Ethinylestradiol + levonorgestrel

Oral
Contraception
Adult: Available preparations: Monophasic regimen (as different preparations): Ethinylestradiol 0.03 mg and levonorgestrel 0.15 mg tab Ethinylestradiol 0.02 mg and levonorgestrel 0.09 mg tab Ethinylestradiol 0.02 mg and levonorgestrel 0.1 mg tab 1 tab once daily in the order directed on the blister pack. Doses must be taken continuously at the same time each day. Refer to individual product guidelines on how to manage missed doses and for detailed dosing instructions. Triphasic regimen (as part of a calendar pack): Phase I: Ethinylestradiol 0.03 mg and levonorgestrel 0.05 mg tab Phase II: Ethinylestradiol 0.04 mg and levonorgestrel 0.075 mg tab Phase III: Ethinylestradiol 0.03 mg and levonorgestrel 0.125 mg tab 1 tab once daily in the order directed on the blister pack. Doses must be taken continuously at the same time each day. Refer to individual product guidelines on how to manage missed doses and for detailed dosing instructions.
Child:
Hepatic impairment: Contraindicated.

Transdermal
Contraception
Adult: Available preparation: Ethinylestradiol 0.03 mg and levonorgestrel 0.12 mg patch In females with a BMI <30 kg/m²: Apply 1 patch each week for 3 weeks (21 total days) followed by 1 patch-free week. Each patch should be applied on the same day each week ("patch change day") and only 1 patch should be worn at a time. Patch-free interval should not exceed 7 days. Repeat new cycle on the next day following transdermal patch-free week. Refer to individual product guidelines for detailed dosing instructions and on how to manage missed doses.
Hepatic impairment: Contraindicated.

Current or history of venous thromboembolism (e.g. DVT, pulmonary embolism), hereditary or acquired predisposition for venous thromboembolism (e.g. factor V Leiden mutation, activated protein C [APC] resistance, antithrombin-III-deficiency, protein C and S deficiency), current or history of arterial thromboembolism (e.g. MI) or prodromal condition (e.g. angina pectoris), hereditary or acquired predisposition for arterial thromboembolism (e.g. hyperhomocysteinaemia, antiphospholipid-antibodies), high risk of arterial thromboembolism due to multiple risk factors or the presence of 1 serious risk factor (e.g. severe dyslipoproteinaemia, diabetes mellitus with vascular symptoms); cerebrovascular disease, coronary artery disease, thrombogenic valvular or rhythm disorders, severe or uncontrolled hypertension; history of migraine with focal neurological symptoms (e.g. aura); current or history of pancreatitis associated with severe hypertriglyceridemia, severe hepatic disease (e.g. active viral hepatitis, severe cirrhosis), benign or malignant liver tumours; known or suspected sex-steroid dependent malignancies (e.g. breast or endometrial cancer), undiagnosed vaginal bleeding; SLE with positive or unknown antiphospholipid antibodies. Women >35 years who smoke; obese (BMI ≥30 kg/m²). Major surgery with prolonged immobilisation. Concomitant use with ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir. Pregnancy.

Patient with CV disease, diabetes mellitus with mild vascular disease or mild nephropathy, adequately controlled hypertension, migraine; history of chloasma gravidarum; history of cholestatic jaundice of pregnancy or jaundice with previous hormonal contraceptive use; current or family history of hypertriglyceridemia, risk factors for coronary artery disease (e.g. high LDL or triglycerides, low HDL), depression; hereditary angioedema, SLE. Discontinue treatment at least 4 weeks before an elective major operation; do not restart until 2 weeks after full ambulation. Not recommended for use in women with complicated organ transplants. Renal impairment. Lactation. Monitoring Parameters Assess pregnancy status prior to therapy and during missed menstrual period. Monitor blood pressure, BMI (baseline and during therapy); lipid profile in patients with hyperlipidaemias and glycaemic control in diabetic patients. Monitor for signs and symptoms of depression, thromboembolic disorders, bleeding irregularities, and vision changes. Perform adequate diagnostic measures to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding.

