NuvaRing^® (Ring) Instructions for Use

Marketing Authorization Holder

N.V. Organon (Netherlands)

ATC Code

G02BB01 (Progestogen- and estrogen-containing intravaginal rings)

Active Substances

Ethinylestradiol (Rec.INN registered by WHO)

Etonogestrel (Rec.INN registered by WHO)

Dosage Form

NuvaRing®

Vaginal ring 2.7 mg+11.7 mg: bag 1 or 3 pcs.

Dosage Form, Packaging, and Composition

Vaginal ring smooth, transparent, colorless or almost colorless, without large visible damage, with a transparent or almost transparent area at the connection point.

Excipients: ethylene and vinyl acetate copolymer (28% vinyl acetate) – 1677 mg, ethylene and vinyl acetate copolymer (9% vinyl acetate) – 197 mg, magnesium stearate – 1.7 mg.

1 pc. – waterproof bags made of aluminum foil (1) – cardboard packs.
1 pc. – waterproof bags made of aluminum foil (3) – cardboard packs.

Clinical-Pharmacological Group

Hormonal contraceptive for intravaginal administration

Pharmacotherapeutic Group

Other agents used in gynecology; contraceptives for topical use; intravaginal contraceptives

Pharmacological Action

Combined hormonal contraceptive medicinal product containing Etonogestrel and Ethinylestradiol.

Etonogestrel is a progestogen (a derivative of 19-nortestosterone) that binds with high affinity to progesterone receptors in target organs. Ethinylestradiol is an estrogen and is widely used in the production of contraceptive agents.

The contraceptive effect is due to a combination of various factors, the most important of which is the suppression of ovulation.

In clinical studies, the Pearl Index (an indicator reflecting the frequency of pregnancy in 100 women during 1 year of contraception) in women aged 18 to 40 years was 0.96 (95% CI: 0.64-1.39) and 0.64 (95% CI: 0.35-1.07) in the statistical analysis of all randomized participants (ITT analysis) and the analysis of study participants who completed the study according to the protocol (PP analysis), respectively. These values were similar to the Pearl Index values obtained in comparative studies of combined oral contraceptives (COCs) containing levonorgestrel/Ethinylestradiol (0.150/0.030 mg) or drospirenone/Ethinylestradiol (3/0.30 mg).

During the use of the drug, the cycle becomes more regular, the pain and intensity of menstrual-like bleeding decrease, which helps to reduce the frequency of iron deficiency conditions. There is evidence of a reduced risk of endometrial and ovarian cancer with the use of drugs containing this combination.

Pharmacokinetics

Ethinylestradiol

Based on measurements of ethinylestradiol concentrations in the cervix and inside the uterus in women using the product and women using oral contraceptives containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol, the observed ethinylestradiol concentration values were comparable.

Ethinylestradiol binds to serum albumin. The apparent V_d is about 15 L/kg.

Ethinylestradiol is metabolized by aromatic hydroxylation. Its biotransformation produces a large number of hydroxylated and methylated metabolites, which circulate both freely and as glucuronide and sulfate conjugates. The apparent clearance is approximately 3.5 L/h.

The concentration of ethinylestradiol in blood plasma decreases in two phases. T_1/2 in the terminal phase varies widely; the median is about 34 h. Ethinylestradiol is not excreted unchanged; its metabolites are excreted by the kidneys and through the intestines in a ratio of 1.3:1. T_1/2 of metabolites is about 1.5 days.

Etonogestrel

Based on measurements of etonogestrel concentrations in the cervix and inside the uterus in women using the product and women using oral contraceptives containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol, the observed etonogestrel concentration values were comparable. Etonogestrel binds to serum albumin and sex hormone-binding globulin (SHBG). The apparent V_d of etonogestrel is 2.3 L/kg. The biotransformation of etonogestrel occurs through known pathways of sex hormone metabolism. The apparent plasma clearance is about 3.5 L/h. The concentration of etonogestrel in blood plasma decreases in two phases. In the terminal phase, T_1/2 is about 29 h. Etonogestrel and its metabolites are excreted by the kidneys and through the intestines with bile in a ratio of 1.7:1. T_1/2 of metabolites is approximately 6 days.

