Controlled-release contraceptive ring for vaginal use. NuvaRing is a flexible, transparent, colourless to almost colourless ring, with an outer diameter of 54 mm and a cross-sectional diameter of 4 mm. NuvaRing releases etonogestrel and ethinylestradiol at an average amount of 120 g and 15

g, respectively for 24 hours, over a period of 3 weeks. The ring contains 11.7 mg etonogestrel and 2.7 mg ethinylestradiol.

Molecular formula C22H28O2 Molecular mass 324.44 Cas No. 54048-10-1 Chemical name

List of excipients:

Evatane(r) (28-25) ARTG No. 12054 Evatane(r) (1020 VN3) ARTG No. 12053 Magnesium stearate

PHARMACOLOGY

Pharmacodynamic properties:

MECHANISM OF ACTION: NuvaRing contains etonogestrel and ethinylestradiol. Etonogestrel is the biologically active metabolite of desogestrel, a progestagen widely used in oral contraceptives. It binds with high affinity to progesterone receptors in the target organs. Ethinyloestradiol is an oestrogen also widely used in contraceptive products. The contraceptive effect of NuvaRing is achieved primarily by inhibition of ovulation.

Pharmacokinetics:

NuvaRing releases relatively low doses of hormones continuously, which are rapidly absorbed by the vaginal mucosa. With the vaginal route of administration, lower doses are administered to achieve effective plasma concentrations than with many current combined oral contraceptives since a "hepatic first-pass" effect is avoided. The maximum serum values for etonogestrel and ethinylestradiol are approximately 40% and 30%, respectively, as compared to those of a comparator combined oral contraceptive (30 g ethinylestradiol / 150

g desogestrel) and occur only once per cycle. The mean etonogestrel serum levels are in the same order of magnitude as those obtained for this comparator, whereas the ethinylestradiol serum levels are approximately 50%.

NuvaRing is used continuously for three weeks. Daily variations in hormonal levels that occur during oral contraceptive use are not a feature with NuvaRing. Vaginal administration avoids daily peak concentrations. NuvaRing is not subject to factors that may affect oral contraceptive tablets' efficacy such as vomiting, food interactions and diarrhoea.

Etonogestrel:

Etonogestrel released by NuvaRing is rapidly absorbed by the vaginal mucosa. Maximum serum concentrations of etonogestrel of approximately 1700 pg/mL are reached at about 1 week after insertion. Serum concentrations show small fluctuations and slowly decrease to approximately 1400 pg/mL after 3 weeks of use. Absolute bioavailability is approximately 100%, compared to approximately 80% for the DSG/EE COC.

Etonogestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). The apparent volume of distribution of etonogestrel is 2.3 L/kg.

Etonogestrel is metabolised by the known pathways of steroid metabolism. The apparent clearance from serum is about 3.5 L/h. No direct interaction was found with the co- administered ethinylestradiol.

Etonogestrel serum levels decrease in two phases. The terminal elimination phase is characterised by a half-life of approximately 29 hours. Etonogestrel and its metabolites are excreted at a urinary to biliary ratio of about 1.7:1. The half-life of metabolite excretion is about 6 days.

Ethinylestradiol:

Ethinylestradiol released by NuvaRing is rapidly absorbed by the vaginal mucosa. Maximum serum concentrations of about 35 pg/mL are reached 3 days after insertion and decrease to 18 pg/mL after 3 weeks of use. Absolute bioavailability is approximately 56%, which is comparable with oral administration of ethinylestradiol.

Ethinylestradiol is highly but non-specifically bound to serum albumin. An apparent volume of distribution of about 15 L/kg was determined.

Ethinylestradiol is primarily metabolised by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as sulphate and glucuronides conjugates. The apparent clearance is about 35 L/h.

Ethinylestradiol serum levels decrease in two phases. The terminal elimination phase is characterised by a large individual variation in half-life, resulting in a median half-life of approximately 34 hours. Unchanged ethinylestradiol is not excreted; ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 1.3:1. The half-life of metabolite excretion is about 1.5 days.

