ANEXATE 0.5 mg/5 ml INJECTABLE SOLUTION

Introduction

Prospect:information for the user

Anexate 0.5mg/5ml injectable solution

Flumazenil

Read the entire prospectus carefully before starting tousethismedication, as it contains important information for you.

• Keep this prospectus, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medication has been prescribed to you only, and you should not give it to others, even if they have the same symptoms as you, as it may harm them.
• If you experience adverse effects, consult your doctor or pharmacist, even if they are not listed in this prospectus. See section 4.

Contents of the prospectus:

1. What Anexate is and what it is used for
2. What you need to know before starting to use Anexate
3. How to use Anexate
4. Possible adverse effects
5. Storage of Anexate
6. Package contents and additional information

1. What Anexate is and what it is used for

Anexate contains an active ingredient called flumazenil, which is an antagonist of a group of drugs called benzodiazepines.

Anexate is used to neutralize the sedative or general anesthetic effect of benzodiazepines in patients undergoing short diagnostic or therapeutic procedures, as well as to counteract paradoxical reactions caused by them (a paradoxical reaction is when the treatment has the opposite effect of what is normally expected).

Anexate is used for diagnostic and/or treatment purposes in cases of benzodiazepine overdose in hospitalized patients in intensive care units. As a diagnostic measure in unconsciousness of unknown cause, in order to determine if it is due to benzodiazepines, other medications, or a brain injury.

Anexate is also used in children over 1 year of age to wake them up from benzodiazepine-induced sedation.

2. What you need to know before starting to use Anexate

Do not use Anexate

• If you are allergic (hypersensitive) to flumazenil or any of the other components of this medication (listed in section 6).

• If you are being treated with benzodiazepines to control potentially life-threatening situations (elevated intracranial pressure, epileptic states).
• If you have taken benzodiazepines and other antidepressants (tricyclic antidepressants) that have made you ill.

Warnings and precautions

Consult your doctor or pharmacist before starting to use Anexate. Inform your doctor if:

• • You have a severe brain injury (and/or unstable pressure in your brain),
• You have epilepsy,
• You have severe liver problems,
• You have been treated with benzodiazepines for a long time,
• You have heart problems,
• You have a history of chronic or transient anxiety.

Anexate specifically corrects the effects of benzodiazepines, so if you do not wake up after administration of Anexate, another reason for this should be considered.

It should not be administered in anesthesia until it has been verified that the peripheral muscle relaxant effects have disappeared.

Since the effect of flumazenil is usually shorter than that of benzodiazepines, it is possible that sedation may reappear. Therefore, you will be closely monitored, preferably in the intensive care unit, until the effect of Anexate has completely disappeared.

After major surgery, postoperative pain should be taken into account and it may be preferable to keep you slightly sedated.

In case of overdose due to a mixture of medications, Anexate will be administered with special caution due to the possible appearance of toxic effects of the other medications (seizures and heart rhythm disorders).

If you have been treated with Anexate to counteract the effects of benzodiazepines, you should be monitored for the necessary time to prevent the appearance of adverse effects.

Anexate is not recommended for the treatment of benzodiazepine dependence or for the treatment of benzodiazepine withdrawal symptoms.

Children and adolescents

As a general rule, it is recommended not to use this medication in children under 1 year of age (see section 3 How to use Anexate).

Use of Anexate with other medications

Inform your doctor or pharmacist that you are taking, have taken, or may need to take any other medication.

Certain medications may interact with Anexate. It is important that you inform your doctor if you are taking any of the following medications:

• Benzodiazepines
• Non-benzodiazepine agonists such as zopiclone, triazolopyridazines, and other antidepressants.

After being treated with Anexate, consult your doctor before taking any other medication.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medication.

It is not known if Anexate passes into breast milk. If you are breastfeeding, you should not be treated with Anexate except in cases of emergency and by parenteral route. Your doctor will decide what is most appropriate in your case.

Driving and using machines

Do not drive because this medication may affect your ability to drive or operate machinery during the 24 hours after being treated with Anexate, as the effect of previously taken or administered benzodiazepines may reappear.

Anexate contains sodium

Anexate 0.5 mg/5 ml injectable solution contains less than 23 mg of sodium (1mmol) per ampoule; this is, essentially "sodium-free".

3. How to use Anexate

Follow the administration instructions of this medication exactly as indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

The doses may be very variable and will depend on your particular case. The dose you receive will also depend on your weight, age, general state of health, level of sedation, and response to this medication.

In anesthesia

The recommended initial dose is 0.2 mg i.v., administered in 15 seconds. If the desired level of consciousness is not achieved within 60 seconds after the first administration, your doctor will administer a new dose of 0.1 mg, repeating it if necessary at 60-second intervals, up to a maximum total dose of 1 mg. The usual dose is between 0.3 and 0.6 mg.

In intensive care units and in the diagnosis of unconsciousness of unknown origin

The recommended initial dose is 0.3 mg i.v. If the desired level of consciousness is not achieved within 60 seconds, your doctor will administer a new dose of 0.1 mg, repeating it if necessary at 60-second intervals, up to a total dose of 2 mg.

In case of reappearance of somnolence, Anexate may be administered as one or more boluses and may be useful as an i.v. infusion of 0.1-0.4 mg per hour, adjusting the infusion rate individually according to the desired level of consciousness.

If unexpected signs of overstimulation appear, diazepam or midazolam should be administered carefully, dosed by intravenous route according to the patient's response. In anesthesia, it is recommended to inject 5 mg of the aforementioned active ingredients intravenously.

