NovaRing, vaginal rings 0.015 mg+0.120 mg/day

Interaction

Interactions with other drugs

Interactions between hormonal contraceptives and other drugs can lead to acyclic bleeding and/or contraceptive failure. The following interactions with combined oral contraceptives in general have been described in the literature.

Help metabolism: Can have interactions with drugs that induce microsomal liver enzymes, which may lead to increased clearance of sex hormones. Interactions have been found, for example, with phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also with oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin and preparations containing St. John’s wort (Hypericum perforatum).

Treatment with any of the drugs listed should be treated temporarily with a barrier method of contraception (condom) in combination with NovaRing® or choose another method of contraception. During concomitant use of drugs that induce microsomal enzymes and for 28 days after their withdrawal, barrier contraceptive methods should be used.

If the concomitant therapy must be continued after 3 weeks of use of the ring, the next ring must be inserted immediately without the usual interval.

Antibiotics: Decreased efficacy of oral contraceptives containing ethinyl estradiol has been noted with concomitant administration of antibiotics such as ampicillin and tetracyclines. The mechanism of this effect is not understood. In a pharmacokinetic interaction study, oral administration of amoxicillin (875 mg, twice daily) or doxycycline (200 mg daily and then 100 mg daily) for 10 days during administration of NovaRing® had little effect on the pharmacokinetics of etonogestrel and ethinylestradiol. If antibiotics (excluding amoxicillin and doxycycline) are used, a barrier method of contraception (condom) should be used during treatment and for 7 days after withdrawal of antibiotics. If concomitant therapy should be continued after 3 weeks of ring use, the next ring should be inserted immediately without the usual interval. Pharmacokinetic studies have shown no effect of concomitant use of antifungal agents and spermicides on the contraceptive efficacy and safety of NovaRing®. When the suppositories are used concomitantly with antifungal drugs, the risk of ring rupture is slightly increased. Hormonal contraceptives may cause metabolic disorders of other drugs. Accordingly, their concentrations in plasma and tissues may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine). To exclude possible interaction it is necessary to read the instructions for use of other drugs.

Laboratory studies

The use of contraceptive hormonal drugs may affect the results of certain laboratory tests, including biochemical measures of liver, thyroid, adrenal and renal function; plasma concentrations of transport proteins such as corticosteroid-binding globulin (CRBG) and hCG; lipid/lipoprotein fractions; carbohydrate metabolites; and clotting and fibrinolysis. The indexes tend to change within the normal range.

Combined use with tampons

Pharmacokinetic data demonstrate that tampon use has no effect on absorption of hormones released from the NovaRing® vaginal ring. In rare cases the ring may be inadvertently removed during tampon removal (see subsection “What to do if the ring has been temporarily removed from the vagina” in the section “Dosage and administration”).

Special Instructions

In the presence of any of the following diseases, conditions or risk factors, the benefits of NovaRing® and the possible risks to each individual woman should be evaluated before starting NovaRing®. If any of the following conditions worsen, worsen, or occur for the first time, women should see their physician to determine whether NovaRing® can be continued.

Circulatory disorders

Hormonal contraceptive use may be associated with venous thrombosis (deep vein thrombosis and pulmonary embolism) and arterial thrombosis and related complications, sometimes with death.

The use of any OCs increases the risk of venous thromboembolism (VTE) compared with the risk of VTE in patients not using OCs. The risk of VTE is highest in the first year of OC use.

Data from a large prospective cohort study of the safety of use of various OCs suggest that the greatest increase in risk, compared with the risk in women not using OCs, occurs in the first 6 months after starting OCs or resuming use after a break (4 weeks or longer). In nonpregnant women not using oral contraceptives, the risk of VTE is 1 to 5 cases per 10,000 women-years (WL).

In women using oral contraceptives, the risk of VTE ranges from 3 to 9 cases per 10,000 WL. The increased risk is less than in pregnancy, where the risk is 5 to 20 cases per 10,000 LDs (pregnancy data are based on the actual duration of pregnancy in standardized studies; based on the assumption that pregnancy lasts 9 months, the risk is 7 to 27 cases per 10,000 LDs). In postpartum women, the risk of VTE is 40 to 65 cases per 10,000 VL. VTE is fatal in 1-2% of cases.

The studies show an increased risk of VTE in women using NovaRing® that is similar to that of women using OCs (see table below for adjusted risk ratio). The large prospective observational TASC (Trans-Atlantic Active Study of Cardiovascular Safety for NovaRing®) study evaluated the risk of VTE in women who started NovaRing® or OC, switched to NovaRing® or OC from other contraceptives, or recommitted to NovaRing® or OC in a typical user population.