CLINICAL TRIALS

Six efficacy and safety studies were performed in healthy, fertile and sexually active women aged 18-40 years. The endpoints included contraceptive efficacy, cycle control parameters, safety, laboratory variables and acceptability parameters. In these studies a total number of 2501 subjects using NuvaRing and 126 subjects using a comparator combined oral contraceptive (30 g ethinylestradiol / 150 g levonorgestrel) were studied. Total NuvaRing exposure was 24,519.9 treatment cycles (1879.34 women-years).

The two large efficacy and safety trials had the objective to collect at least 10 000 cycles of treatment each. In these two trials, a total of 21 in-treatment pregnancies were reported: 11 subjects did not comply with the protocol in the cycle of conception or the preceding cycle. The in-treatment pregnancies of the remaining 10 subjects were considered to be Per Protocol pregnancies representing method-failure during "perfect use". This results in a Pearl Index of 0.765 (95% confidence interval 0.367-1.407). The Pearl Index was higher in the US study (068003) than in the European study (34219). Compliance with the recommended ring/ring-free regimen was lower, and the occurrence of temporary removals higher, in the US study than the European study, which may have contributed to the difference in Pearl Index. The difference in compliance between the US and Europe has previously been reported in literature for other contraceptives. These findings indicate that the instructions for use as described in the Product Information should be followed. Contraceptive efficacy is satisfactory and the data demonstrate that NuvaRing is an efficacious contraceptive product when used in accordance with the use instructions. There are insufficient evaluated data to make direct comparisons concerning the efficacy of NuvaRing relative to other methods. These two studies permitted the occasional use of condoms to prevent the transmission of sexually transmitted diseases.

Intended bleeding was defined as bleeding/spotting which occurs only during the ring-free period. The incidence of intended bleeding over cycles 1-12 ranged from 59.9% to 68.5% in the two large efficacy and safety studies. The incidence of other bleeding patterns was low and consistent over up to 13 cycles of NuvaRing use: breakthrough bleeding/spotting (5.1%- 7.9%), absence of withdrawal bleeding (1.5-2.9%), early withdrawal bleeding (5.6-8.8%), withdrawal bleeding-spotting continuing beyond the ring-free period (mainly spotting days: 15.7-20.5%). The discontinuation rate due to bleeding irregularity was low (0.8%). The bleeding characteristics of NuvaRing were compared to those of a 30 ug EE/150 ug LNG containing COC during 13 cycles in more than 1000 women. The results of this study show that the occurrence of breakthrough bleeding or spotting varied over the Cycles 2-13 from 2.0% to 6.4% in the NuvaRing group and from 3.5% to 12.6% in the LNG/EE OC group. Superiority for the NuvaRing group over the LNG/EE OC group was demonstrated, because a statistically significantly lower incidence was observed in cycles 2 and 9 of the 13 cycles. Cycle 1 was excluded from the analysis because the starting regimens were not comparable. Furthermore, the incidence of intended bleeding patterns was statistically significantly better in the NuvaRing group for each of the cycles 1-12; these occurred in 58.8% to 72.8% of the subjects in the NuvaRing group and in 43.3% to 57.9% of the subjects in the LNG/EE OC group.

In supportive studies the ovulation-inhibiting effect of NuvaRing appeared to be similar to that of a comparator combined oral contraceptive (30 g ethinylestradiol / 150 g desogestrel). Even though NuvaRing was inserted on day 5 and the COC was started on day 1 the study data support inhibition of ovulation in the first cycle with both products. Return of ovulation was assessed by ultrasound measurements and hormone assessments. Return of ovulation is likely to occur after 12 days after ring removal (median 19 days). Return of ovulation implies restoration of fertility. This conclusion is indirectly supported by the return of menses in 90% of women by the 4th week after last NuvaRing removal and the occurrence of 27 post- treatment pregnancies after last ring removal in the two large efficacy and safety trials.

The effects of NuvaRing (n=76) on bone mineral density (BMD) were studied in comparison to a non-hormonal intrauterine device (IUD) (n=31) in women over a period of two years. The observed differences were not considered to be clinically relevant.

