AMIODARONE 50 mg /Ml Инъекционный Раствор

Содержание инструкции

1. Amiodarone Hikma 50 mg/ml, injectable solution
   1. What is Amiodarone Hikma and what is it used for
   2. What you need to know before using Amiodarone Hikma
   3. How to use Amiodarone Hikma
   4. Possible side effects
   5. How to store Amiodarone Hikma
   6. Contents of the pack and other information
   7. MEDICINAL PRODUCT NAME
   8. QUALITATIVE AND QUANTITATIVE COMPOSITION
   9. PHARMACEUTICAL FORM
   10. 2 Dosage and method of administration
   11. 3 Contraindications
   12. 4 Special warnings and precautions for use
   13. 5 Interactions with other medicines and other forms of interaction
   14. 6 Fertility, Pregnancy and Lactation
   15. 7 Effects on ability to drive and use machines
   16. 8 Undesirable effects
   17. 9 Overdosage
   18. 2 Pharmacokinetic properties
   19. 3 Preclinical safety data
   20. 2 Incompatibilities
   21. 3 Shelf life
   22. 4 Special precautions for storage
   23. 5 Nature and contents of the container
   24. 6 Special precautions for disposal and handling
   25. MARKETING AUTHORISATION HOLDER
   26. MARKETING AUTHORISATION NUMBER(S)
   27. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION
   28. DATE OF TEXT REVISION:

Amiodarone Hikma 50 mg/ml, injectable solution

amiodarone hydrochloride

Read this leaflet carefully before using this medicine, as it contains important
information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• If any side effects occur, including those not listed in this leaflet, tell your pharmacist.

Contents of this leaflet:

• 1. What Amiodarone Hikma is and what it is used for
• 2. What you need to know before using Amiodarone Hikma
• 3. How to use Amiodarone Hikma
• 4. Possible side effects
• 5. How to store Amiodarone Hikma
• 6. Contents of the pack and other information

1. What is Amiodarone Hikma and what is it used for

To which group of medicines does Amiodarone Hikma belong?
Amiodarone Hikma belongs to the group of medicines called antiarrhythmics. Antiarrhythmic medicines
correct the heartbeat if the heart is not beating as it should.

What is Amiodarone Hikma used for?
Amiodarone Hikma is used to treat and prevent certain heart rhythm disorders. It is only used if
other medicines are not effective or cannot be used. For example, it is used if you are unable to take
tablets. It is also used if you need a medicine that acts very
quickly.

2. What you need to know before using Amiodarone Hikma

The following paragraph contains information for you and your doctor, to be kept in mind before you are administered Amiodarone Hikma.

Do not use Amiodarone Hikma

• If you are allergic to amiodarone hydrochloride or any of the excipients of this medicine (listed in section 6)
• If your heartbeat is extremely slow (sinus bradycardia) or if you have irregular heart rhythms (sinoatrial block)
• If you have sick sinus syndrome (a specific type of heart rhythm disorder)
• If you have an AV block (a specific type of heart conduction disorder)
• If your thyroid gland is not functioning properly
• If you are taking medicines that increase the risk of “torsades de pointes”. “Torsades de pointes” is a heart condition that causes a very fast heartbeat (see also “Other medicines and Amiodarone Hikma” below).
• Amiodarone must not be administered to premature babies or infants and children up to 3 years of age.

Amiodarone Hikma may be administered to you in an emergency, if you have lost consciousness and need to be resuscitated. In this case, the reasons given above for not using this medicine are not valid.

Warnings and precautions
Amiodarone Hikma is only used in intensive care units. The medicine will only be administered to you by specialist doctors. If this medicine is administered to you, the doctor will regularly check:

• That your liver and thyroid gland are functioning properly (through periodic blood tests)
• That your heart is functioning properly (using an electrocardiograph, a device that records heart activity)
• That your lungs are functioning properly (through imaging tests of the lungs)

Use particular caution in the following circumstances:

• If you suffer from any of the following diseases:
• Severe impairment of lung function (respiratory failure)
• Low blood pressure (arterial hypotension)
• The heart is not pumping blood as it should (congestive heart failure) If this medicine is administered to you to treat the diseases mentioned, caution and extremely careful monitoring are necessary. The medicine should not be administered to you by injection, as this may worsen your condition.
• Slowing of the heartbeat: in some cases, the effect of Amiodarone Hikma is too strong and can slow down the heartbeat. In this case, the doctor will ensure that the heartbeat is restored to normal.
• Changes in heart rhythm: Amiodarone Hikma can cause new heart rhythm disorders or worsen existing disorders.
• Shortness of breath: Amiodarone Hikma can cause lung disorders. For example, it can cause a type of inflammation of the lungs called interstitial pneumonia. If you experience shortness of breath (with or without fatigue, weight loss or fever), the doctor will examine you. You may be given a chest X-ray.
• Liver failure: Amiodarone Hikma can cause liver failure within the first 24 hours after use. For this reason, the doctor will monitor liver function.
• Use of certain other medicines (see “Other medicines and Amiodarone Hikma”).

If Amiodarone Hikma is administered by injection:

• You must not receive a dose greater than 5 mg per kg of body weight.
• The dose must be administered slowly, over at least 3 minutes (unless the medicine is administered for resuscitation).
• The doctor must wait at least 15 minutes before administering another injection.

See also “HOW TO USE AMIODARONE HIKMA?”.
Most of the side effects that occur during treatment occur if an excessive dose of Amiodarone Hikma is administered. Therefore, it is recommended to administer the lowest possible dose of Amiodarone Hikma. This will minimize side effects. See also “If you use more Amiodarone Hikma than you should”.

