OPTALGIN DROPS

PATIENT PACKAGE INSERT

IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS

(PREPARATIONS) - 1986

The preparation shall be sold

without a doctor’s prescription

OPTALGIN

®

Drops for oral administration

Composition

Each 1 ml (25 drops) contains:

Dipyrone 500 mg

For the list of inactive ingredients in the

preparation see section 6 - “Further

Information”.

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 is given without need

for a doctor's prescription. You should

take the medicine correctly. The drops

are not intended for infants weighing

less than 5 kg. Consult a pharmacist

if you need further information. You

should refer to the doctor if the

fever lasts for more than 3 days or

pain persists for more than 7 days,

despite use of the medicine. The risk of

agranulocytosis increases if treatment

continues for more than 7 days (see

“Side Effects” section).

1.

WHAT

IS

THE

MEDICINE

INTENDED FOR?

The medicine is intended for the relief

of moderate to strong pain, such as

headache, toothache and menstrual

pain, and for lowering high fever that

does not respond to other measures

of treatment.

Therapeutic group: Optalgin

Drops

contain an active ingredient belonging

to the pyrazoline group.

2.

BEFORE USING THE MEDICINE

Do not use the preparation if:

∙ Do not use the medicine when you

are pregnant or breastfeeding.

∙ Do not use this medicine if you

have

known

sensitivity

the active ingredient dipyrone

(metamizole), propyphenazone,

phenazone, phenylbutazone or to

any of the inactive ingredients of the

medicine.

∙ Do not use this medicine for mild

pains.

∙ Do not use this medicine if you

have a known deficiency of the

G6PD enzyme (“sensitivity to fava

beans”).

∙ Do not use if you suffer from a blood

system impairment.

∙ Do not use this medicine if you

suffer from acute hepatic porphyria

(an inherited disease in which

there is increased production

and accumulation of porphyrin,

causing disorders, for instance of

the nervous system).

Do not use the medicine if you

have bone marrow depression (for

instance, following chemotherapy).

Special warnings regarding use of

the medicine

Inform the doctor before commencing

treatment if you are suffering, or have

suffered in the past, from:

∙ A tendency for hypersensitivity to

painkillers, medicines for treatment

of arthritis and other medicines.

Allergy related symptoms: in such

cases, the risk of anaphylactic shock

increases (see “Side Effects” section).

∙ If you are prone to allergies: such as

allergies to food, alcoholic beverages,

animals, preservatives, hair dyes,

various medicines, allergy that

causes asthma or chronic skin rash

(urticaria) – Optalgin

should only be

taken under medical supervision.

∙ Impairment in function of the liver,

kidney, blood system (e.g., coagulation

or anemia).

∙ If you suffer from diseases that are

accompanied by a decrease in white

blood cells.

∙ If you suffer from asthma or chronic

respiratory airway infections.

Warnings

Dipyrone may cause rare but life-

threatening effects of anaphylactic

shock and/or agranulocytosis (see

“Side Effects” section).

∙ Do not use this medicine frequently or

for a prolonged period of time without

consulting the doctor.

∙ If you are sensitive to any type of food

or medicine, inform the doctor before

taking the medicine.

∙ Rarely, hypersensitivity to this medicine

may cause leucopenia (too few white

blood cells), thrombocytopenia

(manifested by an increased tendency

to bleed) or agranulocytosis (toxic

damage to white blood cells) and

shock. This reaction is manifested by

high fever, chills, sore throat, difficulty

swallowing and inflammation of the

mouth cavity, the nose or genitals.

When one of these signs occur, and

they may already occur in the first

hour after taking the medicine, stop

taking the medicine immediately and

consult the doctor. When consulting

the doctor you must inform him if

you have taken another medicine

concomitantly with Optalgin

∙ This medicine may cause a red color

in acidic urine. This effect should not

be a cause for concern.

