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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PIRMELLA 1/35 (PIRMELLA 1/35).
| Breastfeeding | Norethindrone and ethinyl estradiol are excreted into breast milk in small amounts; the M/P ratio for ethinyl estradiol is approximately 0.4-0.6. May reduce milk production and volume, particularly in early lactation. Breastfeeding is not recommended, especially during the first 6 months postpartum. Consider progestin-only contraceptives as alternatives. |
| 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. |
■ 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.
| Serious Effects |
["Known or suspected pregnancy","Current or past breast cancer or other estrogen/progestin-sensitive cancer","Hepatic tumors (benign or malignant) or active liver disease","Undiagnosed abnormal uterine bleeding","Current or prior thromboembolic events (DVT, PE)","Cerebrovascular or coronary artery disease","Valvular heart disease with complications","Headaches with focal neurological symptoms (migraine with aura) if over 35","Uncontrolled hypertension (≥160/100 mmHg)","Diabetes with nephropathy, retinopathy, neuropathy, or vascular disease","Major surgery with prolonged immobilization","Known thrombophilic conditions (e.g., factor V Leiden, antithrombin deficiency)","Hypersensitivity to any component","Cigarette smoking in women over 35 years"]
| 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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| 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. |