Tell your doctor or pharmacist if any of the above warnings apply to you or have applied in the past.

Other medicines and Amiodarone Hikma
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including herbal remedies, supplements or dietary supplements obtained without a prescription.
The following medicines can increase the risk of “torsades de pointes”. DO NOT use Amiodarone Hikma at the same time as these medicines:

• Certain medicines used to treat heart rhythm disorders (e.g. quinidine, procainamide, disopyramide and sotalol)
• Vincamine (used to increase blood flow to the brain)
• Certain medicines used to treat severe mental illnesses (e.g. sulpiride, sulpiride, pimozide, thioridazine) and certain medicines called phenothiazines
• Cisapride (used to treat digestive disorders)
• Erythromycin injections (an antibiotic)
• Pentamidine injections (used in certain types of pneumonia)
• Certain antidepressants (e.g. amitriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, trimipramine, maprotiline)
• Antihistamines (medicines used to treat allergies and hay fever, e.g. terfenadine)
• Alofantrine (an anti-malarial drug)

Associations not recommended
The use of the following medicines at the same time as Amiodarone Hikma is not recommended. Otherwise, a severe slowing of the heartbeat may occur.

• Beta-blockers (used to treat high blood pressure, heart failure and increased pressure inside the eye)
• Calcium channel blockers (used to treat high blood pressure and heart rhythm disorders)

Caution
Caution is recommended when using the following medicines at the same time as Amiodarone Hikma. These medicines can lower potassium levels in the blood, resulting in an increased risk of the heart beating too fast (“torsades de pointes”):

• Stimulant laxatives
• Adrenal cortex hormones (glucocorticoids and mineralcorticoids)
• Tetracosactide (used to treat adrenal cortex diseases)
• Diuretics
• Amphotericin B injections (an antibiotic used to treat or prevent certain infections)

Medicines that thin the blood (anticoagulants)
Amiodarone Hikma can enhance the effect of these medicines. This increases the risk of bleeding.
If you are using anticoagulants, consult your doctor.
The doctor may decide to adjust the dose of other medicines. This is especially true for:

• Phenytoin (used in epilepsy)
• Digitoxin (used to treat certain heart diseases)
• Flecainide (used to treat certain heart rhythm disorders)
• Medicines that are broken down by certain liver enzymes, including:
• Certain medicines that lower cholesterol (some statins, e.g. simvastatin)
• Some medicines used to prevent rejection after transplantation (cyclosporine, tacrolimus)
• Fentanyl (a strong painkiller)
• Lidocaine (a local anesthetic)
• Sildenafil (used to treat erectile dysfunction)
• Midazolam and triazolam (sleeping pills)
• Ergotamine, dihydroergotamine (used for migraine)

Surgery:if you are going to have surgery, you must inform the surgeons that you are taking Amiodarone Hikma.

Pregnancy and breastfeeding
This medicine can harm the fetus. Therefore, you must not take Amiodarone Hikma:

• If you are pregnant
• If you believe you are pregnant
• If you are planning a pregnancy If you become pregnant during treatment with Amiodarone Hikma, you should inform your doctor immediately.

You must not use Amiodarone Hikma during breastfeeding. If the use of Amiodarone Hikma is necessary, you must stop breastfeeding.

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

Driving and using machines
During the use of Amiodarone Hikma, vision may become blurred or reduced. Do not drive or use machines if you experience these symptoms. If you experience these symptoms, ask your doctor if you can drive a vehicle or use machines safely.

Amiodarone Hikma contains benzyl alcohol
This medicine contains benzyl alcohol (20mg/ml) as a preservative. This substance can cause toxic and allergic reactions in infants and children up to 3 years of age.

3. How to use Amiodarone Hikma

How is Amiodarone Hikma administered?
Your doctor will determine the exact dose of Amiodarone Hikma needed. Amiodarone Hikma will be
administered to you via direct injection into a vein or via intravenous infusion (drip infusion).

Dosage
Injection
The usual dose is 5 mg per kg of body weight. The medicine will be injected over a period of not
less than 3 minutes.
Intravenous infusion
The usual dose is 5 mg per kg of body weight. The duration of the infusion is between 20 minutes and
2 hours; the infusion is repeated 2 to 3 times a day.
You will also be given a maintenance dose of between 10 and 20 mg per kg of body
weight per day. The maintenance dose is necessary to ensure that the medicine continues to be
effective and to prevent further heart rhythm disturbances.
Your doctor will monitor your response to Amiodarone Hikma and adjust the dose based on your response.
See also “Pay particular attention with Amiodarone Hikma”.

Use in children
Do not administer Amiodarone Hikma to children under the age of 3 years (see also “Do not use
Amiodarone Hikma”).
There are limited data on safety and efficacy in children. Your doctor will decide the appropriate
dose.

