NuvaRing 0.12mg/0.015mg per day vaginal delivery system

Package leaflet: Information for the user

NuvaRing®, 0.120 mg/0.015 mg per 24 hours, vaginal delivery system

Etonogestrel/Ethinylestradiol

Important things to know about combined hormonal contraceptives (CHCs):

They are one of the most reliable reversible methods of contraception if used correctly.

They slightly increase the risk of having a blood clot in the veins and arteries, especially in the

first year or when restarting a combined hormonal contraceptive following a break of 4 or more

weeks.

Please be alert and see your doctor if you think you may have symptoms of a blood clot (see

section 2 “Blood clots”).

Read all of this leaflet carefully before you start using NuvaRing

because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What NuvaRing is and what it is used for

What you need to know before you use NuvaRing

When you should not use NuvaRing

Warnings and precautions

Blood clots

Cancer

Children and adolescents

Other medicines and NuvaRing

Laboratory tests

Pregnancy and breast-feeding

Driving and using machines

How to use NuvaRing

How to insert and remove NuvaRing

Three weeks in, one week out

When to start with the first ring

What to do if…

Your ring is accidentally expelled from the vagina

Your ring has temporarily been out of the vagina

Your ring breaks

You have inserted more than one ring

You have forgotten to insert a new ring after the ring-free interval

You have forgotten to remove the ring

You have missed a menstrual period

You have unexpected bleeding

You want to change the first day of your menstrual period

You want to delay your menstrual period

When you want to stop using NuvaRing

Possible side effects

How to store NuvaRing

Contents of the pack and other information

What NuvaRing contains

What NuvaRing looks like and contents of the pack

Marketing Authorisation Holder and Manufacturer

1.

What NuvaRing is and what it is used for

NuvaRing is a contraceptive vaginal ring used to prevent pregnancy. Each ring contains a small

amount of two female sex hormones – etonogestrel and ethinylestradiol. The ring slowly releases

these hormones into the blood circulation. Because of the low amount of hormones that is released,

NuvaRing is considered a low-dose hormonal contraceptive. Since NuvaRing releases two different

types of hormones it is a so-called combined hormonal contraceptive.

NuvaRing works just like a combined contraceptive pill (the Pill) but instead of taking a pill every

day, the ring is used for 3 weeks in a row. NuvaRing releases two female sex hormones that prevent

the release of an egg cell from the ovaries. If no egg cell is released you cannot become pregnant.

2.

What you need to know before you use NuvaRing

General notes

Before you start using NuvaRing you should read the information on blood clots in section 2. It is

particularly important to read the symptoms of a blood clot – see section 2 “Blood clots”.

In this leaflet, several situations are described where you should stop using NuvaRing, or where

NuvaRing

may be less reliable. In such situations you should not have intercourse or you should take

extra non-hormonal contraceptive precautions – such as using a male condom or another barrier

method. Do

not

use rhythm or temperature methods. These methods can be unreliable because

NuvaRing

alters the monthly changes of the body temperature and of the cervical mucus.

NuvaRing, like other hormonal contraceptives, does not protect against HIV infection (AIDS) or

any other sexually transmitted disease.

2.1

When you should not use NuvaRing

You should not use NuvaRing if you have any of the conditions listed below. If you do have any of

the conditions listed below, you must tell your doctor. Your doctor will discuss with you what other

form of birth control would be more appropriate.

if you have (or have ever had) a blood clot in a blood vessel of your legs (deep vein thrombosis,

DVT), your lungs (pulmonary embolus, PE) or other organs;

if you know you have a disorder affecting your blood clotting - for instance, protein C deficiency,

protein S deficiency, antithrombin – III deficiency, Factor V Leiden or antiphospholipid

antibodies;

if you need an operation or if you are off your feet for a long time (see section ‘Blood clots’);

if you have ever had a heart attack, or a stroke;

if you have (or have ever had) angina pectoris (a condition that causes severe chest pain and may

be a first sign of a heart attack) or transient ischaemic attack (TIA – temporary stroke symptoms);

if you have any of the following diseases that may increase your risk of a clot in the arteries:

severe diabetes with blood vessel damage

very high blood pressure

a very high level of fat in the blood (cholesterol or triglycerides)

a condition known as hyperhomocysteinaemia

if you have (or have ever had) a type of migraine called ‘migraine with aura’;

if you have (had) inflammation of the pancreas (pancreatitis) associated with high levels of fat in

your blood;

if you have (had) severe liver disease and your liver is not yet working normally;

if you have (had) a benign or malignant tumour in the liver;

if you have (had), or if you may have, cancer of the breast or the genital organs;

if you have any unexplained vaginal bleeding;

if you are allergic to ethinylestradiol or etonogestrel, or any of the other ingredients of this

medicine (listed in section 6).

If any of these conditions appear for the first time while using NuvaRing, remove the ring

immediately and contact your doctor. In the meantime, use non-hormonal contraceptive measures.

Do not use NuvaRing if you have hepatitis C and are taking medicinal products containing

ombitasvir/paritaprevir/ritonavir and dasabuvir (see also section 2.4 ‘

Other medicines and

NuvaRing

’).

2.2

Warnings and precautions

Tell your doctor if any of the following conditions apply to you.

If the condition develops, or gets worse while you are using NuvaRing, you should also tell your

doctor.

if a close relative has or has ever had breast cancer;

if you have epilepsy (see section 2.4: ‘

Other medicines and NuvaRing’

if you have liver disease (for instance jaundice) or gallbladder disease (for instance gallstones);

if you have Crohn’s disease or ulcerative colitis (chronic inflammatory bowel disease);

if you have systemic lupus erythematosus (SLE - a disease affecting your natural defence

system);

if you have haemolytic uraemic syndrome (HUS - a disorder of blood clotting causing failure of

the kidneys);

if you have sickle cell anaemia (an inherited disease of the red blood cells);

if you have elevated levels of fat in the blood (hypertriglyceridaemia) or a positive family

history for this condition. Hypertriglyceridaemia has been associated with an increased risk of

developing pancreatitis (inflammation of the pancreas);

if you need an operation, or you are off your feet for a long time (see in section 2 ‘Blood

clots’);

if you have just given birth you are at an increased risk of blood clots. You should ask your

doctor how soon after delivery you can start using NuvaRing;

if you have an inflammation in the veins under the skin (superficial thrombophlebitis);

if you have varicose veins;

if you have a condition that occurred for the first time or worsened during pregnancy or

previous use of sex hormones (e.g. hearing loss, porphyria [a disease of the blood], herpes

gestationis [skin rash with vesicles during pregnancy], Sydenham’s chorea [a disease of the

nerves in which sudden movements of the body occur], hereditary angioedema [y

ou should see

your doctor immediately if you experience symptoms of angioedema such as swollen face,

tongue and/or throat and/or difficulty swallowing or hives together with difficulty breathing

if you have (or have ever had) chloasma (yellowish-brown pigment patches, so called

‘pregnancy patches’, particularly on the face). If so, avoid too much exposure to the sun or

ultraviolet light;

When should you contact your doctor?

Seek urgent medical attention

if you notice possible signs of a blood clot that may mean you are suffering from a

blood clot in the leg (i.e. deep vein thrombosis), a blood clot in the lung (i.e.

pulmonary embolism), a heart attack or a stroke (see ‘Blood clots’ section below).

