SYNAREL

Israel - English - Ministry of Health

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Active ingredient:
NAFARELIN ACETATE
Available from:
PFIZER PFE PHARMACEUTICALS ISRAEL LTD
ATC code:
H01CA02
Pharmaceutical form:
NASAL SOLUTION
Composition:
NAFARELIN ACETATE 2 MG/ML
Administration route:
NASAL
Prescription type:
Required
Manufactured by:
NEOLPHARMA INC, PUERO RICO
Therapeutic group:
NAFARELIN
Therapeutic area:
NAFARELIN
Therapeutic indications:
- Controlled ovarian stimulation programmes prior to in-vitro fertilisation.- Hormonal management of endometriosis, including pain relief and reduction of endometrial lesions. - Uterine fibroids.
Authorization number:
135 64 26707 05
Authorization date:
2011-11-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

21-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

20-11-2018

PATIENT PACKAGE INSERT IN

ACCORDANCE WITH THE PHARMACISTS’

REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with

a doctor’s prescription only

Name of the preparation, its form and strength

Synarel

®

2 mg/mL

Nasal Solution

Nafarelin acetate 2 mg/mL

Each actuation delivers: Nafarelin 200 mcg

A list of inactive and allergenic ingredients in the preparation

is in section 6.

Read this leaflet carefully in its entirety before using the

medicine. This leaflet contains concise information about

the medicine. If you have further questions, refer to the

doctor or pharmacist.

This medicine has been prescribed to treat you. Do not pass

it on to others. It may harm them, even if it seems to you

that their medical condition is similar to yours.

The medicine is not intended for the treatment of young or

adolescent girls under 18 years of age. The medicine is

intended for use in women only.

For information on side effects, please refer to Section 4.

1. WHAT IS THE MEDICINE INTENDED fOR?

∙ As a part of combination treatment for supervised follicular

stimulation, in preparation for in-vitro fertilization.

∙ Hormonal treatment of endometriosis (development of

endometrial cells outside of the uterus).

∙ Treatment of uterine fibroids.

Therapeutic group:

Gonadotropin hormone agonist.

2. BEfORE USING THE MEDICINE

Do not use the medicine if:

x you are sensitive (allergic) to the active ingredient, to the

gonadotropin hormone, to its agonists or to any of the

other ingredients contained in the medicine, detailed in

section 6.

x you are pregnant or may become pregnant during

treatment with the medicine. If you are taking Synarel

as part of fertility treatment, the pregnancy will be

planned for after completion of the treatment period

with this medicine.

x you are breastfeeding.

x you are suffering from undiagnosed vaginal bleeding.

Special warnings regarding use of the medicine

Before treatment with Synarel

®

, tell the doctor if:

∙ you are suffering from polycystic ovaries, as there is a

potential risk for excessive follicular stimulation.

∙ you think you might be pregnant, as there is a risk to the

development of the fetus and/or of miscarriage.

∙ There have been reports of depression, that may be severe,

in patients taking Synarel

. If you are taking Synarel

develop a depressed mood, tell the doctor.

If you are taking, or have recently taken other

medicines, including non-prescription medicines and

nutritional supplements, tell the doctor or pharmacist,

especially if you are taking:

∙ nasal decongestants – do not use such preparations

within the 30 minute period before using Synarel

, as

they can significantly reduce the level of absorption of

the medicine through the nose. If your nose is congested,

Synarel

will still be absorbed properly.

∙ oral contraceptives – if you are taking oral contraceptives,

your attending doctor will ask you to stop using them and

to use a mechanical method of contraception instead

(diaphragm, condom) to prevent pregnancy.

Use of the medicine and food

Food has no effect on administration of the medicine.

Pregnancy and breastfeeding

Do not use the medicine if you are pregnant or planning to

become pregnant (see section: “Do not use the medicine

if:”).

Do not use the medicine if you are breastfeeding.

Driving and using machines

There is no evidence of an effect of the Synarel

preparation

on the ability to drive or operate machines.

Important information regarding some of the ingredients

of the medicine

The Synarel

preparation contains benzalkonium chloride (a

type of preservative). This substance is an irritant and may

cause skin reactions, swelling and bronchospasm.

