Package Insert: Information for the User

Tranxilium 20 mg Powder and Diluent for Injectable Solution

Potassium Chlorazepate

Tranxilium is a medication that belongs to the group of tranquilizers, anxiolytics, derived from benzodiazepines.

It is indicated in situations that require a decrease in agitation, restlessness or a sense of apprehension (anxiolysis) and/or emergency sedation:

• Acute states of anxiety and anguish, neurosis and psychoneurosis (psychiatric diseases that are characterized by anxiety).
• Alcoholism and detoxification treatments for ethanol or other drugs.
• Anesthesia and medical-surgical resuscitation.
• Preparation for endoscopies, clinical explorations and surgical interventions of all types.
• Adjuvant treatment of tetanus, at high doses.
• Myocardial infarction, asthma crises.
• During preparation and development of childbirth.

Before using this medication, you must be sure that you will be able to sleep uninterrupted for 7-8 hours.

If you get up at night, after taking a hypnotic (sleep-inducing medication), you may experience a slow response to stimuli, which can increase the risk of falls and dizziness.

Do not use Tranxilium

• if you are allergic to the active ingredient (dipotassium chlorazepate) or any of the other components of this medication (listed in section 6),
• if you are allergic to a group of medications called benzodiazepines,
• if you have myasthenia gravis (a muscle disorder characterized by abnormal muscle weakness),
• if you have severe liver dysfunction (severe liver damage),
• if you have severe respiratory insufficiency (difficulty breathing),
• if you have severe respiratory insufficiency (worsening of your usual difficulty breathing),
• if you have sleep apnea syndrome (a disorder characterized by episodes of suspended breathing during sleep),
• if you are a child: this medication should not be administered to children.

Warnings and precautions

Consult your doctor or pharmacist before starting to use Tranxilium.

The use of this type of medication can lead to physical and psychological dependence. The risk of dependence increases with the dose, treatment duration, combination with alcohol or certain medications (anxiolytics, hypnotics, psychotropics), or if you have a history of dependence (on medications or other substances).

If physical dependence develops, abrupt discontinuation of treatment may cause a withdrawal syndrome characterized by headache or muscle pain, anxiety, muscle tension, restlessness, agitation, confusion, insomnia, and irritability. In severe cases, the following symptoms have been described:depersonalization, hyperacusis, paresthesia, intolerance to light, sound, and physical contact, tremors, hallucinations, or convulsions.

Consult your doctor or pharmacist if such symptoms appear. Your doctor will indicate the duration of your treatment (which should not exceed 4 to 12 weeks) and the precise manner in which you should reduce the dose gradually until you stop treatment.

Tolerance may develop after prolonged use of this medication.

This medication may induce anterograde amnesia, especially if taken before bedtime and when the duration of sleep is short. To minimize this risk, ensure that you will be able to sleep uninterrupted for 7-8 hours.

With the suspension of treatment, rebound insomnia and anxiety may reappear. This is a transient phenomenon that may be accompanied by mood changes, anxiety, restlessness, or sleep disorders. It is more likely to occur if treatment is discontinued abruptly, so it should be gradually reduced.

Older adults are more susceptible to adverse reactions such as drowsiness, dizziness, muscle weakness, which can cause falls and severe injuries (see section “4. Possible adverse effects”). In these cases, a dose reduction is recommended.

Psychiatric and paradoxical reactions such asrestlessness, agitation, irritability, aggression, delirium, anger attacks, nightmares, hallucinations, psychosis, inappropriate behavior, and other adverse effects on behavior may occur. In this case, consult your doctor about discontinuing treatment. These reactions are more frequent in children and older adults.

You should avoid using this medication in combination with oxibutynate sodium, as it may increase the risk of respiratory problems (respiratory depression).

Do not take Tranxilium with opioids (medications used to relieve intense pain, such as morphine or codeine) unless your doctor prescribes it, as it may increase the risk of sedation, respiratory depression, coma, or even death (see “Use of Tranxilium with other medications”).

