Which combined oral contraceptives (COCs) can be used for the management of acne in female patients?

Combined Oral Contraceptives for Acne Management

Four COCs are FDA-approved for treating acne in women who also desire contraception: ethinyl estradiol/norgestimate, ethinyl estradiol/norethindrone acetate/ferrous fumarate, ethinyl estradiol/drospirenone, and ethinyl estradiol/drospirenone/levomefolate. 1

FDA-Approved COCs for Acne

The following formulations have specific FDA approval for acne treatment:

• Ethinyl estradiol/norgestimate 1
• Ethinyl estradiol/norethindrone acetate/ferrous fumarate (approved for age ≥15 years) 1
• Ethinyl estradiol/drospirenone (approved for age ≥14 years) 1, 2
• Ethinyl estradiol/drospirenone/levomefolate (approved for age ≥14 years) 1

Clinical Selection Algorithm

Start with drospirenone-containing COCs as first-line for women with moderate acne who also desire contraception. 3 This recommendation is based on evidence showing drospirenone may demonstrate slightly superior efficacy compared to other progestins in head-to-head trials. 3

Alternative Options

If drospirenone is contraindicated or not tolerated:

• Norgestimate-containing COCs are effective alternatives 3
• Norethindrone acetate-containing COCs can also be used 3

Mechanism of Action

All FDA-approved COCs work through antiandrogenic properties:

• Decrease ovarian androgen production 1
• Increase sex hormone-binding globulin, reducing free testosterone 1
• Reduce 5-alpha-reductase activity 1
• Block androgen receptor activation 1

Evidence of Efficacy

All COCs evaluated in placebo-controlled trials effectively reduce both inflammatory and non-inflammatory acne lesions. 1 A 2012 Cochrane meta-analysis of 31 trials with 12,579 women demonstrated that nine different COC formulations (containing levonorgestrel, norethindrone acetate, norgestimate, drospirenone, dienogest, or chlormadinone acetate) all worked well to reduce acne compared to placebo. 1, 4

No consistent differences in acne reduction were found based on COC formulation or dosage when comparing different COCs head-to-head. 1 However, COCs containing chlormadinone acetate or cyproterone acetate showed better outcomes than levonorgestrel in limited data. 1

Critical Prescribing Requirements

COCs should ONLY be prescribed for acne in women who also desire contraception. 1, 2 This is an FDA requirement for all acne indications.

Age Requirements

• Drospirenone formulations: ≥14 years and post-menarche 1, 2
• Norethindrone acetate formulations: ≥15 years 1

Avoid COCs in Early Adolescence

Do not use COCs within 2 years of menarche or in patients <14 years unless clinically warranted due to concerns about low-dose estrogen effects on peak bone mass development. 1

Expected Timeline for Response

Counsel patients that visible acne improvement requires 3 months (end of cycle 3) before statistically significant results appear. 1, 3 This delayed response occurs because:

• COCs decrease free testosterone by 40-50%, but hormonal effects take time to translate into visible improvement 3
• Estrogen gradually reduces sebum production over months 3

Combine COCs with topical retinoids or benzoyl peroxide during the initial 3-month period to provide more immediate benefit while waiting for hormonal effects. 1, 3

Safety Considerations and Contraindications

Venous Thromboembolism Risk

All COC use increases VTE risk compared to non-users. 1 Risk stratification:

• Non-users: 1-5 per 10,000 woman-years 1
• Standard COC users: 3-9 per 10,000 woman-years 1
• Drospirenone-containing COC users: ~10 per 10,000 woman-years 1

Drospirenone-containing COCs carry 50-80% higher VTE risk than levonorgestrel-containing COCs. 1 However, this absolute risk remains lower than pregnancy (5-20 per 10,000 woman-years) and postpartum period (40-65 per 10,000 woman-years). 1

Absolute Contraindications

Do not prescribe COCs in women with: 1

• Age >35 years who smoke 2
• Current or history of breast cancer 1
• History of deep vein thrombosis or pulmonary embolism 1
• Ischemic heart disease 1
• Severe decompensated cirrhosis or liver tumor 1
• Migraine with aura at any age 1
• Migraine without aura if age ≥35 years 1

Cardiovascular Risk Factors

MI and stroke risks increase in COC users who smoke, have hypertension, diabetes, or are ≥35 years. 1 However, the WHO reports no increased MI risk in healthy, normotensive, nondiabetic nonsmokers at any age. 1

Common Pitfalls to Avoid

Antibiotic Interaction Misconception

Tetracycline antibiotics do NOT reduce COC effectiveness. 1 Only rifampin and griseofulvin interact with COCs to lessen contraceptive efficacy. 1 Do not withhold appropriate COC therapy due to misconceptions about antibiotic interactions. 3

Combination with Spironolactone

Drospirenone-containing COCs can be safely combined with spironolactone 100 mg daily without significant hyperkalemia risk in healthy women. 1, 5 In a study of 27 women, no significant potassium elevations occurred with this combination. 1, 5

Progestin-Only Contraceptives

Avoid progestin-only contraceptives as they may worsen acne. 3 Only combined estrogen-progestin formulations have the net antiandrogenic effect needed for acne treatment. 1

Monitoring Requirements

Obtain blood pressure measurement before initiating COCs. 3 Routine potassium monitoring is not required in young, healthy women without risk factors for hyperkalemia (renal insufficiency, heart failure, or concomitant ACE inhibitors). 3

Follow-up schedule:

• 3 months: Assess initial response and side effects 3
• 6 months: Assess maximal benefit 3

Additional Benefits

Beyond acne improvement, COCs provide:

• Menstrual cycle regulation 1
• Reduction in menorrhagia and associated anemia 1
• Decreased risk of benign ovarian tumors 1
• Reduced risk of colorectal, ovarian, and endometrial cancers 1