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Home , Baclofen, Gabapentin, Lidocaine, Suppository, Vulvar vestibulitis, Vulvitis

Multidisciplinary Evaluation and Treatment of Vulvar Disorders

The Role of Compounding Pharmacy Tara Thompson PharmD., RPh. Innovation Compounding Pharmacy Disclosures

• Innovation Compounding Pharmacy – Kennesaw, GA Objectives

• To understand the purpose of a compounding pharmacy • To familiarize the benefits & drawbacks of compounding • To delineate compounding options for the vulvar region • To determine appropriate formulations for commonly prescribed vulvar preparations What is Compounding?

• Compounding pharmacists work directly with prescribers including , NP/PAs, physical/sex therapists, and other clinicians to create customized for patients whose healthcare needs cannot be met by manufactured . • 5000 year old profession, the oldest form of pharmacy • Regulated by State Boards of Pharmacy and Accreditation Boards • “Thinking outside of the box” • Manipulating the ! • Customized, individualized tailored to the patient’s specific need

How Do I Choose a Compounding Pharmacy?

• Licensed in your State • Pharmacist Knowledge and Access • Adherence to USP Guidelines, Testing • USP <795> - Non-Sterile Compounding • USP <797> - Sterile Compounding • Diversity of Portfolio to your Practice Needs • Pelvic Health/FSD/IC • Pricing and Patient Care/Access • Reputation • Compounding Ability and Dosage Form Assortment • Most Important – Accreditation and Inspection!! PCAB – Pharmacy Compounding Accreditation Board

• A service of the Accreditation Commission for Healthcare (ACHC) • Offers the most comprehensive compliance in the industry, with standards based on U.S. Pharmacopeial Convention (USP) guidelines • Accredits pharmacies that compound medications whether in the retail, hospital, mail order, or closed door setting • A pharmacy’s commitment to continuous compliance significantly reduces the risk associated with compounding medications and demonstrates a commitment to meeting the highest industry standards for quality and safety • http://www.achc.org/accreditation-locations.html Benefits of Compounding

• Alternate Options to Commercially Available • Vaginal , vulvar/vestibular , etc. • Bladder instillations for (IC) • ↑ Patient Compliance • Patient Sensitivities • • Preservatives, gluten, dyes, lactose, glucose, and sugar • Base sensitivity • GI Upset Avoidance/Bypass (with Preps) • Flavoring • Affordable – combo products, etc. More Benefits of Compounding

• Ability to Adjust Risk Management Profile and Dosing • Dosage Form– Let the med go where you want it to go! • Vaginal/Rectal: , ointment, , suppository, mini-insert, tampon, , oil • Topical: cream, , ointment, oil, • Oral: capsule, solution, , lozenge, troche, gel • Sublingual: troche, rapid-dissolving (RDT), drop • Intramuscular/Subcutaneous/Intravenous , infusion, implant • Combination Therapy • Gaba/Keto/Cyclo/Lido vulvovestibular foam • Diazepam// vaginal suppository • To name a few! Drawbacks of Compounding

• Typically not covered on patient insurance plans • Cannot duplicate commercially-available products (products with a patent) • Not FDA-approved • Healthcare community’s general lack of understanding regarding the role of compounding • Double-blind -controlled studies (lack of) Compounding for the Vulvar Region • Local Therapy • Low/No systemic absorption • Topical agents recommended by expert consensus statement1 • pH balanced, preservative/-free preps • Therapies that are supported by literature/clinical data • Increasing patient comfort and compliance • Therapy directed at diagnosis

The Interstitial Cystitis Survival Guide by Robert Moldwin, MD, New Harbinger Publications, Inc. © 2000 Dosage Forms

