NovaRing, vaginal rings 0.015 mg+0.120 mg/day with applicator 3 pcs

Pharmacotherapeutic group: combined contraceptive (estrogen + gestagen)

ATX code: G02BB01

Pharmacological properties

Pharmacodynamics

The mechanism of action
NovaRing® is a hormonal combined contraceptive containing etonogestrel and ethinylestradiol. Etonogestrel is a progestagen (a derivative of 19-nortestosterone) that binds with high affinity to progesterone receptors in target organs. Ethinylestradiol is an estrogen and is widely used for production of contraceptives.
Contraceptive effect of NovaRing® is caused by combination of various factors, the most important of which is suppression of ovulation.

Efficacy

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

In the background of using NovaRing® the cycle becomes more regular, the pain and intensity of menstrual-like bleeding decrease, which helps to reduce the incidence of iron deficiency. There is data on reduction of risk of endometrial and ovarian cancer during use of the drug.

The nature of bleeding

. A one-year comparison of bleeding patterns in 1000 women using NovaRing® and OCs containing levonorgestrel/ethinylestradiol (0.150/0.030 mg) showed significantly lower rates of breakthrough bleeding or smeary bleeding with NovaRing® compared to OCs. In addition, the incidence of bleeding occurring only during a break in use was significantly higher among women who used NovaRing®.

Impact on bone mineral density

A comparative two-year study between NovaRing® (n=76) and a non-hormonal IUD (n=31) showed no effect on bone mineral density in women.

Children

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

Pharmacokinetics

Etonogestrel

Intake

The etonogestrel released from the NovaRing® vaginal ring is rapidly absorbed through the vaginal mucosa. The maximum plasma concentration of etonogestrel, about 1700 pg/ml, is reached about 1 week after the insertion of the ring. Plasma concentrations vary over a small range and slowly decrease to about 1600 pg/mL after 1 week, 1500 pg/mL after 2 weeks, and 1400 pg/mL after 3 weeks of use. Absolute bioavailability is about 100%, which exceeds bioavailability with oral administration of etonogestrel. According to the results of measurements of cervical and intrauterine concentrations of etonogestrel in women using NovaRing® and women using oral contraceptives containing 0.150 mg of desogestrel and 0.020 mg of ethinylestradiol, the observed values of etonogestrel concentrations were comparable.

Distribution

Atonogestrel binds to plasma albumin and sex hormone-binding globulin (hGBS). The apparent volume of distribution of etonogestrel is 2.3 L/kg.

Metabolism

The biotransformation of etonogestrel occurs by the known pathways of sex hormone metabolism. The apparent blood plasma clearance is about 3.5 L/h. No direct interaction with ethinylestradiol taken simultaneously has been detected.

Elimination

The plasma concentrations of etonogestrel decrease in two phases. In the terminal phase, the elimination half-life is approximately 29 h. Etonogestrel and its metabolites are excreted by the kidneys and through the intestine with the bile at a ratio of about 1.7:1. The elimination half-life of the metabolites is about 6 days.

Ethinylestradiol

Ethinylestradiol released from the NovaRing® vaginal ring is quickly absorbed through the vaginal mucosa. The maximum plasma concentration of approximately 35 pg/ml is reached 3 days after ring insertion and decreases to 19 pg/ml after 1 week, to 18 pg/ml after 2 weeks and 18 pg/ml after 3 weeks of use. Absolute bioavailability is approximately 56% and is comparable to that of oral ethinylestradiol. According to the results of measurements of cervical and intrauterine ethinylestradiol concentrations in women using NovaRing® and women using oral contraceptives containing 0.150 mg of desogestrel and 0.020 mg of ethinylestradiol, the observed values of ethinylestradiol concentrations were comparable.

Ethinylestradiol concentrations were studied in a comparative randomized trial of NovaRing® (vaginal daily release of ethinylestradiol 0.015 mg), a transdermal patch (norelgestromin/ethinylestradiol; daily ethinylestradiol release 0.020 mg) and OCs (levonorgestrel/ethinylestradiol; daily ethinylestradiol release 0.030 mg) during one cycle in healthy women. Systemic exposure to ethinylestradiol over one month (AUC0-?) for NovaRing® was statistically significantly lower than for the patch and OC, at 10.9, 37.4, and 22.5 ng-h/ml, respectively.

Distribution

Ethinylestradiol binds nonspecifically to plasma albumin. The apparent volume of distribution is about 15 l/kg.

Metabolism

Ethinylestradiol is metabolized by aromatic hydroxylation. Its biotransformation produces a large number of hydroxylated and methylated metabolites. They circulate in free form or as sulfate and glucuronide conjugates. The apparent clearance is approximately 35 l/h.

Elimination

The plasma concentrations of ethinylestradiol decrease in two phases. The elimination half-life in the terminal phase varies widely; the median is about 34 h. Ethinylestradiol is not excreted unchanged. Metabolites of ethinylestradiol are excreted by the kidneys and through the intestine with the bile at a ratio of 1.3:1. The elimination half-life of metabolites is about 1.5 days.

