Ulipristal Acetate for PMDD Treatment

Ulipristal Acetate for PMDD Treatment

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Close to 70-90 % of reproductive age women are known to have at least one or more signs of physical discomfort or emotional symptoms during the premenstrual period (luteal phase of the menstrual cycle). 20-40 % of women have these symptoms in mild to moderate severity and meet the criteria for premenstrual syndrome (PMS). A smaller number (~ 8 %) experience more severe symptoms in moderate-severe severity causing functional impairment and are referred to as premenstrual dysphoric disorder (PMDD).

Lifestyle, Dietary & Nutritional modification is the first-line treatment, followed by the use of serotonergic medications. A certain subset of patients do not respond to these first-line treatments and can benefit from other approaches. 

On Dec 10, 2020, Erika Comasco et al recently published this proof-of-concept randomized controlled trial in the American Journal of Psychiatry investigating the role of continuous treatment with Ulipristal Acetate (UPA), as a potential treatment for PMDD. This post will be summarized in the following sections:

  1. AJP Study Findings: design & results. 
  2. UPA Mechanism of Action
  3. Current FDA Indication
  4. Most Common Adverse Reactions
  5. Contraindication/Cautions
  6. Drug Interactions

STUDY DESIGN: 

  • Multicenter, double-blind, randomized, parallel-group clinical trial.
  • N= 95 (women with PMDD).
  • UPA dose: 5 mg/day.
  • Duration: UPA 5 mg/day or placebo during three 28-day treatment cycles.
  • Scale used: Daily Record of Severity of Problems (DRSP).

RESULTS:

(A) DRSP Score Improvement Over 3 Months (mean):

  • UPA (41%) vs Placebo (22%)

(B) DRSP Depressive Symptoms Subscale:

  • UPA (42%) vs Placebo (22%)

(C) DRSP Anger/Irritability Subscale:

  • UPA (47%) vs Placebo (23%)

(D) DRSP physical symptom subscale:

  • Treatment effects not noted.

(E) Remission:

  • 20 in UPA (50 %) and 8 in placebo (21.1%) (statistically significant difference).

 

Ulipristal Acetate (UPA) Mechanism of Action:

  • Selective progesterone receptor modulator with antagonistic and partial agonistic effects (a progesterone agonist/antagonist) at the progesterone receptor.
  • When taken immediately before ovulation –> UPA postpones follicular rupture –> thereby inhibition or delay of ovulation.

 

Current FDA Indication:

  • Emergency contraceptive indicated for the prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure.
  • not intended for routine use as a contraceptive.

 

Most Common Adverse Reactions:

  1. Headache (18%)
  2. Abdominal pain (12%)
  3. Nausea (12%)
  4. Dysmenorrhea (9%)
  5. Fatigue (6%) and
  6. Dizziness (5%)
  7. In post-marketting expereince: Acne was noted.

Note that these adverse reactions were seen at 30 mg/day dose (but the above study used 5 mg/day dose).

 

CONTRAINDICATION/CAUTION:

  • Known or suspected pregnancy (Contraindication)
  • Not for repeated use: only for occasional use. 

 

DRUG INTERACTIONS:

UPA is metabolized by CYP3A4

MEDICATIONS (3A4 INDUCERS) DECREASING UPA CONCENTRATION:

  • Carbamazepine
  • Oxcarbazepine
  • Barbiturates
  • Topiramate
  • Phenytoin
  • Rifampin
  • St. John’s Wort

MEDICATIONS (3A4 INHIBITORS) INCREASING UPA CONCENTRATION:

  • Nefazodone
  • Itraconazole
  • Ketoconazole
  • Grapefruit juice

 

REFERENCES:

  1. Comasco E, Kopp Kallner H, Bixo M, Hirschberg AL, Nyback S, de Grauw H, Epperson CN, Sundström-Poromaa I. Ulipristal Acetate for Treatment of Premenstrual Dysphoric Disorder: A Proof-of-Concept Randomized Controlled Trial. Am J Psychiatry. 2020 Dec 10:appiajp202020030286. doi: 10.1176/appi.ajp.2020.20030286. Epub ahead of print. PMID: 33297719. (pubmed)
  2. ella (ulipristal acetate) package insert (pdf)

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Premenstrual Dysphoric Disorder (PMDD):

This chapter will be summarized in the following nine sections:

  1. Diagnosing PMDD.
  2. PMS vs PMDD.
  3. Evaluating PMDD with Scales.
  4. Treatment Options: Lifestyle modifications and Medications.
  5. What medications are FDA approved for PMDD?
  6. What dose of medication is found effective for physical and mood symptoms in PMDD?
  7. How long it takes for PMDD symptoms to improve with antidepressants?
  8. Are intermittent dosing different than daily dosing (in terms of efficacy)?
  9. What if lifestyle modifications and antidepressants are not effective?

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