If you have suicidal tendencies and depression, use it with extreme caution. Consult your doctor before using this medication, as it may unmask an existing depression. Some studies have shown an increased risk of suicidal ideation, attempted suicide, and suicide in patientswho take certain sedatives and hypnotics, including this medication. However,it has not been establishedwhether this is caused by the medication or if there may be other reasons. If you have suicidal thoughts, contact your doctor as soon as possible for additional medical advice.

Also, consult your doctor if you experience any of the following situations:

• depression or anxiety associated with depression (suicide may be precipitated in these patients),
• psychotic disorders,
• respiratory problems,
• liver diseases, the use of benzodiazepines may cause encephalopathy,
• history of alcohol or drug abuse, as it is not recommended to consume alcoholic beverages during treatment,
• kidney problems, a dose reduction may be necessary,
• muscle weakness.

Use of Tranxilium with other medications

Inform your doctor or pharmacist if you are using, have used recently, or may need to use any other medication.

You should be particularly careful with medications that act on the central nervous system, as they may increase central depression and this could affect your ability to drive or use machines.

You should be particularly careful if you are being treated with the following medications:

• alcohol: avoid medications containing alcohol, as it may potentiate the sedative effect, which may affect your ability to drive or use machines,
• hypnotics: medications to induce sleep,
• anxiolytics/sedatives: medications to treat anxiety,
• non-benzodiazepine tranquilizers,
• antidepressants: medications to treat depression,
• antipsychotics: medications for the treatment of psychosis,
• narcotic analgesics: medications for pain relief,
• antiepileptics: medications for epilepsy treatment,
• anesthetics,
• H1 antihistamines: medications for allergies,
• morphine derivatives: used for pain relief and cough treatment,
• barbiturates: medications that induce sedation of the central nervous system,
• clonidine: a medication that lowers blood pressure and related substances,
• cisapride: a medication for gastroesophageal reflux treatment,
• clozapine: a medication for psychosis treatment,
• enzymes that inhibit certain hepatic enzymes (cytochrome P450),
• opioid medications: the use of Tranxiliumwith opioids (medications used to relieve intense pain, such as morphine or codeine) may increase the risk of sedation, respiratory depression, coma, or even death. Your doctor will decide if you can use them together (see “Warnings and precautions”),
• neuromuscular blockers such as muscle relaxants, curarizants.

The risk of developing a withdrawal syndrome increases when combining Tranxilium with benzodiazepines that have been prescribed as anxiolytics or hypnotics.

Use of Tranxilium with foods, beverages, and alcohol

You should avoid consuming alcohol while using this medication. See section “Use of Tranxilium with other medications: alcohol”.

Pregnancy, lactation, and fertility

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

Pregnancy

There is limited data on the use of Tranxilium in pregnant women. Therefore, it is not recommended to use this medication during pregnancy and in women of childbearing age who do not use contraceptives.

If you discover you are pregnant or are planning to have a baby, consult your doctor immediately to reevaluate the need for treatment.

If you take Tranxilium during the last three months of pregnancy or during delivery at high doses,you may experience drowsiness (sedation), respiratory problems (respiratory depression), muscle weakness (hypotonia), decreased body temperature (hypothermia)and difficulty feeding (problems with lactation causing poor weight gain) in the newborn.

If you take it regularly towards the end of pregnancy, your baby may experience withdrawal symptoms.

In this case, the newborn should be closely monitored during the postnatal period.

Lactation

This medication should not be used during lactation, as it passes into breast milk.

Driving and using machines

Chlorazepate dipotassium may affect your ability to drive or operate machinery, as it may cause drowsiness, decrease your attention, or decrease your reaction time. The appearance of these effects is more likely at the beginning of treatment or when the dose is increased. Do not drive or use machines if you experience any of these effects.

