Special Warning : אזהרת שימוש

4.4       Special warnings and precautions for use

Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of NuvaRing should be discussed with the woman.

In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of NuvaRing should be discontinued.

1.        Circulatory Disorders

Risk of venous thromboembolism (VTE)

•      The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as NuvaRing may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with NuvaRing, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

•      In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman, the risk may be far higher, depending on her underlying risk factors (see below).

•      It is estimated that out of 10,000 women who use a low dose CHC that contains levonorgestrel, about 61 will develop a VTE in one year. Inconsistent results on the risk of VTE with NuvaRing compared with CHCs that contain levonorgestrel have been found 

1   Mid-point range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6
(with relative risk estimates ranging from no increase, RR=0.96, to an almost 2-fold increase, RR=1.90). This corresponds to between about 6 and 12 VTEs in a year out of 10,000 women who use NuvaRing.

•   In both cases, the number of VTEs per year is fewer than the number expected in women during pregnancy or in the postpartum period.

•   VTE may be fatal in 1-2 % of the cases.



Number of VTE events per 10,000 women in one year



•     Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, or retinal veins and arteries.

Risk factors for VTE
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).

NuvaRing is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative, a CHC should not be prescribed (see section 4.3).

Table: Risk factors for VTE
Risk factor                                        Comment
Obesity (body mass index over 30 kg/m²)            Risk increases substantially as BMI rises.
Particularly important to consider if other risk factors also present.

Prolonged immobilisation, major surgery, any In these situations it is advisable to surgery to the legs or pelvis, neurosurgery, or discontinue use of the patch/pill/ring (in the major trauma                                    case of elective surgery at least four weeks in advance) and not resume until two weeks
Note: Temporary immobilisation including air after complete remobilisation. Another travel > 4 hours can also be a risk factor for  method of contraception should be used to VTE, particularly in women with other risk      avoid unintentional pregnancy.
factors.
Antithrombotic treatment should be considered if NuvaRing has not been discontinued in advance.

Positive family history (venous                 If a hereditary predisposition is suspected, thromboembolism ever in a sibling or parent     the woman should be referred to a specialist especially at a relatively early age, e.g.      for advice before deciding about any CHC before 50)                                      use.

Other medical conditions associated with        Cancer, systemic lupus erythematosus, VTE                                             haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease

Increasing age                                  Particularly above 35 years 

•      There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

•      The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium must be considered (for information on “Pregnancy and lactation” see section        4.6).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of deep vein thrombosis (DVT) can include:
- unilateral swelling of the leg and/or foot or along a vein in the leg; - pain or tenderness in the leg which may be felt only when standing or walking; - increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:
- sudden onset of unexplained shortness of breath or rapid breathing; - sudden coughing which may be associated with haemoptysis;
- sharp chest pain;
- severe light headedness or dizziness;
- rapid or irregular heartbeat.
Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.

If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE
The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). NuvaRing is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for ATE
Risk factor                                      Comment
Increasing age                                   Particularly above 35 years 
Smoking                                          Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception.
Hypertension

Obesity (body mass index over 30 kg/m2)          Risk increases substantially as BMI increases.

Particularly important in women with additional risk factors

Positive family history (arterial                If a hereditary predisposition is suspected, thromboembolism ever in a sibling or parent      the woman should be referred to a specialist especially at relatively early age, e.g. below   for advice before deciding about any CHC 50)                                              use.

Migraine                                         An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.

Other medical conditions associated with         Diabetes mellitus, hyperhomocysteinaemia, adverse vascular events                          valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.
Symptoms of ATE

In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of a cerebrovascular accident can include:
− sudden numbness or weakness of the face, arm or leg, especially on one side of the body;
− sudden trouble walking, dizziness, loss of balance or coordination; − sudden confusion, trouble speaking or understanding;
− sudden trouble seeing in one or both eyes;
− sudden, severe or prolonged headache with no known cause;
− loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA).

Symptoms of a myocardial infarction (MI) can include:
− pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;
− discomfort radiating to the back, jaw, throat, arm, stomach;
− feeling of being full, having indigestion or choking;
− sweating, nausea, vomiting or dizziness;
− extreme weakness, anxiety, or shortness of breath;
− rapid or irregular heartbeats.

•    In case of suspected or confirmed VTE or ATE, CHC 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 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.


3.   ALT elevations
•    During clinical trials with patients treated for hepatitis C virus infections (HCV) with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see sections 4.3 and 4.5).

4.   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; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss.
•    Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired 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.
•    New onset or deterioration of Crohn’s disease and ulcerative colitis has been reported to occur with the use of hormonal contraceptives, but the evidence of an association with its use is inconclusive.
•    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, or that the use of NuvaRing affects the treatment of vaginitis (see section 4.5).
•   Very rarely it has been reported that the ring adhered to vaginal tissue, necessitating removal by a healthcare provider. In some cases when the tissue had grown over the ring, removal was achieved by cutting the ring without incising the overlying vaginal tissue.
•   Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

Medical examination/consultation

Prior to the initiation or reinstitution of NuvaRing use a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of NuvaRing compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based upon established practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy

The efficacy of NuvaRing may be reduced in the event of non-compliance (section 4.2), or when concomitant medications that decrease the plasma concentration of ethinylestradiol and/or etonogestrel are used (section 4.5).

Reduced cycle control

Irregular 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 etonogestrel
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.

Broken rings

On very rare occasions NuvaRing has been reported to get disconnected during use (see section 4.5). Vaginal injury associated with ring breakage has been reported. 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 male condom in addition for the next 7 days. The possibility of a pregnancy should be considered and the woman should contact her physician.

Expulsion

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. 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 (for example, before and after intercourse).

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.

Effects on Driving

4.7    Effects on ability to drive and use machines

On the basis of the pharmacodynamic profile, NuvaRing has no or negligible influence on the ability to drive and use machines.