NUVARING

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS REGULATIONS

(PREPARATIONS) 1986

This medicine can be sold under doctor's prescription only

NuvaRing

®

Vaginal ring

Composition:

Active ingredients and quantity:

Etonogestrel 11.7 mg

Ethinylestradiol

2.7 mg

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.

For a list of inactive ingredients see section 6.1 "What NuvaRing contains".

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.

This leaflet contains concise information about NuvaRing. If you have any further questions,

ask your doctor or pharmacist.

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

even if their medical condition seems similar to yours.

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

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

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, “SIDE EFFECTS”).

1.

WHAT NUVARING IS INTENDED FOR?

Therapeutic group: a contraceptive vaginal ring that contains estrogen and a progestagen.

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.

Do not use NuvaRing 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;

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;

you need an operation or if you are off your feet for a long time (see section 2, “BLOOD

CLOTS”);

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

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);

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

you have (or have ever had) a type of migraine called ”migraine with aura”;

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

fat in your blood;

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

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

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

you have any unexplained vaginal bleeding;

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

medicine (listed in section 6);

you are pregnant, or think you may be pregnant. If you get pregnant while using

NuvaRing, you should remove the ring and contact your doctor.

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 Special warnings concerning use of NuvaRing

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”.

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:

Before using NuvaRing, tell your doctor if:

a close relative has or has ever had breast cancer;

you have epilepsy (see section 2.4 ”Other medicines and NuvaRing”);

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

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

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

system);

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

the kidneys);

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

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);

you need an operation, or you are off your feet for a long time (see in section 2, “BLOOD

CLOTS”);

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;

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

you have varicose veins;

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 [you 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];

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;

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 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

Heart attack

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 ”Special warnings concerning use of NuvaRing”).

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.

Psychiatric disorders

Some women using hormonal contraceptives including NuvaRing have reported depression or

depressed mood. Depression can be serious and may sometimes lead to suicidal thoughts. If you

experience mood changes and depressive symptoms contact your doctor for further medical

advice as soon as possible.

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

If you are taking or have recently taken other medicines, including non-prescription

medicines and nutritional supplements, you should tell the attending doctor or pharmacist.

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

other doctor or dentist (or 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).

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

contraceptive method should also be used (for example, a male condom). 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.

Ring breakage has occurred when also using a vaginal product such as a lubricant or treatment for

infection (see section 3.4 ‘What to do if…Your ring breaks’).

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 “What to do

if…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

Always use NuvaRing as instructed by the doctor. You should check with your doctor or

pharmacist if you are unsure.

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. You can however

use a male condom as an extra barrier contraceptive method.

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). When NuvaRing is in place you should not

feel anything. If you feel uncomfortable, gently change the position of NuvaRing (e.g.,push

the ring a bit farther into the vagina) until it is comfortable. 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 3

Choose a comfortable position to insert

the ring

Figure 2

Compress 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).

Your ring has temporarily been out of the vagina

NuvaRing might still protect you from getting pregnant, but this depends on how long it has

been out of your vagina.

If the ring has been out of the vagina for:

less than 3 hours, it will still protect you from pregnancy. You should rinse the ring with cold

to lukewarm water (do not use hot water) and put the ring back in as soon as possible but only

if the ring has been out of the vagina for less than 3 hours. more than 3 hours during the 1

st

and 2

nd

week, it may not protect you from pregnancy. You should rinse the ring with cold to

lukewarm water (do not use hot water) and 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.

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.

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. Vaginal injury associated with ring breakage has been reported

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.

If a child has accidently swallowed the medicine, immediately refer to a doctor or to a hospital's

emergency room and bring the medicine's package with you.

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

If your ring-free interval was 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. SIDE EFFECTS

Like all medicines, NuvaRing can cause side effects, although not everybody gets them.

Do not be alarmed by reading the list of side effects, you may not suffer from any of 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 and/or anaphylaxis [swollen face, lips,

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 side effects: 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 side effects: 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

Rare side effects: 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

Side effects of unknown frequency (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)

vaginal injury associated with ring breakage

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

contraceptives. For more information, see section 2.2, “Special warnings concerning use of

NuvaRing”, Cancer.

