Norelgestromin + Ethinylestradiol

Transdermal
Contraception

Contraindicated.

Current or history of venous thromboembolism (e.g. DVT, pulmonary embolism), current or history of arterial thromboembolism (e.g. MI) or prodromal condition (e.g. angina pectoris), known hereditary or acquired predisposition for venous or arterial thrombosis (e.g. Factor V Leiden mutation and activated protein C [APC]-resistance, antithrombin-III-deficiency, protein C and S deficiency; hyperhomocysteinaemia, antiphospholipid-antibodies [e.g. lupus anticoagulant, anticardiolipin antibodies]), patients at high risk of venous and arterial thromboembolism due to the presence of multiple risk factors or 1 serious risk factor (e.g. obesity [BMI ≥30 kg/m²], major surgery with prolonged immobilisation, >35 years of age who smoke; severe hypertension, severe dyslipoproteinaemia, diabetes mellitus with vascular symptoms); current or history of cerebrovascular disease (e.g. stroke, TIA), thrombogenic valvular or rhythm heart diseases (e.g. subacute bacterial endocarditis with valvular disease, atrial fibrillation), coronary artery disease, uncontrolled hypertension; history of headache/migraine with focal neurological symptoms (e.g. aura); known or suspected breast carcinoma, endometrial carcinoma, or other estrogen- or progestin-dependent cancer, undiagnosed abnormal uterine/genital bleeding; active viral hepatitis, severe (decompensated) cirrhosis, liver tumours (benign or malignant). Hepatic impairment. Pregnancy. Concomitant use with drug combinations containing ombitasvir/paritaprevir/ritonavir, and dasabuvir.

Patient with risk factors or history of chloasma gravidarum, previous cholestasis of pregnancy or prior oral contraceptive use, current or family history of hypertriglyceridaemia, risk factors for CV disease (e.g. hypertension, high LDL and triglycerides, low HDL), diabetes or prediabetes, hereditary angioedema, SLE, history of depression. Patients weighing ≥90 kg; smokers. Not indicated for use prior to menarche, or in postmenopausal women. Not recommended for women with complicated organ transplants. Renal impairment. Lactation.

Significant: Bleeding irregularities (e.g. unscheduled bleeding, spotting, amenorrhoea), increased risk of cervical and breast cancer, chloasma, cholestasis, gallbladder disease, induced or exacerbated angioedema, retinal vein thrombosis; recurrent, persistent or severe headache/migraine, depression; increased blood pressure, adverse changes in lipid levels (including serum triglycerides), impaired glucose tolerance, increased thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin levels. Rarely, hepatocellular carcinoma (prolonged use).
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, abdominal distension.
General disorders and administration site conditions: Fatigue, malaise, application site reactions (e.g. irritation, pruritus, rash, erythema).
Infections and infestations: Vaginal yeast infection.
Investigations: Weight gain.
Musculoskeletal and connective tissue disorders: Muscle spasms.
Nervous system disorders: Dizziness.
Psychiatric disorders: Mood, affect and anxiety disorders; insomnia.
Reproductive system and breast disorders: Breast tenderness, breast disorders; vaginal discharge; dysmenorrhea, uterine spasm; changes in libido.
Skin and subcutaneous tissue disorders: Acne, rash, pruritus, skin reaction.
Potentially Fatal: Venous thromboembolism (e.g. DVT, pulmonary embolism), arterial thromboembolism (e.g. MI), CVA (e.g. TIA, stroke). Rarely, hepatic adenoma.

Transdermal: X

Assess pregnancy status prior to therapy and during a missed menstrual period. Before treatment initiation, check for personal or family history of thromboembolic or thrombotic disorders. Obtain blood pressure at baseline and yearly; weight (BMI) at baseline and during therapy; lipid profile (in patients with hyperlipidaemia); glucose (in diabetics); LFTs. Monitor for signs and symptoms of thromboembolic disorders, bleeding irregularities, depression and vision changes. Perform adequate diagnostic measures to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.

Symptoms: Nausea, vomiting, vaginal bleeding. Management: Symptomatic treatment.

