Intervention: Nuvaring
Trial phase: Phase 4
SMILES: C#CC1(O)CCC2C3CCC4=CC(=O)CCC4C3C(=C)CC21CC.C#CC1(O)CCC2C3CCc4cc(O)ccc4C3CCC21C
Sex: Female
Age groups: Adult
Healthy volunteers: No
Participants at risk: 8
Group description: Nuvaring(R), one nring for a period of 21 days, inserted vaginally. Dose: per ring 11.7 mg etonrgestrel (ENG) and 2.7 mg EE releasing a daily average amount of 0.120 mg etonorgestrel and 0.015 mg EE
Eligibility criteria:
Inclusion Criteria:

Subject is at least 18 but not older than 40 years of age on Day 1 of treatment.
Subject has uterus and ovaria in situ
Subject who does not use hormonal contraception and is willing to use adequate nonhormonal contraceptive measures during the timeframe between screening and start treatment.
Subject is able and willing to refrain from caffeine and/or xanthine containing food and/or beverages (e.g. coffee, tea, cola or chocolate) from 24 hours before the first administration of the trial medication until the last PK blood sample.
Subject is willing not to consume grapefruit containing products 14 days prior to the start of the first administration of the trial medication until the last PK blood sample.
Subject is willing to refrain from smoking from 7 days prior to first administration of the trial medication until the last pharmacokinetic blood sample.
Subject is willing to refrain from alcohol containing products from 24 hours prior to first administration of the trial medication until the last pharmacokinetic blood sample.

Exclusion Criteria:

Contraindications for use of NuvaRing, contraceptive patch and oral contraceptive:
Presence or history of venous thrombosis, with or without the involvement of pulmonary embolism.
Presence or history of arterial thrombosis (e.g. cerebrovascular accident, myocardial infarction) or prodromi of a thrombosis (e.g. angina pectoris or transient ischaemic attack).
Known predisposition for venous or arterial thrombosis, with or without hereditary involvement such as Activated Protein C (APC) resistance, antithrombin-III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) and Factor V Leiden mutation.
Diabetes mellitus with vascular involvement
The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis (to be judged by the (sub-) investigator
Presence or history of severe hepatic disease as long as liver function values had not returned to normal or were judged to be clinically significant by the investigator.
Presence or history of liver tumours (benign or malignant).
Known or suspected malignant conditions of the genital organs or the breasts, if sex-steroid-influenced.
Undiagnosed vaginal bleeding.
Hypersensitivity to the active substances or to any of the excipients of NuvaRing, contraceptive patch and oral contraceptive.
Migraine with focal aura
Known or suspected pregnancy
Breastfeeding, or within 2 months after stopping breastfeeding on the day preceding the first administration of trial medication (Day -1).
Clinically significant abnormal laboratory, ECG (electrocardiogram) vital signs, physical and gynecological findings at screening.
A significant (history of) allergic or other serious disease, particularly gastrointestinal tract disease.
Smoking more than 5 cigarettes or 1 pipe or 1 cigar per day for a period of at least 3 months prior to screening.
Using any systemic medication (including over the counter (OTC) medication) during the 14 days prior to the day preceding the first administration of trial medication (Day -1), except for oral contraceptive used for synchronization and occasional Ibuprofen.
Used any drug or substance that is known to induce drug-metabolizing enzymes within two months prior to the start of synchronization.
Received a contraceptive by injection, an implant or hormonal intra-uterine device within 6 months of the day preceding the first administration of trial medication (Day -1), or a hormonal implant or hormonal intra-uterine device removed within 6 months of the day preceding the first administration of trial medication (Day -1).
Participated in a drug trial and was administered an investigational drug during the 90 days prior to start of synchronization.
Donated blood during the 90 days prior to the day preceding the first administration of trial medication (Day -1).
History (within the last 2 years) of excessive alcohol use, use of solvents or of drug abuse.
Positive drug test at screening and/or admission (Day -1), or a positive alcohol test at admission (Day -1).
Clinically significant abnormal cervical smear result (papaninecolaou (PAP) III or higher) at screening.
Acute or chronic hepatitis B/C or human immune deficiency virus (HIV) 1&2 infection.