Particular patient groups

Children
The pharmacokinetics of NovaRing® have not been studied in healthy adolescent girls under 18 years of age who have already had their periods.

Renal dysfunction
The effect of renal disease on the pharmacokinetics of NovaRing® has not been studied.

Hepatic impairment
The effect of liver disease on the pharmacokinetics of NovaRing® has not been studied. However, in patients with hepatic impairment, impairment of sex hormone metabolism is possible.

Ethnic groups
Pharmacokinetics of the drug in ethnic groups have not been specifically studied.

Indications

Active ingredient

Composition

How to take, the dosage

In order to achieve the contraceptive effect, NovaRing® must be used according to the instructions.

The woman can insert the NovaRing® vaginal ring into the vagina on her own.

The physician should inform the woman how to insert and remove the NovaRing® vaginal ring. The woman should choose a comfortable position to insert the ring, such as standing with one leg raised, squatting or lying down. The NovaRing® vaginal ring should be squeezed and inserted into the vagina until the ring is in a comfortable position. The exact position of the ring in the vagina is not critical to the contraceptive effect (Figure 1-4).

After insertion (see subsection “How to start using NovaRing®”) the ring should remain in the vagina continuously for 3 weeks. It is advisable for the woman to check regularly whether it remains in the vagina. If the ring is accidentally removed, follow the instructions in “What to do if the ring has been temporarily removed from the vagina.

The NovaRing® vaginal ring should be removed after 3 weeks on the same day of the week that the ring was inserted into the vagina. After a one-week break, a new ring is inserted (e.g., if the NovaRing® vaginal ring was inserted on Wednesday at approximately 10 p.m., it should be removed on Wednesday after 3 weeks at approximately 10 p.m. A new ring is inserted the following Wednesday). To remove the ring, you must pick it up with your index finger or squeeze it with your index and middle finger and pull it out of the vagina (Figure 5). The used ring should be placed in a bag (keep it out of reach of children and pets) and thrown away. Bleeding associated with discontinuation of NovaRing® usually begins 2-3 days after removal of the NovaRing® vaginal ring and may not stop completely until a new ring is placed.

How do I start using NovaRing®?

Deviations from the recommended regimen

The contraceptive effect and cycle control may be compromised if the woman does not adhere to the recommended regimen. The following recommendations should be followed to avoid reduced contraceptive effect.

Interaction

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

The following interactions with combined oral contraceptives in general have been described in the literature.

Hepatic metabolism: interactions with drugs that induce microsomal liver enzymes may occur, 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 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 study of pharmacokinetic interactions, 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 the 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 suppositories are used concomitantly with antifungal drugs, the risk of ring rupture is slightly increased.

Hormonal contraceptives may cause disruption of metabolism of other drugs. Accordingly, their plasma and tissue concentrations may increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

To rule out possible interactions, the instructions for use of other drugs should be consulted.

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 usually change within the normal range.

Particular 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.

The use of hormonal contraceptives can be associated with the development of 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 different OCs suggest that the greatest increase in risk, compared with the risk in women not using OCs, is 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 is 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 WL (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 WL). 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). A large prospective observational TASC (Transatlantic Active Study of Cardiovascular Safety with NovaRing®) study evaluated the risk of VTE in women who started NovaRing® or OC, switched to NovaRing® or OC from other contraceptives, or resumed NovaRing® or OC in a typical user population. Women were followed for 24 to 48 months. The results showed a similar risk of VTE in women using NovaRing® (incidence 8.3 per 10,000 LL) and in women using OCs (incidence 9.2 per 10,000 LL). 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 OCs

In extremely rare cases of thrombosis of other blood vessels (e.g., hepatic arteries and veins, 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:

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

Risk factors for arterial thromboembolic complications:

. Biochemical factors that may indicate an inherited or acquired predisposition to venous or arterial thrombosis include resistance to activated protein C, 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 cause 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 long-term use of OCs further increases this risk, but it is unclear how much of 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

Contraindications

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

Cautions

If any of the following diseases, conditions, or risk factors are present, the benefits of NovaRing® and the possible risks to the individual woman should be evaluated before starting NovaRing® (see “Special Precautions”). If any of the following conditions worsen, worsen, or occur for the first time, women should see their physician to decide whether to continue using NovaRing®.

NovaRing® should be used with caution in the following cases:

Side effects

When using the drug, side effects may occur with varying frequencies: frequently (?1/100), infrequently (< 1/100, ?1/1,000), rarely (< 1/1,000, ?1/10,000).

Overdose

Pregnancy use

NovaRing® is designed to prevent pregnancy. If a woman wants to stop using the drug to get pregnant, it is recommended that she wait until her natural cycle is restored in order to conceive, as this will help to 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 and reduce the amount and 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.