May decrease the serum concentrations and efficacy with enzyme inducers (e.g. phenytoin, carbamazepine, oxcarbazepine, topiramate, felbamate, barbiturates, primidone, bosentan, rifampicin, rifabutin, griseofulvin, ritonavir, nelfinavir, nevirapine, efavirenz, modafinil, aprepitant). May elevate the plasma concentration with CYP3A4 inhibitors (e.g. ketoconazole, voriconazole).
Ethinylestradiol: May decrease the serum levels of lamotrigine. May increase the plasma concentrations of ciclosporin, tizanidine, and theophylline. May increase the serum concentration when given with etoricoxib and ascorbic acid.
Potentially Fatal: Ethinylestradiol: Increased risk of ALT elevations when used concomitantly with drugs containing ombitasvir/paritaprevir/ritonavir and dasabuvir.

Plasma levels and efficacy may be decreased by St. John's wort. May increase the serum concentrations with grapefruit juice.

May interfere with the results of certain tests for lipids, glucose tolerance, coagulation factors, plasma levels of carrier proteins (e.g. corticosteroid-binding globulin, lipid/lipoprotein fractions), parameters of carbohydrate metabolism and fibrinolysis; liver, renal, thyroid, and adrenal function.

Description:
Mechanism of Action: Norelgestromin and ethinylestradiol suppress ovulation by negative feedback mechanism on the hypothalamus that changes the normal gonadotropin secretion pattern of FSH and LH by the anterior pituitary gland, thereby blocking the follicular FSH phase and the midcycle surge of gonadotropins. The combination may also alter the tubal transport of the ova through the fallopian tubes, and exert changes in the cervical mucus and endometrium leading to inhibition of sperm penetration and an unfavourable environment for nidation, respectively.
Norelgestromin, the main active metabolite of norgestimate, is a 3rd generation progestin.
Ethinylestradiol is a synthetic estrogen with effects similar to estradiol.
Pharmacokinetics:
Absorption: Rapidly absorbed. Time to peak plasma concentration: Approx 48 hours.
Ethinylestradiol: Bioavailability: Transdermal: Approx 60% greater (compared to oral).
Distribution: Norelgestromin: Plasma protein binding: >97%; mainly to albumin (for norelgestromin) and sex hormone-binding globulin (for norgestrel).
Ethinylestradiol: Enters breast milk. Volume of distribution: 2.2-3.8 L/kg. Plasma protein binding: >90%, mainly to albumin.
Metabolism: Norelgestromin: Metabolised in the liver to form norgestrel and various conjugated and hydroxylated metabolites.
Ethinylestradiol: Metabolised in the liver via aromatic hydroxylation by CYP3A4 isoenzyme to form various hydroxylated metabolites and their sulfate and glucuronide conjugates; undergoes extensive enterohepatic recirculation.
Excretion: Norelgestromin: Via urine and faeces. Elimination half-life: Approx 28 hours (after removal of transdermal patch).
Ethinylestradiol: Via urine (60%) and faeces (40%), as metabolites. Elimination half-life: Approx 17 hours (after removal of transdermal patch).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 9568628, Norelgestromin. https://pubchem.ncbi.nlm.nih.gov/compound/Norelgestromin. Accessed Feb. 22, 2022.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5991, Ethinylestradiol. https://pubchem.ncbi.nlm.nih.gov/compound/Ethinylestradiol. Accessed Apr. 27, 2022.

Store between 20-25°C. Do not refrigerate or freeze. Protect from light and moisture.

Other Contraceptives

G03AA13 - norelgestromin and ethinylestradiol ; Belongs to the class of progestogens and estrogens in fixed combinations. Used as systemic contraceptives.

Anon. Ethinylestradiol (Ethinyl Estradiol) and Norelgestromin. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 16/11/2021.

Anon. Ethinylestradiol (Ethinyl Estradiol). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 16/11/2021.

Buckingham R (ed). Ethinylestradiol. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/11/2021.

Ethinyl Estradiol; Norelgestromin. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com. Accessed 16/11/2021.

Evra 203 micrograms/24 Hours + 33.9 micrograms/24 Hours Transdermal Patch (Gedeon Richter Plc.). MHRA. https://products.mhra.gov.uk. Accessed 16/11/2021.

Evra Transdermal Patch (Johnson & Johnson Sdn Bhd). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 16/11/2021.

Joint Formulary Committee. Ethinylestradiol with Norelgestromin. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/11/2021.

Xulane Patch (A-S Medication Solutions). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 16/11/2021.

Zafemy Patch (Amneal Pharmaceuticals LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 16/11/2021.