Very rarely NuvaRing may break. For more information, see section 3.4 What to do if

Your ring

breaks.

If a side effect appears, if any of the side effects gets serious or if you notice a side effect not

mentioned in this leaflet, consult your doctor.

Side effects can be reported to the Ministry of Health by using the link "Reporting side effects due

to medicinal treatment" at the home page of the Ministry of Health's web site (www.health.gov.il)

which refers to the online side effects reporting form, or by using the link:

https://sideeffects.health.gov.il

5.

HOW TO STORE NUVARING?

Avoid Poisoning! This medicine, as all other medicines, must be stored in a safe place out of

the reach and sight of children and/or infants, in order to avoid poisoning. Do not induce

vomiting unless explicitly instructed to do so by a doctor.

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

doctor for advice.

Do not use NuvaRing after the expiry date (exp. date) which is stated on pack. The expiry

date refers to the last day of the indicated month.

Storage conditions:

Storage in the pharmacy:

Store refrigerated 2°C-8°C (this temperature range is commonly found in a home

refrigerator).

Storage by the patient:

Store your NuvaRing in the original sachet at a temperature between 2°C-30°C.

You should use NuvaRing up to 4 months from the time you acquired it, but not after the

expiry date.

Even if kept in their original container and stored as recommended, medicines may be kept

for a limited period only.

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. FURTHER INFORMATION

6.1 What NuvaRing contains?

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

In addition to the active ingredients, NuvaRing also contains:

Ethylene vinylacetate copolymer (28% and 9% vinylacetate) (a type of plastic that will not

dissolve in the body) and magnesium stearate.

6.2 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 sachet that is made of aluminum foil.

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.

Manufacturer:

N.V. Organon Oss, The Netherlands.

License holder:

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121, Petah-Tikva 49170.

Revised in June 2020.

Drug registration no. listed in the official registry of the Ministry of Health:

132.14.30926

NuvaRing

Vaginal Ring

1.

NAME OF THE MEDICINAL PRODUCT

NuvaRing

®

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 ring

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.

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. The exact position of

NuvaRing in the vagina is not critical for the contraceptive effect of the ring (see Figures 1-4).

NuvaRing

Vaginal Ring

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

NuvaRing

Vaginal 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.

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 application is considered undesirable, the woman

NuvaRing

Vaginal Ring

should follow the advice given for ‘No hormonal contraceptive use in the preceding cycle’. In the

meantime, 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.

NuvaRing

Vaginal Ring

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)

Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g.

deep venous thrombosis [DVT] or pulmonary embolism [PE]).

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.

Major surgery with prolonged immobilisation (see section 4.4).

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)

Arterial thromboembolism - current arterial thromboembolism, history of arterial

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

pectoris).

Cerebrovascular disease – current stroke, history of stroke or prodromal

condition (e.g. transient ischaemic attack, TIA).

NuvaRing

Vaginal Ring

Known hereditary or acquired predisposition for arterial thromboembolism, such

as hyperhomocysteinaemia and antiphospholipid antibodies (anticardiolipin-

antibodies, lupus anticoagulant).

History of migraine with focal neurological symptoms.

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.

Known or suspected pregnancy.

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.

NuvaRing

Vaginal Ring

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.

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

NuvaRing

Vaginal Ring

Risk factors for VTE

The risk for venous thromboembolic complications in CHC users may increase substantially in a

woman with additional risk factors, particularly if there are multiple risk factors (see table).

NuvaRing is contraindicated if a woman has multiple risk factors that put her at high risk of

venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible

that the increase in risk is greater than the sum of the individual factors – in this case her total

risk of VTE should be considered. If the balance of benefits and risks is considered to be

negative, a CHC should not be prescribed (see section 4.3).

Table: Risk factors for VTE

Risk factor

Comment

Obesity (body mass index over 30 kg/m²)

Risk increases substantially as BMI rises.

Particularly important to consider if other risk

factors also present.

Prolonged immobilisation, major surgery, any

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

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)

NuvaRing

Vaginal Ring

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.