If you are taking, or have recently

taken other medicines

including non-prescription medicines,

nutritional supplements and vitamins,

tell the doctor or pharmacist. You

should especially inform the doctor or

pharmacist if you are taking or have just

finished treatment with a medicine from

one of the following groups:

∙ non-steroidal anti-inflammatory drugs

(NSAIDs) such as aspirin.

∙ anticoagulants (warfarin).

∙ ciclosporin (for transplantations) - the

ciclosporin level may be reduced.

∙ chlorpromazine (an antipsychotic

medicine).

Use of Optalgin

®

and food

Take the medicine with a glass of water.

It can be taken before or after a meal.

Pregnancy

Do not use this medicine if you are

pregnant.

Breastfeeding

Do not breastfeed during treatment with

this medicine.

Use in children

This medicine is not intended for infants

weighing less than 5 kg.

Driving

Use of this medicine at higher than

recommended dosages may affect

your reaction time, your ability to drive

and to operate machinery. Therefore,

avoid driving a vehicle, operating

machinery and any other activity

requiring alertness. The risk increases

if the medicine is taken together with

alcohol.

3.

HOW SHOULD YOU USE THE

MEDICINE?

Always use the medicine according to

the doctor’s instructions. Check with the

doctor or pharmacist if you are unsure.

The dosage and treatment regimen will

be determined by the doctor only.

The usual dosage unless otherwise

instructed by the doctor:

Take the appropriate dosage according

to the table below.

Take the medicine at intervals of

6-8 hours.

It is recommended that the dosage

be given by the weight of the child in

accordance with the table. Only if the

child’s weight is unknown will the dosage

be determined by the child’s age.

Do not take a dose more than 3 times

hours.

The drops are not intended for infants

weighing less than 5 kg.

Do not exceed the recommended

dose.

Make sure the bottle cap is tightly

closed after use.

If the fever lasts for more than 3 days

or pain persists for more than 7 days,

despite use of the medicine, refer to

the doctor.

The risk of agranulocytosis increases

if treatment continues for more than 7

days (see “Side Effects” section).

Adults and adolescents from 15 years

of age and above (above 53 kg body

weight):

25-50 drops up to 3 times a day.

Infants and children:

Age

Body

weight

(Kg)

Dosage

(No. of drops)

3-11

months

2-5 drops up to

3 times daily

1-3 years

9-15

4-12 drops up to

3 times daily

4-6 years

16-23

6-19 drops up to

3 times daily

7-9 years

24-30 10-25 drops up to

3 times daily

10-12 years 31-45 12-37 drops up to

3 times daily

13-14 years 46-53 19-44 drops up to

3 times daily

If you accidently took an overdose, or

if a child accidentally swallowed the

medicine, immediately refer to a doctor

or proceed to a hospital emergency room

and bring the package of medicine with

you.

Effects of overdose:

Nausea, vomiting, abdominal pain,

impairment of kidney function, and in

rarer cases: dizziness, convulsions,

unconsciousness, drop in blood pressure,

shock, heart rhythm disorders.

When taking a very high dosage of the

medicine your urine may turn red.

If you forget to take the medicine: do

not take two doses together to make up

for a missed dose.

Adhere

to

the

treatment

as

recommended by the doctor.

4.

SIDE EFFECTS

As with any medicine, use of Optalgin

may cause side effects in some users.

Do not be alarmed when reading the list

of side effects. You may not suffer from

any of them.

Refer to the doctor immediately if you

experience:

The main side effects of the medicine

are hypersensitivity reactions. They

include:

Anaphylactic shock and agranulocytosis.

These are rare but life-threatening

effects. They can occur even if you

took the medicine in the past with no

complications. They can already occur

in the first hour after taking the medicine,

but also a few hours later.

∙ Anaphylactic shock - an acute

hypersensitivity reaction manifested

by cold sweat, severe rash all over

the body, swelling of the skin or the

pharynx, mucosal blisters, dizziness,

severe shortness of breath, nausea,

vomiting, stomach irritation, rapid

pulse, feeling of tightness in the chest

and a sharp drop in blood pressure

(rare): stop treatment and call for

medical help immediately!