Significant: New onset or exacerbation of migraines or unusually frequent or severe headaches, jaundice, hepatitis, significant increase in blood pressure, severe upper abdominal pain or liver enlargement, increased risk of breast and cervical cancer; chloasma, breakthrough bleeding or spotting, cholestasis, pancreatitis, gallbladder disease; changes in lipid levels, persistent hypertriglyceridaemia, glucose intolerance; retinal vascular thrombosis; depression; exacerbated symptoms of hereditary or acquired angioedema; acute or chronic disturbances of liver function. Gastrointestinal disorders: Nausea, vomiting, abdominal pain, diarrhoea. General disorders and administration site conditions: Fatigue; application site reaction (patch). Investigations: Weight gain. Metabolism and nutrition disorders: Fluid retention. Nervous system disorders: Dizziness, nervousness. Reproductive system and breast disorders: Metrorrhagia, menorrhagia, dysmenorrhoea; breast tenderness, pain, and hypertrophy; decreased libido, vaginitis, candidiasis. Skin and subcutaneous tissue disorders: Acne, rash, urticaria.
Potentially Fatal: Venous thromboembolism (e.g. DVT, pulmonary embolism), arterial thromboembolism (e.g. MI), CVA (e.g. TIA, stroke). Rarely, benign and malignant liver tumours leading to intra-abdominal haemorrhage.

Symptoms: Nausea, vomiting, abdominal pain, dizziness, drowsiness, breast tenderness, withdrawal bleeding. Management: Symptomatic treatment.

Decreased serum concentration with CYP3A4 inducers (e.g. phenytoin, carbamazepine, oxcarbazepine, topiramate, felbamate, barbiturates, primidone, bosentan, rifampicin, griseofulvin, ritonavir, nevirapine). Increased serum concentration with moderate and strong CYP3A4 inhibitors (e.g. voriconazole, erythromycin, verapamil, diltiazem). May decrease the serum concentration of lamotrigine. May increase the serum concentration of ciclosporin. Ethinylestradiol: May increase the serum concentration of tizanidine and theophylline. Increased serum concentration with etoricoxib and ascorbic acid.
Potentially Fatal: Increased risk of ALT elevations in concomitant use with ombitasvir/paritaprevir/ritonavir, dasabuvir, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir.

May diminish the therapeutic efficacy and increase the risk of breakthrough bleeding with St. John's wort. Increased plasma concentration with grapefruit juice.

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

Ethinylestradiol and levonorgestrel 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. They also alter the tubal transport of the ova through the fallopian tubes and the genital tract. The changes in cervical mucus and the endometrium lead to the inhibition of sperm penetration and an unfavourable environment for nidation, respectively. Ethinylestradiol is a synthetic estrogen with actions similar to estradiol. Levonorgestrel is a progestogen derived from nortestosterone that has antiandrogenic activity and is a more potent inhibitor of ovulation.
Absorption: Ethinylestradiol: Rapidly and completely absorbed from the gastrointestinal tract. Bioavailability: 20-65%. Time to peak plasma concentration: 2-3 hours (initial); 12 hours (secondary). Levonorgestrel: Oral: Rapidly and almost completely absorbed. Bioavailability: Nearly 100%. Time to peak plasma concentration: Oral: Approx 2 hours.
Distribution: Ethinylestradiol: Enters breast milk. Volume of distribution: 2.2-3.8 L/kg. Plasma protein binding: >90%, mainly to albumin. Levonorgestrel: Enters breast milk. Volume of distribution: Approx 1.8 L/kg. Plasma protein binding: Approx 50% (to albumin); approx 47% (to sex hormone-binding globulin).
Metabolism: Ethinylestradiol: Metabolised in the liver via aromatic hydroxylation by the CYP3A4 isoenzyme to form various hydroxylated and methylated metabolites; undergoes further extensive enterohepatic recirculation. Levonorgestrel: Metabolised in the liver by the CYP3A4 isoenzyme to inactive metabolites.
Excretion: Ethinylestradiol: Via urine (60% as metabolites); faeces (40% as metabolites). Elimination half-life: 12-23 hours (oral); approx 21 hours (topical). Levonorgestrel: Mainly via urine (45%); faeces (32%). Elimination half-life: Oral: 22-49 hours (oral); approx 42 hours (topical).

Oral: Store between 20-25°C. Transdermal: Store between 20-25°C.

Oestrogens & Progesterones & Related Synthetic Drugs

G03AC03 - levonorgestrel ; Belongs to the class of progestogens. Used as systemic contraceptives.
G03CA01 - ethinylestradiol ; Belongs to the class of natural and semisynthetic estrogens used in estrogenic hormone preparations.
L02AA03 - ethinylestradiol ; Belongs to the class of estrogens.
G03AD01 - levonorgestrel ; Belongs to the class of emergency contraceptives. Used as systemic contraceptives.