In patients with impaired liver function, the metabolism of sex hormones may be impaired.

Indications

Contraception.

ICD codes

Dosage Regimen

Insert one ring into the vagina. Leave the ring in place for three consecutive weeks (21 days).

Remove the ring on the same day of the week it was inserted. Discard the used ring appropriately.

Observe a ring-free interval of exactly one week (7 days). Withdrawal bleeding usually occurs during this interval.

Insert a new ring after the 7-day interval, even if bleeding has not finished. This maintains contraceptive efficacy.

For first-time users, insert the ring between day one and day five of the menstrual cycle. No additional contraceptive protection is required if started on day one.

If insertion occurs after day five of the cycle, use a barrier method (e.g., condoms) for the first seven days of ring use.

When switching from a combined hormonal contraceptive (pill, patch), insert the ring within seven days after the last active dose of the previous method. No additional protection is needed.

Following a first-trimester abortion or miscarriage, insert the ring immediately. No additional contraceptive protection is required.

Following childbirth or a second-trimester abortion, insert the ring no sooner than four weeks postpartum. Use an alternative method prior to ring initiation.

If the ring is expelled for less than three hours, rinse it with cool water and reinsert promptly. Contraceptive efficacy is maintained.

If the ring is expelled for more than three hours during weeks one or two, reinsert it immediately. Use a barrier method for the next seven days.

If the ring is expelled for more than three hours during week three, discard that ring. Either insert a new ring to start a new cycle or have a ring-free week before inserting a new ring. Use a barrier method for seven days.

If the ring ruptures, discard it and insert a new ring. Contraceptive protection remains effective.

To postpone a withdrawal bleed, insert a new ring immediately after the previous one is removed, omitting the ring-free week. Breakthrough bleeding may occur.

Adverse Reactions

Immune system disorders hypersensitivity.

Metabolism and nutrition disorders increased appetite, weight gain.

Nervous system disorders headache, migraine, dizziness, hypoesthesia, depression, decreased libido, mood changes, fatigue, irritability.

Urinary system disorders cervicitis, cystitis, urinary tract infections, dysuria, urinary urgency.

Gastrointestinal disorders abdominal pain, nausea, bloating, diarrhea, vomiting, constipation.

Reproductive system and breast disorders vaginal infection, breast engorgement and pain, female genital itching, painful menstrual-like bleeding, pelvic pain, vaginal discharge, absence of menstrual-like bleeding, breast discomfort, breast enlargement, breast induration, cervical polyps, contact (during intercourse) bleeding, painful intercourse, cervical ectropion, fibrocystic mastopathy, heavy menstrual-like bleeding, acyclic bleeding, pelvic discomfort, premenstrual-like syndrome, vaginal burning sensation, vaginal odor, vaginal pain, vulvar and vaginal mucosa discomfort and dryness.

Musculoskeletal and connective tissue disorders back pain, muscle spasms, limb pain.

Skin and subcutaneous tissue disorders acne, alopecia, eczema, pruritus, rash, urticaria.

Eye disorders visual impairment.

Cardiac disorders venous thromboembolism, hot flush, increased blood pressure.

General disorders and administration site conditions discomfort when using the vaginal ring, expulsion of the vaginal ring, malaise, edema, foreign body sensation, difficulties in using the contraceptive, ring rupture (damage).