You should be particularly careful when driving and using machines due to the risk of drowsiness, amnesia, alteration of concentration, and muscle function associated with the use of this medication. Combination with other medications may potentiate its sedative effect.

Additionally, periods of insufficient sleep may increase the deterioration of alertness (see section “Use of Tranxilium with other medications”).

Tranxilium 20 mg powder and solvent for injectable solution contains potassium

Patients with renal insufficiency or those on low-potassium diets should note that this medication contains 16.94 mg (0.43 mmol) of potassium per package (vial plus solvent).

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

The duration of this treatment is limited.Your doctor will inform you of the duration of your treatment with Tranxilium. Do not stop the treatment before,nor interrupt it abruptly, in order to avoid the possibility of the appearance of a withdrawal syndrome or rebound insomnia (seesection“Warnings and precautions”).

The administration route of Tranxilium is intramuscular and intravenous infusion.

Intramuscular injections must be deep.

By direct intravenous route, the injection must be slow and in a large vein. It is necessary to have a respiratory resuscitation equipment available.

Avoid mixing in the same syringe.

Use the specific solvent for each presentation.

• Adults:

In states of psychomotor agitation, confusion, or aggression: 1 to 10 vials (20 to 200 mg of clorazepate dipotassium) per day, using the intramuscular or intravenous route, followed by oral therapy.

Premedications: 1 to 2.5 vials (20 to 50 mg of clorazepate dipotassium) per day, using the intramuscular or intravenous route:

• IV: 15 minutes to 30 minutes before the intervention.
• IM: 30 minutes to 1 hour before the intervention.

Alcoholism (pre-delirium, delirium tremens): 2.5 to 5 vials (50 to 100 mg of clorazepate dipotassium) every 3 or 4 hours. The dose should be reduced by half after 2 or 3 days.

After 5 days of treatment, Tranxilium should be administered orally (150 to 300 mg per day).

• In elderly patients and patients with kidney problems, it is recommended to reduce the dose; usually, half of the indicated average dose is sufficient.

If you use more Tranxilium than you should

Overdose typically manifests by different degrees of depression of the central nervous system, ranging from drowsiness (sleepiness) to coma.

Deep sleep is the main sign of an overdose that can even become coma, depending on the dose administered.

In moderate cases, symptoms include drowsiness, confusion, and lethargy; in more serious cases, ataxia(loss of coordination of movements), hypotonia, hypotension (decreased blood pressure), respiratory depression, rarely coma, and very rarely death.

The prognosis is positive, the overdose does not represent a vital threat, at least in the absence of combination with other central depressants (psychoactive agents, alcohol) and always provided the subject is treated.

In case of overdose, the patient should be transported to a specialized center and the usual precautions taken: monitoring of respiratory and cardiovascular parameters.

Flumazenil may be used for the diagnosis and/or treatment of overdose as an antidote.

If you have used more Tranxilium than you should, consult your doctor, pharmacist, or call the Toxicological Information Service, phone: 91 562 04 20, indicating the medication and the amount used.

If you forgot to use Tranxilium

Do not use a double dose to compensate for the missed doses.

If you interrupt the treatment with Tranxilium

Abrupt discontinuation of treatment may produce a withdrawal syndrome that manifests by headache or muscle pain, anxiety, muscle tension, restlessness, confusion, insomnia, and irritability (seesection“Warnings and precautions”).

If you have any other doubts about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Side effects are presented grouped by organ and system classification and by frequency:

Very common:can affect more than1 in 10 patients

Common:can affect up to1 in 10 patients

Uncommon:can affect up to1 in 100 patients

Rare:can affect up to1 in 1,000 patients

Very rare:can affect up to1 in 10,000 patients

Frequency not known: cannot be estimated from available data.

Side effects are related to the dose and the individual patient's sensitivity.

Immunological disorders:

• Uncommon:hypersensitivity reactions.