For a description of the symptoms of these serious side effects please go to “How to

recognise a blood clot”.

if you have a medical condition that makes it difficult to use NuvaRing – for example, if you

are constipated, have a prolapse of the uterine cervix or have pain during intercourse;

if you have an urgent, frequent, burning, and/or painful urination, and cannot locate the ring in

the vagina. These symptoms may indicate accidental placement of NuvaRing into the urinary

bladder.

BLOOD CLOTS

Using a combined hormonal contraceptive such as NuvaRing increases your risk of developing a

blood clot compared with not using one. In rare cases a blood clot can block blood vessels and cause

serious problems.

Blood clots can develop

in veins (referred to as a ‘venous thrombosis’, ‘venous thromboembolism’ or VTE);

in the arteries (referred to as an ‘arterial thrombosis’, ‘arterial thromboembolism’ or ATE).

Recovery from blood clots is not always complete. Rarely, there may be serious lasting effects or,

very rarely, they may be fatal.

It is important to remember that the overall risk of a harmful blood clot due to NuvaRing is

small.

HOW TO RECOGNISE A BLOOD CLOT

Seek urgent medical attention if you notice any of the following signs or symptoms.

Are you experiencing any of these signs?

What are you possibly

suffering from?

swelling of one leg or along a vein in the leg or foot especially when

accompanied by:

pain or tenderness in the leg which may be felt only when

standing or walking

increased warmth in the affected leg

change in colour of the skin on the leg e.g. turning pale, red or

blue

Deep vein thrombosis

sudden unexplained breathlessness or rapid breathing;

sudden cough without an obvious cause, which may bring up blood;

sharp chest pain which may increase with deep breathing;

severe light headedness or dizziness;

rapid or irregular heartbeat;

severe pain in your stomach;

If you are unsure, talk to a doctor as some of these symptoms such as

coughing or being short of breath may be mistaken for a milder condition

such as a respiratory tract infection (e.g. a ‘common cold’).

Pulmonary embolism

Symptoms most commonly occur in one eye:

immediate loss of vision or

painless blurring of vision which can progress to loss of vision

Retinal vein thrombosis

(blood clot in the eye)

chest pain, discomfort, pressure, heaviness

sensation of squeezing or fullness in the chest, arm or below the

Heart attack

breastbone;

fullness, indigestion or choking feeling;

upper body discomfort radiating to the back, jaw, throat, arm and

stomach;

sweating, nausea, vomiting or dizziness;

extreme weakness, anxiety, or shortness of breath;

rapid or irregular heartbeats

sudden weakness or numbness of the face, arm or leg, especially on

one side of the body;

sudden confusion, trouble speaking or understanding;

sudden trouble seeing in one or both eyes;

sudden trouble walking, dizziness, loss of balance or coordination;

sudden, severe or prolonged headache with no known cause;

loss of consciousness or fainting with or without seizure.

Sometimes the symptoms of stroke can be brief with an almost immediate

and full recovery, but you should still seek urgent medical attention as you

may be at risk of another stroke.

Stroke

swelling and slight blue discolouration of an extremity;

severe pain in your stomach (acute abdomen).

Blood clots blocking

other blood vessels

BLOOD CLOTS IN A VEIN

What can happen if a blood clot forms in a vein?

The use of combined hormonal contraceptives has been connected with an increase in the risk

of blood clots in the vein (venous thrombosis). However, these side effects are rare. Most

frequently, they occur in the first year of use of a combined hormonal contraceptive.

If a blood clot forms in a vein in the leg or foot it can cause a deep vein thrombosis (DVT).

If a blood clot travels from the leg and lodges in the lung it can cause a pulmonary embolism.

Very rarely a clot may form in a vein in another organ such as the eye (retinal vein thrombosis).

When is the risk of developing a blood clot in a vein highest?

The risk of developing a blood clot in a vein is highest during the first year of taking a combined

hormonal contraceptive for the first time. The risk may also be higher if you restart taking a combined

hormonal contraceptive (the same product or a different product) after a break of 4 weeks or more.

After the first year, the risk gets smaller but is always slightly higher than if you were not using a

combined hormonal contraceptive.

When you stop using NuvaRing your risk of a blood clot returns to normal within a few weeks.

What is the risk of developing a blood clot?

The risk depends on your natural risk of VTE and the type of combined hormonal contraceptive you

are taking.

The overall risk of a blood clot in the leg or lung (DVT or PE) with NuvaRing is small.

Out of 10,000 women who are not using any combined hormonal contraceptive and are not

pregnant, about 2 will develop a blood clot in a year.

Out of 10,000 women who are using a combined hormonal contraceptive that contains

levonorgestrel, norethisterone, or norgestimate, about 5-7 will develop a blood clot in a year.

Out of 10,000 women who are using a combined hormonal contraceptive that contains

norelgestromin, or etonogestrel such as NuvaRing, between about 6 and 12 women will develop

a blood clot in a year.

The risk of having a blood clot will vary according to your personal medical history (see

“Factors that increase your risk of a blood clot” below).

Risk of developing a blood clot

in a year

Women who are

not using

a combined hormonal pill/patch/ring

and are not pregnant

About 2 out of 10,000 women

Women using a combined hormonal contraceptive pill containing

levonorgestrel, norethisterone or

norgestimate

About 5-7 out of 10,000 women

Women using NuvaRing

About 6-12 out of 10,000

women

Factors that increase your risk of a blood clot in a vein

The risk of a blood clot with NuvaRing is small but some conditions will increase the risk. Your risk

is higher:

if you are very overweight (body mass index or BMI over 30 kg/m

if one of your immediate family has had a blood clot in the leg, lung or other organ at a young

age (e.g. below the age of about 50). In this case you could have a hereditary blood clotting

disorder;

if you need to have an operation, or if you are off your feet for a long time because of an injury

or illness, or you have your leg in a cast. The use of NuvaRing may need to be stopped several

weeks before surgery or while you are less mobile. If you need to stop using NuvaRing ask your

doctor when you can start using it again;

as you get older (particularly above about 35 years);

if you gave birth less than a few weeks ago.

The risk of developing a blood clot increases the more conditions you have.

Air travel (>4 hours) may temporarily increase your risk of a blood clot, particularly if you have some

of the other factors listed.

It is important to tell your doctor if any of these conditions apply to you, even if you are unsure. Your

doctor may decide that NuvaRing needs to be stopped.

If any of the above conditions change while you are using NuvaRing, for example a close family

member experiences a thrombosis for no known reason, or you gain a lot of weight, tell your doctor.

BLOOD CLOTS IN AN ARTERY

What can happen if a blood clot forms in an artery?

Like a blood clot in a vein, a clot in an artery can cause serious problems. For example, it can cause a

heart attack or a stroke.

Factors that increase your risk of a blood clot in an artery

It is important to note that the risk of a heart attack or stroke from using NuvaRing is very small but

can increase:

with increasing age (beyond about 35 years);

if you smoke.

When using a combined hormonal contraceptive like NuvaRing you are advised

to stop smoking. If you are unable to stop smoking and are older than 35 your doctor may

advise you to use a different type of contraceptive;

if you are overweight;

if you have high blood pressure;

if a member of your immediate family has had a heart attack or stroke at a young age (less than

about 50). In this case you could also have a higher risk of having a heart attack or stroke;

if you, or someone in your immediate family, have a high level of fat in the blood (cholesterol

or triglycerides);

if you get migraines, especially migraines with aura;

if you have a problem with your heart (valve disorder, disturbance of the rhythm called atrial

fibrillation);

if you have diabetes.