Vaginal Vulvovestibular Vulvovestibular Rectal/Vaginal Rectal/Vaginal Cream Foam Cream Suppository Mini Insert Capsule Urethral Suppository and Vestibulodynia – 2015 Consensus Terminology2 • A. Vulvar caused by a specific disorder a • a. Infectious (eg, recurrent , herpes) • b. Inflammatory (eg, lichen sclerosus, lichen planus, immunobullous disorders) • c. Neoplastic (eg, Paget disease, squamous cell carcinoma) • d. Neurologic (eg, postherpetic , nerve compression or nerve injury, neuroma) • e. Trauma (eg, female genital cutting, obstetric) • f. Iatrogenic (eg, postoperative, chemotherapy, radiation) • g. Hormonal deficiencies (eg, genitourinary syndrome of [vulvovaginal atrophy], lactational ) • B. Vulvodynia: vulvar pain of at least 3 months’ duration, without a clear identifiable cause, which may have potential associated factors; The following are the descriptors: • a. Localized (eg, vestibulodynia, clitorodynia) or generalized or mixed (localized and generalized) • b. Provoked (eg, insertional, contact) or spontaneous or mixed (provoked and spontaneous) • c. Onset (primary or secondary) • d. Temporal pattern (intermittent, persistent, constant, immediate, delayed) a Women may have both a specific disorder (eg, lichen sclerosis) and vulvodynia.

. Neurologic Conditions

• Rationale: women with vestibulodynia have a congenital disorder with a significant increase in the number of intraepithelial nerve endings within the vulvar vestibule3 • Higher numbers of nerve fibers reported in the vestibule of women with vestibulodynia compared with controls4 • Neuroproliferative Topical Agents • Gabapentin 2-6% 5-6 • Well-tolerated topically, very effective in generalized vulvodynia, unprovoked • Centrally acting, target areas of nerves/ that control the concept of pain, complex synergy between increased GABA synthesis • 80% of women in study demonstrated at least 50% improvement in pain scores. Sexual function improves in 17/20 with evaluable results. • 0.5-5% 7-8 • Centrally acting, inhibit NMDA receptors, and NO synthase which decreases pain perception. Blocks Ca channels, depresses Na channels, and alters cholinergic neurotransmission • Proctodynia? Neurologic, cont.

• 2% 7-8 • Reduces peripheral nerve desensitization, affects A receptors and sodium channels • Oral amitriptyline: 60% effective but high profile (drowsiness, dry mouth, stigmata) 9 • First-line recommendation 10-11 • Baclofen 2-3% 12 • GABA • 2-4%13-14 • Centrally acting and anti-spasmodic, inhibits sodium channels, thus reducing muscular hyperactivity • Lidocaine 2.5-7.5%15-17, EMLA (Lidocaine2.5%- 2.5%) • Local – blockade of sodium channels on peripheral nociceptors and block transmission of discharges from peripheral sensory nerves • Not recommended as long term treatment option • Overnight cottonball application Neurologic Combos - Examples

• Lidocaine 2-5%/ Gabapentin 2-6%/ Ketamine 5%) • Amitriptyline 2%/ Baclofen 2%/ Gabapentin 2% (ABG) • Gabapentin 5%/ Ketamine 5%/ Cyclobenzaprine 3%/ Lidocaine 5% • Amitriptyline 2%/ Baclofen 2% cream (ABC)

• Cream, Ointment, Suppository, Foam • Synergistic action • Targets several mechanisms of actions Hormonal Conditions

• Place in vulvar atrophy/atrophic vestibulitis 10,19-23 • 0.01-0.03%/Testosterone 0.1% cream BID • Estradiol 0.01%/vitamin E 200IU/gram cream • ± Lidocaine • DHEA 2.5-10mg • E/T levels altered and decreased receptor saturation in women on OCP, hysterectomy/oophorectomy, chemotherapy, tx, menopause. • hormones act in their original forms to target the specific receptors present in the vestibule or in order to restore the natural presence of hormones in the female. • Increased SHBG and decreased free testosterone and estradiol are frequently found in women with PVD who are on hormonal contraceptives. 18,20 Inflammatory, Allergic Vulvitis, and Lichens Conditions

• Rationale: procytokines have been identified in vulvodynia patient, suggesting inflammation may be playing a role despite the lack of inflammation histologically. 27 • Women with lichen sclerosus have a 4 - 6% risk of developing vulvar carcinoma. LS has been found in greater than 60% of cases of squamous carcinoma of the vulva. • Anti-Inflammatories • Clobetasol propionate 0.05% cream 28-29 • Topical Ultrapotent • Act by the induction of phospholipase A2 inhibitory proteins, called lipocortins, which control biosynthesis of potent inflammatory mediators such as prostaglandins and leukotrienes by inhibiting release of their common precursor . • First line for vulvar lichen sclerosis • Superior to pimecrolimus 30, tacrolimus 31, and testosterone 32 • Superior to in vulval vestibulitis 33 Inflammatory, cont.