Women were followed for 24-48 months. Results showed a similar risk of VTE in women using NovaRing® (8.3 cases per 10,000 VL) and in women using OCs (9.2 cases per 10,000 VL). For women using OCs other than those containing desogestrel, gestoden, and drospirenone, the incidence of VTE was 8.5 cases per 10,000 LL.

A FDA-initiated retrospective cohort study showed that women who began NovaRing® had a VTE rate of 11.4 per 10,000 LL compared to 9.2 per 10,000 LL for women who began levonorgestrel OCs.

Risk assessment (risk ratio) of VTE in women using NovaRing® compared with the risk of VTE in women using OC

The epidemiological study, population:

1. TASC (Dinger, 2012) Women who started using the drug (including again after a break) and switched from other contraceptives.
2. FDA-initiated study (Sydney, 2011) Women who began using combined hormonal contraceptives (CHCs) for the first time during the study period.

The comparison drug(s):

1. All available OCs during the study¹. OR2: 0.8 (0.5-1.5) Available OCs except those containing desogestrel, gestoden, drospirenone.
2. All available OCs during study period³.

Risk ratio (OR) (95% CI):

1. OR²: 0.8 (0.5-1.5); OR²: 0.9 (0.4-2.0).
2. OR⁴: 1.09 (0.55-2.16); OR⁴: 0.96 (0.47-1.95).

¹ – Including low-dose OCs containing the following progestins: chlormadinone acetate, cyproterone acetate, desogestrel, dienogestrone, drospirenone, ethinodiol diacetate, gestodene, levonorgestrel, norethindrone, norgestimat or norgestrel.

² – Based on age, BMI, duration of use, history of VTE.

³ – Including low-dose OCs containing the following progestins: norgestimat, norethindrone, or levonorgestrel.

⁴ – Taking into account age, place, and year of study inclusion.

In extremely rare cases of thrombosis of other blood vessels (e.g., arteries and veins of the liver, mesenteric vessels, kidneys, brain, and retina) with OC use are known. It is not known whether these cases are related to the use of OCs.

Possible symptoms of venous or arterial thrombosis may include unilateral swelling and/or pain in the lower extremity, localized fever in the lower extremity, hyperemia or discoloration of the skin on the lower extremity; sudden severe chest pain, possibly irradiating to the left arm; an attack of shortness of breath, coughing Any unusual, severe, prolonged headache; sudden partial or total loss of vision; double vision; slurred speech or aphasia; dizziness; collapse, with or without a focal seizure; sudden weakness or marked numbness on one side or any part of the body; motor disturbances; “acute” abdomen.

Risk factors for venous thromboses and embolisms:

• Age;
• He has a family history of disease (venous thromboses and embolisms in brothers/sisters at any age or in parents at a young age). If a hereditary predisposition is suspected, a woman should be referred to a specialist for consultation before starting any hormonal contraceptives;
• Long-term immobilization, major surgery, any surgery on the lower extremities or serious trauma. In these situations, it is recommended to stop using the drug (for elective surgery at least 4 weeks in advance) and then resume use no earlier than 2 weeks after full restoration of motor activity;
• Overweight (BMI greater than 30 kg/m²);
• Possible superficial venous thrombophlebitis in varicose veins.

There is no consensus about the possible role of these conditions in the etiology of venous thrombosis.

Risk factors for arterial thromboembolic complications:

• Age;
• Smoking (with heavy smoking and with age, the risk increases even more significantly, especially in women over 35);
• Dyslipoproteinemia;
• Obsesity (body mass index more than 30 kg/m²);
• Migraine;
• Cardiac valve defects;
• Atrial fibrillation;
• Presence of a family history of disease.Presence of disease in family history (arterial thrombosis in brothers/sisters at any age or in parents at a relatively early age). If a hereditary predisposition is suspected, a woman should be referred to a specialist for consultation before starting any hormonal contraceptives. Biochemical factors that may indicate an inherited or acquired predisposition to venous or arterial thrombosis include activated protein C resistance, hyperhomocysteinemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antibodies to phospholipids (antibodies to cardiolipin, lupus anticoagulant).

Other conditions that may lead to unwanted circulatory disturbances include diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome and chronic inflammatory bowel disease (such as Crohn’s disease or ulcerative colitis), and sickle cell anemia.

An increased risk of thromboembolism in the postpartum period should be considered. An increase in the frequency or severity of migraines (which may be a prodromal symptom of cerebrovascular disorders) during use of hormonal contraceptives may be a reason for immediate discontinuation of hormonal contraceptives.