If you have more than one of these conditions or if any of them are particularly severe, the risk of

developing a blood clot may be increased even more.

If any of the above conditions change while you are using NuvaRing, for example, you start smoking,

a close family member experiences a thrombosis for no known reason, or you gain a lot of weight, tell

your doctor.

Cancer

The information given below was obtained in studies with combined oral contraceptives and it may

also apply to NuvaRing. Information about vaginal administration of contraceptive hormones (as in

NuvaRing) is not available.

Breast cancer has been found slightly more often in women using combined pills, but it is not known

whether this is caused by the treatment. For example, it may be that tumours are found more in

women on combined pills because they are examined by the doctor more often. The increased

occurrence of breast cancer becomes gradually less after stopping the combined pill.

It is important to regularly check your breasts and you should contact your doctor if you feel any

lump. You should also tell your doctor if a close relative has, or ever had breast cancer (see

section 2.2 ‘

Warnings and precautions

’).

In rare cases, benign liver tumours, and in even fewer cases malignant liver tumours have been

reported in pill users. Contact your doctor if you have unusual severe abdominal pain.

For users of the combined Pill it has been reported that cancer of the endometrium (the lining of the

womb) and cancer of the ovaries occur less frequently. This may also be the case for NuvaRing but

this has not been confirmed.

2.3

Children and adolescents

The safety and efficacy of NuvaRing in adolescents under the age of 18 have not been studied.

2.4

Other medicines and NuvaRing

Always tell your doctor which medicines or herbal products you are already using. Also tell any other

doctor or dentist (or the pharmacist) who prescribes another medicine that you use NuvaRing. They

can tell you if you need to take additional contraceptive precautions (for example, male condoms) and

if so, for how long, or, whether the use of another medicine you need must be changed.

Some medicines

can have an influence on the blood levels of NuvaRing;

can make it

less effective in preventing pregnancy

can cause unexpected bleeding.

These include medicines used for the treatment of:

epilepsy (e.g. primidone, phenytoin, barbiturates, carbamazepine, oxcarbazepine,

topiramate, felbamate);

tuberculosis (e.g. rifampicin);

HIV infection (e.g. ritonavir, nelfinavir, nevirapine, efavirenz);

Hepatitis C virus infection (e.g. boceprevir, telaprevir);

other infectious diseases (e.g. griseofulvin);

high blood pressure in the blood vessels of the lungs (bosentan);

depressive moods (the herbal remedy St. John’s wort (Hypericum perforatum)).

If you are taking medicines or herbal products that might make NuvaRing less effective, a barrier

contraceptive method should also be used. Since the effect of another medicine on NuvaRing may last

up to 28 days after stopping the medicine, it is necessary to use the additional barrier contraceptive

method for that long. Note: Do not use NuvaRing with a diaphragm, cervical cap, or female condom.

NuvaRing may influence the effect of other medicines, e.g.

- medicines containing ciclosporin

- the anti-epileptic lamotrigine (this could lead to an increased frequency of seizures)

Do not use NuvaRing if you have Hepatitis C and are taking medicinal products containing

ombitasvir/paritaprevir/ritonavir and dasabuvir as this may cause increases in liver function blood test

results (increase in ALT liver enzyme).

Your doctor will prescribe another type of contraceptive prior to the start of treatment with these

medicinal products.

NuvaRing can be restarted approximately 2 weeks after completion of this treatment. See section 2.1

When you should not use NuvaRing’

Ask your doctor or pharmacist for advice before taking any medicine.

You can use tampons while using NuvaRing. Insert NuvaRing before inserting a tampon. You should

be careful when removing a tampon to be sure that the ring is not accidentally pulled out. If the ring

does come out, simply rinse the ring in cool to lukewarm water and immediately reinsert it.

Using spermicides or vaginal yeast products will not reduce the contraceptive efficacy of NuvaRing.

Laboratory tests

If you are having any blood or urinary test, tell your health care professional that you are using

NuvaRing as it may affect the results of some tests.

2.5

Pregnancy and breast-feeding

NuvaRing must not be used by women who are pregnant, or who think they may be pregnant. If you

get pregnant while using NuvaRing you should remove the ring and contact your doctor.

If you want to stop NuvaRing because you want to get pregnant, see section 3.5 ‘

When you want to

stop using NuvaRing’.

NuvaRing is not usually recommended for use during breast-feeding. If you wish to use NuvaRing

while breast-feeding, please seek the advice of your doctor.

2.6

Driving and using machines

NuvaRing is unlikely to affect your ability to drive or use machines.

3.

How to use NuvaRing

You can insert and remove NuvaRing yourself. Your doctor will tell you when to start using

NuvaRing for the first time. The vaginal ring must be put in on the correct day in your monthly cycle

(see section 3.3 ‘

When to start with the first ring

’) and left in place for 3 weeks in a row. Regularly

check that NuvaRing is in your vagina (for example, before and after intercourse) to ensure that you

are protected from pregnancy. After the third week, you take NuvaRing out and have a one week

break. You will usually have your monthly period during this ring-free interval.

While using NuvaRing, you should not use certain female barrier contraceptive methods, such as a

vaginal diaphragm, cervical cap, or female condom. These contraceptive barrier methods should not

be used as your back-up method of birth control because NuvaRing may interfere with the correct

placement and position of a diaphragm, cervical cap, or female condom.

3.1

How to insert and remove NuvaRing

Before inserting the ring, check that it is not out of date (see section 5 ‘

How to store

NuvaRing’

Wash your hands before inserting or removing the ring.

Choose the position for inserting that is most comfortable to you, like standing with one leg up,

squatting, or lying down.

Remove NuvaRing from its sachet.

Hold the ring between your thumb and index finger, press the opposite sides together and insert

the ring into the vagina (see Figures 1– 4). Alternatively, you may choose to use the NuvaRing

Applicator (not included with NuvaRing) to help you insert the ring. The NuvaRing Applicator

may not be available in all countries. When NuvaRing is in place you should not feel anything.

If you feel uncomfortable, gently push NuvaRing a bit farther into the vagina. The exact

position of the ring inside the vagina is not important.

After 3 weeks you remove NuvaRing from the vagina. You can do this by hooking your index

finger under the front rim of the ring or by grasping the rim and pulling it out (see Figure 5). If

you locate the ring in your vagina, but are unable to remove it, you should contact your doctor.

Dispose of the used ring with the normal household waste, preferably inside the reclosable

sachet. Do not flush NuvaRing down the toilet.

Figure 1

Take NuvaRing out of the

sachet

Figure 2

Compress the ring

Figure 3

Choose a comfortable position to insert the ring

Figure 4A

Figure 4B

Figure 4C

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).

Figure 5

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.

3.2

Three weeks in, one week out

Starting with the day you put it in, the vaginal ring must be left in place

without interruption

for 3 weeks.

After 3 weeks you remove the ring on the same day of the week and at approximately the same

time as it was put in. For example, if you put NuvaRing in on a Wednesday at about 22.00 h,

you should remove the ring 3 weeks later, on Wednesday, at about 22.00 h.