Acceptability of NuvaRing was assessed in the two large efficacy and safety studies. The large majority of users felt that the ring could easily be inserted (97%) or removed (98%). In total, 35.4% of the subjects in these trials discontinued: 15.1% because of an adverse event/serious adverse event, 0.8% because of bleeding irregularity, 0.9% to become pregnant, and 18.5% because of other reasons (mainly loss to follow-up, 2 women for unspecified reasons and 3 for "non acceptance of NuvaRing concept"). Male discomfort during sexual intercourse was reported by 2% of clinical trial subjects. Combined oral contraceptives (COCs) have, in addition to protection against pregnancy, several positive properties which, together with the negative properties (see 'PRECAUTIONS'), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. Apart from this, there is evidence of a reduced risk of endometrial cancer and ovarian cancer but it is not known whether these apply to NuvaRing. Furthermore, the higher-dosed COCs (50 g mg ethinylestradiol), have been shown to reduce the incidence of ovarian cysts, pelvic inflammatory disease, benign breast disease and ectopic pregnancy. Confirmation is required as to whether these benefits also apply to lower dosed COCs or NuvaRing.

CONTRAINDICATIONS

NuvaRing should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during the use of NuvaRing, it should be removed immediately. Presence or history of venous thrombosis, with or without pulmonary embolism. Presence or history of arterial thrombosis (e.g. cerebrovascular accident, myocardial infarction) or prodromi of a thrombosis (e.g. transient ischaemic attack or angina pectoris).

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 and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant). History of migraine with focal neurological symptoms. Diabetes mellitus with vascular involvement. The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication (refer to PRECAUTIONS). Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia. Presence or history of severe hepatic disease as long as liver function values have not returned to normal. 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. Known or suspected pregnancy. Hypersensitivity to the active substances or to any of the excipients of NuvaRing.

PRECAUTIONS

If 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 NuvaRing use should be discontinued. All data presented below are based upon epidemiological data obtained with combined oral contraceptives (COC). 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.

Epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. These events occur rarely. Use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all hormonal contraceptives. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. The approximate incidence of VTE in users of low oestrogen dose (< 50 g ethinylestradiol) OCs is up to 4 per 10,000 woman years compared to 0.5-3 per 10,000 woman years in non-OC users. The incidence of VTE associated with pregnancy is 6 per 10,000 pregnant woman years. VTE is fatal in 1-2% of cases.

Several epidemiology studies indicate that third generation oral contraceptives, including those containing desogestrel (etonogestrel, the progestin in NuvaRing, is the biologically active metabolite of desogestrel), are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. In general, these studies indicate an approximate two-fold increased risk, which corresponds to an additional one to two cases of venous thromboembolism per 10,000 women-years of use. However, data from additional studies have not shown this two-fold increase in risk. It is not known how NuvaRing influences the risk of VTE 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: 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 increases with:

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, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease. The increased risk of thromboembolism in the puerperium must be considered (refer to Use in Pregnancy). An increase in frequency or severity of migraine during hormonal contraceptive use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the use of hormonal contraceptives. When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with hormonal contraceptive use.

The most important risk factor for cervical cancer is persistent human papilloma virus (HPV) infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk, but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives. It is unknown how this effect relates to NuvaRing.

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 haemorrhages. Therefore, a hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women using NuvaRing.

Women with hypertriglyceridaemia, 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. 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; haemolytic 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 oestrogens 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 low-dose hormonal contraceptives (containing < 50g ethinylestradiol). However, diabetic women should be carefully monitored while using NuvaRing especially in the first months of use. Crohn's disease and ulcerative colitis have been associated 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 while 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. As with other hormonal combination contraceptives there was a tendency in the clinical studies for some subjects to experience clinically significant weight changes. In US study 068003, 10.3% had a 7% weight loss while 18.1% experienced a 7% weight gain during therapy. In the European study 34219, 8.4% had a 7% weight loss while 10.2% experienced a 7% weight gain during therapy. 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, or that the use of NuvaRing affects the treatment of vaginitis (see INTERACTIONS). Very rarely it has been reported that the ring adhered to vaginal tissue, necessitating removal by a healthcare provider. Cases of toxic shock syndrome have been associated with tampons and certain barrier contraceptives. Very rare cases of TSS have been reported by NuvaRing users; in some cases the women were also using tampons. No causal relationship between the use of NuvaRing and TSS has been established. If a patient exhibits signs or symptoms of TSS, the possibility of this diagnosis should not be excluded and appropriate medical evaluation and treatment initiated.