If you use more Amiodarone Hikma than you should
If you are given an excessive amount of Amiodarone Hikma, the following may occur:

• Nausea; in exceptional cases, vomiting
• Constipation
• Sweating
• Slow and irregular heartbeat

These effects may also appear after 1 – 3 days. If large amounts of Amiodarone Hikma have been administered, the following may also occur:

• Low blood pressure
• Heart problems
• Rarely, increased thyroid activity (hyperthyroidism) The symptoms of hyperthyroidism include weight loss, increased appetite, intolerance to heat, fatigue, weakness, hyperactivity, irritability, apathy, depression, increased urine production and sweating. If you experience any of these symptoms, inform your doctor immediately.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects have been observed:

Common (affecting less than 1 in 10 people, but more than 1 in 100):

• Bradycardia (slow heartbeat)
• Fall in blood pressure and fast heartbeat. These side effects occur immediately after the injection. These effects are generally moderate and transient. If you are given too much Amiodarone Hikma too quickly, these side effects may be serious.
• At the injection or infusion site, the following may occur:
• Pain
• Redness of the skin (erythema)
• Fluid accumulation (edema)
• Localized destruction of soft tissues (necrosis)
• Extravasation of fluids
• Swelling due to fluid infiltration into the skin
• Inflammation
• Hardening (tissues harder than normal)
• Inflammation of blood vessels with or without blood clot formation (phlebitis and thrombophlebitis)
• Infection
• Inflammation of the tissues under the skin (cellulitis)
• Alteration of skin color

Rare(affecting less than 1 in 1,000 people, but more than 1 in 10,000):

• Allergic reactions (hypersensitivity). The symptoms of these reactions include:
• Thrombocytopenia (deficiency of platelets in the blood, with bruising and a tendency to bleeding)
• Blood vessel disorders
• Kidney disorders

Very rare(affecting less than 1 in 10,000 or not known (frequency cannot be estimated on the
basis of available data):

• Headache
• Increased pressure inside the skull, with headache, nausea and vomiting (benign intracranial hypertension)
• Severe slowing of the heartbeat (bradycardia) (may cause discontinuation of treatment)
• Appearance of new heart rhythm disturbances, which may be fatal.
• Worsening of existing heart rhythm disturbances, which may be fatal.
• Cardiac conduction disturbances (e.g. AV block)
• Hot flashes
• Difficulty breathing due to sudden contraction of the muscles of the airways (bronchospasm). This may happen if you already suffer from severe breathing problems, especially if you have asthma. Usually, patients recover quickly from this side effect after stopping treatment.
• Lung diseases (interstitial pneumonia). Usually, patients recover quickly from this side effect after stopping treatment. However, some cases have been fatal.
• Severe breathing difficulties (adult respiratory distress syndrome). Usually, patients recover quickly from this side effect after stopping treatment. However, some cases have been fatal.
• Nausea
• Changes in liver function. The doctor will monitor liver function regularly to detect any abnormalities. These abnormalities are often transient or improve with dose reduction.
• Acute liver dysfunction, with increased levels of liver enzymes and/or jaundice. The liver may suddenly stop working properly. This can be fatal. If this side effect occurs, the doctor will consider stopping treatment with Amiodarone Hikma.
• Sweating
• Anaphylactic shock. The symptoms of anaphylactic shock include:
• Collapse of blood pressure
• Pallor
• Restlessness
• Weak and rapid pulse
• Cold and clammy skin
• Decreased state of consciousness Shock is due to a sudden and marked dilation of blood vessels, caused by a severe allergy.
• Feeling unwell, confusion or weakness, nausea, loss of appetite, feeling of irritability. This may be due to a condition called “inappropriate secretion of antidiuretic hormone” (SIADH).

Not known(frequency cannot be estimated on the basis of available data):

• Severe anemia
• Numbness and tingling in the hands and feet
• Paresthesia (tingling sensation)
• Lack of muscle coordination
• Tremors
• Vomiting
• Metallic taste
• Skin reactions such as burns or erythema
• Thyroid disorders (hyperactive and hypoactive thyroid)
• (Muscle pathologies
• Corneal microdeposits, sometimes associated with halos of colored light, reversible after discontinuation of treatment
• Optic nerve disorders
• Epididymitis (disorder or pain of the testicle)
• Insomnia
• Nightmares If you get any side effects, even if not listed in this leaflet, tell your doctor or pharmacist. Reporting of suspected adverse reactions Reporting suspected adverse reactions that occur after authorization of the medicine is important, as it allows continuous monitoring of the benefit/risk ratio of the medicine. Healthcare professionals are required to report any suspected adverse reactions through

5. How to store Amiodarone Hikma

Keep this medicine out of sight and reach of children.
Do not store Amiodarone Hikma at a temperature above 25 °C. Do not refrigerate or freeze.
Store in the original packaging to protect the medicine from light.
The diluted product is physically and chemically stable for 24 hours at room temperature.
However, from a microbiological point of view, it is advisable to use the product immediately after
dilution.
For single use only. Discard any unused solution.
Do not use Amiodarone Hikma after the expiry date, stated on the packaging after “EXP”. The
expiry date refers to the last day of the month.
Medicines should not be disposed of via drains or household waste. Ask your
pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What Amiodarone Hikma contains

• The active substance is amiodarone hydrochloride

Each ml of Amiodarone Hikma 50 mg/ml injectable solution contains 50 mg of amiodarone
hydrochloride.
Each vial contains 3 ml of Amiodarone Hikma.

The excipients are:
Polysorbate 80 (E433)
Benzyl alcohol
Water for injections

Description of the appearance of Amiodarone Hikma and contents of the pack
Amiodarone Hikma is a clear, pale yellow solution.
Each pack contains 10 x 5 ml clear glass vials.
Each vial contains 3 ml of Amiodarone Hikma.