After you have removed the ring, you do not use a ring for 1 week. During this week a vaginal

bleed should occur. Usually this starts 2–3 days after removal of NuvaRing.

Start a new ring exactly after the 1 week interval (again on the same day of the week and

approximately the same time), even if you have not stopped bleeding.

If the new ring is inserted more than 3 hours too late, the protection from pregnancy may be

reduced. Follow the instructions in section 3.4

‘What to do if…You have forgotten to insert a

new ring after the ring-free interval’

If you use NuvaRing as described above, your vaginal bleed will take place every month on roughly

the same days.

3.3

When to start with the first ring

You have not used a hormonal contraceptive during the last month

Insert the first NuvaRing on the first day of your natural cycle (i.e. the first day of your

menstrual period). NuvaRing starts working straight away. You don’t need to take any other

contraceptive precautions.

You can also start NuvaRing between day 2 and day 5 of your cycle, but if you have sexual

intercourse during the first 7 days of NuvaRing use make sure that you also use an additional

contraceptive method (such as a male condom). You only have to follow this advice when you

use NuvaRing for the first time.

You have used a combined Pill during the last month

Start using NuvaRing at the latest the day following the tablet-free period of your present Pill.

If your Pill pack also contains inactive tablets, start NuvaRing at the latest on the day after the

last inactive tablet. If you are not sure which tablet this is, ask your doctor or pharmacist. Never

extend the hormone-free interval of your current Pill pack beyond its recommended length.

If you have used the Pill consistently and correctly and if you are sure that you are not pregnant,

you can also stop taking the Pill on any day of your current Pill pack and start using NuvaRing

immediately.

You have used a transdermal patch during the last month

Start using NuvaRing at the latest the day following your usual patch-free break. Never extend

the patch-free break beyond its recommended length.

If you have used the patch consistently and correctly and if you are sure that you are not

pregnant, you can also stop using the patch on any day and start using NuvaRing immediately.

You have used a minipill (progestagen-only pill) during the last month.

You can stop taking the minipill any day and start NuvaRing the next day, at the same time you

would normally have taken your pill. But make sure you also use an additional contraceptive

method (such as a male condom) for the first 7 days of ring use.

You have used an injectable or implant or a progestagen-releasing IUD during the last month.

Start using NuvaRing when your next injection is due or on the day that your implant or your

progestagen-releasing IUD is removed. But make sure you also use an additional contraceptive

method (such as a male condom) for the first 7 days of ring use.

After having a baby.

If you have just had a baby, your doctor may tell you to wait until after your first normal period

before you start using NuvaRing. Sometimes it is possible to start sooner. Your doctor will

advise you. If you are breast-feeding and want to use NuvaRing, you should discuss this first

with your doctor.

After a miscarriage or an abortion.

Your doctor will advise you.

3.4

What to do if…

Your ring is accidentally expelled from the vagina

NuvaRing may accidentally be expelled from the vagina – for example, if it has not been inserted

properly, while removing a tampon, during sexual intercourse, during constipation, or if you have a

prolapse of the womb. Therefore, you should regularly check whether the ring is still in your vagina

(for example, before and after intercourse).

If the ring is out for less than 3 hours it will still protect you from pregnancy. You can rinse the ring

with cold to lukewarm water (do not use hot water) and put it back in. If the ring is out for more than

3 hours, it may not protect you from pregnancy, see the advice in section 3.4 ‘

What to do if… Your

ring has temporarily been out of the vagina

’.

Your ring has temporarily been out of the vagina

When it is in the vagina, NuvaRing slowly releases hormones into the body to prevent pregnancy. If

the ring has been out of the vagina for more than 3 hours, it may not protect you from pregnancy. So,

the ring must not be outside the vagina for longer than 3 hours in every twenty-four hour period.

If the ring has been out of the vagina for

less than 3 hours

, it will still protect you from

pregnancy. You should put the ring back in as soon as possible but at the latest within 3 hours.

If the ring has been out of the vagina, or you suspect that the ring has been out of the vagina, for

more than 3 hours during the 1st and 2

nd

week

, it may not protect you from pregnancy. Put

the ring back in the vagina as soon as you remember, and leave the ring in place without

interruption for at least 7 days. Use a male condom if you have sexual intercourse during these

7 days. If you are in your 1

week, and you had sexual intercourse during the past 7 days, there

is a possibility you may be pregnant. In that case contact your doctor.

If the ring has been out of the vagina, or you suspect that the ring has been out of the vagina, for

more than 3 hours in the 3

rd

week

it may not protect you from pregnancy. You should discard

that ring and choose between one of the following two options:

1 – Insert a new ring immediately

This will start the next three-week use period. You may not have your period, but breakthrough

bleeding and spotting may occur.

2 – Do not insert the ring again. Have your period first and insert a new ring no later than

7 days from the time the previous ring was removed or fell out.

You should only choose this option if you have used NuvaRing continuously during the

previous 7 days.

If NuvaRing was out of the vagina for an unknown amount of time, you may not be protected

from pregnancy. Perform a pregnancy test and consult your doctor prior to inserting a new ring.

Your ring breaks

Very rarely NuvaRing may break. If you notice that your NuvaRing has broken, discard it and start

with a new ring as soon as possible. Use extra contraceptive precautions (e.g. a male condom) during

the next 7 days. If you had sexual intercourse before you noticed the ring breakage, please contact

your doctor.

You have inserted more than one ring

There have been no reports of serious harmful effects due to an overdose of the hormones in

NuvaRing. If you have accidentally inserted more than one ring, you may feel sick (nausea) or have

vomiting or vaginal bleeding. Remove excess rings and contact your doctor if these symptoms persist.

You have forgotten to insert a new ring after the ring-free interval

If your

ring-free interval

longer than 7 days

, put a new ring as soon as you remember. Use

extra contraceptive precautions (such as a male condom) if you have sexual intercourse during the

next 7 days.

If you had sexual intercourse in the ring-free interval, there is a possibility you may

be pregnant

. In that case contact your doctor immediately. The longer the ring-free interval, the

higher the risk that you have become pregnant.

You have forgotten to remove the ring

If your ring has been left in place for between 3 and

4 weeks

, it will still protect you from

pregnancy. Have your regular ring-free interval of one week and subsequently insert a new ring.

If your ring has been left in place for

more than 4 weeks

there is a possibility of becoming

pregnant. Contact your doctor before you start with a new ring.

You have missed a menstrual period

You have followed the instructions for NuvaRing

If you have missed a menstrual period but you followed the instructions for NuvaRing, and

have not used other medicines, it is very unlikely that you are pregnant. Continue to use

NuvaRing as usual. If you miss your menstrual period twice in a row, however, you may be

pregnant. Tell your doctor immediately. Do not start the next NuvaRing until your doctor has

checked you are not pregnant.

If you have not followed the instructions for NuvaRing

If you have missed a menstrual period and you did not follow the instructions, and you do not

have your expected period in the first normal ring-free interval, you may be pregnant. Contact

your doctor before you start with a new NuvaRing.

You have unexpected bleeding

While using NuvaRing, some women have unexpected vaginal bleeding between menstrual periods.

You may need to use sanitary protection. In any case, leave the ring in the vagina and continue to use

the ring as normal. If the irregular bleeding continues, becomes heavy or starts again, tell your doctor.