A complete medical history and physical examination should be taken prior to the initiation or reinstitution of NuvaRing use, guided by the CONTRAINDICATIONS and PRECAUTIONS, and should be repeated periodically. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of a hormonal contraceptive. The frequency and nature of these further periodic checks should be based upon established clinical practice guidelines and adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including routine cervical cytology. Women should be advised that NuvaRing does not protect against HIV infections (AIDS) and other sexually transmitted diseases.

The efficacy of NuvaRing may be reduced in the event of non-compliance or concomitant medication. Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

Irregular bleeding (spotting or breakthrough bleeding) may occur during the use of NuvaRing, (refer to 'BLEEDING PATTERN'). 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 under DOSAGE AND ADMINISTRATION, 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.

The extent and possible pharmacological role of exposure of male sexual partners to ethinylestradiol and etonogestrel through absorption through the penis have not been examined.

On rare occasions NuvaRing has been reported to get disconnected during use (see INTERACTIONS). Since NuvaRing's core is solid, its contents will remain intact and release of hormones will not be significantly affected. In the event of disconnection of the ring, expulsion is likely to occur (see 'What to do if NuvaRing is removed or expelled from the vagina during the 3 weeks of ring use'). If NuvaRing is broken, the woman should discard the ring and replace with a new ring.

NuvaRing 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. Therefore, it is good habit for the woman to regularly verify the presence of NuvaRing. If NuvaRing is accidentally expelled, the woman should follow the instructions given in 'What to do if NuvaRing is removed or expelled from the vagina during the 3 weeks of ring use').

Carcinogenicity/Mutagenicity:

No study has been conducted to investigate the carcinogenicity of NuvaRing. In a 24-month carcinogenicity study in rats with subdermal implants releasing 10 and 20 g etonogestrel per day, (approximately 0.3 and 0.6 times the systemic steady state exposure of women using NuvaRing), no drug-related increase in tumour incidence was observed. Studies with a combination of ethinylestradiol and desogestrel in rats and mice elicited an increased incidence of pituitary and mammary gland tumours. Long-term animal studies of natural and synthetic oestrogens have also shown an increased incidence of carcinomas in the breast, uterus, cervix, vagina, testis and liver. An increased risk of tumours in oestrogen-sensitive target organs, such as uterus, breast and ovary, is associated with prolonged oestrogen therapy in women. In rare cases, benign liver adenomas, and even more rarely, malignant liver tumours have been reported in users of combined oral contraceptives. Although benign, hepatic adenomas may rupture and cause death through intra-abdominal haemorrhage.

Etonogestrel was negative in assays for reverse gene mutation in bacteria, chromosomal aberrations in mammalian cells, and micronuclei formation in mice. Data on the genotoxic potential of ethinylestradiol are currently limited, but there is some evidence available in the literature suggesting that oestrogens may be weakly genotoxic at high doses. The genotoxic potential of the ethylene vinylacetate polymers has not been investigated.

Fertility:

NuvaRing is indicated for the prevention of pregnancy. If the woman wants to stop using NuvaRing because she wants to get pregnant, she is advised to wait until she has a natural period before trying to conceive as this will help her calculate when the baby is due.