3. HOW SHOULD yOU USE THE MEDICINE?

Always use according to the doctor's instructions. Check

with the doctor or pharmacist if you are not sure.

The dosage and treatment regimen will be determined by

the doctor only.

Do not exceed the recommended dose.

Mode of administration: This medicine is intended for

external use only – nasal solution (not for swallowing)!

Directions for use – see instructions for use further on in

the leaflet.

Duration of treatment:

∙ As a part of combination treatment for supervised

follicular stimulation, in preparation for in-vitro fertilization

– duration of treatment will be determined by the doctor

and will usually not exceed 8 weeks.

∙ Hormonal treatment of endometriosis (development of

endometrial cells outside of the uterus) – duration of

treatment will not exceed 6 months.

∙ Treatment of uterine fibroids – duration of treatment will

not exceed 3 months.

If you took an overdose or if a child accidentally swallowed

the medicine, immediately refer to a doctor or to a hospital

emergency room and bring the package of the medicine

with you.

If you forgot to take this medicine at the designated

time, take the dose as soon as you remember and the next

dose as usual. Do not take a double dose to compensate

for the forgotten dose.

If you missed one or more doses, vaginal bleeding may

occur. In addition, ovulation may occur, and if you had sexual

intercourse without adequate protection during the period

of treatment, the risk of pregnancy increases. In this case,

it is important to stop using Synarel

and refer to a doctor

to make sure that you are not pregnant (therefore, it is very

important to use mechanical methods of contraception when

using this medicine).

Adhere to the treatment regimen as recommended by the

doctor.

Even if there is an improvement in your health, do not stop

treatment with the medicine without consulting the doctor.

If some of the medicine remains, beyond the 60 actuations,

discard it.

Do not take medicines in the dark! Check the label and

the dose each time you take medicine. Wear glasses if you

need them.

If you have any further questions regarding use of this

medicine, consult the doctor or pharmacist.

4. SIDE EffECTS

As with any medicine, use of Synarel

may cause side

effects in some patients. Do not be alarmed by the list of

side effects. You may not suffer from any of them.

Discontinue use and refer to a doctor immediately in

the event of allergy to the preparation. The allergy may be

manifested by shortness of breath, chest pain or rash, with

or without itching.

Synarel

may lead to enlargement of the ovaries due to

excess egg production (OHSS – Ovarian Hyperstimulation

Syndrome). This condition can lead to pain in the pelvis,

stomach or calf, swelling or bloated feeling, passing less

urine, breathing difficulties or an increase in weight. If you

experience one or more of these effects, refer to your doctor

immediately.

Additional side effects are listed below according to their

frequency:

Very common side effects (effects which occur in more than

1 in 10 patients):

weight increase, mood swings, decreased libido, headache,

hot flushes, irritation and/or inflammation of the nasal

mucosa, acne, seborrhea, muscle pain, reduction in breast

size, vaginal dryness, edema.

Common side effects (effects which occur in 1-10 in 100

patients):

allergic reaction which may include shortness of breath,

chest pain and a rash, with or without itching, itching which

may be accompanied by swelling, skin rash including hives,

estrogen deficiency, weight decrease, depression, tingling

sensation, hypertension, hypotension, increased hair growth,

artificial amenorrhea, abnormal vaginal bleeding, increased

libido, insomnia, bone density decrease.

Uncommon side effects (effects that occur in 1-10 in 1,000

patients):

hair loss, joint pain, breast enlargement, ovarian cyst

formation.

Side effects of unknown frequency (effects whose frequency

has not yet been established):

Migraine, blurred vision, palpitations, increase in liver

enzymes, short term increase in symptoms of endometriosis

(development of endometrial cells outside the uterus),

enlargement of the ovaries due to excess egg production.

Tell your doctor if you are about to undergo medical tests, as

treatment with the medicine may affect the results.

If a side effect occurs, if one of the side effects worsens or

if you suffer from a side effect not mentioned in this leaflet,

consult with the doctor.