Marketing Authorisation Holder and Manufacturer
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó, 8, 8A e 8B - Fervença
2705-906 Terrugem SNT
Portugal
Tel.:+ 351 219 608 410
Fax: + 351 219 615 102
[email protected]

For further information on Amiodarone Hikma, contact the local representative of the Marketing
Authorisation Holder:
Sales concessionaire for Italy
Hikma Italia SpA
Viale Certosa 10
27100 Pavia

This medicinal product is authorised in the Member States of the EEA under the following
denominations:
Germany
Austria Sedacoron®
Netherlands
Italy
Portugal
 ------------------------------------------------------------------------------------------------------------
The following information is intended exclusively for medical professionals or healthcare
operators:

SUMMARY OF PRODUCT CHARACTERISTICS

1. MEDICINAL PRODUCT NAME

Amiodarone Hikma 50 mg/ml injectable solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 vial of 3 ml of injectable solution contains the equivalent of 150 mg of amiodarone hydrochloride.
1 ml contains 50 mg of amiodarone hydrochloride.
Excipients with known effect: each 3 ml vial contains 60.6 mg of benzyl alcohol.
For the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Injectable solution
Clear solution of pale yellow colour, in a transparent colourless glass vial
pH: 3.7-4.3

4. CLINICAL INFORMATION

4.1 Therapeutic indications

Amiodarone Hikma is indicated for the prophylaxis and treatment of severe cardiac arrhythmias, in cases in
which other therapies are ineffective or contraindicated:

• Atrial arrhythmias, including atrial fibrillation and atrial flutter;
• AV nodal arrhythmias and AV re-entrant tachycardia, e.g. as a manifestation of Wolff-Parkinson-White syndrome;
• Life-threatening ventricular arrhythmias, including persistent or non-persistent ventricular tachycardia or episodes of ventricular fibrillation;

Amiodarone Hikma is used in patients for whom a rapid response is desired or for whom
oral administration is not possible.

4.2 Dosage and method of administration

Use amiodarone only in facilities equipped with the necessary equipment for cardiac monitoring, defibrillation and cardiac pacing.
Infusion
For dilution with 5% glucose solution, see also section 6.6.

Loading dose
Administer 5 mg per kg of body weight in 250 ml of physiological glucose solution over 20
minutes - 2 hours and repeat 2 - 3 times every 24 hours. Adjust the infusion rate based on the effect
obtained.
The effect occurs within a few minutes and gradually decreases; therefore, the loading dose must be
followed by a maintenance dose.

Maintenance dose / prophylactic treatment

• 10 - 20 mg per kg of body weight in physiological glucose solution every 24 hours (average 600 - 800 mg/ 24 hours up to a maximum of 1200 mg/ 24 hours, corresponding to 4-5 vials, maximum 8 vials) for a few days. To preserve the stability of the solution, do not use concentrations lower than 300 mg in 500 ml and do not add other medicines to the infusion solution. To prevent possible local reactions (phlebitis), do not use concentrations higher than 3 mg/ml. It is advisable to start with a maintenance oral dose on the first day of infusion. Repeated or continuous infusions into peripheral veins can cause local reactions (inflammation). For repeated or continuous infusions, it is recommended to use a central venous route.

Caution: if administered by infusion, amiodarone may reduce the size of the
drops; if necessary, adjust the infusion rate.
Direct intravenous injection (“bolus”)
In cases of extreme emergency, at the doctor's discretion, the drug may be administered via
slow injection. Administer 5 mg per kg of body weight over a time not less than 3 minutes. The
duration of the injection must never be less than 3 minutes, except for cases of
cardiopulmonary resuscitation in shock-resistant ventricular fibrillation. A second
bolus injection should not be administered before 15 minutes have elapsed from the first
injection, even if only one vial has been injected (risk of irreversible shock).
Patients treated in this way must be subjected to careful monitoring in an intensive care unit.
Administer the bolus injection only in an emergency and do not use other medicines in the same
syringe.
The recommended dose of 5 mg per kg via direct injection must not be exceeded.
Cardiopulmonary resuscitation in shock-resistant ventricular fibrillation
The initial dose is 300 mg (or 5 mg/kg of body weight) diluted in 20 ml of 5% dextrose
solution, to be administered by rapid injection. If ventricular fibrillation persists, administration of an additional dose of 150 mg (or 2.5 mg/kg of body weight) may be considered.

Paediatric population
The safety and efficacy of amiodarone in children have not been established. The data currently
available are described in sections 5.1 and 5.2.
Following the presence of benzyl alcohol, amiodarone in intravenous administration is
contraindicated in newborns and children up to 3 years of age.
Transition from intravenous to oral therapy
Start with an oral maintenance dose of amiodarone as soon as an adequate response has been obtained.
Then gradually discontinue i.v. administration of amiodarone. In patients
treated concurrently with amiodarone and simvastatin, the dose of simvastatin should not exceed 20
mg/day.
Method of administration
For information regarding the dilution of the medicine before administration, see
section 6.6.

4.3 Contraindications

• Sinus bradycardia, sinoatrial block (risk of sinus arrest)
• Sick sinus syndrome, without a pacemaker
• AV block of second or third degree, without a pacemaker. In these cases, the intravenous administration of amiodarone may be carried out in specialized units and only in conjunction with a pacemaker
• Thyroid dysfunction
• Concomitant use of medicines that prolong the QT interval (see section 4.5)
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Following the presence of benzyl alcohol, the intravenous administration of amiodarone is
contraindicated in neonates and children up to 3 years of age.
The aforementioned contraindications do not refer to the use of amiodarone for cardiopulmonary resuscitation in ventricular fibrillation resistant to shock.