Psychiatric disorders:

• Frequency not known: slow thinking, reduction of mental reflexes (bradiphrenia).
• In some patients (particularly children and elderly patients) paradoxical reactions may be observed (see also the "Warnings and precautions" section):

Uncommon: irritability, agitation, confusion.

Frequency not known: aggression, hallucination.

• Frequency not known: rebound syndrome with worsening of the anxiety that motivated this treatment may appear.
• Frequency not known: prolonged use (especially at high doses) may lead to physical dependence, and withdrawal symptoms may occur upon discontinuation of treatment (see the "Warnings and precautions" section). This occurs more rapidly with short-acting benzodiazepines than with long-acting benzodiazepines (several days).

Nervous system disorders:

• Very common: drowsiness (particularly in elderly patients and especially during the day if used as a hypnotic).
• Common: dizziness.
• Uncommon: muscle hypotonia.
• Frequency not known: cognitive disorders such as memory alteration (anterograde amnesia). Anterograde amnesia may develop at therapeutic doses, with a higher risk at increased doses. Amnestic effects may be associated with inappropriate behavior (see the "Warnings and precautions" section), attention alteration, and speech disorders.

Eye disorders:

• Frequency not known: double vision (diplopia).

Skin and subcutaneous tissue disorders:

• Uncommon: pruritic skin rash, maculopapular rash.

General disorders and administration site conditions:

• Common: asthenia.
• Frequency not known: falls (see the "Warnings and precautions" section).

In addition, the following side effects have been reported with benzodiazepines: emotional numbing, reduced alertness, headache, loss of coordination of movements (ataxia), gastrointestinal alterations, changes in sexual appetite (changes in libido), and amnestic effects that may be associated with inappropriate behavior.

Psychiatric or paradoxical reactions with restlessness, delirium, anger attacks, nightmares, psychosis, and inappropriate behavior and other behavioral side effects.

Depression: the use of benzodiazepines may unmask pre-existing depression.

Dependence: administration of the product (even at therapeutic doses) may lead to physical dependence: withdrawal symptoms may occur upon discontinuation of treatment (see the "Warnings and precautions" section).

Psychological dependence may occur. Cases of benzodiazepine abuse have been reported.

Reporting of side effects

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

Keep out of sight and reach of children.

Store below 25°C.

Store in the original packaging to protect it from light and humidity.

Do not use Tranxilium after the expiration date shown on the packaging after CAD. The expiration date is the last day of the month indicated.

Medicines should not be disposed of through drains or in the trash. Dispose of packaging and medicines you no longer need at the SIGRE collection point at the pharmacy. If in doubt, ask your pharmacist how to dispose of unused packaging and medicines. By doing so, you will help protect the environment.

Composition of Tranxilium 20 mg powder and solvent for injectable solution

• The active ingredient is chlorazepate dipotassium. Each vial contains 20 mg of lyophilized chlorazepate dipotassium.
• The other components are:

- Vial: mannitol and potassium carbonate.

- Ampoule of solvent:di-hydrogen phosphate of potassium, hydrogen phosphate of dipotassiumand water for injectable preparations.

Appearance of the product and contents of the packaging

Each package contains 1 vial and 1 ampoule of solvent (2 ml).

The glass vial of amber color contains a white to light yellowish powder.

The solvent ampoulecontains an incolor and transparent solution.

Other presentations:

• Tranxilium 5 mg hard capsules, package with 30 capsules.
• Tranxilium 10 mg hard capsules, package with 30 capsules.
• Tranxilium 15 mg hard capsules, package with 20 capsules.
• Tranxilium 50 mg film-coated tablets, package with 20 film-coated tablets.

Holder of the marketing authorization and responsible for manufacturing

Holder:

Neuraxpharm Spain, S.L.U.

Avda. Barcelona, 69,

08970 Sant Joan Despí (Barcelona)

Spain

Responsible for manufacturing:

Sanofi S.r.l.

Via Valcanello, 4

03012 Anagni (FR)

Italy

Last review date of this leaflet: September 2020

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