Side effects can be reported to the Ministry of Health by

clicking on the link “Report Side Effects of Drug Treatment”

found on the Ministry of Health homepage (www.health.gov.il)

that directs you to the online form for reporting side effects,

or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

You should put the safety clip and the plastic cap back on the

tip of the bottle whenever you are not using the medicine.

Avoid poisoning! This medicine, and any other medicine,

should be kept in a safe place out of the reach of children and/

or infants in order to avoid poisoning. Do not induce vomiting

unless explicitly instructed to do so by the doctor.

Do not use the medicine after the expiry date (exp. date)

that appears on the bottle. The expiry date refers to the last

day of that month.

Store below 25°C and protect from light and freezing.

After first opening: the preparation can be used for 4 weeks.

Keep the bottle upright.

6. fURTHER INfORMATION

In addition to the active ingredient, the medicine also

contains:

Sorbitol, glacial acetic acid, benzalkonium chloride, purified

water and sodium hydroxide or hydrochloric acid to adjust

the pH.

The medicine contains 71.4 mg/mL sorbitol.

What the medicine looks like and the contents of the

package:

A metered spray bottle containing 8 mL solution, which

provides 60 doses (actuations).

Registration holder and address: Pfizer PFE Pharmaceuticals

Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725.

Manufacturer and address: Pharmacia & Upjohn Co.,

Kalamazoo, USA.

Registration number of the medicine in the National Drug

Registry of the Ministry of Health: 135.64.26707

This leaflet format has been determined by the Ministry

of Health and the content thereof has been checked and

approved in January 2018 and updated according to the

guidelines of the Ministry of Health in October 2018

Synarel

®

How to use Synarel

®

Nasal Solution

Important tips in regards to Synarel

∙ The pump should produce a very fine mist (like fog), which

can only be produced by pressing quickly and firmly. It

is normal to see a few larger droplets of liquid within the

fine mist. However, if Synarel

comes out of the pump as

a thin stream of liquid instead of a fine mist, Synarel

not work well, and you should consult the pharmacist.

∙ Be sure to clean the spray tip after priming the pump

before first use. Clean the spray tip before and after every

use, otherwise it may get clogged, which may lead to you

not receiving the right amount of medicine prescribed for

you. Always replace the safety clip and the plastic cap

after use to help prevent the tip from becoming clogged.

∙ The pump is made to deliver a set amount of medicine,

no matter how hard you press it.

∙ Do not try to enlarge the tiny hole in the spray tip. If the

hole is enlarged, the pump will deliver a wrong amount of

Synarel

Priming the pump for use

Before use of Synarel

for the first time, you must prime the

pump. This only needs to be done once, before the first use.

1. Remove and save the safety clip and the plastic cap to

expose the tip of the bottle.

Hold the bottle away from you, in an upright position, with

two fingers resting on the 'shoulders' and your thumb on

the bottom of the bottle.

2. Prime the pump by pressing the bottle upwards several

times firmly and quickly until the air is expelled from the

pump and a fine spray appears. This action usually requires

about 5-7 presses. It is not necessary to repeat this action

during subsequent uses. You will waste the medicine

if you prime the pump this way each time you use it.

3. Clean the spray tip after priming it for use:

Hold the bottle in a horizontal position and rinse the spray

tip with warm water, while wiping the tip with your finger

or with a damp cloth for 15 seconds.

Do not clean the tip of the bottle with a sharp object, as

it could cause an incorrect dosage to be sprayed. Do not

separate the pump from the bottle, as this will release

the initial pressure.

Wipe the tip with a soft, dry clean cloth or tissue paper.

Using the pump

1. Gently blow your nose to clean the nostrils.

2. Remove and save the safety clip and the plastic cap to

expose the tip of the bottle. Hold the bottle as described

above.

3. Clean the tip of the bottle. Hold the bottle in a horizontal

position and rinse the tip with warm water, while wiping the

tip with your finger or a clean soft cloth for 15 seconds.

Do not clean the tip of the bottle with a sharp object,

as it could cause an incorrect dosage to be sprayed. Do

not separate the pump from the bottle, as this will release

the initial pressure.

Wipe the tip with a soft, dry clean cloth or tissue paper.

4. Bend your head forward slightly. Close one nostril and

insert the tip into the other nostril, aiming towards the

back and outer side of the nostril.