NuvaRing

Vaginal Ring

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

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

NuvaRing

Vaginal Ring

Epidemiological studies indicate that the long-term use of oral contraceptives displays a

risk factor for the development of cervical cancer in women infected with human

papillomavirus (HPV). However, there is still uncertainty about the extent to which this

finding is influenced by confounding effects (e.g. differences in number of sexual partners

or in use of barrier contraceptives). No epidemiological data on the risk of cervical cancer

in users of NuvaRing are available (see ‘medical examination/consultation’).

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased

relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently

using COCs. The excess risk gradually disappears during the course of the 10 years after

cessation of COC use. Because breast cancer is rare in women under 40 years of age,

the excess number of breast cancer diagnoses in current and recent COC users is small

in relation to the overall risk of breast cancer. The breast cancers diagnosed in ever-users

tend to be less advanced clinically than the cancers diagnosed in never-users. The

observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in

COC users, the biological effects of COCs or a combination of both.

In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have

been reported in users of COCs. In isolated cases, these tumours have led to life-

threatening intra-abdominal haemorrhages. Therefore, a hepatic tumour should be

considered in the differential diagnosis when severe upper abdominal pain, liver

enlargement or signs of intra-abdominal haemorrhage occur in women using NuvaRing.

3.

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with

medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without

ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN)

occurred significantly more frequently in women using ethinylestradiol-containing

medications such as combined hormonal contraceptives (CHCs) (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.

Exogenous oestrogens may induce or exacerbate symptoms of (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

NuvaRing

Vaginal Ring

jaundice and/or pruritus related to cholestasis, which occurred first during pregnancy or

previous use of sex steroids necessitates the discontinuation of the ring.

Although estrogens and progestagens may have an effect on peripheral insulin resistance

and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in

diabetics using hormonal contraception. However, diabetic women should be carefully

monitored while using NuvaRing especially in the first months of use.

New onset or deterioration of Crohn’s disease and ulcerative colitis has been reported to

occur with the use of hormonal contraceptives, but the evidence of an association with its

use is inconclusive.

Chloasma may occasionally occur, especially in women with a history of chloasma

gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or

ultraviolet radiation whilst using NuvaRing.

If a woman has any of the following conditions, she may not be able to insert NuvaRing

correctly or may in fact lose the ring: prolapse of the uterine cervix, cystocele, and/or

rectocele, severe or chronic constipation.

Very rarely it has been reported that NuvaRing is inadvertently inserted in the urethra and

possibly ending up in the bladder. Therefore, incorrect positioning should be considered in

the differential diagnosis in case of symptoms of cystitis.

During the use of NuvaRing, women may occasionally experience vaginitis. There are no

indications that the efficacy of NuvaRing is affected by the treatment of vaginitis, or that

the use of NuvaRing affects the treatment of vaginitis (see section 4.5).

Very rarely it has been reported that the ring adhered to vaginal tissue, necessitating

removal by a healthcare provider. In some cases when the tissue had grown over the ring,

removal was achieved by cutting the ring without incising the overlying vaginal tissue.

Depressed mood and depression are well-known undesirable effects of hormonal

contraceptive use (see section 4.8). Depression can be serious and is a well-known risk

factor for suicidal behaviour and suicide. Women should be advised to contact their

physician in case of mood changes and depressive symptoms, including shortly after

initiating the treatment.

Medical examination/consultation

Prior to the initiation or reinstitution of NuvaRing use a complete medical history (including

family history) should be taken and pregnancy must be ruled out. Blood pressure should be

measured and a physical examination should be performed, guided by the contraindications

(see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to

the information on venous and arterial thrombosis, including the risk of NuvaRing compared

with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the

event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the

advice given. The frequency and nature of examinations should be based upon established

practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections

(AIDS) and other sexually transmitted diseases.

Reduced efficacy

NuvaRing

Vaginal Ring

The efficacy of NuvaRing may be reduced in the event of non-compliance (section 4.2), or when

concomitant medications that decrease the plasma concentration of ethinylestradiol and/or

etonogestrel are used (section 4.5).

Reduced cycle control

Irregular bleeding (spotting or breakthrough bleeding) may occur during the use of NuvaRing. If

bleeding irregularities occur after previously regular cycles while NuvaRing has been used

according to the recommended regimen, then non-hormonal causes should be considered, and

adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may

include curettage.

In some women a withdrawal bleed may not occur during the ring-free interval. If NuvaRing has

been used according to the instructions described in section 4.2, it is unlikely that the woman is

pregnant. However, if NuvaRing has not been used according to these instructions prior to the

first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out

before use of NuvaRing is continued.

Male exposure to ethinyl estradiol and etonogestrel

The extent and possible pharmacological role of exposure of male sexual partners to

ethinylestradiol and etonogestrel through absorption through the penis have not been

examined.

Broken rings

On very rare occasions NuvaRing has been reported to get disconnected during use (see

section 4.5). Vaginal injury associated with ring breakage has been reported.

The woman is

advised to remove the broken ring and reinsert a new ring as soon as possible and use a

barrier method such as a male condom in addition for the next 7 days. The possibility of a

pregnancy should be considered and the woman should contact her physician.

Expulsion

NuvaRing has been reported to get expelled, for example if the ring has not been inserted

properly, while removing a tampon, during sexual intercourse, or in case of severe or chronic

constipation. Prolonged expulsion may lead to contraceptive failure and/or breakthrough

bleeding. Therefore, to ensure efficacy the woman should be advised to regularly verify the

presence of NuvaRing (for example, before and after intercourse).

If NuvaRing is accidentally expelled and is left outside of the vagina for less than 3 hours

contraceptive efficacy is not reduced. The woman should rinse the ring with cool to lukewarm

(not hot) water and reinsert it as soon as possible, but at the latest within 3 hours.

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

more than 3 hours contraceptive efficacy may be reduced. In that case, the applicable advice

given in section 4.2 ‘What to do if the ring was temporarily outside the vagina’ should be

followed.

4.5

Interaction with other medicinal products and other forms of interaction

NuvaRing

Vaginal Ring

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.

NuvaRing

Vaginal Ring

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.

There have been reports of ring breakage during concomitant use of intravaginal preparations,

including antimycotic, antibiotic and lubricant products (see section 4.4, ‘Broken Rings’). Based

on pharmacokinetic data, vaginally administered antimycotics and spermicides are unlikely to

affect the contraceptive efficacy and safety of NuvaRing.

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’ in

section 4.2).

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

NuvaRing

Vaginal Ring

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 estrogens, 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

reactions,

including

angioedema

and anaphylaxis

NuvaRing

Vaginal Ring

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,

Galactorrhoea

Penis disorders

NuvaRing

Vaginal Ring

) 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.

On very rare occasions NuvaRing has been reported to get disconnected during use (see

sections 4.4

and 4.5).

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. Any

suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form:

https://sideeffects.health.gov.il

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.

Uterine spasm,

Vaginal burning

sensation,

Vaginal odour,

Vaginal pain,

Vulvovaginal

discomfort,

Vulvovaginal

dryness

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

Vaginal ring

discomfort,

Vaginal ring

expelled

Vaginal ring

complication

Vaginal injury

associated with

ring

breakage

NuvaRing

Vaginal Ring

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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

progestagen and estrogen, 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 estrogen 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

NuvaRing

Vaginal Ring

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

-∞) 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

NuvaRing

Vaginal Ring

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

NuvaRing

Vaginal Ring

Prior to dispensing:

36 months, store in a refrigerator (2°C - 8°C).

At the time of dispensing:

The dispenser places a date of dispensing on the packaging and also the date until which the

product should be inserted. 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, do not store above 30°C.

Store in the original package.

6.5

Nature and contents of container

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.

Each box contains 1 or 3 rings.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

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.

7.

MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme (Israel – 1996) Company Ltd., P.O.Box 7121, Petah-Tikva 49170.

8.

MANUFACTURER

N.V. Organon Oss, The Netherlands.

9.

MARKETING AUTHORISATION NUMBER

132.14.30926

Revided on June 2020.