What special considerations, contraindications, and drug interactions should be evaluated before prescribing norethindrone?

Special Considerations with Norethindrone

Before prescribing norethindrone, you must evaluate for absolute contraindications including active thromboembolic disease, uncontrolled hypertension (systolic ≥160 mmHg or diastolic ≥100 mmHg), breast or endometrial cancer, hepatic disease with abnormal function, undiagnosed genital bleeding, and pregnancy. 1, 2

Absolute Contraindications

When norethindrone is combined with ethinyl estradiol, the contraindication list expands significantly and includes: 1

• Cardiovascular: Cerebrovascular or coronary artery disease, deep vein thrombosis, thromboembolic disorders, valvular heart disease with complications 1
• Hypertension: Blood pressure ≥160/100 mmHg or severe hypertension of any degree 1
• Hepatic: Cholestatic jaundice of pregnancy, jaundice with previous pill use, hepatic adenomas or carcinomas, hepatocellular disease with abnormal liver function 1
• Malignancy: Breast or endometrial carcinoma 1, 2
• Neurologic: Headaches with focal neurologic symptoms 1, 3
• Metabolic: Diabetes with vascular involvement 1
• Surgical: Planned surgery with prolonged immobilization 1
• Other: Undiagnosed genital bleeding, known hypersensitivity 1, 2

Critical Drug Interactions

Rifamycin Antibiotics (Most Important)

When prescribing rifampin, rifabutin, or rifapentine, you must add barrier contraception immediately, as these drugs substantially decrease norethindrone levels and compromise contraceptive effectiveness. 1, 2 The CDC assigns a category 3 rating (risks usually outweigh benefits) for combined hormonal contraceptives with rifampin or rifabutin therapy. 1

Antiretroviral Medications

Ritonavir-boosted protease inhibitors cause substantial decreases in contraceptive steroid levels with potential to compromise effectiveness: 1

• Darunavir/ritonavir: Decreases ethinyl estradiol by >30% 1
• Fosamprenavir/ritonavir: Decreases both ethinyl estradiol and norethindrone by >30%, with elevated liver transaminases 1
• Lopinavir/ritonavir: Decreases ethinyl estradiol by >30% 1
• Nelfinavir: Decreases ethinyl estradiol by >30% 1
• Tipranavir/ritonavir: Decreases ethinyl estradiol by >30% with increased skin and musculoskeletal adverse events 1

Other Significant Interactions

The American Academy of Dermatology identifies numerous medications requiring dose separation or monitoring: 1

• Anticonvulsants: Barbiturates, carbamazepine, phenytoin, primidone, topiramate reduce contraceptive effectiveness 1
• Antibiotics: Cephalosporins, chloramphenicol, macrolides, penicillins, tetracyclines, sulfonamides may reduce effectiveness 1
• Other: Griseofulvin, modafinil, nevirapine, St. John's wort, bosentan, aprepitant 1

Medications Requiring Monitoring

When combined with bile acid sequestrants, norethindrone-containing oral contraceptives should be given 4 hours before the sequestrant to prevent decreased absorption. 1 For patients on warfarin, monitor INR frequently during norethindrone initiation and periodically thereafter. 1

Baseline and Ongoing Monitoring Requirements

Before Initiation

• Pregnancy test: Mandatory negative result before starting therapy 1, 3
• Blood pressure: Baseline measurement required 1, 3
• Cardiovascular risk assessment: Screen for personal or family history of thromboembolic disease 3

During Treatment

• Blood pressure: Check at every visit, as hypertension is common and increases stroke risk 3
• Bleeding patterns: Assess at each visit for breakthrough bleeding, amenorrhea, or irregular menstruation 3
• Headache screening: Monitor for new-onset or worsening migraines, particularly with aura, which require immediate discontinuation 3
• Hepatic surveillance: Watch for jaundice, right upper quadrant pain, or signs of liver dysfunction 3
• Medication review: Verify all medications at each visit for potential interactions 3

Special Population Considerations

Age-Related Risks

Women ≥35 years have substantially increased stroke risk, particularly with smoking or other cardiovascular risk factors. 3 Stroke risk increases after 1 year of use and continues rising with each additional 5 years of therapy, with an odds ratio of 1.19 per 10 μg estrogen. 3

Pregnancy and Lactation

• Pregnancy category X when combined with ethinyl estradiol 1
• Breastfeeding: The WHO recommends avoiding breastfeeding if possible, as infant risk cannot be ruled out 2
• Pediatric use: Safety and efficacy not established before menarche 1, 2

Switching from Combined Hormonal Contraceptives

When switching to norethindrone 0.35 mg (progestin-only pill), the CDC recommends starting immediately after the last active combined pill without waiting for withdrawal bleeding. 4 Use backup contraception (condoms) for 2 days after starting, as the progestin-only pill may not provide immediate effectiveness. 4 Critical timing consideration: Delays of more than 3 hours in taking norethindrone 0.35 mg reduce contraceptive effectiveness. 4

Common Adverse Effects

Most Frequent

• Weight gain: Reported in 16.1% of patients, with mean BMI increase of 1.2 kg/m² at 12 months 5
• Gastrointestinal: Nausea, vomiting, abdominal cramps 1
• Breakthrough bleeding: More common in new OCP users and women aged 18-35 years, typically decreases after cycle 2 6
• Breast tenderness: Common endocrine effect 1

Serious Adverse Effects

• Thromboembolic events: Edema, varicose vein aggravation 1
• Hepatic: Cholestatic jaundice 1
• Dermatologic: Chloasma, melasma, erythema nodosum 1
• Psychiatric: Depression, mood changes 1

Clinical Pearls

For patients with thromboembolic risk factors, norethindrone 0.35 mg alone (without estrogen) is safer than combined hormonal contraceptives. 4 However, the American Diabetes Association notes increased diabetes risk in certain populations, particularly Latino breastfeeding women, requiring careful monitoring. 4

When used for endometriosis suppression postoperatively, norethindrone acetate 5-15 mg daily effectively reduces median pain scores from 5 to 0 and bleeding scores from 2 to 0, with 55.2% of patients reporting no side effects. 5