5. Press the bottle firmly between thumb and fingers once

only while gently inhaling in through the nostril. If the

doctor has instructed you to use four sprays every day,

now repeat this action in the other nostril.

6. Remove the sprayer from the nose and tilt your head

backwards for a few seconds to let the spray spread over

the back of the nose.

7. Clean the tip of the pump. Hold the bottle in a horizontal

position and rinse the tip with warm water, while wiping the

tip with your finger or a clean soft cloth for 15 seconds.

Do not clean the bottle tip with a sharp object, as this

could cause an incorrect dosage to be sprayed. Do not

remove the pump from the bottle, as this will release the

priming pressure.

Wipe the tip with a soft, dry clean cloth or tissue paper.

It is important to clean the tip before and after use to

prevent it from getting clogged, which can lead to you

receiving an incorrect dose of the medicine.

8. Put the safety clip and the plastic cap back in place. This

is important in order to prevent the spray tip from getting

clogged

SYNA SOL PL SH 251018

SYNA SOL PL SH 251018

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

SYNAREL

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Solution containing 2mg/ml of nafarelin (as acetate) supplied in bottles fitted with a metered spray

pump that delivers 200 micrograms of nafarelin base per spray.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Nasal spray, solution

Clear, colourless to slightly yellow, solution

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Nafarelin acetate is indicated for:

Use in controlled ovarian stimulation programmes prior to in-vitro fertilisation

Hormonal management of endometriosis, including pain relief and reduction of endometrial lesions.

Uterine fibroids

4.2

Posology and method of administration

Synarel

is for administration by the intranasal route only.

The 60 dose unit bottle is sufficient for 30 days' treatment at 400 mcg (2 sprays) per day, and 15

days' treatment at 800 mcg (4 sprays) per day.

Patients should be advised that the use of the contents of the container beyond the abovementioned

treatment-days may result in delivery of an insufficient amount of nafarelin acetate.

Controlled Ovarian Stimulation prior to in-vitro Fertilisation

400 mcg or 800 mcg daily administered as follows:

400 mcg: one spray (200mcg) to one nostril in the morning and one spray (200 mcg) to the other

nostril in the evening.

800 mcg: one spray to each nostril (2x200 mcg) in the morning, and one spray to each nostril

(2x200 mcg) in the evening.

In the use of Synarel

in endometriosis, the aim is to induce chronic pituitary desensitisation,

which gives a menopause-like state maintained over many months. However, in the use of

Synarel

associated with controlled ovarian stimulation prior to in-vitro fertilisation, the aims of

the treatment protocols are different, as follows:

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"long

protocol"

administration,

Synarel

continued

through

period

transient

gonadotrophin

stimulation

lasting

10-15

days

("the

flare

effect")

through

pituitary

desensitisation, (down-regulation). Down-regulation may be defined as serum estradiol <50pg/ml

and serum progesterone <1ng/ml , and the majority of patients down-regulate within 4 weeks.

Therapy should be continued until down regulation is achieved; if this does not occur within 12

weeks nafarelin acetate should be discontinued.

Once down-regulation is achieved, controlled ovarian stimulation with gonadotrophines, e.g. hMG,

is commenced, and the Synarel

dosage maintained until an appropriate stage of follicular

development, when both are withdrawn and chorionic gonadatropin is given to induce ovulation

The "short protocol" employs the flare effect as part of the gonadotrophin stimulation process,

which is supplemented by concurrent administration of exogenous gonadotrophins. This usually

takes 10-15 days, at which time, hCG is administered.

Treatment by the short protocol should begin in the early follicular phase (day 2). Treatment by the

long protocol may begin in either the early follicular phase (day 2) or the mid-luteal phase (usually

day 21).

Clinical trials using the long protocol have shown that achievement of down-regulation is more

predictable when using a Synarel® dosage of 800 mcg per day.

Endometriosis

Experience with nafarelin for the treatment of endometriosis has been limited to women 18 years

of age and older.

