PIRMELLA 1/35
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PIRMELLA 1/35 (PIRMELLA 1/35).
Combination of norethindrone (progestin) and ethinyl estradiol (estrogen) that suppresses gonadotropin secretion via negative feedback on the hypothalamic-pituitary-ovarian axis, inhibiting ovulation. Additionally, causes cervical mucus thickening and endometrial atrophy, reducing sperm penetration and implantation.
| Metabolism | Norethindrone: primarily via CYP3A4 to conjugated metabolites; ethinyl estradiol: primarily via CYP3A4 and sulfation (SULT1E1) with enterohepatic circulation. |
| Excretion | Renal 60–80% as metabolites (glucuronide conjugates), biliary/fecal 10–20%. |
| Half-life | Terminal half-life 24–30 hours for ethinyl estradiol; 13–18 hours for norethindrone. Steady state reached after 7–10 days. |
| Protein binding | Ethinyl estradiol: 97–98% bound to albumin and SHBG; norethindrone: 80–85% bound to SHBG and albumin. |
| Volume of Distribution | Ethinyl estradiol: 4.0–4.5 L/kg; norethindrone: 3.5–4.0 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Oral: ethinyl estradiol ~45% (first-pass metabolism); norethindrone ~65%. |
| Onset of Action | Oral: 7 days for full contraceptive effect; immediate if started on day 1 of menses. |
| Duration of Action | 24 hours; requires daily dosing to maintain contraceptive efficacy. |
| Molecular Weight | Norethindrone: 298.42 Da; Ethinyl estradiol: 296.40 Da |
| Action Class | Combination hormonal contraceptive (estrogen-progestin) |
One tablet orally once daily for 21 days, followed by 7 placebo tablets during the withdrawal bleed.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Contraindicated in severe renal impairment (GFR <30 mL/min) due to potential fluid retention and hypertension. |
| Liver impairment | Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). In Child-Pugh class A, use with caution and consider alternative contraception. |
| Pediatric use | Not indicated for use before menarche; after menarche, dosing is same as adult: one tablet orally once daily for 21 days followed by 7 placebo tablets. |
| Geriatric use | Not indicated for use in postmenopausal women. No specific dose adjustment in elderly if still menstruating, but consider increased risk of thromboembolism and cardiovascular events. |
| 1st trimester | Contraindicated due to risk of birth defects (limb defects, cardiac anomalies) and potential for pregnancy disruption. Use is not recommended during the first trimester. |
| 2nd trimester | Avoid use; risk of fetal harm including masculinization of female fetuses if progestin with androgenic activity. Non-hormonal contraception preferred. |
| 3rd trimester | Avoid use; possible adverse effects on fetal development and potential for withdrawal bleeding in newborn. Use only if clearly needed and no alternative. |
Clinical note
Comprehensive clinical and safety monograph for PIRMELLA 1/35 (PIRMELLA 1/35).
| Placental transfer | Yes, both estrogen and progestin cross the placenta. Evidence from animal studies and human case reports indicates transfer with potential for fetal effects. |
| Breastfeeding | Combined hormonal contraceptives can reduce milk production and quality, especially in early postpartum. Small amounts of estrogen and progestin pass into breast milk; effects on infant are unknown but potential for adverse effects. Avoid use during breastfeeding if possible; progestin-only pills or non-hormonal methods preferred. |
■ FDA Black Box Warning
Cigarette smoking increases risk of serious cardiovascular events (thrombosis, myocardial infarction, stroke). Risk increases with age and smoking intensity, especially in women over 35 years who smoke. COCs should not be used by women over 35 who smoke.
| Common Effects | Nausea, Headache, Breast tenderness, Weight changes, Irregular menstrual bleeding, Mood changes, Acne |
| Serious Effects | Venous thromboembolism (VTE), Arterial thromboembolism (e.g., stroke, myocardial infarction), Hepatic adenoma or hepatocellular carcinoma, Hypertension, Gallbladder disease, Cerebrovascular events, Pulmonary embolism |
Thrombophlebitis or thromboembolic disordersCerebrovascular or coronary artery diseaseKnown or suspected breast cancerUndiagnosed abnormal genital bleedingKnown or suspected pregnancyLiver tumors (benign or malignant) or active liver diseaseHypersensitivity to any componentSmoking over age 35 (especially >15 cigarettes/day)
| Precautions | Increased risk of thromboembolic events (VTE, arterial thrombosis), Risk of myocardial infarction and stroke, especially in smokers over 35, Elevated blood pressure, Hepatic neoplasia (benign and malignant), Gallbladder disease, Carbohydrate and lipid metabolism effects, Ocular disorders (retinal thrombosis), Headache/migraine, Unscheduled bleeding and spotting, Depression |
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| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | First trimester: Norethindrone and ethinyl estradiol carry a known risk of teratogenicity, including cardiovascular defects and limb reduction defects, with an estimated relative risk of 1.3-1.4 for major malformations. Second and third trimesters: Exposure may lead to feminization of male fetuses (norethindrone) and potential adverse effects on fetal neurodevelopment; risk of intrauterine growth restriction and preterm delivery increased with high-dose estrogen. Postnatal effects include vaginal adenosis and clear cell adenocarcinoma in females exposed in utero to diethylstilbestrol, but data for this combination are limited. Overall, contraindicated in pregnancy due to known risks. |
| Fetal Monitoring | If exposure occurs during pregnancy, fetal ultrasound for anatomic survey and echocardiography recommended. Monitor maternal blood pressure, liver function, and glucose levels due to hormonal effects. In breastfeeding infants, monitor for signs of jaundice, weight gain, and growth. |
| Fertility Effects | The combination of norethindrone and ethinyl estradiol suppresses ovulation, thus preventing pregnancy. Return to fertility may be delayed upon discontinuation, typically with return of ovulation within 1-3 months. No permanent impairment of fertility. |
| Food/Dietary | No significant food interactions. Grapefruit juice may slightly increase estrogen levels but not clinically significant. Consistent dietary habits recommended to avoid gastrointestinal upset; taking with food can reduce nausea. No restrictions with alcohol, but excessive intake may impair liver function affecting hormone metabolism. |
| Clinical Pearls | Combination oral contraceptive containing 1mg norethindrone and 35mcg ethinyl estradiol. Prescribe for contraception, dysmenorrhea, or menstrual regulation. Counsel patients to take at the same time daily to maintain hormone levels and reduce risk of breakthrough bleeding. Monitor blood pressure at baseline and annually due to estrogen component. Consider alternative contraception in women with migraine with aura, uncontrolled hypertension, or history of thromboembolism. Smoking cessation strongly advised in patients over 35 due to increased thrombotic risk. |
| Patient Advice | Take one tablet daily at the same time, preferably after a meal to reduce nausea. · If you miss a pill, follow the package instructions or consult your healthcare provider; use backup contraception for 7 days. · Common side effects include nausea, breast tenderness, and spotting, which often improve within a few cycles. · Report symptoms of blood clots: sudden leg pain/swelling, chest pain, shortness of breath, or severe headache. · This medication does not protect against sexually transmitted infections; use condoms for STI prevention. · If you are a smoker and over 35, discuss smoking cessation due to increased risk of serious cardiovascular events. |