Contraindications

Thrombosis (arterial or venous) and thromboembolism currently or in history (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular disorders); conditions preceding thrombosis (including transient ischemic attacks, angina) currently or in history; predisposition to the development of venous or arterial thrombosis, including hereditary diseases: resistance to activated protein C, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant); migraine with focal neurological symptoms currently or in history; diabetes mellitus with vascular complications; severe or multiple risk factors for venous or arterial thrombosis: hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives), arterial hypertension, heart valve damage, atrial fibrillation, major surgery, prolonged immobilization, extensive trauma, obesity (BMI>30 kg/m²), smoking in women over 35 years of age; pancreatitis (including in history) in combination with severe hypertriglyceridemia; severe liver diseases; malignant or benign liver tumors (including in history); established or suspected hormone-dependent malignant tumors (e.g., of the genital organs or breast); vaginal bleeding of unknown etiology; pregnancy (including suspected); breastfeeding period; hypersensitivity to any of the active or excipients.

With caution

Presence of risk factors for thrombosis and thromboembolism: hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebrovascular accident at a young age in any of the immediate relatives), smoking, obesity, dyslipoproteinemia, arterial hypertension, migraine without focal neurological symptoms, heart valve diseases, cardiac rhythm disorders, prolonged immobilization, major surgical interventions; superficial phlebitis; dyslipoproteinemia; heart valve defect; adequately controlled arterial hypertension; diabetes mellitus without vascular complications; acute or chronic liver function disorders; jaundice and/or pruritus caused by cholestasis; cholelithiasis; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea (chorea minor); hearing loss due to otosclerosis; (hereditary) angioedema; chronic inflammatory bowel diseases (Crohn’s disease and ulcerative colitis); sickle cell anemia; chloasma; conditions that complicate the use of the vaginal ring: cervical prolapse, cystocele, rectocele, severe chronic constipation.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in severe liver diseases (until liver function tests normalize).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Special Precautions

In the presence of any of the diseases, conditions or risk factors listed below, the benefits and possible risks should be assessed for each individual woman even before she starts using the medicinal product. In case of exacerbation of diseases, worsening of the condition or occurrence of any of the listed conditions for the first time, the woman should consult a doctor.

The use of hormonal contraceptives may be associated with the development of venous thrombosis (deep vein thrombosis and pulmonary embolism) and arterial thrombosis, as well as related complications, sometimes fatal.

The use of any COC increases the risk of developing venous thromboembolism (VTE) compared to the risk of developing VTE in patients not using COCs. The greatest risk of developing VTE is observed in the first year of using COCs. Data from a large prospective cohort study on the safety of various COCs suggest that the greatest increase in risk, compared to the risk level in women not using COCs, is observed in the first 6 months after starting COCs or resuming their use after a break (4 weeks or more). In non-pregnant women not using oral contraceptives, the risk of developing VTE is from 1 to 5 cases per 10,000 woman-years (WY). In women using oral contraceptives, the risk of developing VTE is from 3 to 9 cases per 10,000 WY. However, the risk increases to a lesser extent than during pregnancy, when it is 5-20 cases per 10,000 WY (pregnancy data are based on the actual duration of pregnancy in standard studies; when recalculated for a 9-month pregnancy duration, the risk is from 7 to 27 cases per 10,000 WY). In postpartum women, the risk of developing VTE is from 40 to 65 cases per 10,000 WY. VTE is fatal in 1-2% of cases.

Women using COCs should be advised to consult a doctor if possible symptoms of thrombosis appear. If thrombosis is suspected or confirmed, the use of COCs should be discontinued. In this case, effective means of contraception should be used, since anticoagulants (coumarins) have a teratogenic effect.

The most important risk factor for cervical cancer is infection with the human papillomavirus (HPV). Epidemiological studies have shown that long-term use of COCs leads to an additional increase in the degree of such risk, but it remains unclear how much this is associated with other factors such as more frequent cervical smear examinations and differences in sexual behavior, including the use of barrier contraceptives.

Breast cancer diagnosed in women using COCs is clinically less pronounced than cancer detected in women who have never used COCs. The increased risk of developing breast cancer may be due both to the fact that in women taking COCs, the diagnosis of breast cancer is established at an earlier stage, and to the biological effects of COCs, or a combination of both of these factors.