The recommended daily dose of nafarelin acetate is one spray (200 mcg of nafarelin free base)

into one nostril in the morning and one spray into the other nostril in the evening (total of 400

mcg/day). Treatment should be started between days 2 and 4 of the menstrual cycle. The

recommended duration of therapy is six months only. Retreatment is not recommended.

The 400 mcg daily dose may not produce amenorrhea in all patients. For these patients, if the

symptoms of endometriosis persist, the dose may be increased to 800 mcg daily. The 800 mcg

dose is administered as one spray into each nostril in the morning (a total of two sprays) and again

in the evening. This high dose should be maintained for 6 weeks and then reduced to 2 x

200 mcg/day.

Retreatment cannot be recommended since safety data beyond 6 months are not available.

Uterine Fibroids

The recommended dose of nafarelin acetate for uterine fibroid patients is one spray (200 mcg of

nafarelin free base) to one nostril in the morning and one spray into the other nostril in the evening

(400 mcg/day). The duration therapy should not exceed 3 months. Efficacy beyond 3 months has

not been established

Important Tips about using Synarel

The pump should produce a fine mist, which can only happen by a quick and firm pumping action. It is

normal to see some larger droplets of liquid within the fine mist. However, if Synarel comes out of the

pump as a thin stream of liquid instead of a fine mist, Synarel may not work as well, and the patient

should talk to a pharmacist.

Be sure to clean the Spray Tip after priming (at the time of the first use). The spray tip should then be

cleaned before and after every use. Failure to do this may result in a clogged tip that may cause the patient

not to get the right amount of medicine that is prescribed for them. Always replace the safety clip and the

plastic dust cap on the nasal piece after use to help prevent the tip becoming clogged.

The pump is made to deliver only a set amount of medicine, no matter how hard you pump it.

Do not try to make the tiny hole in the spray tip larger. If the hole is made larger the pump will deliver a

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wrong dose of Synarel.

Priming the Spray Pump: Before the patient uses a bottle of Synarel for the first time, they have to

prime the spray pump. This only needs to be done once, before they use the first dose.

1. Remove and save the safety clip and the plastic dust cap to uncover the nasal piece. Hold the bottle

with in an upright position away from you with two fingers on the 'shoulders' and your thumb on the

bottom of the bottle.

2. Prime the pump by pressing the bottle upwards several times firmly and quickly until the air is expelled

and a fine spray appears. This usually requires about 5 - 7 presses. It is not necessary to prime the pump

again during subsequent use. You will waste your medicine if you prime the pump every time you use it.

3. Clean the Spray Tip after Priming:

Hold the bottle in a horizontal position and rinse the spray tip with warm water, while wiping the tip with

your finger or a clean soft cloth for 15 seconds.

Do not clean the spray tip with a pointed object. This could cause an improper dose of the spray to be

delivered. Do not remove the pump from the bottle, as this will release the priming pressure.

Wipe the tip dry with a clean soft cloth or tissue.

Using the Spray Pump

1. Gently blow the nose to clear the nostrils.

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2. Remove the safety clip and the plastic cap to uncover the nasal piece. Hold the bottle as shown

previously.

Clean the tip of pump.

Hold the bottle in a horizontal position and rinse the spray tip with warm water, while wiping the tip with

your finger or a clean soft cloth for 15 seconds.

Do not clean the spray tip with a pointed object. This could cause an improper dose of the spray to be

delivered. Do not remove the pump from the bottle, as this will release the priming pressure.

Wipe the tip dry with a clean soft cloth or tissue.

4. Bend head forward slightly. Close one nostril and put the spray tip into the other, aiming towards the

back and outer side of the nose.

5. Press the bottle firmly up between thumb and fingers once only whilst gently breathing in through the

nostril. For patients using 4 sprays per day, Synarel should now be sprayed into the other nostril.

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6. Remove the sprayer from the nostril. Bend head backwards for a few seconds to let the spray spread

over back of the nose.

7. Clean the tip of pump. Hold the bottle in a horizontal position and rinse the spray tip with warm

water, while wiping the tip with your finger or a clean soft cloth for 15 seconds.

Do not clean the spray tip with a pointed object. This could cause an improper dose of the

spray to be delivered. Do not remove the pump from the bottle, as this will release the priming pressure.