Women using CGC should be advised to consult a physician if possible symptoms of thrombosis occur. If thrombosis is suspected or confirmed, the use of CGC should be discontinued. Effective contraception should be used because anticoagulants (coumarins) have teratogenic effects.

Tumor Risk

The most important risk factor for cervical cancer is infection with human papillomavirus (HPV). Epidemiological studies have shown that prolonged use of OCs further increases this risk, but it is unclear how this is related to other factors, such as more frequent cervical smears and differences in sexual behavior, including use of barrier contraceptives. It remains unclear how this effect is related to the use of NovaRing®.

A meta-analysis of results from 54 epidemiologic studies found a small increase (1.24) in the relative risk of breast cancer in women taking combined hormonal oral contraceptives. The risk gradually declines over a 10 year period after withdrawal. Breast cancer rarely develops in women under the age of 40, so the additional incidence of breast cancer in women who are taking or have taken OCs is small compared to the overall risk of developing breast cancer. The breast cancer diagnosed in women who use OCs is clinically less severe than the cancer diagnosed in women who have never used OCs. The increased risk of breast cancer may be due to either the earlier diagnosis of breast cancer in women who use OC, or to the biological effects of OC, or a combination of both.

In rare cases, women who took OC have developed benign, and even more rarely, malignant liver tumors. In some cases, these tumors have resulted in life-threatening bleeding into the abdominal cavity. The physician should consider the possibility of a liver tumor in the differential diagnosis of disease in a woman taking NovaRing® if symptoms include acute upper abdominal pain, liver enlargement or signs of intra-abdominal bleeding.

Other conditions

• Women with hypertriglyceridemia or a related family history have an increased risk of pancreatitis when taking hormonal contraceptives.
• Many women taking hormonal contraceptives experience a slight increase in blood pressure, but clinically significant increases in blood pressure are rare. A direct link between the use of hormonal contraceptives and the development of arterial hypertension has not been established. If a persistent increase in blood pressure is noted during the use of NovaRing® , a physician should be consulted to decide if the vaginal ring should be removed and to prescribe an antihypertensive therapy. When blood pressure is adequately controlled with antihypertensive medications, NovaRing® may be resumed.
• The following conditions have been noted to develop or worsen during pregnancy and during the use of combined oral contraceptives, although their relationship to contraceptive use is not conclusively established: Jaundice and/or pruritus caused by cholestasis, gallstones formation, porphyria, systemic lupus erythematosus, hemolytic-uremic syndrome, Sydenham’s chorea (small chorea), herpes of pregnancy, hearing loss due to otosclerosis, (hereditary) angioedema.
• Acute or chronic liver disease may warrant discontinuation of NovaRing® until normalization of liver function parameters. Relapse of cholestatic jaundice previously seen during pregnancy or with the use of sex hormone therapy may require discontinuation of NovaRing®.
• While estrogens and progestagens may affect peripheral insulin resistance and tissue glucose tolerance, no evidence exists to support changing hypoglycemic therapy with hormonal contraceptives. However, diabetic women should be kept under constant medical supervision while using NovaRing®, especially during the first months of contraception.
• The following conditions may prevent proper insertion of the ring or contribute to its prolapse: cervical prolapse, bladder hernia and/or rectal hernia, severe chronic constipation.
• In very rare cases, women have inadvertently inserted the NovaRing® vaginal ring into the urethra and possibly into the bladder. If symptoms of cystitis occur, the possibility of improper insertion of the ring should be considered.
• Cases of vaginitis have been described during the use of NovaRing®. There is no evidence that treatment of vaginitis affects the efficacy of NovaRing®, nor is there evidence that NovaRing® affects the efficacy of vaginitis treatment.
• There have been very rare cases described where the ring was difficult to remove, requiring removal by a healthcare professional.

Medical examination/consultation

Before NovaRing® is prescribed or renewed, the woman’s medical history (including family history) should be carefully reviewed and a gynecological exam performed to rule out pregnancy. Blood pressure should be measured, mammary glands, pelvic organs, including cytological examination of cervical smears and some laboratory tests should be performed to exclude contraindications and reduce the risk of possible side effects of the drug. The frequency and nature of medical examinations depend on the individual characteristics of each patient, but medical examinations are carried out at least once every 6 months. The woman should read the instructions for use and follow all recommendations. The woman should be informed that NovaRing® does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Decreased effectiveness

The effectiveness of Novaring® may be reduced if the regimen or concomitant therapy is not used appropriately.