You want to change the first day of your menstrual period.

If you follow the instructions for NuvaRing, your menstrual period (withdrawal bleed) will begin in

the ring-free interval. If you want to change the day it starts, you can make the ring-free interval

shorter (but never longer!).

For example, if your period usually begins on a Friday, you can change this to a Tuesday (3 days

earlier) from next month onwards. Simply insert your next ring 3 days earlier than usual.

If you make your ring-free interval very short (for example, 3 days or less), you may not have your

usual bleeding. You may have spotting (drops or flecks of blood) or breakthrough bleeding while

using the next ring.

If you are not sure how to proceed, contact your doctor for advice.

You want to delay your menstrual period

Although it is not the recommended regimen, delay of your menstrual period (withdrawal bleed) is

possible by inserting a new ring immediately after removing the current ring, with no ring-free

interval between rings. You can leave the new ring inserted for up to a maximum of 3 weeks. You

may experience spotting (drops or flecks of blood) or breakthrough bleeding while using this new

ring. When you want your period to begin, just remove the ring. Have your regular ring free interval

of one week and subsequently insert a new ring.

You can ask your doctor for advice before deciding to delay your menstrual period.

3.5

When you want to stop using NuvaRing

You can stop using NuvaRing any time you want.

If you do not want to become pregnant, ask your doctor about other methods of birth control.

If you stop using NuvaRing because you want to get pregnant, you should wait until you have had a

natural period before trying to conceive. This helps you calculate when the baby will be due.

4.

Possible side effects

Like all medicines, NuvaRing can cause side effects, although not everybody gets them. If you get any

side effect, particularly if severe or persistent, or have any change to your health that you think may

be due to NuvaRing, please talk to your doctor.

An increased risk of blood clots in your veins (venous thromboembolism (VTE)) or blood clots in

your arteries (arterial thromboembolism (ATE)) is present for all women taking combined hormonal

contraceptives. For more detailed information on the different risks from taking combined hormonal

contraceptives, please see section 2, “What you need to know before you use NuvaRing”.

If you are allergic to one of the ingredients of Nuvaring (hypersensitivity) you may experience the

following symptoms (frequency unknown): angioedema [swollen face, tongue and/or throat and/or

difficulty swallowing] or hives together with difficulty breathing. If this happens, remove NuvaRing

and contact your doctor immediately.

Users of NuvaRing have reported the following side effects.

Common: may affect up to 1 in 10 women

abdominal pain, feeling sick (nausea)

yeast infection of the vagina (such as ‘thrush’); discomfort in the vagina due to the ring; genital

itching; secretion from the vagina

headache or migraine; depressive moods; lower sex drive

breast pain; pelvic pain; painful menstrual periods

acne

weight gain

the ring falling out

Uncommon: may affect up to 1 in 100 women

disturbed vision; dizziness

swollen abdomen; vomiting, diarrhoea or constipation

feeling tired, unwell or irritable; mood changes; mood swings

extra fluid in the body (oedema)

bladder or urinary tract infection

difficulty or pain when passing urine; strong desire or need to pass urine; passing urine more

often

problems during intercourse, including pain, bleeding or partner feeling the ring

increased blood pressure

increased appetite

back pain; muscle spasms; pain in legs or arms

less sensitive skin

sore or larger breasts; fibrocystic breast disease (cysts in the breasts which may become swollen

or painful)

inflammation of the cervix; cervical polyps (growths in the cervix); rolling outward of the

margin of the cervix (ectropion)

changes to menstrual periods (e.g. periods can be heavy, long, irregular or stop altogether);

pelvic discomfort; premenstrual syndrome; spasm of the uterus

vaginal infection (fungal and bacterial); burning feeling, smell, pain, discomfort or dryness in

the vagina or vulva

hair loss, eczema, itching, rash or hot flushes

ring breakage

Rare: may affect up to 1 in 1,000 women

harmful blood clots in a vein or artery, for example:

in a leg or foot (i.e. DVT)

in a lung (i.e. PE)

heart attack

stroke

mini-stroke or temporary stroke-like symptoms, known as a transient ischaemic attack

(TIA)

blood clots in the liver, stomach/intestine, kidneys or eye.

The chance of having a blood clot may be higher if you have any other conditions that increase this

risk. (See section 2 for more information on the conditions that increase risk for blood clots and the

symptoms of a blood clot.)

breast discharge

Not known (cannot be estimated from the available data)

chloasma (yellowish-brown pigmentation patches on the skin, particularly of the face)

penis discomfort of the partner (such as irritation, rash, itching)

inability to remove ring without medical assistance (e.g., because of adherence to vaginal wall)

Breast cancer and liver tumours have been reported in users of combined hormonal contraceptives.

For more information, see section 2.2

Warnings and precautions, Cancer

Reporting of side effects

If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side

effects not listed in this leaflet.

You can also report side effects directly (see details below). By reporting side effects, you can help

provide more information on the safety of this medicine.

United Kingdom:

Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA

Yellow Card in the Google Play or Apple App Store

Ireland:

HPRA Pharmacovigilance Earlsfort Terrace, IRL - Dublin 2 Tel: +353 1 6764971, Fax:

+353 1 6762517, Website: www.hpra.ie; e-mail: medsafety@hpra.ie.

Malta:

ADR Reporting at: www.medicinesauthority.gov.mt/adrportal

5.

How to store NuvaRing

Keep NuvaRing out of the sight and reach of children.

If you discover that a child has been exposed to the hormones from NuvaRing, ask your doctor for

advice.

Store below 30

C. Store in the original package in order to protect from light and moisture.

Do not use a NuvaRing if it was dispensed to you more than 4 months ago. The dispensing date is

stated on the carton and sachet.

Do not use NuvaRing after the expiry date which is stated on the carton and sachet.

Do not use NuvaRing if you notice a colour change in the ring or any visible signs of deterioration.

Dispose of the used ring with the normal household waste, preferably inside the reclosable sachet. Do

not flush NuvaRing down the toilet. As with other medicines, do not throw away unused or outdated

rings via wastewater or household waste. Ask your pharmacist how to throw away any unused rings

no longer required. These measures will help protect the environment.

6.

Contents of the pack and other information

What NuvaRing contains

The active substances are: etonogestrel (11.7 mg) and ethinylestradiol (2.7 mg)

The other ingredients are: ethylene vinylacetate copolymers (28% and 9% vinylacetate) (a type

of plastic that will not dissolve in the body) and magnesium stearate.

Etonogestrel and ethinylestradiol are released from the ring at a rate of 0.120 mg/day and

0.015 mg/day, each for 3 weeks.

What NuvaRing looks like and contents of the pack

NuvaRing is a flexible, transparent, colourless to almost colourless ring, 54 mm wide.

Each ring is packed in a reclosable foil sachet. The sachet is packed in a cardboard box together with

this package leaflet. Each box contains 1 or 3 rings.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holders

The Marketing Authorisation Holder

in the UK and Malta is Merck Sharp & Dohme Ltd, Hertford

Road, Hoddesdon, Hertfordshire, EN11 9BU, UK.

The Marketing Authorisation Holder

in Ireland is Merck Sharp & Dohme Ireland (Human Health)

Ltd, Red Oak North, South County Business Park, Leopardstown, Dublin 18, Ireland.