Use in Pregnancy:

Category B3. NuvaRing is contraindicated in pregnancy. If pregnancy occurs with NuvaRing in situ, the ring should be removed. In animal studies, maternal administration of high doses of oestrogens has produced urogenital malformations in the offspring. Maternal administration of high doses of progestogens has also elicited masculinisation of the female fetus in animal studies. The clinical relevance of these animal findings is not certain. Epidemiological studies have revealed neither an increased risk of birth defects in children born to women who use COCs prior to pregnancy, nor a teratogenic effect when COCs were used inadvertently during early pregnancy. However, although this probably applies to all COCs it is not clear whether this is also the case for NuvaRing. Due to the intravaginal administration, intrauterine concentrations of the contraceptive steroids in NuvaRing are likely to be higher than in COC users. An effect on the fetus can therefore not be excluded. Clinical experience of the outcomes of pregnancies exposed to NuvaRing have not been reported.

Use in Lactation:

No postnatal toxicity data are currently available in animals or humans concerning the safety of the use of NuvaRing when breastfeeding. Contraceptive steroids and/or their metabolites are known to be excreted into the milk. Lactation may be influenced by oestrogens, as they may reduce the quantity and change the composition of breast milk. Therefore, the use of NuvaRing should generally not be recommended until the nursing mother has completely weaned her child.

INTERACTIONS WITH OTHER MEDICINES

Interactions between hormonal contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature. Hepatic metabolism: interactions can occur with medicinal products that induce microsomal enzymes, which can result in increased clearance of sex hormones (e.g. phenytoin, phenobarbital, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin, chloramphenicol, neomycin, nitrofurantoin, tetracyclines and products containing St. John's wort). Other enzyme inducers that may interact with hormonal contraceptives are: barbiturates.

Women on treatment with any of these medicinal products should temporarily use a barrier method in addition to NuvaRing or choose another method of contraception. With hepatic microsomal enzyme inducing drugs, the barrier method should be used during the time of administration and for 28 days after their discontinuation. If concomitant drug administration runs beyond the 3 weeks of a ring-cycle, the next ring should be inserted immediately, without having the usual ring-free period. Contraceptive failures have also been reported with antibiotics, such as penicillins and tetracyclines. The mechanism of this effect has not been elucidated. In a pharmacokinetic interaction study, oral administration of amoxicillin (875 mg, two times daily) or doxycycline (200 mg on day 1, followed by 100 mg per day for 10 days during use of NuvaRing), did not significantly affect pharmacokinetics of etonongestrel and ethinylestradiol (EE). Women on treatment with antibiotics (except amoxicillin and doxycycline) should use a barrier method until 7 days after discontinuation. If concomitant drug administration runs beyond the 3 weeks of a ring-cycle, the next ring should be inserted immediately, without having the usual ring- free interval. Other medicines that have been reported but not yet confirmed to reduce contraceptive efficacy are: phenylbutazone, sufamethoxypyrizadine, hydantoins. A single-dose vaginal administration of 100 mg water-based nonoxynol-9 spermicide gel did not affect the serum concentrations of etonogestrel or ethinylestradiol. A single-dose vaginal administration of an oil-based 1200 mg miconazole nitrate capsule increased the serum concentrations of etonogestrel and ethinylestradiol by approximately 17% and 16%, respectively. Following multiple doses of 200 mg miconazole nitrate by vaginal suppository or vaginal cream, the mean serum concentrations of etonogestrel and ethinylestradiol increased by up to 40%. However, based on pharmacokinetic data, vaginally administered antimycotics and spermicides are unlikely to affect the contraceptive efficacy and safety of NuvaRing. During concomitant use of antimycotic ovules the chance of ring breakage may be slightly higher (see Section 'Broken rings'). Hormonal contraceptives may interfere with the metabolism or pharmacodynamics of other drugs. Accordingly, plasma and tissue concentrations, or clinical effects may be affected. Some of these drugs include: anticoagulants, some anti-diabetic drugs, cyclosporine, theophylline, imipramine and lamotrigine. Plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine). The prescribing information of concomitant medications should be consulted to identify potential interactions.