Use in children and adolescents

Children over 1 year of age

The recommended initial dose is 10 micrograms/Kg (up to 200 micrograms) administered intravenously over 15 seconds. If the desired level of consciousness is not achieved after 45 seconds, your doctor may administer, if necessary, new doses equal to the initial dose at 60-second intervals (up to a maximum of 4) up to a maximum total dose of 50 micrograms/Kg or 1 mg, using the smaller of the two doses. There is no data on the safety and efficacy of repeated administration of flumazenil in children in case of resedation.

Children under 1 year of age

Since experience is limited, Anexate should be used with caution in the recovery of conscious sedation in children under 1 year of age, for the treatment of overdose in children, neonatal resuscitation, and to reverse the sedative effects of benzodiazepines used for the induction of general anesthesia in children.

Until sufficient data is available, Anexate should not be used in children under 1 year of age, unless the risks to the patient (especially in case of accidental overdose) have been weighed against the benefits of treatment.

If you use more Anexate than you should

Although no symptoms of overdose have been observed, if you have been administered more Anexate than you should, consult your doctor or pharmacist immediately.

In case of overdose or accidental ingestion, consult the Toxicology Information Service. Phone: (91) 562 04 20.

4. Possible adverse effects

Like all medications, Anexate can cause adverse effects, although not all people experience them.

Anexate is well tolerated in children and adults. In adults, it is well tolerated even at doses higher than those recommended.

The frequency of these adverse effects is classified into the following categories:

• Very common: may affect more than 1 in 10 patients
• Common: may affect up to 1 in 10 patients
• Uncommon: may affect up to 1 in 100 patients
• Rare: may affect up to 1 in 1000 patients
• Very rare: may affect up to 1 in 10,000 patients
• Frequency not known: the frequency cannot be estimated from the available data.

Generally, these reactions disappear quickly without the need for special treatment.

Immune system disorders

• Frequency not known: Hypersensitivity reactions (allergy), including anaphylaxis, may occur.

Psychiatric disorders

• Uncommon: Anxiety and fear after rapid administration of Anexate, usually did not require treatment.

• Frequency not known: Withdrawal syndrome, with symptoms such as agitation (excitement, restlessness), anxiety (anxiety, fear), emotional lability (attacks of laughter or crying), confusion, and sensory distortions (illusions, hallucinations).

These symptoms may occur after rapid administration of flumazenil in patients with high doses and/or treated for prolonged periods with benzodiazepines.

Panic attacks (in patients with a history of panic reactions), abnormal crying, agitation, and aggressive reactions.

Generally, the adverse effects in children are similar to those in adults. When this medication has been used to wake up the child from sedation, abnormal crying, agitation, and aggressive reactions have been reported.

Nervous system disorders

• Frequency not known: Seizures in patients with epilepsy or severe liver problems, especially after long-term treatment with benzodiazepines or in cases of overdose due to a mixture of medications.

Cardiac disorders

• Uncommon: Palpitations (strong and rapid heartbeats) after rapid administration of flumazenil.

Vascular disorders

• Frequency not known: Temporary increase in blood pressure (upon waking).

Gastrointestinal disorders

• Common: Postoperative nausea and vomiting, especially if opioids (narcotics) have also been used.

Skin and subcutaneous tissue disorders

• Frequency not known: Flushing.

General disorders and administration site conditions

• Frequency not known: Chills, after rapid administration of flumazenil.

In case of overdose due to a mixture of medications, especially with tricyclic antidepressants, toxic effects such as seizures or cardiac arrhythmias may appear, these effects may arise when flumazenil reverses the effect of benzodiazepines.

If you consider that any of the adverse effects you are experiencing is serious or if you notice any adverse effect not mentioned in this prospectus, inform your doctor or pharmacist.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is not listed in this prospectus. You can also report them directly through the Spanish Medication Surveillance System for Human Use: www.notificaRAM.es/. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

5. Storage of Anexate

Keep this medication out of the sight and reach of children.

No special storage conditions are required.

Do not use this medication after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

6. Package contents and additional information

Composition of Anexate

The active ingredient is flumazenil. Each milliliter of solution contains 0.1 mg of flumazenil.

The other components are: sodium edetate, glacial acetic acid, sodium chloride, sodium hydroxide, and water for injectable preparations.

Appearance of the product and package contents

Anexate 0.5 mg/5 ml is presented as an injectable solution. Each package contains 5 ampoules of 5 ml each, containing 0.5 mg of flumazenil.

Marketing authorization holder and manufacturer

Marketing authorization holder

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 24

17489 Greifswald

Germany

Manufacturer

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 23-24

17489 Greifswald

Germany

Local representative

Laboratorios Rubió S.A.

C/ Industria 29

Pol. Industrial Comte de Sert

08755 Castellbisbal (Barcelona)

Spain

Date of the last revision of this prospectus: October 2020

Detailed and updated information about this medication is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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This information is intended only for doctors or healthcare professionals:

Anexate is recommended for intravenous use only and should be administered by an anesthesiologist or experienced doctor.

Anexate can be administered diluted or undiluted. Anexate is compatible with 5% glucose solutions in water, Ringer's lactate, and normal saline solutions.

When Anexate is extracted and placed in a syringe, or mixed with any of these solutions, the solution should be discarded after 24 hours. It should be carefully dosed to achieve the desired effect.

Anexate can also be used in conjunction with other resuscitation measures. Since the duration of action of some benzodiazepines exceeds that of Anexate, repeated doses may be required if sedation reappears after waking.

Rapid injection of Anexate should be avoided. In patients who have received high doses and/or prolonged treatment with benzodiazepines in the weeks preceding administration, rapid injection of doses equal to or greater than 1 mg may cause withdrawal symptoms, including palpitations, agitation, anxiety, emotional lability, and mild sensory distortions.

Anexate is not recommended for the treatment of benzodiazepine dependence or for the control of benzodiazepine withdrawal symptoms.