Manufacturer:

N.V. Organon, Kloosterstraat 6, 5349 AB Oss, The Netherlands.

This medicinal product is authorised in the Member States of the EEA under the following

name:

NuvaRing

0.120 mg/0.015 mg per 24 hours, vaginal delivery system

Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany,

Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, The Netherlands,

Norway, Romania, Poland, Portugal, Slovak Republic, Slovenia, Spain, Sweden, United Kingdom.

This leaflet was last revised in July 2017.

© Merck Sharp & Dohme Limited, 2017. All rights reserved.

PIL.NVRNG.17.UK.5034.WS 232

Object 1

Nuvaring

Summary of Product Characteristics Updated 17-Jan-2018 | Merck Sharp & Dohme Limited

1. Name of the medicinal product

NuvaRing®, 0.120 mg/0.015 mg per 24 hours, vaginal delivery system

2. Qualitative and quantitative composition

NuvaRing contains 11.7 mg etonogestrel and 2.7 mg ethinylestradiol. The ring releases etonogestrel and

ethinylestradiol at an average amount of 0.120 mg and 0.015 mg respectively per 24 hours, over a period

of 3 weeks.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Vaginal delivery system.

NuvaRing is flexible, transparent, and colourless to almost colourless ring, with an outer diameter of 54

mm and a cross-sectional diameter of 4 mm.

4. Clinical particulars

4.1 Therapeutic indications

Contraception.

NuvaRing is intended for women of fertile age. The safety and efficacy have been established in women

aged 18 to 40 years.

The decision to prescribe NuvaRing should take into consideration the individual woman's current risk

factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with NuvaRing

compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).

4.2 Posology and method of administration

Posology

To achieve contraceptive effectiveness, NuvaRing must be used as directed (see 'How to use NuvaRing'

and 'How to start NuvaRing').

Paediatric population

The safety and efficacy of NuvaRing in adolescents under the age of 18 have not been studied.

Method of 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. An optional alternative is to insert the ring using the

NuvaRing Applicator which is distributed separately or is included in the package. The NuvaRing

Applicator may not be available in all countries. The exact position of NuvaRing in the vagina is not

critical for the contraceptive effect of the ring (see Figures 1-4).

Once NuvaRing has been inserted (see 'How to start NuvaRing') it is left in the vagina continuously for 3

weeks. Advise women to regularly check for the presence of NuvaRing in the vagina (for example, before

and after intercourse). If NuvaRing is accidentally expelled, the woman should follow the instructions

given in section 4.2, 'What to do if the ring is temporarily outside the vagina' (for more information, see

also section 4.4, '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 22.00 h the ring should be removed again on the

Wednesday 3 weeks later at about 22.00 h. 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 in section 6.6. 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.

Use with other female vaginal barrier methods

NuvaRing may interfere with the correct placement and position of certain female barrier methods, such

as a diaphragm, cervical cap, or female condom. These contraceptive methods should not be used as

back-up methods with NuvaRing.

How to insert NuvaRing with fingers only:

Figure 1

Take NuvaRing out of the sachet

Figure 3

Choose a comfortable position to insert the ring

Figure 2

Compress the ring

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).

Figure 5:

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.

How to insert NuvaRing with the applicator:

1: Prepare

Wash your hands before opening the package. Open ONLY

immediately before use. DO NOT use if the contents or packaging are

visibly damaged.

The applicator is for use with the NuvaRing ring ONLY, not with other

products.

Review the picture of the applicator to familiarise yourself with the

parts of the applicator.

A. Plunger

B. Finger Grip

C. Barrel

D. Barrel Opening

E. NuvaRing

2: Load & Position

Pull the plunger back gently until it stops.

Squeeze opposite sides of the ring together and insert the ring into the

barrel opening.

Gently push the ring into the barrel. The tip of the ring should stick out

slightly from the barrel opening.

Choose the position for inserting the ring that is most comfortable for

you, like lying down, squatting, or standing with one leg up.

3: Insert & Dispose

Place your thumb and middle finger on the finger grip.

Gently insert the barrel into the vagina until your fingers (on the finger

grip) touch your body.

Then use your index finger to gently push the plunger entirely into the

barrel.

Some women have experienced a brief mild pinching sensation when

using the applicator.

The ring is pushed out of the applicator. Gently remove the applicator.

Confirm that the ring is NOT in the applicator. Dispose of the used

applicator with the normal household waste. DO NOT flush the

applicator down the toilet. DO NOT reuse the applicator.

HOW TO START NUVARING

No hormonal contraceptive use in the preceding cycle

NuvaRing has to be inserted on the first day of the woman'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 is

recommended in addition for the first 7 days of NuvaRing use.

Changing from a combined hormonal contraceptive

The woman should insert NuvaRing at the latest on the day following the usual tablet-free, patch-free or

placebo tablet interval of her previous combined hormonal contraceptive.

If the woman has been using her previous method consistently and correctly and if it is reasonably certain

that she is not pregnant she may also switch from her previous combined hormonal contraceptive on any

day of the cycle.

The hormone-free interval of the previous method should never be extended beyond its recommended

length.

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 (from an implant, or the IUS on the day of its

removal, from an injectable when the next injection would be due) but should in all of these cases use an

additional barrier method for the first 7 days of NuvaRing use.

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, see section 4.6.

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.

DEVIATIONS FROM THE RECOMMENDED REGIMEN

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 in case of a lengthened ring-free interval

The woman should insert a new ring as soon as she remembers. A barrier method such as a male 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 the ring was temporarily outside the vagina

NuvaRing should be left in the vagina for a continuous period of 3 weeks. If the ring is accidentally

expelled, it can be rinsed with cool to lukewarm (not hot) water and should be reinserted immediately.

If NuvaRing has been out 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.

If NuvaRing has been out of the vagina, or is suspected to have been out of the vagina for more than 3

hours during the 1

st

or 2

nd

week of use, contraceptive efficacy may be reduced. The woman should

reinsert the ring as soon as she remembers. A barrier method such as a male condom should be used 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.

If NuvaRing has been out of the vagina, or is suspected to have been out of the vagina for more than 3

hours during the 3

rd

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:

1. Insert a new ring immediately

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.

2. Have a withdrawal bleeding 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.

If NuvaRing was out of the vagina for an unknown amount of time, the possibility of pregnancy should be

considered. A pregnancy test should be performed prior to inserting a new ring.

What to do in case of lengthened ring-use

Although this is not the recommended regimen, as long as NuvaRing has been used for maximally 4

weeks, contraceptive efficacy is still adequate. 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

If in exceptional cases a period needs to be delayed, 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.

4.3 Contraindications

CHCs should not be used in the following conditions. Should any of the conditions appear for the first

time during the use of NuvaRing, it should be removed immediately.

Presence or risk of venous thromboembolism (VTE)

o Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis

[DVT] or pulmonary embolism [PE]).

o Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance

(including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency.

o Major surgery with prolonged immobilisation (see section 4.4).

o A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4).

Presence or risk of arterial thromboembolism (ATE)

o Arterial thromboembolism - current arterial thromboembolism, history of arterial thromboembolism

(e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris).

o Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g.

transient ischaemic attack, TIA).

o Known hereditary or acquired predisposition for arterial thromboembolism, such as

hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus

anticoagulant).

o History of migraine with focal neurological symptoms.

o A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence

of one serious risk factor such as:

diabetes mellitus with vascular symptoms

severe hypertension

severe dyslipoproteinaemia.

Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.

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.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 of NuvaRing

NuvaRing is contraindicated for concomitant use with medicinal products containing

ombitasvir/paritaprevir/ritonavir and dasabuvir (see sections 4.4 and section 4.5).

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 6

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 (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/m

Risk increases substantially as BMI rises.

Particularly important to consider if other risk

factors also present.

Prolonged immobilisation, major surgery, any

surgery to the legs or pelvis, neurosurgery, or major

trauma

Note: Temporary immobilisation including air travel

> 4 hours can also be a risk factor for VTE,

particularly in women with other risk factors.

In these situations it is advisable to discontinue use

of the patch/pill/ring (in the case of elective surgery

at least four weeks in advance) and not resume until

two weeks after complete remobilisation. Another

method of contraception should be used to avoid

unintentional pregnancy.

Antithrombotic treatment should be considered if

NuvaRing has not been discontinued in advance.

Positive family history (venous thromboembolism

ever in a sibling or parent especially at a relatively

early age, e.g. before 50)

If a hereditary predisposition is suspected, the

woman should be referred to a specialist for advice

before deciding about any CHC use.

Other medical conditions associated with VTE

Cancer, systemic lupus erythematosus, 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/m

Risk increases substantially as BMI increases.

Particularly important in women with additional risk

factors

Positive family history (arterial thromboembolism

ever in a sibling or parent especially at relatively

early age, e.g. below 50)

If a hereditary predisposition is suspected, the

woman should be referred to a specialist for advice

before deciding about any CHC 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 adverse

vascular events

Diabetes mellitus, hyperhomocysteinaemia, 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 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. 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) (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;

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 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 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.

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 ETHINYLESTRADIOL 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). 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.

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

4.5 Interaction with other medicinal products and other forms of interaction

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS

Note: The prescribing information of concomitant medications should be consulted to identify potential

interactions.

Effects of other medicinal products on NuvaRing

Interactions can occur with drugs or herbal products that induce microsomal enzymes which can result in

increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive

failure.

Management

Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is

generally seen within a few weeks. After the cessation of drug therapy, enzyme induction may be

sustained for about 4 weeks.

Short-term treatment

Women on treatment with enzyme-inducing drugs or herbal products should temporarily use a barrier

method or another method of contraception in addition to NuvaRing. Note: NuvaRing should not be used

with a diaphragm, cervical cap, or female condom. The barrier method must be used during the whole

time of the concomitant drug therapy and for 28 days after its 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.

Long-term treatment

In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-

hormonal method of contraception is recommended.

The following interactions have been reported in the literature.

Substances increasing the clearance of combined hormonal contraceptives

Interactions can occur with medicinal or herbal products that induce microsomal enzymes, specifically

cytochrome P450 enzymes (CYP), which can result in increased clearance reducing plasma

concentrations of sex hormones and may decrease the effectiveness of combined hormonal

contraceptives, including NuvaRing. These products include phenytoin, phenobarbital, primidone,

bosentan, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate,

griseofulvin, some HIV protease inhibitors (e.g. ritonavir) and non-nucleoside reverse transcriptase

inhibitors (e.g. efavirenz), and products containing the herbal remedy St. John's wort.

Substances with variable effects on the clearance of combined hormonal contraceptives

When co-administered with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g.

nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and/or combinations with

HCV medicinal products (e.g. boceprevir, telaprevir), can increase or decrease plasma concentrations of

progestagens, including etonogestrel, or estrogen. The net effect of these changes may be clinically

relevant in some cases.

Substances decreasing the clearance of combined hormonal contraceptives

The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g.

fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations of

estrogens or progestogens, including etonogestrel.

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 disconnection may be slightly higher (see section 4.4, 'Broken Rings').

Hormonal contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and

tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).

Pharmacodynamic interactions

Concomitant use with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with

or without ribavirin, may increase the risk of ALT elevations (see sections 4.3 and 4.4). Therefore,

NuvaRing users must switch to an alternative method of contraception (e.g., progestagen-only

contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen.

NuvaRing can be restarted 2 weeks following completion of treatment with this combination drug

regimen.

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 the ring was temporarily outside the vagina').

4.6 Fertility, pregnancy and lactation

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.

Pregnancy

NuvaRing is not indicated during pregnancy. If pregnancy occurs with NuvaRing in situ, the ring should

be removed. Extensive epidemiological studies have revealed neither an increased risk of birth defects in

children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were

used inadvertently during early pregnancy.

A clinical study in a small number of women showed that despite the intravaginal administration,

intrauterine concentrations of contraceptive steroids with NuvaRing are similar to the levels observed in

COC users (see section 5.2). Clinical experience of the outcomes of pregnancies exposed to NuvaRing

has not been reported.

The increased risk of VTE during the postpartum period should be considered when re-starting NuvaRing

(see sections 4.2 and 4.4).

Breastfeeding

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. Small amounts of the contraceptive steroids and / or their

metabolites may be excreted with the milk but there is no evidence that this adversely affects the infant's

health.

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.

4.8 Undesirable effects

The most frequently reported undesirable effects in the clinical trials with NuvaRing were headache and

vaginal infections and vaginal discharge, each reported by 5-6% of the women.

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial

infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been

observed in women using CHCs, which are discussed in more detail in section 4.4.

Also other undesirable effects have been reported in women using CHCs: these are discussed in more

detail in section 4.4.

Adverse drug reactions that have been reported in clinical trials, observational studies, or during

postmarketing use with NuvaRing are listed in the Table below. The most appropriate MedDRA term to

describe a certain adverse event is listed.

All adverse reactions are listed by system organ class and frequency; common (≥ 1/100 to < 1/10),

uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and not known (cannot be estimated

from the available data).

System Organ

Class

Common

Uncommon

Rare

Not known

Infections and

infestations

Vaginal infection

Cervicitis, Cystitis,

Urinary tract

infection

Immune system

disorders

Hypersensitivity

Metabolism and

nutrition disorders

Increased appetite

Psychiatric

disorders

Depression, Libido

decreased

Affect lability,

Mood altered,

Mood swings

Nervous system

disorders

Headache, Migraine

Dizziness,

Hypoaesthesia

Eye disorders

Visual disturbance

Vascular disorders

Hot flush

Venous

thromboembolism

Arterial

thromboembolism

Gastrointestinal

disorders

Abdominal pain,

Nausea

Abdominal

distension,

Diarrhoea,

Vomiting,

Constipation

Skin and

subcutaneous

tissue disorders

Acne

Alopecia, Eczema,

Pruritus, Rash

Chloasma

Urticaria

Musculoskeletal

and connective

tissue disorders

Back pain, Muscle

spasms, Pain in

extremity

Renal and urinary

disorders

Dysuria,

Micturition

urgency,

Pollakiuria

Reproductive

system and breast

disorders

Breast tenderness,

Genital pruritus

female,

Dysmenorrhoea,

Pelvic pain, Vaginal

discharge

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

Galactorrhoea

Penis disorders

General disorders

and administration

site conditions

Fatigue, Irritability,

Malaise, Oedema,

Sensation of

foreign body

Vaginal ring site tissue

overgrowth

Investigations

Weight increased

Blood pressure

increased

Injury, poisoning

and procedural

complications

Medical device

discomfort, Vaginal

contraceptive device

expelled

Contraceptive

device

complication,

Device breakage

) Listing of adverse events based on spontaneous reporting.