4.4 Special warnings and precautions for use

Amiodarone can only be prescribed by competent specialists. Its use requires careful and regular monitoring of liver and thyroid function, an ECG and a chest radiograph.
The administration of direct intravenous injections (bolus injections) is not recommended due to the risk of haemodynamic effects, such as severe hypotension and circulatory collapse. Bolus injections should only be used in emergencies – in coronary care units and under ECG monitoring – in case of failure of alternative therapeutic options.
Use Amiodarone Hikma only under constant monitoring of ECG and blood pressure.
Use the product with extreme caution – with haemodynamic monitoring – in patients with severe impairment of pulmonary function, arterial hypotension or stable congestive heart failure. These patients should not receive a bolus injection (risk of exacerbation).
The recommended dose of 5 mg per kg, administered by direct injection, must not be exceeded.
If the effect of the product is too strong (e.g. marked bradycardia), appropriate measures must be taken, e.g. the use of a pacemaker or beta stimulation.
The use of Amiodarone Hikma is not a contraindication to subsequent external defibrillation.

Cardiac pathologies (see section 4.8)
Amiodarone can induce new cardiac arrhythmias or exacerbate existing arrhythmias, sometimes with fatal consequences. However, compared to other antiarrhythmics, the incidence of such effects appears to be less frequent. Use caution especially in patients with heart failure or first-degree AV block. In addition, the appearance of torsade de pointes, a polymorphic ventricular tachycardia associated with QT prolongation, has been described. This particular arrhythmia occurs especially in patients with a markedly prolonged QT interval and/or in association with medicines that can induce hypokalaemia, certain antiarrhythmic agents and certain agents that prevent repolarization (see also section 4.5).
On the ECG, changes in the T wave and the possible appearance of U waves are due to the prolongation of the repolarization phase induced by amiodarone.
As occurs with other antiarrhythmic agents, this phenomenon can induce atypical ventricular tachycardias (“torsade de pointes”) in exceptional cases.

Endocrine pathologies (see section 4.8)
Intravenous administration of amiodarone can induce hyperthyroidism, particularly in patients with a history of thyroid disorders, patients with iodine deficiency or patients who are taking or have previously taken amiodarone orally. If thyroid dysfunction is suspected, serum TSH levels must be measured. If hyperthyroidism is confirmed, intravenous amiodarone therapy should be discontinued. In severe cases, sometimes resulting in fatal events, emergency individual therapy with antithyroid drugs and/or corticosteroids must be initiated.
The administration of Amiodarone leads to a reduction in the peripheral conversion of thyroxine (T4) to tri-iodothyronine (T3), with a consequent increase in T4, a modest reduction in T3 and an increase in reversible T3 concentrations. The baseline serum concentration of TSH (thyroid-stimulating hormone) increases transiently during the first months of treatment.
Occasionally patients become clinically hypo- or hyperthyroid and it seems to be mainly related to iodine intake with the diet.
An assessment of thyroid function is recommended in patients before starting treatment with Amiodarone and periodically during treatment.

Pulmonary pathologies (see section 4.8)
Cases of pulmonary toxicity (interstitial pneumonia) have been observed during the use of amiodarone intravenously, sometimes with fatal consequences. It is recommended to perform a chest radiograph and pulmonary function tests in case of dyspnoea (on exertion), regardless of any changes in the patient's general condition (fatigue, weight loss, fever).
Pulmonary adverse effects are generally reversible and resolve rapidly after discontinuation of treatment. Corticosteroid treatment may be considered.
In most cases, clinical symptoms resolve within 3 or 4 weeks, with a less rapid normalization of radiological examinations and pulmonary function (up to a few months).

Hepatic pathologies (see section 4.8)
Severe hepatic failure can occur within the first 24 hours after the administration of amiodarone i.v. and can sometimes be fatal. Therefore, careful monitoring of transaminases is recommended from the start of treatment.

Drug interactions (see section 4.5)
The use of amiodarone in association with the following medicines is not recommended: beta-blockers, calcium channel antagonists (verapamil, diltiazem), stimulant laxatives that can induce hypokalaemia.
At the end of therapy, in case of repeated intravenous administrations, concentrations of amiodarone still effective can persist in the serum for several weeks, due to the long half-life of amiodarone. With the further reduction of amiodarone levels, arrhythmias can recur. It is recommended to subject patients to regular monitoring after the end of therapy.
Benzyl alcohol:
Amiodarone Hikma contains 20mg/ml of benzyl alcohol.
Benzyl alcohol can cause toxic and allergic reactions in neonates and children up to 3 years of age.
Undesirable effects
Adverse effects are generally due to an excessive dose. It is therefore recommended to use the lowest possible dose, in order to minimize the number and severity of adverse effects.

4.5 Interactions with other medicines and other forms of interaction

• The concomitant use of medicines that prolong the QT interval and therefore increase the risk of potentially fatal torsade de pointes is contraindicated:
• Certain antiarrhythmics, such as class 1a antiarrhythmics (e.g., quinidine, procainamide and disopyramide) and sotalol.
• Other medicines such as vincamine, certain neuroleptics (sultopride, sulpiride), cisapride, erythromycin i.v., pentamidine administered parenterally, due to the increased risk of potentially lethal torsade de pointes, tricyclic antidepressants and other medicines that prolong the QT interval, such as some antipsychotics (pimozide, thioridazine, some phenothiazines), certain tetracyclic antidepressants (e.g., maprotiline), some antihistamines (e.g., terfenadine) and alofantrine.
• The concomitant use of the following medicines is not recommended:
• Beta-blockers or calcium channel antagonists (verapamil, diltiazem). Cardiac automatism disturbances (marked bradycardia) may occur in case of concomitant use.
• Use with caution when using the following medicines concomitantly:
• Contact laxatives: they can induce hypokalemia and therefore increase the risk of torsade de pointes; use another type of laxative.
• Other medicines that can induce hypokalemia, such as:
• diuretics, alone or in combination;
• systemic glucocorticoids and mineralocorticoids, tetracosactide;
• amphotericin B (i.v.).