Laboratory Tests:

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins (e.g. corticosteroid binding globulin and sex hormone binding globulin), lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

Interaction with tampons:

Pharmacokinetic data show that the use of tampons has no effect on the systemic absorption of the hormones released by NuvaRing. On rare occasions NuvaRing might be expelled while removing a tampon (see advice for 'What to do if NuvaRing is removed or expelled from the vagina during the 3 weeks of ring use').

ADVERSE EFFECTS

The most serious undesirable effects associated with the use of hormonal contraceptives are listed under PRECAUTIONS. Adverse effects that have been reported in users of NuvaRing are listed in the Table below. The most appropriate MedDRA term (version 11.0) to describe a certain adverse effect is listed:

System Organ Class	Frequency of adverse effects
	Common >= 1/100	Uncommon < 1/100, >= 1/1000	Rare < 1/1000, >= 1/10000	Post Marketing 1
Skin and subcutaneous tissue disorders	Acne	Pruritus, rash, alopecia, eczema		Urticaria
Nervous system disorders	Headache, migraine	Dizziness, hypoaesthesia
Immune system disorders				Hypersensitivity
Psychiatric disorders	Depression, libido decreased	Anxiety, mood altered
Gastrointestinal disorders	Abdominal pain, nausea, toothache,	Abdominal distension, vomiting, constipation, diarrhoea
Metabolism and nutrition disorders		Increased appetite
Investigations	Weight increased	Blood pressure increased

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System Organ Class	Common >= 1/100	Uncommon < 1/100, >= 1/1000	Rare < 1/1000, >= 1/10000	Post Marketing 1
Renal and urinary disorders	n.a.	Dysuria, micturition urgency, pollakiuria
Injury, poisoning and procedural complications	Medical device discomfort, vaginal contraceptive device expelled	Contraceptive device complication, device breakage
Reproductive system and breast disorders	Breast tenderness, dysmenorrhoea, pelvic pain, vaginal discharge genital pruritus female	Amenorrhoea, breast discomfort, breast enlargement, breast mass, cervical polyp, coital bleeding, dyspareunia, ectropion of cervix, fibrocystic breast disease, menorrhagia, metrorrhagia, pelvic discomfort, premenstrual syndrome, uterine spasm, vaginal burning sensation, vaginal odour, vaginal pain, vulvovaginal discomfort, vulvovaginal dryness		Penis disorders 2 , galactorrhoea
Neoplasm	n.a.	breast fibroadenosis
Infections and infestations	Vaginal infection	Cervicitis, cystitis, urinary tract infection
Eye disorders		Visual disturbance
Respiratory System	Bronchitis, coughing pharyngitis, rhinitis, sinusitis, URTI

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System	Common	Uncommon	Rare	Post Marketing 1
Organ Class	>= 1/100	< 1/100,	< 1/1000,
Organ Class	>= 1/100	>= 1/1000	>= 1/10000
General disorders and administration site conditions	Allergic reaction, fever, influenza- like symptoms	Fatigue, irritability, malaise, oedema, sensation of foreign body, abdomen enlarged, herpes simplex
Musculoskele- tal and connective tissue disorders		Back pain, muscle spasms, pain in extremity
Vascular disorders		Hot flush	Venous thromboe mbolism 3

Listing of adverse events based on spontaneous reporting. It is not possible to determine the exact frequency.

'Penis disorders' includes reports of 'local reaction on penis'.

Observational cohort study data: >= 1/10000 to < 1/1000 women years.

