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Prescriber’s Guide

Estriol Vaginal Cream

WHAT IS THIS MEDICATION?

Estriol Vaginal Cream is a vaginally administered steroid.

HOW IS THIS MEDICATION SUPPLIED?

Estriol vaginal cream is commonly compounded in a hypoallergenic base in following strengths:

  • 0.005 – 1% Vaginal Cream
HOW DOES THIS MEDICATION WORK IN THE HUMAN BODY?

Estriol contains the natural female hormone estriol. Unlike other estrogens, estriol is short acting since it has only a short retention time in the nuclei of endometrial cells. It substitutes for the loss of estrogen production in menopausal women and alleviates menopausal symptoms.5, 12

In case of postmenopausal women with atrophy of the lower urogenital tract, estriol induces the normalization of the urogenital epithelium and helps to restore the normal microflora and the physiological pH in the vagina. As a result, it increases the resistance of the urogenital epithelial cells to infection and inflammation reducing vaginal complaints such as dyspareunia, dryness, itching, vaginal and urinary infections, micturition complaints and mild urinary incontinence.1-8

WHAT CLINICAL STUDIES HAVE BEEN PERFORMED ON THIS MEDICATION?

Estriol has consistently shown relief from vaginal dryness, atrophy, as well as pain during sexual intercourse, normalizing vaginal flora and improving the maturity index.1-8

Low doses of Estriol have also been clinically shown to be effective in treatment of postmenopausal women suffering from vaginal atrophy undergoing aromatase inhibitor treatment.1

50 postmenopausal women with hormone receptor-positive breast cancer receiving nonsteroidal aromatase inhibitors received a 12-week course of low dose estriol 0.005% In a phase II, randomized, double-blind, placebo-controlled trial for evaluation of vaginal maturation, vaginal pH, and vulvovaginal atrophy. Active treatment significantly improved maturation value and pH, vaginal dryness and global scores of symptoms and signs. Treatment also improved all domains of the Female Sexual Function Index (FSFI), with the exception of pain. At doses of 0.005%, estradiol and estrone levels remained mostly undetectable.1

There is a reasonable amount of long-term data on estriol intravaginal treatment that doses are safe and do not present with endometrial hyperplasia.9, 10

WHAT IS THIS MEDICATION USED FOR?

Estriol has been studied for the following uses as related to atrophy of the lower urogenital tract:

  • For the treatment of vaginal complaints such as dyspareunia, dryness and itching.1-8
  • Pre- and post-operative therapy in postmenopausal women undergoing vaginal surgery.13
  • Postmenopausal women with hormone-receptor positive breast cancer receiving nonsteroidal aromatase inhibitors1
WHAT IS THE DOSAGE FOR THIS MEDICATION?

Administer Estriol vaginal cream intravaginally daily at bedtime for 2-3 weeks, then decrease to 2-3 times weekly.

DRUG INTERACTIONS

Estriol is a substate for Cyp 3A4 and PGP. Efficacy may be decreased with CYP 3A4 inducers (Phenytoin, Smoking, Oxcarbazepine, Phenobarbital, Rifabutin, St. John’s Wort, etc.)

Estriol is a substrate for Cyp 3A4. Levels may increase with grapefruit juice, protease inhibitors, Azole anti-fungals, cimetidine, cyclosporin, cobistat, macrolides, amiodarone, verapamil, diltiazem, etc.)

WHAT SIDE EFFECTS CAN BE CAUSED BY THIS MEDICATION?

From literature and safety surveillance monitoring, the following adverse reactions have been reported.

  • Fluid Retention
  • Nausea
  • Breast discomfort and pain
  • Postmenopausal spotting
  • Cervical Discharge
  • Application site irritation and pruritis
  • Flu like symptoms
WHAT PRECAUTIONS SHOULD BE KEPT IN MIND WHEN PRESCRIBING THIS MEDICATION?

Current or Past History of Breast Cancer.
Use of exogenous estrogen is contraindicated in women with a known or suspected history of breast cancer; although recent trials1 indicate benefits for vaginal atrophy in hormone receptor positive breast cancer undergoing aromatase inhibitor therapy.

IS THIS MEDICATION SAFE DURING BREASTFEEDING AND CAN I USE IT FOR KIDS?
Pregnancy

This medicine is contraindicated during pregnancy. If pregnancy occurs during medication with Estriol, treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent fetal exposure to estrogens indicate no teratogenic or fetotoxic effects.

Lactation

Estriol is not indicated during lactation. Estriol is excreted in breast milk and may decrease milk production.

Pediatric

Safety and effectiveness have not been established in pediatric patients

Renal impairment

The effect of renal impairment on the pharmacokinetics of Estriol has not been studied.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of Estriol has not been studied.