Meanwhile, until the doctor arrives,

lay the patient down on his back and

raise his legs. It is advisable to warm

his body with a blanket.

∙ Rarely, hypersensitivity to this medicine

may cause leucopenia (too few white

blood cells), thrombocytopenia

(reduction in platelets manifested by

an increased tendency for bleeding)

or agranulocytosis (toxic damage

of the white blood cells). The risk

of agranulocytosis increases if the

medicine is taken for more than 7

days. This reaction is manifested by

high fever, chills, sore throat, difficulty

swallowing and inflammation of the

mouth cavity, the nose or genitals,

worsening of your general condition

(such as tiredness or weakness).

taking

antibiotics

concomitantly – it is possible that

these signs will be weaker. If any of

the above signs occurs, stop taking

the medicine immediately and consult

with the doctor.

∙ Skin or mucosal effects: In isolated

cases there may be:

Stevens-Johnson

syndrome

Lyell's syndrome - these are acute

and life-threatening skin reactions

including rash or mucosal blisters -

stop treatment and refer to the doctor

immediately!

∙ In rare cases, mainly in cases of a

drop in blood volume, in patients

with a history of kidney diseases and

in cases of overdose, there may be:

kidney dysfunction, such as reduction

in or absence of urinary output, kidney

inflammation or secretion of protein

into the urine (rare): stop treatment

immediately and refer to the doctor!

If a side effect occurs, if any of the side

effects worsen, or if you are suffering

from side effect not mentioned in the

leaflet, consult 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/getsequ

ence/getsequence.aspx?formType=Ad

versEffectMedic@moh.gov.il

5.

HOW SHOULD THE MEDICINE BE

STORED?

∙ Avoid poisoning! This medicine and

any other medicine should be kept

in a closed 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 take medicines in the dark!

Check the label and the dose

each time you take a medicine. Wear

glasses if you need them.

∙ Do not use the medicine after the

expiry date (Exp. Date) that appears

on the package. The expiry date refers

to the last day of that month.

∙ Store in a dry place, below 25°C.

∙ The medicine can be used for up

to 3 months after first opening the

bottle, but not after the expiry date

of the preparation.

6.

FURTHER INFORMATION

In addition to the active ingredient the

medicine also contains: water

What does the medicine look like and

what are the contents of the package:

The medicine comes in two packages:

10 ml and 15 ml. The medicine drops

are yellowish in color.

Manufacturer:

Teva Pharmaceutical Industries Ltd.,

P.O.B. 3190, Petach-Tikva.

This

leaflet

checked

approved by the Ministry of Health in

September 2014.

Registration number of the medicine

in the National Drug Registry of the

Ministry of Health: 020.15.20487.00

34O161034-03

34O161034-03

OPTA DROP PL SH 160517

OPTA DROP PL SH 160517

Optalgin Caplets/Tablets SPC, SZ, 10/2019 Notification

SUMMARY OF PRODUCT CHARACTERISTICS

Optalgin

®

Caplets

Optalgin

®

Tablets

1.

NAME OF THE MEDICINAL PRODUCT

Optalgin

Caplets

Optalgin

Tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Optalgin Caplets

Each caplet contains 500 mg Dipyrone.

Optalgin Tablets

Each tablet contains 500 mg Dipyrone.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Caplets

Optalgin caplets are white to creamy, oblong film coated caplets, scored on one side.

The caplet can be

divided into equal halves.

Tablets

Optalgin tablets are white to off-white, round flat beveled tablets with a score line on one side and

engraved "TEVA" on the other side. The tablet can be divided into equal halves.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

Relief of moderate to severe pain as in headache, toothache, dysmenorrhea, and for high fever that does not

respond to other measures.

4.2.

Posology and method of administration

Posology

Dosage is determined by the intensity of the pain or fever and individual sensitivity of response to

Optalgin.

It is essential to choose the lowest dose that controls pain and fever.

Adults

1-2 caplets or 1-2 tablets up to 4 times daily.

Do not exceed 8 caplets or 8 tablets daily.

Depending on the maximum daily dose, the single dose can be taken in intervals of 6 to 8 hours.

Optalgin Caplets/Tablets SPC, SZ, 10/2019 NOTIFICATION

Adults and adolescents aged 15 years and over (> 53 kg) can take up to 1000 mg per single dose. Where

the effect is inadequate, the respective single dose can be administered up to 4 times daily, depending on

the maximum daily dose.

Children and infants

For children and infants dosage refer to Optalgin drops.

Elderly patients

The dose should be reduced in the elderly, since elimination of the metabolites of Optalgin may be

prolonged.

Debilitated patients and patients with reduced creatinine clearance

The dose should be reduced in debilitated patients and in patients with reduced creatinine clearance,

since elimination of the metabolites of Optalgin may be prolonged.

Impaired renal or hepatic function

Since the elimination rate is reduced when renal or hepatic function is impaired, multiple high doses

should be avoided. No dose reduction is required when only used for a short time. There is no

experience with long-term use.

Method of administration

The tablets are to be swallowed whole with sufficient liquid (e.g., a glass of water).

Duration of use

The duration of use depends upon the type and severity of the disease. In the event of longer-term treatment

with Optalgin, regular monitoring of blood count is required, including differential blood count.

4.3. Contraindications

Hypersensitivity to the active substance Dipyrone (metamizole), other pyrazolones or pyrazolidines

(this also includes patients who have developed agranulocytosis following use of such substances), or to

any of the excipients listed in section 6.1.

Patients with known analgesic-asthma-syndrome or analgesic-intolerance of urticaria-angioedema type,

i.e. patients who react to salicylates, paracetamol or other non-narcotic analgesics (e.g., diclofenac,

ibuprofen, indomethacin, naproxen) with bronchospasm or other anaphylactoid symptoms (e.g.,

urticaria, rhinitis, angioedema).

Bone marrow failure (e.g., after treatment with cytostatics) or hematopoietic disorders.

Acute intermittent hepatic porphyria (risk of triggering an attack of porphyria).

In children under 4 years of age or in patients with a body weight of less than 16 kg.

4.4

Special warnings and precautions for use

Optalgin contains the pyrazolone derivative Dipyrone and are associated with rare but life-threatening risks

of shock and agranulocytosis (see section 4.8).

Patients who experience anaphylactoid reactions to Dipyrone are at particular risk of experiencing similar

reactions to other non-narcotic analgesics.

Patients who experience an anaphylactic reaction or another immunologically mediated reaction to

Dipyrone (e.g., agranulocytosis) are at particular risk of experiencing similar reactions to other

pyrazolones and pyrazolidines.

Optalgin Caplets/Tablets SPC, SZ, 10/2019 NOTIFICATION

Agranulocytosis

If signs of agranulocytosis or thrombocytopenia occur (see section 4.8), administration of Optalgin must be

discontinued immediately and blood count (including differential blood count) must be monitored.

Treatment must be discontinued even before laboratory test results become available.

Pancytopenia

If pancytopenia occurs, treatment must be discontinued immediately and complete blood count must be

monitored until it normalizes (see section 4.8). All patients should be instructed to consult their doctor

immediately if signs and symptoms occur during treatment which may indicate blood dyscrasia (e.g.,

malaise, infection, persistent fever, bruising, bleeding, pallor).

Anaphylactic/anaphylactoid reactions

The risk of potentially severe anaphylactoid reactions to Optalgin is significantly increased in patients

with:

Analgesic-asthma-syndrome or analgesic-intolerance of urticaria-angioedema type (see section 4.3).

Bronchial asthma, particularly with concurrent rhinosinusitis and nasal polyps.

Chronic urticaria.

Intolerance to coloring agents (e.g., tartrazine) or preservatives (e.g., benzoates).

Alcohol intolerance. Such patients react to even minimal amounts of alcohol with symptoms such as

sneezing, watery eyes and severe flushing. Alcohol intolerance of this kind may be indicative of as yet

undiagnosed analgesic-asthma-syndrome

(see section 4.3).

Anaphylactic shock may occur, primarily in susceptible patients. Special care should therefore be taken

when administered to patients with asthma or atopy.

Severe skin reactions

There have been reports of the life-threatening skin reactions Stevens-Johnson syndrome (SJS) and toxic

epidermal necrolysis (TEN) following use of Dipyrone. If symptoms or signs of SJS or TEN develop (such

as progressive rash, often associated with blisters or mucosal lesions), treatment with Optalgin must be

discontinued immediately and not resumed at any stage.

Patients should be advised of the signs and symptoms and should be monitored closely for skin reactions,

especially in the first few weeks of treatment.

Isolated hypotensive reactions

Optalgin may induce hypotensive reactions (see also section 4.8).

These reactions may be dose-dependent. This is more likely with parenteral than enteral administration.

The risk of such reactions is also increased in:

Patients

with, for example, pre-existing hypotension, volume depletion or dehydration, unstable

circulation or incipient circulatory failure (e.g., in patients with myocardial infarction or multiple

trauma).

Patients with high fever.

Careful indication testing and close monitoring are therefore required in such patients. Preventive measures

(e.g., circulatory stabilization) may be required to reduce the risk of hypotensive reactions.

Optalgin should only be used with careful monitoring of hemodynamic parameters in patients in whom a

reduction in blood pressure must be avoided at all costs, e.g., patients with severe coronary heart disease or

relevant cerebrovascular stenosis.

Optalgin should only be used after careful risk-benefit assessment and appropriate precautions in patients

with renal or hepatic impairment (see section 4.2).

Optalgin Caplets/Tablets SPC, SZ, 10/2019 NOTIFICATION

Patients should be asked relevant questions prior to the administration of Optalgin. Optalgin should only be

used after carefully weighing the potential risks against the anticipated benefits in patients at increased risk

of anaphylactoid reactions. If Optalgin are administered in such cases, patients should be placed under

close medical supervision, with emergency facilities available.

4.5

Interaction with other medicinal products and other forms of interaction

Dipyrone may cause a decrease in serum cyclosporine levels. These must therefore be monitored if

Optalgin is used concomitantly.

Severe hypothermia may develop following concomitant use of Optalgin and chlorpromazine.

Co-administration of Dipyrone and methotrexate may increase the hematotoxicity of methotrexate,

especially in elderly patients. This combination should therefore be avoided.

Dipyrone may reduce the anti-platelet activity of low-dose aspirin in the event of concomitant use.

Dipyrone should therefore be used with caution in patients taking low-dose aspirin for cardioprotection.

Dipyrone may reduce bupropion blood levels. Caution should therefore be exercised with concomitant

administration of Dipyrone and bupropion.

The pyrazolones are known to interact with oral anticoagulants, captopril, lithium and triamterene, and

to cause potential changes in the effectiveness of antihypertensives and diuretics. It is not known to

what extent Dipyrone also triggers such interactions.

Effect on assay methods

There have been reports of Dipyrone interference with Trinder and Trinder-like reaction assays (e.g.,

determination of serum levels of creatinine, triglyceride, HDL cholesterol or uric acid).Therefore, In cases

of these tests the patient should take Optalgin only after giving a blood sample.

4.6. Pregnancy and breast-feeding

Pregnancy

There are no adequate data from the use of Dipyrone in pregnant women. Dipyrone crosses the placental

barrier. Dipyrone has not been associated with teratogenic effects in animal studies (see section 5.3).

Although Dipyrone is a weak inhibitor of prostaglandin synthesis, the possibility of premature closure of

the ductus arteriosus (Botalli) and perinatal complications due to a reduction in platelet aggregability in the

mother and child cannot be excluded.

The use of Dipyrone in the third trimester (after week 28) should be used at the lowest effective dose. The

daily dose should be up to 3 grams, for only 3-4 days. Longer treatment needs close medical supervision

Breast-feeding

The metabolites of Dipyrone are excreted in breast milk.

The use of Dipyrone should be limited to cases

which do not respond to the use of paracetamol or ibuprofen.

4.7

Effects on ability to drive and use machines

Within the recommended dosage range there is no known impairment of the ability to concentrate and

react. As a precaution, however, at least at higher dosages, the possibility of impairment of the ability

Optalgin Caplets/Tablets SPC, SZ, 10/2019 NOTIFICATION

to concentrate and react should be taken into account, and patients should avoid using machines,

driving or other hazardous activities. This applies in particular in conjunction with alcohol.

4.8

Undesirable effects

The frequency of adverse reactions is defined using the following convention:

Very common

1/10

Common

1/100, < 1/10

Uncommon

1/1,000, < 1/100

Rare

1/10,000, < 1/1,000

Very rare

< 1/10,000

Not known

Frequency cannot be estimated from available data

Blood and Lymphatic System Disorders

Rare:

Leukocytopenia.

Very rare:

Agranulocytosis (including fatal cases), thrombocytopenia.

Not known:

Aplastic anemia, pancytopenia (including fatal cases).

These reactions can occur even if Dipyrone was previously administered without complications.

There is isolated evidence that the risk of agranulocytosis may increase if Dipyrone is used for more than

one week.

This reaction is not dose-dependent and can occur at any time during treatment. It is manifested by high

fever, chills, sore throat, dysphagia and inflammation of the mouth, nose, throat and genital or anal

area. These signs may be minimal, however, in patients receiving antibiotics. There is little or no

swelling of the lymph nodes or spleen. Erythrocyte sedimentation rate is significantly accelerated, whilst

granulocytes are considerably reduced or completely absent. Hemoglobin, erythrocyte and platelet

values are generally, but not always, normal (see section 4.4).

Immediate discontinuation is essential for recovery. Therefore optalgin treatment must be discontinued

immediately, without waiting for the results of laboratory-diagnostic tests, in the event of unexpected

deterioration in general condition, persistent or recurrent fever, or painful mucosal changes (especially in

the mouth, nose and throat region).

If pancytopenia occurs, treatment must be discontinued immediately and complete blood count must be

monitored until it normalizes (see section 4.4).

Immune System Disorders

Rare:

Anaphylactoid or anaphylactic reactions*.

Very rare:

Analgesic-asthma-syndrome

In patients with analgesic-asthma-syndrome, intolerance

reactions are typically manifested in the form of asthma

attacks.

Not known:

Anaphylactic shock*.

*These reactions may occur in particular following parenteral application and may be severe and life-

threatening, in some cases even fatal. They can also occur if Dipyrone was previously administered

without complications.

Such reactions may occur during injection or immediately after administration, but may also develop hours

later. In the majority of cases, however, they develop within the first hour of administration. Milder

Optalgin Caplets/Tablets SPC, SZ, 10/2019 NOTIFICATION

reactions are typically manifested in the form of skin and mucosal reactions (e.g., itching, burning

sensation, redness, urticaria, swelling), dyspnea and (in rarer cases) gastrointestinal complaints. Such

milder reactions may become more severe, progressing to generalized urticaria, severe angioedema (also in

the laryngeal region), severe bronchospasm, cardiac arrhythmias, hypotension (sometimes with preceding

hypertension) and circulatory shock.

Optalgin should therefore be discontinued immediately in the event of skin reactions.

Cardiac disorders

Frequency not known: Kounis syndrome.

Vascular Disorders

Uncommon:

Hypotensive reactions during or after administration, which may

be pharmacologically induced and may not be accompanied by

other signs of anaphylactoid or anaphylactic reaction. Such

reactions can lead to severe hypotension. Rapid intravenous

injection increases the risk of hypotensive reactions.

Dose-dependent critical hypotension may also occur in the event of hyperpyrexia, without further signs of

hypersensitivity.

Skin and Subcutaneous Tissue Disorders

Uncommon:

Fixed drug eruption.

Rare:

Rash (e.g., maculopapular exanthema).

Very rare:

Stevens-Johnson syndrome or toxic epidermal necrolysis

(discontinue treatment, see section 4.4).

Renal and urinary disorders

Very rare:

Acute deterioration of renal function, which may progress in

very rare cases to proteinuria, oliguria or anuria, or acute renal

failure, acute interstitial nephritis.

General disorders and administration site conditions

There have been reports of red urine discoloration, which may be attributable to the harmless Dipyrone

metabolite rubazonic acid, present at low concentrations.

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

Overdose Symptoms:

Nausea, vomiting, abdominal pain, renal impairment/acute renal failure (e.g., in the form of interstitial

nephritis) and (more rarely) central nervous symptoms (dizziness, somnolence, coma, convulsions) and

hypotension, progressing to shock and tachycardia have been observed following acute overdose.

After very high doses, excretion of rubazonic acid may cause red discoloration of the urine.

Optalgin Caplets/Tablets SPC, SZ, 10/2019 NOTIFICATION

Therapeutic measures following overdose:

No specific antidote is known for Dipyrone. If the Dipyrone was only recently taken, attempts can be made

to limit systemic absorption using primary detoxification measures (e.g., gastric lavage) or absorption-

reducing measures (e.g., activated charcoal). The main metabolite (4-N-methylaminoantipyrine) can be

eliminated by hemodialysis, hemofiltration, hemoperfusion or plasma filtration.

Treatment of intoxication and prevention of severe complications may require general and specialist

intensive care monitoring and treatment.

Emergency measures in the event of severe hypersensitivity reactions (shock):

Stop administration at the first sign of hypersensitivity reactions (e.g., cutaneous reactions such as

urticaria and flushing, agitation, headache, sweating, nausea). In addition to standard emergency measures

such as Trendelenburg positioning, maintenance of patent airways and administration of oxygen, the

administration of sympathomimetics, volume expanders or glucocorticoids may be necessary.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics; Other analgesics and antipyretics; Pyrazolones

ATC code: N02BB02

Dipyrone is a pyrazolone derivative and has analgesic, antipyretic and spasmolytic properties. The

mechanism of action is not fully understood. Some research findings suggest that Dipyrone and the main

metabolite (4-N-methylaminoantipyrine) may have both a central and a peripheral mechanism of action.

5.2

Pharmacokinetic properties

After oral administration, Dipyrone is completely hydrolyzed to the pharmacologically active 4-N-

methylaminoantipyrine (MAA). The bioavailability of MAA is approx. 90% and is slightly higher after

oral administration than after parenteral administration. Concomitant intake of food does not have a

relevant effect on Dipyrone kinetics.

The clinical efficacy is mainly due to MAA, but also to a certain extent to the metabolite 4-

aminoantipyrine (AA). The AUC values for AA represent approx. 25% of the AUC values for MAA. The

metabolites 4-N-acetylaminoantipyrine (AAA) and 4-N-formylaminoantipyrine (FAA) appear to be

pharmacologically inactive.

It should be noted that all of the metabolites display non-linear pharmacokinetics. The clinical significance

of this phenomenon is unknown. Accumulation of the metabolites is of little significance with short-term

treatment.

Dipyrone crosses the placental barrier. The metabolites of Dipyrone are excreted in breast milk.

Plasma protein binding is 58% for MAA, 48% for AA, 18% for FAA and 14% for AAA.

Dipyrone's plasma half-life following intravenous administration is approx. 14 minutes. After intravenous

administration approx. 96% of a radiolabeled dose is recovered in the urine and approx. 6% in the feces.

Following a single oral dose, 85% of the urinary metabolites excreted were identified. Of this percentage,

MAA accounted for 3±1%, AA 6±3%, AAA 26±8% and FAA 23±4%. Renal clearance after a single oral

dose of 1 g Dipyrone was 5±2 mL/min for MAA, 38±13 mL/min for AA, 61±8 mL/min for AAA and

49±5 mL/min for FAA. The associated plasma half-lives were 2.7±0.5 hours for MAA, 3.7±1.3 hours for

AA, 9.5±1.5 hours for AAA and 11.2±1.5 hours for FAA.

Elderly

Optalgin Caplets/Tablets SPC, SZ, 10/2019 NOTIFICATION

The AUC is 2 to 3 times higher with treatment of elderly patients. Following a single oral administration,

the half-life of MAA and FAA increased approx. 3-fold in patients with hepatic cirrhosis, whereas the half-

lives of AA and AAA did not increase to the same extent. High doses should be avoided in such patients.

Renal impairment

The data available for patients with renal impairment indicate a reduced elimination rate for some

metabolites (AAA and FAA). High doses should therefore be avoided in such patients.

5.3

Preclinical safety data

Subchronic and chronic toxicity studies have been performed on various animal species. Rats were orally

administered with Dipyrone at doses of 100 mg to 900 mg/kg body weight for 6 months. At the highest

dose (900 mg/kg bw), an increase in reticulocytes and Heinz bodies was observed after 13 weeks.

Dogs were administered with Dipyrone at doses of 30 to 600 mg/kg bw for 6 months. Dose-dependent

hemolytic anemia and changes in renal and hepatic function have been observed from 300 mg/kg bw.

There are contradictory results for Dipyrone from in vitro and in vivo studies in the same test systems.

Long-term studies in rats have not produced any evidence of tumorigenic potential. Increased liver cell

adenomas were observed at high doses in two out of three long-term studies in mice.

Embryo toxicity studies in rats and rabbits have not revealed any evidence of teratogenic effects.

Embryolethal effects have been observed in rabbits from a non-maternally toxic daily dose of 100 mg/kg

bw. In rats, embryolethal effects only occurred at doses in the maternally toxic range. Daily doses in excess

of 100 mg/kg bw led to prolonged gestation in rats and impaired parturition with increased maternal and

pup mortality.

Fertility tests revealed a slightly decreased pregnancy rate in the parental generation at doses above 250

mg/kg bw/day. The fertility of the F1 generation was not affected.

The metabolites of Dipyrone are excreted in breast milk. There is no experience with regard to their effects

on suckling pups.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Optalgin Caplets:

Starch, gelatin, magnesium stearate, talc, colloidal silicon dioxide, hydroxypropyl methylcellulose, titanium

dioxide, polyethylene glycol, polysorbate 80.

Optalgin Tablets:

Starch, gelatin, magnesium stearate, talc, colloidal silicon dioxide.

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

Optalgin Caplets/Tablets SPC, SZ, 10/2019 NOTIFICATION

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

Optalgin caplets in a bottle: after first opening, the product can be used until the expiry date.

6.4

Special precautions for storage

Optalgin caplets/ tablets: Store in a dry place, below 25

6.5

Nature and contents of container

Optalgin Caplets: Pack containing 21 or 42 caplets in blisters or bottle containing 50 caplets.

Optalgin Tablets: Pack containing 20 tablets in blisters.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7

LICENCE HOLDER AND MANUFACTURER

Teva Pharmaceutical Industries Ltd.

P.O.Box 3190, Petah Tikva

8

REGISTRATION NUMBER

Optalgin Caplets: 066.25.27767

Optalgin Tablets: 016.87.20611

This leaflet format has been determined by the Ministry of Health and its content has

been checked and approved by the Ministry of health in 7/2019 and updated according to

MoH instructions in 11/2019.