norethisterone
Regulatory sources consulted
Approved indications
- Treatment of secondary amenorrhea after excluding pregnancy and pituitary causes.
- Treatment of endometriosis.
Contraindications
Absolute
- Pregnancy or breastfeeding; current or prior venous or arterial thrombosis, prodromal symptoms, or high thrombotic risk; migraine with focal neurologic symptoms.
- Diabetes with vascular involvement, severe liver disease, liver tumor, hormone-dependent neoplasia, undiagnosed genital bleeding, or hypersensitivity.
- Concomitant use of ombitasvir/paritaprevir/ritonavir with or without dasabuvir.
Clinical warnings
- Major warning · Stop for symptoms of thrombosis, visual changes, jaundice, or liver deterioration. Monitor depression and diabetes. — CIMA/AEMPS, ficha técnica 39927
- Major warning · It is not reliable contraception; use a nonhormonal method if contraception is needed. — CIMA/AEMPS, ficha técnica 39927
Drug interactions
- ModerateEnzyme inducers
Mechanism: They may increase clearance, reduce effectiveness, and alter bleeding patterns.
Recommendation: Review the combination; a nonhormonal alternative may be needed.
CIMA/AEMPS, ficha técnica 39927https://cima.aemps.es/cima/dochtml/ft/39927/FT_39927.html
- ModerateStrong or moderate CYP3A4 inhibitors
Mechanism: Azole antifungals, verapamil, macrolides, diltiazem, or grapefruit juice may increase plasma concentrations of estrogen, progestin, or both; the clinical relevance is unknown.
Recommendation: Review the combination and monitor tolerability; do not assume an unestablished dose adjustment.
CIMA/AEMPS, ficha técnica 39927https://cima.aemps.es/cima/dochtml/ft/39927/FT_39927.html
- HighCyclosporine or lamotrigine
Mechanism: Progestins may increase cyclosporine concentrations or decrease lamotrigine concentrations.
Recommendation: Monitor cyclosporine toxicity and clinical control with lamotrigine; review dosing with the clinical team.
CIMA/AEMPS, ficha técnica 39927https://cima.aemps.es/cima/dochtml/ft/39927/FT_39927.html
- ModerateTheophylline or tizanidine
Mechanism: Ethinylestradiol formed by partial conversion of oral norethisterone inhibits elimination of CYP1A2 substrates and may mildly increase theophylline or moderately increase tizanidine.
Recommendation: Monitor adverse effects and review the CYP1A2 substrate dose if needed.
CIMA/AEMPS, ficha técnica 39927https://cima.aemps.es/cima/dochtml/ft/39927/FT_39927.html
Adverse events
Common (≥1%)
Uterine bleeding or spotting · Amenorrhea or hypomenorrhea · Headache · Nausea · Edema
Rare but serious
Venous or arterial thrombosis · Liver tumor with intra-abdominal bleeding
Pregnancy and lactation
Contraindicated during pregnancy and breastfeeding.
Recent literature (PubMed)
In the past, the primary approach for the treatment of endometriosis was represented by surgery; however, after the introduction of non-invasive diagnosis of endometriosis with the development of imaging technologies, medical treatment became the preferred approach, particularly in young patients. Hormonal drugs, by blocking menstruation, are the most effective for the treatment of endometriosis-related pain, independently of phenotype (ovarian, deep, or superficial endometriosis). Gonadotropin-releasing hormone analogs and oral antagonists act on hypothalamus-pituitary-ovary axis inducing iatrogenic menopause, thus reducing dysmenorrhea and all pain symptoms. The side effects, such as hot flushes and bone loss, may be reduced by an add-back therapy. However, the cost in terms of women's health remains high in view of a long-term treatment. Progestins are considered the first-line treatment, highly effective, and with reduced side effects. In addition to the well-known and largely used Norethisterone acetate and Medroxyprogesterone acetate, recently Dienogest has become one of the most used drugs in all endometriosis phenotypes for long-term treatment. Besides, Intrauterine levornogestrel or subcutaneous etonogestrel are valid alternative for long-term treatment.
An oral fixed-dose combination of relugolix/estradiol/norethisterone (also known as norethindrone) acetate [Myfembree® (USA); Ryeqo® (EU)] (hereafter referred to as relugolix combination therapy) has been approved in the USA for the management of moderate to severe pain associated with endometriosis in premenopausal women and in the EU for the symptomatic treatment of endometriosis in adult women of reproductive age with a history of previous medical or surgical treatment for their endometriosis. The gonadotropin-releasing hormone (GnRH) receptor antagonist relugolix decreases estradiol and progesterone levels, while the addition of estradiol/norethisterone acetate mitigates hypoestrogenic effects including bone mineral density (BMD) loss and vasomotor symptoms. In two pivotal phase III trials, relugolix combination therapy significantly improved dysmenorrhoea and non-menstrual pelvic pain in premenopausal women with moderate to severe endometriosis. The combination also reduced overall pelvic pain and dyspareunia, reduced analgesic and opioid use, and improved health-related quality of life. The efficacy of relugolix combination therapy was sustained over the longer term (up to 2 years). Relugolix combination therapy was generally well tolerated and BMD loss over time was minimal. With the convenience of a once daily oral dosing regimen, relugolix combination therapy is a valuable addition to the options currently available for the management of endometriosis-associated pain. Endometriosis is a disease where tissue similar to the lining of the uterus grows outside the uterus and may reach other organs. This causes chronic pain as a result of increased inflammation and scar tissue. Women with endometriosis may experience painful menstrual periods, pelvic pain between periods, pain during sex, painful bowel movements and painful urination. Recently, a fixed-dose tablet comprising relugolix, estradiol and norethisterone (also known as norethindrone) acetate [Myfembree
Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids. PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed. Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were exclu
Progestogens (norethisterone acetate, medroxyprogesterone acetate, dydrogesterone, micronized progesterone, levonorgestrel, drospirenone, and trimegestone) added to estrogen for endometrial protection are reviewed. They can be given orally or vaginally, norethisterone acetate can also be given transdermally, and levonorgestrel can be given through the intrauterine route. Sequential use of progestogens protects the endometrium if exposure lasts for at least 12 days/month; longer intervals are not safe. Continuous use of progestogens, whether oral, transdermal, or intrauterine, provides the most effective protection. Progestogen addition is accompanied with significant elevations in breast cancer risk, the largest drawback of progestogen use, and dydrogesterone, micronized progesterone, and a levonorgestrel intrauterine device may be safest in this regard. Progestogens also double deep vein thrombosis risk and diminish the positive effect of estrogen on colorectal cancer and vascular health. Recent data imply a neutral effect of progestogens in combination with estrogen on Alzheimer's disease risk, but the risk of vascular dementia is decreased. In conclusion, progestogens are a double-edged sword, effectively protecting the endometrium but causing several side effects and reducing many estrogen-induced benefits. With modern endometrial diagnostic tools, the safety of low-dose unopposed estrogen regimens should be assessed in a prospective controlled trial in women with an intact uterus.