Decrease in cycle control

Accyclic bleeding (spotting or sudden bleeding) may occur during use of NovaRing®. If such bleeding occurs after regular cycles during the correct use of NovaRing® , it is necessary to consult an attending gynecologist for the necessary diagnostic examinations, including the exclusion of organic pathology or pregnancy. A diagnostic curettage may be necessary.

Some women do not bleed after ring removal. If NovaRing® was used according to the instructions, it is unlikely that the woman is pregnant. If you do not follow the instructions and do not bleed after removing the ring, or if you do not bleed for two consecutive cycles, pregnancy should be ruled out.

Effects of ethinylestradiol and etonogestrel on the sexual partner

Possible pharmacological effects and degree of exposure of male sexual partners to ethinylestradiol and etonogestrel (due to absorption through penile tissue) have not been studied.

Ring rupture

In rare cases, ring rupture has been observed with NovaRing®. The core of NovaRing® is solid, so its contents remain intact and hormone release does not change significantly. If the ring ruptures, it usually falls out of the vagina (see “What to do if the ring has been temporarily removed from the vagina” in “Dosage and administration”). If the ring breaks, a new ring must be inserted.

Loss of the ring

Sometimes the NovaRing® vaginal ring has fallen out of the vagina, for example if it has not been inserted correctly, if a tampon has been removed, during intercourse or if there is severe or chronic constipation. It is therefore advisable for the woman to regularly check the presence of the NovaRing® vaginal ring in the vagina. If the NovaRing® vaginal ring has fallen out of the vagina, the recommendations in the section “What to do if the ring has been temporarily removed from the vagina” under “Dosage and administration” should be followed.

Influence on ability to drive and operate vehicles and other mechanisms requiring increased concentration

Based on information about the pharmacodynamic properties of NovaRing® , it is not expected to affect the ability to drive and operate machinery.

Contraindications

NovaRing® is contraindicated for any of the following conditions. If any of these conditions occur while using NovaRing® , the drug should be stopped immediately.

• Thrombosis (arterial or venous) and thromboembolic events (including deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular events)
• Predisposition to develop venous or arterial thrombosis, including inherited diseases: Activated protein C resistance, antithrombin III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, and antiphospholipid antibodies (antibodies to cardiolipin, lupus anticoagulant);
• Diabetes mellitus with vascular lesions;
• Pronounced or multiple risk factors for venous or arterial thrombosis: Hereditary predisposition to thrombosis (thrombosis, myocardial infarction or cerebral circulation disorder at a young age in any immediate family member), hypertension, cardiac valve lesions, atrial fibrillation, extended surgery, prolonged immobilization, extensive trauma, obesity (body weight >30 kg/m2), smoking in women over 35 years old (see
• Pancreatitis with severe hypertriglyceridemia at present or in anamnesis.
• Severe liver disease;
• Liver tumors (malignant or benign), including a history;
• Known or suspected hormone-dependent malignancies (e.g., genital or breast);
• Vaginal bleeding of unclear etiology;
• Pregnancy, including suspected pregnancy;
• Hypersensitivity to any of the active ingredients or excipients of NovaRing®.

With caution: In the presence of any of the following diseases, conditions, or risk factors, the benefits of NovaRing® and the possible risks to each individual woman should be evaluated before starting NovaRing® . If any of the following conditions worsen, worsen, or occur for the first time, a woman should see her doctor to determine whether NovaRing® can be continued.

NovaRing® should be used with caution in the following cases: Risk factors for thrombosis and thromboembolism: hereditary predisposition to thrombosis (thrombosis, myocardial infarction or stroke at a young age in any close relative), smoking, obesity, dyslipoproteinemia, arterial hypertension, migraine without focal neurological symptoms, heart valve disease, heart rhythm disorders, long-term immobilization, serious surgical interventions thrombophlebitis of superficial veins; dyslipoproteinemia; heart valve defects; adequately controlled arterial hypertension; diabetes mellitus without vascular complications; acute or chronic liver disease; jaundice and/or pruritus due to cholestasis; cholelithiasis; porphyria; systemic lupus erythematosus; hemolytic-uremic syndrome; Sydenham’s chorea (minor chorea); Hearing loss due to otosclerosis; (hereditary) angioedema; chronic inflammatory bowel disease (Crohn’s disease and ulcerative colitis); sickle cell anemia; chloasma; conditions that may make it difficult to use a vaginal ring cervical prolapse, bladder hernia, herniated rectum, severe chronic constipation.

.

Side effects

Side effects may occur with varying frequency when using the drug:

• frequent ( ≥ 1/100);
• infrequent (< 1/100, ≥ 1/1,000);
• infrequent (< 1/1,000, ≥ 1/10,000).

