Prospect:Information for the User

Appendix 1mg/10ml Injectable Solution

Flumazenil

Read this prospect carefully before starting touseethismedication, because it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• This medication has been prescribedonlyto you and should not be given to other people even if they have the same symptomsas you, as it may harm them.
• Ifyou experience adverse effects, consult your doctor or pharmacist even if they are not listed in this prospect.See section 4.

1.What is Flumazenil and for what it is used

2.What you need to know before starting to useFlumazenil

3.Howto useFlumazenil

4.Possible adverse effects

5.Storage of Flumazenil

6.Contents of the package and additional information

Anexate contains an active ingredient called flumazenil, which is an antagonist of a group of medications 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 the 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 therapeutic purposes in benzodiazepine overdoses, in hospitalized patients in intensive care units. As a diagnostic measure in unconsciousness of unknown cause, in order to check if it is due to benzodiazepines, other medications or a brain injury.

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

Do not use Anexate

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

• If you are being treated with benzodiazepines to control situations that may potentially put your life at risk (elevated intracranial pressure, epileptic states).

If you have taken benzodiazepines and other antidepressants (tricyclic antidepressants) simultaneously and have become 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 intracranial pressure),
• 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, therefore, if you do not wake up after the administration of Anexate, another reason should be considered.

It should not be administered during anesthesia until it has been confirmed 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 recur. 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 lightly sedated.

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

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 withdrawal symptoms from benzodiazepines.

Children and adolescents

As a general rule, it is recommended not to use this medication in children under one year (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 essential to 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, or think you may be pregnant, or intend to become pregnant, consult your doctor or pharmacist before using this medication.

The passage of Anexate into breast milk is unknown. If you are breastfeeding, you should not be treated with Anexate except in emergency cases and by parenteral route. Your doctor will decide what is best for your case.

Driving and operating machinery

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

Anexate contains sodium

Anexate 1 mg/10 ml injectable solution contains 36.7 mg of sodium (main component of table salt/for cooking) in each ampoule. This is equivalent to 1.9% of the maximum daily sodium intake recommended for an adult.

Follow exactly the administration instructions of this medication 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 will receive may also depend on your weight, age, general health status, the level of sedation you have, as well as your response to this medication.

In anesthesia

The recommended initial dose is 0.2 mg i.v., administered in 15 seconds. In case the desired level of consciousness is not obtained within 60 seconds after the first administration, your doctor will administer a new dose of 0.1 mg, repeating it, if necessary, at intervals of 60 seconds, 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

As an initial dose, 0.3 mg i.v. is recommended. In case the desired level of consciousness is not obtained within 60 seconds, your doctor will administer a new dose of 0.1 mg, repeating it, if necessary, at intervals of 60 seconds up to a total dose of 2 mg.

In case of reappearance of somnolence, Anexate may be administered as one or more bolus and it may be useful to perform 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 intravenously according to the patient's response. In anesthesia, it is recommended to inject 5 mg of the active principles mentioned intravenously.

Use in children and adolescents

Children over one year

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

Children under one year

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

Until sufficient data are available, Anexate should not be used in children under 1 year, unless the risks for the patient (especially in case of accidental overdose) have been evaluated 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 Toxicological Information Service.Telephone: (91) 562 04 20.

Like all medicines, Anexate may cause side effects, although not everyone will 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 side effects is classified in 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.

These reactions usually disappear quickly without the need for special treatment.

Immune system disorders

• Frequency not known: May appear hypersensitivity reactions (allergy), including anaphylaxis.

Mental health disorders

• Uncommon: anxiety and fear after a rapid administration of Anexate, generally did not require treatment.

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

These symptoms may occur after a 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.

In general, side effects in children are similar to those of adults. When this medication has been used to awaken 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 mixed-drug overdose.

Cardiac disorders

• Uncommon: Palpitations (strong and rapid heartbeats) after a 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: Redness.

General disorders and administration site conditions

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

In the case of mixed-drug overdose, especially with tricyclic antidepressants, toxic effects such as seizures or cardiac arrhythmias may appear, these effects may occur when flumazenil reverses the effect of benzodiazepines.

If you consider that any of the side effects you are experiencing are severe or if you notice any side effect not mentioned in this leaflet, inform your doctor or pharmacist.

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a side effect that does not appear in this leaflet. You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use: www.notificaRAM.es/. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keepthis medicationout ofsight and reachof 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.

Composition of Anexate

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

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

Appearance of the product and contents of the package

Anexate 1 mg/10 ml is presented as an injectable solution. Each package contains 5 ampoules of 10 ml each, containing 1 mg of flumazenil.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 24

17489 Greifswald

Germany

Responsible for manufacturing

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

Last review date of this leaflet: October 2020

“Detailed and updated information on this medication is available on the website of the Spanish Agency of Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/”

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This information is intended solely for medical professionals or healthcare professionals:

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

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

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

It should be avoided to inject Anexate rapidly. In patients receiving high doses and/or prolonged treatment with benzodiazepines in the weeks preceding its administration, rapid injection of doses equal to or greater than 1 mg may cause withdrawal symptoms, including palpitations, agitation, anxiety, emotional lability, as well as mild confusion and sensory distortions.

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