DOSAGE AND ADMINISTRATION

HOW TO USE NUVARING The woman herself can insert NuvaRing in the vagina. The physician should advise the woman how to insert and remove NuvaRing. For insertion the woman should choose a position that is most comfortable for her, e.g. standing with one leg up, squatting, or lying down. NuvaRing should be compressed and inserted into the vagina until it feels comfortable. The exact position of NuvaRing in the vagina is not critical for the contraceptive effect of the ring (see Figures 1-4). However, it must be inserted correctly to minimize the chance of expulsion. Once NuvaRing has been inserted (see 'How to start NuvaRing') it is left in the vagina continuously for 3 weeks. If NuvaRing is accidentally expelled (e.g. while removing a tampon), it can be rinsed with cool to lukewarm (not hot) water and should be reinserted immediately. In the unusual case of women whose partners object to the presence of the ring during sexual intercourse, the ring should not be temporarily removed; rather it is preferable to switch to another method of contraception. In the two major clinical studies 2.7% of women experienced ring expulsion. NuvaRing must be removed after 3 weeks of use on the same day of the week as the ring was inserted. After a ring-free interval of one week a new ring is inserted (e.g. when NuvaRing is inserted on a Wednesday at about 10 pm the ring should be removed again on the Wednesday 3 weeks later at about 10 pm. The following Wednesday a new ring should be inserted). NuvaRing can be removed by hooking the index finger under the ring or by grasping the ring between the index and middle finger and pulling it out (Figure 5). The used ring should be placed in the sachet (keep out of the reach of children and pets) and discarded as described under 'Special precautions for disposal and other handling'. The withdrawal bleed usually starts 2-3 days after removal of NuvaRing and may not have finished completely before the next ring insertion is due.

Insert the ring into the vagina with one hand (Figure 4A), if necessary the labia may be spread with the other. Push the ring into the vagina until the ring feels comfortable (Figure 4B). Leave the ring in place for 3 weeks (Figure 4C).

NuvaRing can be removed by hooking the index finger under the ring or by grasping the ring between the index and middle finger and pulling it out.

No hormonal contraceptive use in the preceding cycle

NuvaRing has to be inserted on the first day of the women's natural cycle (i.e. the first day of her menstrual bleeding). Starting on days 2-5 is allowed, but during the first cycle a barrier method (such as male condoms or spermicide) should be used in addition for the first 7 days of NuvaRing use. See 'Clinical Trials'.

Changing from a combined hormonal contraceptive

The woman should insert NuvaRing at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC.

Changing from a progestagen-only method (minipill, implant or injection) or from a progestagen-releasing intrauterine system (IUS)

The woman may switch on any day from the minipill. She should switch from an implant or the IUS on the day of its removal and from an injectable on the day when the next injection would be due. In all of these cases, the woman should use an additional barrier method for the first 7 days.

Following first-trimester abortion

The woman may start immediately. When doing so, she needs not to take additional contraceptive measures. If an immediate switch is considered undesirable, the woman should follow the advice given for 'no hormonal contraceptive use in the preceding cycle'. In the mean time, she should be advised to use an alternative contraceptive method.

Following delivery or second-trimester abortion

For breast-feeding women, refer to 'Use in Lactation'. Women should be advised to start during the fourth week after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days of NuvaRing use. However, if intercourse has already occurred, pregnancy should be excluded or the woman has to wait for her first menstrual period, before starting NuvaRing use.

Following amenorrhoea or oligomenorrhoea

Exclude the possibility of pregnancy and then start NuvaRing. The woman should be advised to additionally use a barrier contraceptive method for the first seven days of NuvaRing use. If unprotected intercourse has occurred consider the delay between conception and a positive pregnancy test. DEVIATIONS FROM THE RECOMMENDED REGIME Contraceptive efficacy and cycle control may be compromised if the woman deviates from the recommended regimen. To avoid loss of contraceptive efficacy in case of a deviation, the following advice can be given:

What to do if the patient forgets to insert a new NuvaRing after the 7 day ring free period.

The woman should insert a new ring as soon as she remembers. A barrier method such as a condom should be used in addition for the next 7 days. If intercourse took place during the ring- free interval, the possibility of a pregnancy should be considered. The longer the ring-free interval, the higher the risk of a pregnancy.

What to do if NuvaRing is removed or expelled from the vagina during the 3 weeks of ring use.