In rare cases, women taking COCs have developed benign, and even more rarely, malignant liver tumors. In some cases, these tumors led to the development of life-threatening bleeding into the abdominal cavity. The doctor should consider the possibility of a liver tumor in the differential diagnosis of diseases in a woman if the symptoms include acute pain in the upper abdomen, liver enlargement or signs of intra-abdominal bleeding.

Women with hypertriglyceridemia or a relevant family history have an increased risk of developing pancreatitis when taking hormonal contraceptives.

In many women taking hormonal contraceptives, a slight increase in blood pressure is observed, but a clinically significant increase in blood pressure is rare. A direct connection between the use of hormonal contraceptives and the development of hypertension has not been established. If a persistent increase in blood pressure is noted during use, it is necessary to consult the attending physician to decide on the need to remove the vaginal ring and prescribe antihypertensive therapy. With adequate control of blood pressure with antihypertensive drugs, it is possible to resume the use of the drug.

During pregnancy and during the use of COCs, the development or worsening of the following conditions was noted, although their relationship with the use of contraceptives has not been definitively established: jaundice and/or pruritus caused by cholestasis, gallstone formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham’s chorea (chorea minor), herpes gestationis, hearing loss due to otosclerosis, (hereditary) angioedema.

Acute or chronic liver function disorders may be grounds for discontinuation until liver function tests normalize. Recurrence of cholestatic jaundice, observed previously during pregnancy or when using sex steroid drugs, requires discontinuation of the drug.

Women with diabetes mellitus should be under constant medical supervision, especially in the first months of contraception.

There is evidence of worsening of Crohn’s disease and ulcerative colitis when using hormonal contraceptives.

In rare cases, skin pigmentation of the face (chloasma) may be observed, especially if it occurred previously during pregnancy. Women predisposed to developing chloasma should avoid exposure to sunlight and ultraviolet radiation.

During use, acyclic bleeding (spotting or sudden bleeding) may occur. If such bleeding is observed after regular cycles with correct use, you should consult your gynecologist for the necessary diagnostic tests, including to exclude organic pathology or pregnancy. Diagnostic curettage may be required.

The use of contraceptive hormonal drugs may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of transport proteins (e.g., corticosteroid-binding globulin and sex hormone-binding globulin), lipid/lipoprotein fractions, carbohydrate metabolism parameters and coagulation and fibrinolysis parameters. The parameters generally change within normal limits.

Drug Interactions

Interaction between hormonal contraceptives and other drugs can lead to the development of acyclic bleeding and/or contraceptive failure.

Interaction with drugs that induce hepatic microsomal enzymes is possible, which can lead to an increase in the clearance of sex hormones. Interaction has been established with the following drugs: phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin and preparations containing St. John’s wort.

When treating with any of the listed agents, a barrier method of contraception (condom) should be used temporarily or another method of contraception should be chosen. During concomitant use of drugs that cause induction of hepatic microsomal enzymes and for 28 days after their discontinuation, barrier methods of contraception should be used.

A decrease in the effectiveness of oral contraceptives containing Ethinylestradiol has been noted with concomitant use of antibiotics such as ampicillin and tetracyclines. The mechanism of this effect has not been studied. In a pharmacokinetic interaction study, oral administration of amoxicillin (875 mg 2 times/day) or doxycycline (200 mg/day, then 100 mg/day) for 10 days during the use of the product had little effect on the pharmacokinetics of etonogestrel and ethinylestradiol. When using antibiotics (excluding amoxicillin and doxycycline), a barrier method of contraception (condom) should be used during treatment and for 7 days after discontinuation of antibiotics. If concomitant therapy must be continued after 3 weeks of using the ring, the next ring must be inserted immediately without the usual interval.

Hormonal contraceptives can cause disturbances in the metabolism of other medicinal products. Consequently, their concentrations in plasma and tissues may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.