Wipe the tip dry with a clean soft cloth or tissue.

Cleaning the spray tip before and after use is important to prevent clogging of the tip that may cause you

to get the wrong dose of medicine.

8. Replace the safety clip and the plastic dust cap on the nasal piece. This is important as it helps to

prevent the spray tip becoming clogged.

4.3

Contraindications

A small loss of trabecula bone mineral content occurs during 6 months treatment with nafarelin.

Although this is mostly reversible within 6 months of stopping treatment, there are no data on

the effects of repeat courses on bone loss. Retreatment with Synarel

or use for longer than 6

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months is, therefore, not recommended. (See Special warnings and precautions for use section

on 'Changes in bone density').

Synarel

should not be administered to patients who:

are hypersensitive to GnRH, GnRH agonist analogues or any of the excipients in

Synarel

have undiagnosed vaginal bleeding;

are pregnant or may become pregnant whilst taking Synarel

(see 'use in pregnancy and

lactation');

are breast-feeding.

4.4

Special warnings and precautions for use

When regularly used at the recommended dose, nafarelin inhibits ovulation. Patients should be

advised to use non-hormonal, barrier methods of contraception. In the event of missed doses

there may be breakthrough ovulation and a potential for conception. If a patient becomes

pregnant during treatment, administration of the drug must be discontinued and the patient must

be informed of a potential risk to fetal development and/or miscarriage. As there is a risk of

miscarriage in the patient population, a causal association with nafarelin acetate is uncertain.

NB Synarel

treatment will be stopped at least 3 days before fertilised embryos are placed in the

uterine cavity.

As with other drugs in this class ovarian cysts have been reported to occur in the first two

months of therapy with Synarel

. Many, but not all, of these events occurred in patients with

polycystic ovarian disease. These cystic enlargements may resolve spontaneously, generally by

about four to six weeks of therapy, but in some cases may require discontinuation of drug and/or

surgical intervention.

After a course of therapy, if further treatment of endometriosis and fibroids with nafarelin

acetate is contemplated, it is recommended that bone density be assessed before retreatment

begins to ensure that values are within normal limits.

In adults, after six months of nafarelin acetate treatment there was very little, if any decrease

in the mineral content of the distal radius and second metacarpal. There was a reduction in

vertebral trabecular bone density and total vertebral mass, averaging 8.7% and 4.3%,

respectively. Substantial recovery of bone occurred during the post-treatment period. Total

vertebral bone mass, measured by dual photon absorptiometry (DPA) decreased by a mean of

5.9% at the end of treatment. Mean total vertebral mass, re-examined by DPA six months

after completion of treatment, was 1.4% below pretreatment levels.

Controlled ovarian stimulation prior to in vitro fertilisation; Transient ovarian cyst formation is

a recognised complication of GnRH agonist use. These cysts tend to regress spontaneously over

a number of weeks and are more common when GnRH agonists are commenced in the follicular

phase of the cycle.

There are no clinical data available on the use of Synarel

in ovulation induction regimens

involving patients with polycystic ovarian syndrome. Caution is advised in this patient group as

they are at greater risk of excessive follicular recruitment when undergoing ovulation induction

regimes.

Administration of nafarelin in therapeutic doses results in suppression of the pituitary-gonadal

system. Normal function is usually restored within 8 weeks after treatment is discontinued.

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Diagnostic tests of pituitary-gonadal function conducted during the treatment and up to 8 weeks

after discontinuation of nafarelin therapy may therefore be misleading.

Sneezing during or immediately after dosing may impair absorption of nafarelin acetate. If

sneezing occurs upon administration, repeating the dose may be advisable.

If the use of a nasal decongestant is required, it is recommended that the nasal decongestant

be used at least 30 minutes after nafarelin acetate dosing (see Section 4.5)

Nafarelin

acetate

contains

preservative

benzalkonium

chloride,

which

cause

contractions of the respiratory passage. The preservative (benzalkonium chloride) in nafarelin

acetate may cause oedemas in the nasal mucosa, especially on long term use. If a persistent

oedema

nasal

mucosa

suspected,

medicinal

product

nasal

without

preservative should be chosen, if possible. If such products for nasal use are not available, the

use of other formulations of the medicinal product should be considered.

