones(estradiol, estriol and progesterone) safer or more efficacious than commonly used synthetic versions in BHRT? Kent Holtorf M.D. Post Graduate Medicine 2009 * Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: The ESTHER study. Marianne Canonico, PhD; Emmanuel Oger, MD, PhD; Geneviève Plu Bureau, MD, PhD; Jacqueline Conard, PhD; Guy Meyer, MD; Hervé Lévesque, MD; Nathalie Trillot, MD; Marie Thérèse Barrellier, MD; Denis Wahl, MD, PhD; Joseph Emmerich, MD, PhD; Pierre Yves Scarabin, MD, MSc; for the Estrogen and Thromboembolism Risk (ESTHER) Study Group. Circulation 2007;115; References * Effects of Oral and Transdermal Estrogen/Progesterone Regimens on Blood Coagulation and Fibrinolysis in Postmenopausal Women: A Randomized Controlled Trial Scarabin, Pierre Yves; Alhenc Gelas, Martine; Plu Bureau, Genevieve; Taisne, Pascale; Agher, Rachid; Aiach, Martine Volume 17(11), November 1997, pp * Menopause Nov;20(11): doi: /GME.0b013e31828d39a2. Percutaneous progesterone delivery via cream or gel application in postmenopausal women: a randomized cross over study of progesterone levels in serum, whole blood, saliva, and capillary blood. Du JY 1, Sanchez P, Kim L, Azen CG, Zava DT, Stanczyk FZ * Clinical Gynelecologic Endocrinology and Infertility: 6 th Edition. Pg. 201, 643, Speroff Obtaining CE/CME Credit If you would like to receive continuing education credit for this activity, please visit: All Rights Reserved 17