HOW DOES THIS MEDICATION MOVE THROUGH THE HUMAN BODY?
Absorption

Intravaginal administration of estriol ensures optimal availability at the site of action. Estriol is also absorbed into the general circulation, as is shown by a sharp rise in the plasma levels of unconjugated estriol.

Distribution

Peak plasma levels are reached 1-2 hours after application. After vaginal application of 0.5 mg estriol, Cmax is approximately 100 pg/ml, Cmin is approximately 25 pg/ml and Caverage is approximately 70 pg/ml. After 3 weeks of daily administration of 0.5 mg vaginal estriol, Caverage has decreased to 40 pg/ml.

Metabolism

Nearly all (90%) estriol is bound to albumin in the plasma and in contrast with other estrogens, hardly any estriol is bound to sex hormone-binding globulin (SHBG). The metabolism of estriol consists principally of conjugation and deconjugation during the enterohepatic circulation.

Elimination

Estriol, being a metabolic end product, is mainly excreted via the urine in the conjugated form. Only a small part (±2 %) is excreted via the feces, mainly as unconjugated estriol.

WHAT CAN HAPPEN IF TOO MUCH OF THIS MEDICATION IS TAKEN?

The acute toxicity of estriol in animals is very low. Overdosage with Estriol cream after vaginal administration is unlikely. However, in cases where large quantities are ingested, nausea, vomiting and withdrawal bleeding in females may occur. No specific antidote is known. Symptomatic treatment can be given if necessary.

HOW IS THIS MEDICATION STORED?

Store at room temperature.

REFERENCES
  1. Hirschberg, Angelica Lindén MD, PhD1; Sánchez-Rovira, Pedro MD, PhD2; Presa-Lorite, Jesús MD3; Campos-Delgado, Miriam MD4; Gil-Gil, Miguel MD5; Lidbrink, Elisabet MD, PhD6; Suárez-Almarza, Javier Pharm, BSND7; Nieto-Magro, Concepción MD, PhD7 Efficacy and safety of ultra-low dose 0.005% estriol vaginal gel for the treatment of vulvovaginal atrophy in postmenopausal women with early breast cancer treated with nonsteroidal aromatase inhibitors: a phase II, randomized, double-blind, placebo-controlled trial, Menopause: May 2020 - Volume 27 - Issue 5 - p 526-534
  2. Barentsen R. The climacteric in The Netherlands: a review of Dutch studies on epidemiology, attitudes and use of hormone replacement therapy. Eur J Obstet Gynecol Reprod Biol. 1996;64 Suppl:S7-S11.
  3. Ishiko O, Hirai K, Sumi T, Tatsuta I, Ogita S. Hormone replacement therapy plus pelvic floor muscle exercise for postmenopausal stress incontinence. A randomized, controlled trial. J Reprod Med. 2001;46(3):213-220.
  4. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993 Sep9; 329:753-6
  5. Melis GB, Cagnacci A, Bruni V, et al. Salmon calcitonin plus intravaginal estriol: an effective treatment for the menopause. Maturitas. 1996;24(1-2):83-90.
  6. Trevoux R, van der Velden WH, Popovic D. Ovestin vaginal cream and suppositories for the treatment of menopausal vaginal atrophy. Reproduction. 1982 Apr-Jun;6(2):101-6
  7. Yoshimura T, Okamura H. Short term oral estriol treatment restores normal premenopausal vaginal flora to elderly women. Maturitas. 2001 Sep28;39(3):253-7
  8. Bottiglione F, Volpe A, Esposito G, Aloysio DD. Transvaginal estriol administration in postmenopausal women:a double blind comparative study of two different doses. Maturitas. 1995Nov:22(3):227-32.
  9. Head KA. Estriol: safety and efficacy. Altern Med Rev. 1998;3(2):101-113.
  10. Voojijs GP, Geurts TBP. Review of the Endometrial Safety During Intravaginal Treatment with Estriol. European Journal of Obstetrics & Gynecology and Reproductive Biology.1995Sep;62(1):101-6
  11. Granberg S, Eurenius K, Lindgren R, Wilhelmsson L. The effects of oral estriol on the endometrium in postmenopausal women. Maturitas. 2002 Jun25;42(2):149-56
  12. Ushiroyama T, Sakai M, Higashiyama Tet al. Estrogen replacement therapy in postmenopausal women: a study of the efficacy of estriol and changes in plasma gonadotropin levels. Gynecol Ednocrinol 2001;15:74-80
  13. Gaspar A, et al. Efficacy of Erbium: YAG Laser Treatment Compared to Topical Estriol Treatment for Symptoms of Genitourinary Syndrome of Menopause. Laswers in Surger and Medicine 49:160-168 (2017).
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Harbor Compounding Pharmacy

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Costa Mesa, CA 92627