Hypokalemia must be avoided and, if necessary, corrected.
The QT interval should be monitored. In case of torsade de pointes, do not administer antiarrhythmics
(ventricular pacing is recommended; magnesium i.v. may be administered).

• Oral Anticoagulants Amiodarone increases warfarin concentration through inhibition of cytochrome p450 2C9. Therefore, amiodarone may potentiate the effect of coumarin derivatives, resulting in an increased risk of bleeding. For this reason, in patients treated with anticoagulants, prothrombin time should be monitored frequently and the anticoagulant dose adjusted, both during and after treatment with amiodarone.
• Digitalis Cardiac automatism disturbances (marked bradycardia) and atrioventricular conduction (synergistic effect) may occur. Digoxin levels in the serum may increase due to reduced digoxin clearance. Monitoring is recommended, including plasma digoxin levels and ECG; furthermore, patients should be monitored for clinical signs of digitalis intoxication. A reduction in the dose of digoxin may be necessary.
• Phenytoin Amiodarone increases plasma levels of phenytoin through inhibition of cytochrome p450 2C9. Therefore, during the combined use of amiodarone and phenytoin, plasma levels of phenytoin may increase (appearance of neurological abnormalities).

Monitoring is necessary; if symptoms of phenytoin overdose are observed, reduce the dose of
phenytoin; determine plasma levels of phenytoin.

• General Anesthesia / Oxygen Therapy In patients treated with amiodarone and undergoing general anesthesia, the following complications have been reported, among others: bradycardia (refractory to atropine), hypotension, conduction disturbances and reduced cardiac output. Some cases of postoperative respiratory complications, sometimes with fatal consequences, have been reported. This may be due to the interaction with high concentrations of oxygen in the blood. In case of surgery, it is important to inform the anesthesiologist if therapy with amiodarone is ongoing.
• Flecainide Amiodarone increases plasma levels of flecainide through inhibition of CYP 2D6. If necessary, adjust the dose of flecainide.
• Medicines Metabolized by Cytochrome P450 3A4 Amiodarone is an inhibitor of CYP 3A4. If medicines, whose metabolism depends on this enzymatic system, are administered concomitantly with amiodarone, the plasma concentrations of these medicines may increase, resulting in an increased risk of toxicity.
• Cyclosporine: in association with amiodarone there is a risk of increased plasma levels of cyclosporine. If necessary, modify the dose of cyclosporine.
• Fentanyl: in association with amiodarone, the effect of fentanyl may be potentiated, resulting in an increased risk of toxicity.
• Other medicines metabolized by P450 3A4 include statins, such as simvastatin, tacrolimus, lidocaine, sildenafil, midazolam, triazolam, dihydroergotamine, ergotamine and, among the drugs mentioned above, cisapride, calcium channel antagonists, cyclosporine, quinidine, terfenadine, pimozide and erythromycin.

4.6 Fertility, Pregnancy and Lactation

Pregnancy
Insufficient data are available regarding the safety of amiodarone administered during
pregnancy.
Amiodarone and N-desmethylamiodarone cross the placenta and concentrations in the child
reach 10 - 25 % of maternal plasma concentrations. The most frequent complications
include growth retardation, premature delivery and alteration of thyroid function in the
newborn. Hypothyroidism, bradycardia and prolongation of the QT interval have been observed in
neonates. In isolated cases, increased thyroid volume or heart murmurs have been found. The frequency
of malformations does not appear to be increased. However, the possibility of
occurrence of cardiac defects should be considered. Therefore, Amiodaron Hikma should not be used during pregnancy,
unless absolutely necessary.
Women of childbearing potential can plan a pregnancy no earlier than six months after the end
of therapy, in order to avoid fetal exposure during the first period of gestation.
Lactation
Passage into breast milk has been demonstrated for both the active ingredient and the active metabolite.
If treatment during lactation is necessary or if amiodarone has been administered during
pregnancy, discontinue breastfeeding.
Fertility
High serum levels of LH and FSH, indicative of testicular dysfunction, have been found in male
patients after long-term treatment.

4.7 Effects on ability to drive and use machines

No data are available in this regard. Since vision may be blurred and/or reduced,
the possible effect on the ability to drive vehicles and use machines should be considered.

4.8 Undesirable effects

The drug-related adverse reactions most commonly observed following intravenous administration
of amiodarone are infusion phlebitis, bradycardia and hypotension.
The frequency of the adverse reactions reported below is based on the following convention:
very common ( ≥1/10);
common (from ≥1/100 to <1/10);
uncommon (from ≥1/1,000 to <1/100);
rare (from ≥ 1/10,000 to <1/1,000);
very rare (<1/10,000), not known (the frequency cannot be estimated based on available data).

Immune system disorders

Very rare

• Anaphylactic shock Frequency not known
• Hemolytic or aplastic anemia

Nervous system disorders

Very rare

• Benign intracranial hypertension (pseudotumor cerebri).
• Headache Frequency not known
• Peripheral neuropathy
• Paresthesia, ataxia, tremors

Cardiac disorders

Common

• Dose-dependent bradycardia. Very rare
• Marked bradycardia (in cases of sinus node dysfunction and in the elderly) or, more rarely, sinus arrest: this may necessitate discontinuation of treatment.
• Onset of new arrhythmias and exacerbation of existing arrhythmias, including atypical ventricular tachycardias (torsade de pointes) (see also sections 4.4 and 4.5).
• Conduction disturbances (sinoatrial block, AV block).