• Triamcinolone acetonide 0.1% cream 34 • Intermediate-acting synthetic • Contact • Cromolyn 4% cream 35-36 • Rationale: Increased mast-cell in patient with chronic idiopathic vulvar vestibulitis • inhibits the release of histamine and inflammation mediations from mast cells in vulvar tissue, “mast cell stabilizer” Infectious Conditions

• Chronic Candidal Vulvovaginitis/ • 600mg vaginal capsules/suppositories 41 • When used as a vaginal capsule, boric acid has been effective in the treatment of vulvovaginal candidiasis (VVC), recurrent vulvovaginal candidiasis, and bacterial vaginosis (BV). • Decreases pH in the , difficult for yeast to grow because of cell wall destruction (hole- puncher). Bacteriostatic and fungistatic. • Safe, alternative, economic option for women with recurrent and chronic symptoms of when conventional treatment fails because of the involvement of non-albicans Candida spp. or azole-resistant strains. Infectious Conditions, cont.

• Recurrent/Resistant Bacterial Vaginosis • Lactobacillus Acidophilus 300 MU /gram Vaginal Cream 42 (probiotic vaginal cream) • Rationale: absent or low concentrations of lactobacilli associated with BV, often leading to pain as symptom • Vaginal lactobacilli were isolated from 73.7% of 825 women without BV, and from 29.8% of 131 women with BV (p <0.001) • Normal vaginal, digestive, urinary, microbiota dominated by lactobacilli. Most known for its probiotic effect, but has been shown useful in the treatment of vaginal caused by

bacteria (BV and recurrent BV) and yeast. H2O2 -producing L.acidophilus • Production of lactic acid by lactobacilli, which is mainly responsible for the low vaginal pH,

contributes, probably even more than production of H2O2, to the inhibition of growth of G. vaginalis. Secondary to Hypertonic Pelvic Floor

• Diazepam 5-20 mg vaginal suppositories24-26 • +- Baclofen, Lidocaine, Ketamine, Amitriptyline • Levator Ani Syndrome, • . Enhances the action of GABA by tightly binding to A-type GABA receptors, thus opening the membrane channels and allowing the entry of chloride ions. • Pelvic floor muscle dysfunction is almost universally present in women with vulvodynia. High resting tension, muscle irritability, tenderness to palpation, and overall are extremely common. The role of these abnormalities in the occurrence of pain is confirmed by improvement with normalization of pelvic floor function through physical therapy or biofeedback. • Rectal Data: peak [conc]:1.5 hours; : (rectal, gel), 90% relative to diazepam injectable. Elimination: (rectal, gel), about 46 hours Targeting Vanilloid Receptors

• 0.025-0.5% cream or ointment 37, 40 • Rationale: increased vanilloid receptor (VR1) innervation found in women with vulvodynia. 38 Agonist effects on vanilloid receptors located in the peripheral terminals of nociceptors. After hyperesthesia to the initial exposure, capsaicin produces a long-lasting desensitization to burning and pain. 39 • Preceded by Lidocaine/Prilocaine • Derived from hot peppers - severe burning on application. • After initial use, long –lasting desensitization • Two uncontrolled studies • Not recommended as first-line treatment but as a last-effort or alternative to surgery. Thank you!

[email protected] References 1. Haefner HK, Collins ME, Davis GD, Edwards L, Foster DC, Hartmann Eh, et al. The vulvodynia guideline. J Lower Gen Tract Dis 2005; 9: 40–51.

2. Bornstein J, Goldstein AT, Stockdale CK. 2015 ISSVD, ISSWSH, and IPPS Consensus terminology and classification of persistent vulvar pain and vulvodynia. J Lower Gen Tract Dis 2016;20(2):128; with permission

3. Bohm-Starke N, Hilliges M, Falconer C, Rylander E. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest 1998; 46: 256–60.

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