There

increased

risk

incident

depression

(which

severe)

patients

undergoing treatment with GnRH agonists, such as nafarelin acetate. Patients should be

informed accordingly and treated as appropriate if symptoms occur.

4.5

Interaction with other medicinal products and other forms of interaction

No pharmacokinetic-based drug-drug interaction studies have been conducted with nafarelin

acetate. Nafarelin would not be expected to participate in pharmacokinetic-based drug-drug

interactions because degradation of the compound is primarily by the action of peptidases, not

cytochrome P-450 enzymes. Additionally, because nafarelin is only about 80% bound to plasma

proteins (albumin), drug interactions at the protein-binding level would not be expected to occur.

Rhinitis

does

impair

nasal

absorption

nafarelin.

decongestant

oxymetazoline hydrochloride by subjects with perennial rhinitis 30 minutes prior to nafarelin

acetate administration significantly reduced the extent of nasal absorption of nafarelin acetate

(39% decrease in AUC0-8h; 49% decrease in Cmax) compared to the absorption attained in

subjects

with

normal

nasal

mucosa.

concomitant

decongestants

should

discouraged in patients receiving nafarelin acetate (see Section 4.4.)

4.6

Fertility, pregnancy and lactation

When administered intramuscularly to rats on days 6-15 of pregnancy at doses of 0.4, 1.6 and

6.4 mcg/kg/day (0.6, 2.5 and 10.0 times the intranasal human dose of 400mcg per day), 4/80

fetuses in the highest dose group had major fetal abnormalities that were not seen in a repeat

study in rats. Moreover, studies in mice and rabbits failed to demonstrate an increase in fetal

abnormalities. In rats, there was a dose-related increase in fetal mortality, and a decrease in fetal

weight with the highest dose. These effects on rat fetal mortality are logical consequences of the

alterations in hormonal levels brought about by nafarelin in this species.

Use of nafarelin in human pregnancy has not been studied.

Synarel

should not therefore be used during pregnancy or suspected pregnancy. Before starting

treatment with Synarel

, pregnancy must be excluded. If a patient becomes pregnant during

treatment, administration of the drug must be discontinued and the patient must be informed of a

potential risk to fetal development. (see Section 4.3).

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Controlled ovarian stimulation prior to in vitro fertilisation: Pregnancy should be excluded

before starting treatment with Synarel

, and the medication should be stopped on the day of

administration of hCG. Barrier methods of contraception should be employed whilst Synarel

being taken.

It is not known whether or to what extent nafarelin is excreted into human breast milk. The

effects, if any on the breast-fed child have not been determined and therefore Synarel

should

not be used by breast-feeding women. (see Section 4.3).

4.7

Effects on ability to drive and use machines

Not applicable.

4.8

Undesirable effects

Initial treatment with nafarelin acetate may cause transient exacerbation of endometriosis and

chronic treatment may induce a menopausal state.

The following undesirable effects have been observed and reported during treatment of 282

adult patients with nafarelin acetate with the following frequencies: Very common (≥1/10);

Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Not known: Cannot be

estimated from the available data.

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Adult population

MedDRA

System Organ Class

Frequency

Undesirable Effects

Immune system disorders

Common

Drug hypersensitivity

(Chest pain, Dyspnoea,

Pruritus, Rash, Urticaria)

Endocrine disorders

Common

Oestrogen deficiency

Metabolism and nutrition

disorders

Very common

Weight increased

Common

Weight decreased

Psychiatric disorders

Very common

Affect lability, Libido

decreased

Common

Depression, Insomnia,

Libido increased

Nervous system disorders

Very common

Headache

Common

Paraesthesia

Vascular disorders

Very common

Hot flush

Common

Hypertension,

Hypotension

Respiratory, thoracic and

mediastinal disorders

Very common

Rhinitis

Skin and subcutaneous

tissue disorders

Very common

Acne, Seborrhoea

Common

Hirsutism

Uncommon

Alopecia

Musculoskeletal and

connective tissue disorders

Very common

Myalgia

Uncommon

Arthralgia

Reproductive system and

breast disorders

Very common

Breast atrophy,

Vulvovaginal dryness

Common

Artificial menopause,

Uterine haemorrhage

Uncommon

Breast enlargement,

Ovarian cyst

Not known

Ovarian hyperstimulation

syndrome

General disorders and

administration site

conditions

Very common

Oedema

Investigations

Common

Bone density decreased

In addition to the above mentioned undesirable affects, migraine, blurred vision, palpitations,

shortness of breath, increased levels of SGOT/SGPT and serum alkaline phosphatase have

been reported but the frequencies are not known.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse reactions by

using an online form

Synarel LPD CC 14102018

2017-0032771

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic

@moh.health.gov.il )

4.9

Overdose

In animals, subcutaneous administration of up to 60 times the recommended human dose

(expressed on a mcg/kg basis) had no adverse effects. Orally-administered nafarelin is subject to

enzymatic degradation in the gastro-intestinal tract and is therefore inactive. At present there is

no clinical experience with overdosage of nafarelin.

Based on studies in monkeys, nafarelin is not absorbed after oral administration.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

ATC code: H01CA02

Nafarelin is a potent agonistic analogue of gonadotrophin releasing hormone (GnRH). Given as

a single dose, nafarelin stimulates release of the pituitary gonadotrophins, LH and FSH, with

consequent increase of ovarian and testicular steroidogenesis. During repeated dosing this

response to stimulation gradually diminishes. Within three to four weeks, daily administration

leads to decreased pituitary gonadotrophin secretion and/or the secretion of gonadotrophin

secretion and/or the secretion of gonadotrophins with lowered biological activity. There is a

consequent suppression of gonadal steroidogenesis and inhibition of functions in tissues that

depend on gonadal steroids for their maintenance.

5.2

Pharmacokinetic properties

Nafarelin is rapidly absorbed into the circulation after intranasal administration. Maximum

plasma

concentration

achieved

minutes

after

dosing

plasma

half-life

approximately 4 hours. Bioavailability of the intranasal dose averages 2.8% (range 1.2-5.6%).

5.3

Preclinical safety data

Carcinogenesis/mutagenesis: As seen with other GnRH agonists, nafarelin given parenterally in

high doses to laboratory rodents for prolonged periods induced hyperplasia and neoplasia of

endocrine organs, including the anterior pituitary (adenoma/carcinoma) of both mice and rats;

tumours of the pancreatic islets, adrenal medulla, testes and ovaries occurred only in long-term

studies in rats. No metastases of these tumours were observed. Monkeys treated with high

doses

nafarelin

year

develop

tumours

proliferative

changes.

Experience in humans is limited but there is no evidence for tumorigenesis of GnRH analogues

in human beings.

In vitro studies conducted in bacterial and mammalian systems provided no indication of a

mutagenic potential for nafarelin.

Impairment of fertility: Reproduction studies in rats of both sexes have shown full reversibility

of fertility suppression when drug treatment was discontinued after continuous administration

for up to six months.

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6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Synarel

contains:

Sorbitol, glacial acetic acid, benzalkonium chloride and purified water.

Sodium hydroxide or hydrochloric acid to adjust pH.

6.2

Incompatibilities

None stated.

6.3

Shelf life

The expiry date of the product is indicated on the packaging materials

After first opening: can be used for 4 weeks.

6.4

Special precautions for storage

Store upright below 25°C.

Protect from light and freezing.

6.5

Nature and contents of container

Bottle of 60 dose units. Each bottle contains nafarelin acetate solution (2 mg/mL) as nafarelin

base.

6.6

Instructions for use and handling

After first opening: can be used for 4 weeks.

In order to ensure that the correct dose of medicine is administered, it is important that the spray tip is

cleaned after priming (at the time of the first use). The spray tip should then be cleaned before and after

every use to avoid the tip becoming clogged (see section 4.2).

7.

Manufacturer

PHARMACIA & UPJOHN COMPANY, KALAMAZOO, USA

License holder:

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St, Hertzliya Pituach 46725

The content of this leaflet was approved by the Ministry of Health in January 2018 and updated according to the

guidelines of the Ministry of Health in October 2018

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