NuvaRing should be left in the vagina for a continuous period of 3 weeks. If the ring is accidentally expelled and is left outside of the vagina for less than 3 hours contraceptive efficacy is not reduced. The woman should reinsert the ring as soon as possible, but at the latest within 3 hours.

more than 3 hours during the 1st or 2nd week,

contraceptive efficacy may be reduced. The woman should reinsert the ring as soon as she remembers. A barrier method such as a condom should be used in addition to NuvaRing until NuvaRing has been in the vagina continuously for 7 days. The longer the time NuvaRing has been out of the vagina and the closer this is to the ring-free interval, the higher the risk of a pregnancy.

more than 3 hours during the 3rd week

of the three-week use period, contraceptive efficacy may be reduced. The woman should discard that ring, and one of the following two options should be chosen:

Note: Inserting a new ring will start the next three-week use period. The woman may not experience a withdrawal bleed from her previous cycle. However, breakthrough spotting or bleeding may occur. Have a withdrawal bleed and insert a new ring no later than 7 days (7x24 hours) from the time the previous ring was removed or expelled. Note: This option should only be chosen if the ring was used continuously for the preceding 7 days.

What to do if NuvaRing is not removed after 3 weeks

The contraceptive efficacy of NuvaRing is adequate for up to 4 weeks. In circumstances where the ring has been in use for between 3 and 4 weeks, the woman may maintain her one-week ring-free interval and subsequently insert a new ring. If NuvaRing has been left in place for more than 4 weeks, contraceptive efficacy may be reduced and pregnancy should be ruled out before inserting a new NuvaRing.

If the woman has not adhered to the recommended regimen and subsequently has no withdrawal bleed in the following ring-free interval, pregnancy should be ruled out before inserting a new NuvaRing.

HOW TO SHIFT PERIODS OR HOW TO DELAY A PERIOD To delay a period the woman may insert a new ring without having a ring-free interval. The next ring can be used for up to 3 weeks again. The woman may experience bleeding or spotting. Regular use of NuvaRing is then resumed after the usual one-week ring-free interval. To shift her period to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming ring-free interval by as many days as she likes. The shorter the ring-free interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough bleeding and spotting during the use of the next ring.

OVERDOSAGE

There have been no reports of serious deleterious effects from an overdose of hormonal contraceptives. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

PRESENTATION AND STORAGE CONDITIONS

Presentation: Sachet containing one NuvaRing. The sachet is made of aluminum foil with an inner layer of low-density polyethylene and an outer layer of polyester. It is reclosable and waterproof. The sachet is packed in a printed cardboard box together with the package leaflet. Each box contains 1 or 3 rings.

Shelf life and special storage precautions:

40 months Prior to dispensing: 36 months, store in a refrigerator (2degC-8degC). At the time of dispensing: The dispenser places a date of dispensing on the box and the sachet(s). The product should not be inserted after the expiry date or 4 months from the date of dispensing, whichever comes first. After dispensing: 4 months, do not store above 30degC. Store NuvaRing in the original package. Protect from light and freezing.

Special precautions for disposal and other handling

Refer to DOSAGE AND ADMINISTRATION. The dispenser has to indicate the date of dispensing and the date before which NuvaRing has to be used on the box. After removal, NuvaRing should be replaced in the reclosable sachet and disposed of with the normal household waste in a manner that avoids accidental contact with others. NuvaRing should not be flushed down the toilet.

NAME AND ADDRESS OF THE SPONSOR

Merck Sharp & Dohme (NZ) Ltd P O Box 99 851 Newmarket Auckland 1149 Tel: 0800 500 673

Trial	Country	Study design	Duration of treatment	NuvaRing N	Comparator N	Efficacy, safety, vaginal bleeding	Specific safety
34219	Europe	Open-label, non- comparative	13 cycles	1145		X
34220	Finland	Open-label, comparative	6 cycles	40	43	X	Lipid metabolism
34221	Iceland	Open-label, comparative	6 cycles	44	43	X	Coagulation & fibrinolysis
34222	UK & Netherlands	Open-label, comparative	6 cycles	37	40	X	Carbohydrate metabolism, adrenal & thyroid function
068003	USA & Canada	Open-label, non- comparative	13 cycles	1177		X
068004	USA	Open-label, non- comparative	13 cycles	58		X	Local effects

NEW ZEALAND DATA SHEET

NAME OF THE MEDICINE

DESCRIPTION