Hormone-dependent tumours (e.g. liver tumours, breast cancer) have been reported in association with

CHC use. For further information see section 4.4.

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme

inducers) with hormonal contraceptives (see section 4.5).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other gynecologicals, Intravaginal contraceptives, vaginal ring with

progestagen and oestrogen, ATC code: G02BB01

Mechanism of action

NuvaRing contains etonogestrel and ethinylestradiol. Etonogestrel is a 19-nortestosterone-derived

progestagen and binds with high affinity to progesterone receptors in the target organs. Ethinylestradiol is

an oestrogen widely used in contraceptive products. The contraceptive effect of NuvaRing is based on

various mechanisms, the most important of which is the inhibition of ovulation.

Clinical efficacy and safety

Clinical studies were performed worldwide (US, EU, and Brazil) in women between the ages of 18 and

40 years. The contraceptive efficacy appeared to be at least comparable with that known for combined

oral contraceptives. The following table shows the Pearl Indices (number of pregnancies per 100 woman

years of use) found in the clinical studies with NuvaRing.

Analysis Method

Pearl Index

95 % CI

No of Cycles

ITT (user + method

failure)

0.96

0.64 – 1.39

37,977

PP (method failure)

0.64

0.35 – 1.07

28,723

With the use of higher-dosed COCs (0.05 mg ethinylestradiol) the risk of endometrial and ovarian cancer

is reduced. Whether this also applies to a lower-dosed contraceptive like NuvaRing remains to be

determined.

BLEEDING PATTERN

A large comparative study with 150/30 µg levonorgestrel/ethinylestradiol OC (n= 512 vs n= 518)

evaluating vaginal bleeding characteristics over 13 cycles showed low incidences of breakthrough

spotting or bleeding for NuvaRing (2.0-6.4%). Furthermore, vaginal bleeding was exclusively restricted

to the ring-free interval for most subjects (58.8-72.8 %).

EFFECTS ON BONE MINERAL DENSITY

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. No adverse effects on

bone mass have been observed.

Paediatric population

The safety and efficacy of NuvaRing in adolescents under the age of 18 have not been studied.

5.2 Pharmacokinetic properties

Etonogestrel

Absorption

Etonogestrel released by NuvaRing is rapidly absorbed by the vaginal mucosa. Maximum serum

concentrations of etonogestrel of approximately 1,700 pg/mL are reached at about 1 week after insertion.

Serum concentrations show small fluctuations and slowly decrease to approximately 1,600 pg/mL after 1

week, 1,500 pg/mL after 2 weeks and 1,400 pg/mL after 3 weeks of use. Absolute bioavailability is

approximately 100%, which is higher than after oral administration. Cervical and intrauterine etonogestrel

levels were measured in a small number of women using NuvaRing or an oral contraceptive containing

0.150 mg desogestrel and 0.020 mg ethinylestradiol. The observed levels were comparable.

Distribution

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.

Biotransformation

Etonogestrel is metabolized 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.

Elimination

Etonogestrel serum levels decrease in two phases. The terminal elimination phase is characterized 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

Absorption

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 19 pg/mL after 1

week, 18 pg/mL after 2 weeks and 18 pg/mL after 3 weeks of use. The monthly systemic ethinylestradiol

exposure (AUC

0-ω

) with NuvaRing is 10.9 ng.h/mL. Absolute bioavailability is approximately 56%,

which is comparable with oral administration of ethinylestradiol. Cervical and intrauterine

ethinylestradiol levels were measured in a small number of women using NuvaRing or an oral

contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol. The observed levels were

comparable.

Distribution

Ethinylestradiol is highly but non-specifically bound to serum albumin. An apparent volume of

distribution of about 15 L/kg was determined.

Biotransformation

Ethinylestradiol is primarily metabolized 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.

Elimination

Ethinylestradiol serum levels decrease in two phases. The terminal elimination phase is characterized 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.

Special populations

Paediatric population

The pharmacokinetics of NuvaRing in healthy postmenarcheal female adolescents under the age of 18

have not been studied.

Effect of renal impairment

No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of NuvaRing.

Effect of hepatic impairment

No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of NuvaRing.

However, steroid hormones may be poorly metabolized in women with impaired liver function.

Ethnic groups

No formal studies were performed to assess pharmacokinetics in ethnic groups.

5.3 Preclinical safety data

Non-clinical data with ethinylestradiol and etonogestrel reveal no special hazard for humans based on

conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential,

and toxicity to reproduction, other than those already known for humans.

Environmental Risk Assessment (ERA)

Environmental risk assessment studies have shown that 17α-ethinylestradiol and etonogestrel may pose a

risk to surface water organisms (see section 6.6).

6. Pharmaceutical particulars

6.1 List of excipients

Ethylene vinylacetate copolymer, 28% vinylacetate;

ethylene vinylacetate copolymer, 9% vinylacetate;

magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

40 months.

6.4 Special precautions for storage

Prior to dispensing:

3 years, store in a refrigerator (2 °C - 8 °C).

At the time of dispensing:

The dispenser places a date of dispensing on the packaging. The product should be inserted no later than 4

months from the date of dispensing, but in all cases prior to the expiry date, whichever comes first.

After dispensing:

4 months, store below 30°C.

Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

NuvaRing

Sachet containing one NuvaRing. The sachet is made of aluminum foil with an inner layer of low-density

polyethylene and an outer layer of polyethylene terephthalate (PET). It is reclosable and waterproof. The

sachet is packed in a printed cardboard box together with the package leaflet.

NuvaRing Applicator

Distributed separately or included in the package. The NuvaRing Applicator may not be available in all

countries. The applicator is a plastic, non-sterile device made from a polypropylene polymer, containing a

friction reduction additive (comprising of less than 5%). It is intended for single use (i.e. disposable).

Each applicator is individually packed. The applicator has a CE marking which is embossed on the

device.

The product is supplied as:

- Pack of 1 ring

- Pack of 1 ring and 1 applicator

- Pack of 3 rings

- Pack of 3 rings and 3 applicators

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

NuvaRing

See section 4.2. The dispenser has to indicate the date of dispensing on the packaging. It is recommended

for the 3-rings presentation to indicate this date on the ply carton as well as on the sachet. NuvaRing

should be inserted no later than 4 months from the date of dispensing, but in all cases prior to the expiry

date, which ever comes first. 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. This

medicinal product may pose a risk to the environment (see section 5.3). NuvaRing should not be flushed

down the toilet. Any unused (expired) rings should be disposed of in accordance with local requirements.

NuvaRing Applicator

The NuvaRing Applicator must not be reused; it is designed for one time use. If the applicator is

accidently dropped, it should be washed with cool to lukewarm (NOT hot) water. The applicator should

be disposed of with the normal household waste immediately after use. It should not be flushed down the

toilet.

7. Marketing authorisation holder

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

8. Marketing authorisation number(s)

PL 00025/0565

9. Date of first authorisation/renewal of the authorisation

05 June 2008/12 June 2011

10. Date of revision of the text

11 January 2018

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