Infectious and parasitic diseases:often ≥1/100 – vaginal infection; infrequent < 1/100, ≥1/1,000 – cervicitis, cystitis, urinary tract infections.

Immune system disorders:postmarketing data¹ – hypersensitivity.

Disorders of metabolism and nutrition: infrequent <1/100, ≥1/1,000 – increase in appetite.

Mental disorders:often ≥ 1/100 – depression, decreased libido; infrequent < 1/100, ≥1/1,000 – change in mood.

Nervous system disorders:often ≥ 1/100 – headache, migraine; infrequent < 1/100, ≥ 1/1,000 – dizziness, hypoesthesia.

Visual disorders: infrequent < 1/100, ≥ 1/1 000 – visual disturbance.

Vascular disorders: infrequent < 1/100, ≥ 1/1,000 – “Tides”; rare < 1/1,000, ≥ 1/10,000 – venous thromboembolism³.

Gastrointestinal Disorders:often ≥ 1/100 – abdominal pain, nausea; infrequent < 1/100, ≥ 1/1,000 – abdominal bloating, diarrhea, vomiting, constipation.

Skin and subcutaneous tissue disorders:often ≥ 1/100 – acne; infrequent < 1/100, ≥ 1/1,000 – alopecia, eczema, skin itching, rash; postmarketing data¹ – urticaria.

Muscular and connective tissue disorders: frequently < 1/100, ≥ 1/1,000 – back pain, muscle cramps, pain in the extremities.

Recreational and urinary tract disorders: infrequent < 1/100, ≥ 1/1 000 – dysuria, imperative urge to urinate, pollakiuria.

Hdisorders of the genitals and the mammary gland: often ≥ 1/100 – breast engorgement and tenderness, genital itching in women, painful menstrual-like bleeding, pelvic pain, vaginal discharge; infrequent < 1/100, ≥ 1/1,000 – absence of menstrual-like bleeding, discomfort in the breasts, breast enlargement, breast thickening, cervical polyps, contact (during intercourse) bloody discharge (bleeding), painful sensations during intercourse, cervical ectropion, Cystic fibrosis, heavy menstrual bleeding, acyclic bleeding, pelvic discomfort, premenstrual syndrome, burning sensation in the vagina, vaginal odor, vaginal pain, discomfort and dryness of the vulva and vaginal mucosa; postmarketing use data¹ – local reactions in the partner².

General disorders and disorders at the site of administration: frequently ≥ 1/100 – discomfort when applying the vaginal ring, vaginal ring prolapse; infrequent < 1/100, ≥ 1/1,000 – fatigue, irritability, malaise, swelling, foreign body sensation, difficulty applying contraceptive, ring rupture (damage).

Influence on laboratory and instrumental findings:often ≥ 1/100 – increase in body weight; infrequent < 1/100, ≥ 1/1,000 – increase in blood pressure.

¹ – The list of side effects is based on data from spontaneous reports. It is not possible to accurately determine the frequency.

² – “local reactions in the partner” include reports of “local reactions on the penile side” (e.g., pain, hyperemia, bruising and abrasions).

³ – Observational cohort study data: ≥1/10,000 to < 1/1,000 female years.

Overdose

Serious consequences of an overdose of hormonal contraceptives have not been described.

Symptoms: Possible symptoms include nausea, vomiting and slight bleeding from the vagina in young girls.

Treatment: There are no antidotes. Treatment is symptomatic.

Pregnancy use

NovaRing® is designed to prevent pregnancy. If a woman wants to stop using the drug to get pregnant, it is recommended to wait until the natural cycle is restored to conceive, as this will help correctly calculate the date of conception and delivery.

Pregnancy

The use of NovaRing® during pregnancy is contraindicated. If pregnancy occurs, the ring should be removed. Extensive epidemiologic studies have found no increased risk of birth defects in children born to women who took OCs before pregnancy and no teratogenic effects when women took OCs early in pregnancy without knowing about it. Although this is true for all OCs, it is not known whether this is also true for NovaRing®. A clinical study in a small group of women showed that despite the fact that NovaRing® is injected into the vagina, the concentrations of contraceptive sex hormones inside the uterus with NovaRing® are similar to those with OCs. No pregnancy outcomes have been described in women who used NovaRing® in a clinical trial.

Breastfeeding

The use of NovaRing® during breastfeeding is not indicated. The composition of the drug may affect lactation, reduce the amount and change the composition of breast milk. Small amounts of contraceptive sex hormones and/or their metabolites may be excreted with milk, but no evidence of adverse effects on child health has been obtained.

Children

The safety and effectiveness of NovaRing® for adolescent girls under the age of 18 years has not been studied.