|WARNINGSIf any of the conditions/risk factors mentioned below is present, the benefits of the use of NuvaRing should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether its use should be discontinued. All data presented below are based upon epidemiological data obtained with combined oral contraceptives. No epidemiological data are available on vaginal route of administration for the hormones but the warnings are also considered applicable to the use of NuvaRing.|
1. Circulatory Disorders• The use of hormonal contraceptives has been associated with the occurrence of venous thrombosis (deep venous thrombosis and pulmonary embolism) and arterial thrombosis and associated complications, sometimes with fatal consequences.• Use of any combined oral contraceptive (COC) carries an increased risk of venous thromboembolism (VTE) compared with no use. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 per 100 000 pregnant woman years. VTE is fatal in 1%-2% of cases.It is not known how NuvaRing influences the risk compared with other combined hormonal contraceptives.• Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral, or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.• Symptoms of venous or arterial thrombosis can include: unusual, unilateral leg pain and / or swelling; sudden severe pain in the chest, whether or not it radiates to the left arm; sudden breathlessness; sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure; weakness or very marked numbness suddenly affecting one side or one part of the body; motor disturbances; 'acute' abdomen.• The risk of venous thromboembolism (VTE) increases with:- increasing age;- a positive family history (i.e. venous thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use;- prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization.- obesity (body mass index over 30 kg/m2);- and possibly also with superficial thrombophlebitis and varicose veins. There is no consensus about the possible role of these conditions in the etiology of venous thrombosis.• The risk of arterial thromboembolic complications increases with:- increasing age;- smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);- dyslipoproteinemia;- obesity (body mass index over 30 kg/m2);- hypertension;- migraine;- valvular heart disease;- atrial fibrillation; - a positive family history (arterial thrombosis ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use.• Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).• Other medical conditions, which have been associated with adverse circulatory events, include diabetes mellitus, systemic lupus erythematosus, hemolytic uraemic syndrome, chronic inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis).• The increased risk of thromboembolism in the puerperium must be considered (for information on 'Pregnancy and Lactation' see Section 4.6).• An increase in frequency or severity of migraine (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of NuvaRing use.• Women using COCs should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).
2. Tumours• Epidemiological studies indicate that the long-term use of oral contraceptives displays a risk factor for the development of cervical cancer in women infected with human papillomavirus (HPV). However, there is still uncertainty about the extent to which this finding is influenced by confounding effects (e.g. differences in number of sexual partners or in use of barrier contraceptives). No epidemiological data on the risk of cervical cancer in users of NuvaRing are available (see 'medical examination/consultation').• A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both.• In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal hemorrhages. Therefore, a hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women using NuvaRing.
3. Other conditions• Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives.• Although small increases in blood pressure have been reported in many women using hormonal contraceptives, clinically relevant increases are rare. A definitive relationship between hormonal contraceptive use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of NuvaRing then it is prudent for the physician to suspend the use of the ring and treat the hypertension. Where considered appropriate, NuvaRing use may be resumed if normotensive values can be achieved with antihypertensive therapy.• The following conditions have been reported to occur or deteriorate with both pregnancy and during the use of hormonal contraceptives, but the evidence of an association with its use is inconclusive: jaundice and / or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss, (hereditary) angioedema.• Acute or chronic disturbances of liver function may necessitate the discontinuation of the use of NuvaRing until markers of liver function return to normal. Recurrence of cholestatic jaundice and/ or pruritus related to cholestasis, which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of the ring.• Although estrogens and progestagens may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using hormonal contraception. However, diabetic women should be carefully monitored while using NuvaRing especially in the first months of use.• A deterioration of Crohn's disease and colitis ulcerosa has been reported in association with the use of hormonal contraceptives.• Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst using NuvaRing.• If a woman has any of the following conditions she may not be able to insert NuvaRing correctly or may in fact lose the ring: prolapse of the uterine cervix, cystocele and/or rectocele, severe or chronic constipation. Very rarely it has been reported that NuvaRing is inadvertently inserted in the urethra and possibly ending up in the bladder. Therefore, incorrect positioning should be considered in the differential diagnosis in case of symptoms of cystitis.
• During the use of NuvaRing, women may occasionally experience vaginitis. There are no indications that the efficacy of NuvaRing is affected by the treatment of vaginitis, nor that the use of NuvaRing affects the treatment of vaginitis (see Section 4.5 'Interactions').
• Very rarely it has been reported that the ring adhered to vaginal tissue, necessitating removal by a healthcare provider.MEDICAL EXAMINATION/CONSULTATIONPrior to the initiation or reinstitution of NuvaRing use a complete medical history (including a family medical history) should be taken and pregnancy should be excluded. The blood pressure and a physical examination should be taken, guided by the contraindications (Section 4.3) and warnings (Section 4.4). The woman should be advised to carefully read the package leaflet and to follow the advice given. The frequency and nature of further periodic checks should be based upon established clinical practice and adapted to the individual woman.Women should be advised that NuvaRing does not protect against HIV infections (AIDS) and other sexually transmitted diseases.REDUCED EFFICACYThe efficacy of NuvaRing may be reduced in the event of non-compliance (Section 4.2), or concomitant medication (Section 4.5).REDUCED CYCLE CONTROLIrregular bleeding (spotting or breakthrough bleeding) may occur during the use of NuvaRing. If bleeding irregularities occur after previously regular cycles while NuvaRing has been used according to the recommended regimen, then non-hormonal causes should be considered, and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.In some women a withdrawal bleed may not occur during the ring-free interval. If NuvaRing has been used according to the instructions described in Section 4.2, it is unlikely that the woman is pregnant. However, if NuvaRing has not been used according to these instructions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before use of NuvaRing is continued.MALE EXPOSURE TO ETHINYL ESTRADIOL AND ETONOGESTRELThe extent and possible pharmacological role of exposure of male sexual partners to ethinylestradiol and etonogestrel through absorption through the penis have not been examined.BROKEN RINGSOn very rare occasions NuvaRing has been reported to get disconnected during use (see Section 4.5 'Interactions'). The woman is advised to remove the broken ring and reinsert a new ring as soon as possible and use a barrier method such as a condom in addition for the next 7 days. The possibility of a pregnancy should be considered and the woman should contact her physician.EXPULSIONNuvaRing has been reported to get expelled, for example if the ring has not been inserted properly, while removing a tampon, during sexual intercourse, or in case of severe or chronic constipation. Prolonged expulsion may lead to contraceptive failure and/or breakthrough bleeding. Therefore, to ensure efficacy the woman should be advised to regularly verify the presence of NuvaRing.If NuvaRing is accidentally expelled and is left outside of the vagina for less than 3 hours contraceptive efficacy is not reduced. The woman should rinse the ring with cool to lukewarm (not hot) water and reinsert it as soon as possible, but at the latest within 3 hours.If NuvaRing has been out of the vagina, or is suspected to have been out of the vagina for more than 3 hours contraceptive efficacy may be reduced. In that case, the applicable advice given in Section 4.2 'What to do if the ring was temporarily outside the vagina' should be followed.