Vascular disorders

Common

• Hypotension and increased heart rate immediately after injection. These effects are generally mild and transient. Cases of severe hypotension or shock have been observed in case of overdose or too rapid administration (bolus injection). Very rare
• Hot flashes.

Respiratory, thoracic and mediastinal disorders

Very rare

• Interstitial pneumonia (see section 4.4).
• Acute RDS (adult respiratory distress syndrome), sometimes with fatal consequences.
• Bronchospasm in patients with severe respiratory disorders, particularly in asthmatic patients.

Gastrointestinal disorders

Very rare

• Nausea. Frequency not known
• Vomiting
• Metallic taste

Hepatobiliary disorders

Very rare

• Mild to moderate increase in transaminase levels (1.5 to 3 times the normal limit) at the beginning of treatment; these increases are often transient or regress after dose reduction.
• Acute liver function alterations, with increased serum transaminases and/or jaundice, including hepatic failure, sometimes with fatal consequences (see section 4.4).

Skin and subcutaneous tissue disorders

Very rare

• Sweating. Frequency not known
• Persistent photosensitivity for several months after discontinuation of treatment

Endocrine disorders

Very rare

• Syndrome of inappropriate antidiuretic hormone secretion (SIADH). Frequency not known
• Hyperthyroidism (sometimes fatal) (see section 4.4)
• Hypothyroidism (see section 4.4)

Musculoskeletal and connective tissue disorders

Frequency not known

• myopathy

Eye disorders

Frequency not known

• Microdeposits in the cornea sometimes associated with colored light halos, reversible after discontinuation of treatment
• Optic neuropathy

Reproductive system and breast disorders

Frequency not known

• Epididymitis

Systemic disorders and conditions related to the site of administration

Common

• At the injection or infusion site: pain, erythema, edema, necrosis, extravasation, infiltration, inflammation, induration, thrombophlebitis, phlebitis, cellulitis, infection, changes in pigmentation. Frequency not known
• insomnia, nightmares

Some rare cases have been observed with various clinical symptoms indicative of hypersensitivity reactions:
vasculitis, reduced renal function with increased creatinine levels, thrombocytopenia, anaphylaxis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions that occur after the authorization of the medicinal product
is important, as it allows continuous monitoring of the benefit/risk balance of the
medicinal product. Healthcare professionals are required to report any suspected adverse reactions through

4.9 Overdosage

In case of acute overdosage or too rapid intravenous administration, the following effects may be observed: nausea, vomiting, constipation, sweating, bradycardia and prolongation of the QT interval. In case of marked overdosage, hypotension, cardiac arrest and torsade de pointes are also expected. In exceptional cases, hyperthyroidism may occur.
In case of marked overdosage, prolonged ECG monitoring is recommended. Consider transfer to an intensive care unit. Hypotension can be treated with infusions or vasopressors. The use of alpha-adrenergic or beta-adrenergic agents or temporary pacing may be indicated.
Avoid the use of antiarrhythmic class Ia and III drugs, as they may induce an increase in the QT interval and torsade de pointes. Further treatments should be supportive and symptomatic.
Amiodarone and its metabolites are not dialyzable.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic category: class III antiarrhythmic agents
ATC code: C01B D01
Mechanism of action
Amiodarone is a diiodinated benzofuran derivative, classified as a class III antiarrhythmic for its ability to increase the duration of the cardiac action potential in atrial and ventricular myocytes by blocking cardiac K+ channels (mainly the rapid component of the repolarizing current K+, IKr). Therefore, amiodarone prolongs the refractory period of the action potential, determining the suppression of ectopies, re-entry arrhythmias and prolongation of the QTc interval on the ECG. Furthermore, amiodarone blocks cardiac Na+ currents (class I effect) and Ca2+ currents (class IV effect). The latter effect can slow conduction in the sinoatrial and atrioventricular nodes.
With long-term administration, amiodarone also appears to inhibit the transport of ionic channels from the endoplasmic reticulum to the cell membrane in cardiac myocytes, and this effect may contribute to the action of amiodarone on cardiac electrophysiology with prolonged administration.
Pharmacodynamic effects
In addition, amiodarone is a non-competitive antagonist of ß-adrenergic and α-adrenergic receptors and, therefore, possesses hemodynamic effects: dilation of coronary arteries and peripheral vasodilation with a consequent reduction in systemic blood pressure.
Some effects of amiodarone are similar to those of hypothyroidism, and this may be due to an inhibition of thyroid hormone synthesis. Amiodarone is a potent inhibitor of the activity of iodothyronine-5'-monodeiodinase (the main enzyme for T4-T3 conversion). In the rat, increases in serum thyroid-stimulating hormone (TSH), thyroxine (T4) and reverse triiodothyronine (rT3) and decreases in serum triiodothyronine (T3) have been observed following deiodination of T4 to T3. These antithyroid effects of amiodarone may contribute to its action on cardiac electrophysiology.
The main metabolite of N-desethylamiodarone has effects on cardiac electrophysiology similar to those of the parent compound.
Clinical safety and efficacy
The safety and efficacy of intravenous amiodarone in patients with out-of-hospital cardiac arrest due to refractory ventricular fibrillation have been analyzed in two double-blind studies: in the ARREST study, amiodarone was compared with placebo, while in the ALIVE study, amiodarone was compared with lidocaine. The primary endpoint of both studies was survival to hospital admission.
In the ARREST study, 504 patients - with out-of-hospital cardiac arrest due to ventricular fibrillation or pulseless ventricular tachycardia refractory to defibrillation with 3 or more shocks and epinephrine – were treated with 300 mg of amiodarone diluted in 20 ml of 5% dextrose solution in rapid intravenous injection (246 patients) or placebo (258 patients). In the 197 patients (39%) who survived the journey to the hospital, amiodarone significantly increased the probability of resuscitation and hospital admission: 44% in the group treated with amiodarone versus 34% in the group treated with placebo (p = 0.03). After adjustment for other independent predictive factors, the adjusted hazard ratio for survival to hospital admission was 1.6 (95% confidence interval from 1.1 to 2.4; p = 0.02) in the group treated with amiodarone compared to the group treated with placebo. The incidence of hypotension (59% versus 25%, p = 0.04) or bradycardia (41% versus 25%, p = 0.004) was higher in patients treated with amiodarone than in patients treated with placebo.
In the ALIVE study, 347 patients – with ventricular fibrillation refractory to defibrillation with 3 or more shocks, epinephrine and another defibrillation shock or with recurrent ventricular fibrillation after initial successful defibrillation – were administered amiodarone (5 mg/kg) or lidocaine (1.5 mg/kg). Amiodarone significantly increased the probability of resuscitation and hospital admission: 22.8% in the group treated with amiodarone (41 patients out of 180) versus 12% in the group treated with lidocaine (20 patients out of 167), p = 0.009. After adjustment for other factors influencing survival, the adjusted hazard ratio for survival to hospital admission was 2.49 (95% confidence interval, from 1.28 to 4.85; p = 0.007) in the group treated with amiodarone compared to the group treated with lidocaine. The percentage of patients with cardiac arrest after administration of the initial study drug, after defibrillation, was significantly higher in the group treated with lidocaine (28.9%) compared to the group treated with amiodarone (18.4%), p = 0.04.
Paediatric population
No controlled paediatric studies have been conducted.
In published studies, the safety of amiodarone has been evaluated in 1118 paediatric patients with various arrhythmias. The following dosages have been used in clinical studies.
Intravenous administration

• loading dose: 5mg/kg of body weight over 20 minutes to 2 hours
• maintenance dose: 10 to 15 mg/kg/day for several hours to several days If oral therapy is needed it can be started simultaneously with the normal loading dose,

5.2 Pharmacokinetic properties

Amiodarone has a low elimination rate and a marked affinity for tissues.
Intravenous administration:
After the injection, the plasma concentration decreases rapidly due to distribution into the
tissues. The maximum effect is reached after 15 minutes from the dose and gradually decreases over the following 4
hours. Tissue saturation is achieved with repeated intravenous administrations or
continuous oral administration.
No pediatric studies have been conducted. In the limited available published data for pediatric patients
no differences emerged compared to adults.

5.3 Preclinical safety data

In a 2-year carcinogenicity study in rats, at clinically relevant exposures, amiodarone caused an increase in follicular thyroid tumors (adenomas and/or carcinomas) in both sexes.
Since the mutagenicity results were negative, an epigenetic rather than genotoxic mechanism has been proposed for this type of tumor induction.
Carcinomas were not observed in mice, but dose-dependent follicular hyperplasia of the thyroid was highlighted.
These effects on the thyroid in rats and mice are most likely related to the effects of amiodarone on the synthesis and/or release of thyroid hormones.
The relevance of these findings in humans is low.

6. PHARMACEUTICAL INFORMATION

6.1 List of excipients

Polysorbate 80 (E433)
Benzyl alcohol
Water for injections

6.2 Incompatibilities

Amiodarone Hikma is incompatible with saline solution and can only be administered in a 5% dextrose solution.
The use of administration devices containing plasticizers, such as DEHP (di-2-ethylhexyl phthalate), in the
presence of amiodarone, can cause DEHP to pass into the solution. In order to minimize patient
exposure to DEHP, it is recommended to administer diluted solutions of
amiodarone via infusion sets not containing DEHP, such as polyolefin sets (PE, PP) or glass sets.
No other medications should be added to Amiodarone infusions.

6.3 Shelf life

2 years.
The diluted product is physically and chemically stable for 24 hours at room temperature.
However, from a microbiological point of view, it is advisable to use the product immediately after
dilution.
For single use only. Discard any unused solution.

6.4 Special precautions for storage

Do not store at temperatures above 25 °C. Do not refrigerate or freeze.
Store in the original packaging to protect the medicine from light.
For storage conditions after dilution of the medicine, see paragraph 6.3.

6.5 Nature and contents of the container

Each box contains 10 transparent glass vials of 5 ml (containing 3 ml of solution).

6.6 Special precautions for disposal and handling

Dilute the vials with 5% glucose. Use a maximum of 250 ml of 5% glucose solution per vial.
Larger dilutions are unstable.
Amiodarone Hikma, diluted in 5% dextrose solution at a concentration < 0.6 mg/ml, is not
stable. Solutions containing less than 2 vials of Amiodarone Hikma in 500 ml of
5% dextrose solution are unstable and must not be used.
See section 4.2.

7. MARKETING AUTHORISATION HOLDER

Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó, 8, 8A e 8B - Fervença
2705-906 Terrugem SNT
Portugal
Tel.:+ 351 219 608 410
Fax: + 351 219 615 102
[email protected]

8. MARKETING AUTHORISATION NUMBER(S)

Amiodarone Hikma 50mg/ml injectable solution 10 glass ampoules of 3ml
AIC n. 038320014

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15 May 2008
Date of last renewal: 10 September 2010

10. DATE OF TEXT REVISION: