Midazolam Bioindustria Lim: detailed information

Package leaflet: Information for the user

MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/ml injectable solution

MIDAZOLAM BIOINDUSTRIA L.I.M. 15 mg/3 ml injectable solution
MIDAZOLAM BIOINDUSTRIA L.I.M. 50 mg/10 ml injectable solution
MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/5 ml injectable solution
Midazolam
Generic medicine
Read this leaflet carefully before using this medicine because 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 nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet:

What MIDAZOLAM BIOINDUSTRIA L.I.M. is and what it is used for
What you need to know before using MIDAZOLAM BIOINDUSTRIA L.I.M.
How to use MIDAZOLAM BIOINDUSTRIA L.I.M.
Possible side effects
How to store MIDAZOLAM BIOINDUSTRIA L.I.M.
Contents of the pack and other information

1. What MIDAZOLAM BIOINDUSTRIA L.I.M. is and what it is used for

This medicinal product contains the active substance midazolam, which belongs to a group of medicines called benzodiazepines, used for the treatment of conditions such as anxiety, insomnia, or uncontrolled muscle movements (seizures).
MIDAZOLAM BIOINDUSTRIA L.I.M. is indicated in adults to induce sleep (short-acting hypnotic effect) in the following cases:

before and during medical examinations, procedures, or intensive therapy to achieve a deep calming effect on the body with or without anesthesia (conscious sedation);
before administering anesthesia (premedication prior to anesthesia induction, anesthesia induction, or as a sedative component in combined anesthesia).

MIDAZOLAM BIOINDUSTRIA L.I.M. is indicated in children to induce sleep (short-acting hypnotic effect) in the following cases:

before and during medical examinations, procedures, or intensive therapy to achieve a deep calming effect on the body with or without local anesthesia (conscious sedation);
before administering anesthesia (premedication prior to anesthesia induction).

2. What you should know before using MIDAZOLAM BIOINDUSTRIA L.I.M.

Do not use MIDAZOLAM BIOINDUSTRIA L.I.M.

if you are allergic to midazolam, to other similar medicines (benzodiazepines), or to any of the other ingredients of this medicine (listed in section 6);
if you have severe breathing problems (severe respiratory insufficiency or acute respiratory depression).

Warnings and precautions
Talk to your doctor or nurse before MIDAZOLAM BIOINDUSTRIA L.I.M. is administered to you.
This medicine will be administered only by medical personnel and in a specialized setting to monitor your health condition (respiratory and cardiovascular function) and to allow intervention in case of emergency.
MIDAZOLAM BIOINDUSTRIA L.I.M. will be administered to you with great caution if:

you are over 60 years old;
you have breathing problems (chronic respiratory insufficiency), kidney problems (chronic renal insufficiency), liver problems (impaired liver function), or heart problems (reduced cardiac function);
the person to whom the medicine is to be administered is a child, especially if they have heart problems (cardiovascular instability);
you currently abuse or have previously abused alcohol, drugs, or medicines;
you suffer from myasthenia gravis, a disease causing muscle weakness and fatigue.

MIDAZOLAM BIOINDUSTRIA L.I.M. must not be administered together with substances acting on the central nervous system, as this may cause excessive drowsiness and breathing problems (see section “MIDAZOLAM BIOINDUSTRIA L.I.M. with alcohol”).
This medicine may cause:

tolerance: i.e., reduced effectiveness after prolonged use.
dependence: meaning the need to continue taking the medicine. The risk increases with dose and duration of treatment. The risk is higher if you have previously abused drugs or alcohol. In some cases, an excessive need to take the medicine (abuse) may occur.
withdrawal symptoms: abruptly stopping treatment may cause symptoms such as headache, muscle pain, anxiety, restlessness, confusion, irritability, difficulty sleeping (insomnia), mood changes, hallucinations, and involuntary movements (seizures). Therefore, it is advisable to gradually reduce the dosage.
memory loss (anterograde amnesia), the duration of which increases with dose.
reactions such as agitation, involuntary movements (tonic/clonic seizures and muscle tremors), and inappropriate behavior (hyperactivity, hostility, angry reactions, aggression, paroxysmal excitement, and aggressive acts). These reactions may occur with high doses and/or when the injection is administered rapidly. These reactions are more likely if you are elderly or if the patient is a child.

After receiving MIDAZOLAM BIOINDUSTRIA L.I.M., your discharge from hospital or outpatient clinic will occur only upon the doctor’s instruction and only if someone is present to accompany you.
Premature infants and newborns
MIDAZOLAM BIOINDUSTRIA L.I.M. must be administered with extreme caution in premature infants (preterm and ex-preterm infants not undergoing intubation) as it may cause breathing problems (apnea).
In newborns (under 6 months of age), MIDAZOLAM BIOINDUSTRIA L.I.M. must be administered only in intensive care units, with extreme caution, and avoiding rapid injection. Rapid intravenous injection may cause circulatory problems in newborns with heart and circulation disorders. The doctor must monitor the infant’s condition (respiratory rate and oxygen saturation) during treatment.
Other medicines and MIDAZOLAM BIOINDUSTRIA L.I.M.
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicine.
In particular, inform your doctor if you are taking any of the following medicines:

antifungals, medicines used to treat fungal infections (such as ketoconazole, voriconazole, fluconazole, itraconazole, posaconazole);
antibiotics, medicines used to treat bacterial infections (such as erythromycin, clarithromycin, telithromycin, roxithromycin, or rifampicin);
HIV protease inhibitors, medicines used to treat AIDS (such as lopinavir, ritonavir, and saquinavir);
diltiazem and verapamil, and antihypertensives (with central action) used for high blood pressure;
atorvastatin, used for high cholesterol;
aprepitant, used to prevent vomiting;
nafazodone, used for depression;
carbamazepine and phenytoin, medicines used for epileptic seizures;
opioids, used for pain or cough;
other benzodiazepines;
barbiturates, sedative medicines;
anesthetics such as propofol, ketamine, etomidate;
sedative antidepressants, medicines used as sedatives and for conditions such as depression;
H1 antihistamines (older generation), medicines used for allergies;
St. John’s wort (Hypericum perforatum), used for depression;
medicines that interfere with the metabolism and elimination of midazolam.

Concomitant use of MIDAZOLAM BIOINDUSTRIA L.I.M. and opioids (strong painkillers, medicines for substitution therapy, and some cough medicines) increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be life-threatening. For this reason, concomitant use should only be considered when no other therapeutic alternatives are possible.
However, if your doctor prescribes MIDAZOLAM BIOINDUSTRIA L.I.M. together with opioids, the dose and duration of concomitant treatment must be limited by the doctor. Inform your doctor about all opioid medicines you are taking and follow the doctor’s dosage recommendations carefully. It may be helpful to inform friends or family members to watch for the signs and symptoms listed above. Contact your doctor if you experience any of these symptoms.
MIDAZOLAM BIOINDUSTRIA L.I.M. with alcohol
Do not drink alcohol after receiving MIDAZOLAM BIOINDUSTRIA L.I.M., as it may cause excessive drowsiness and breathing problems (respiratory depression).
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or nurse before this medicine is administered.
Pregnancy
Avoid taking this medicine during pregnancy, as it may cause serious harm to both you and the newborn.
Breastfeeding
Discontinue breastfeeding for 24 hours after taking the medicine, as MIDAZOLAM BIOINDUSTRIA L.I.M. may pass into breast milk.
Driving and using machines
This medicine may cause sedation, impair memory, and reduce concentration. After administration of MIDAZOLAM BIOINDUSTRIA L.I.M., avoid driving or operating tools or machinery until your doctor tells you it is safe to do so. It is also advisable to have someone accompany you home after discharge.
MIDAZOLAM BIOINDUSTRIA L.I.M. contains sodium
MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/ml, 15 mg/3 ml, and 5 mg/5 ml injectable solution contain less than 23 mg (1 mmol) of sodium per vial, i.e., they are practically “sodium-free”.
MIDAZOLAM BIOINDUSTRIA L.I.M. 50 mg/10 ml injectable solution contains 31.5 mg (1.4 mmol) of sodium per vial. This should be taken into account in individuals with reduced kidney function or those on a low-sodium diet.

3. How to use MIDAZOLAM BIOINDUSTRIA L.I.M.

This medicine will be administered to you by specialized healthcare personnel. If you have any doubts, consult your doctor or nurse.
This medicine must be administered to you through a slow infusion.
Your doctor will determine the dose based on your age and your health condition.
If you use more MIDAZOLAM BIOINDUSTRIA L.I.M. than you should
Since this medicine will be administered by specialized personnel, it is unlikely that you will receive an excessive dose.
However, following administration of an excessive dose of this medicine, drowsiness, loss of coordination (ataxia), difficulty speaking (dysarthria), and involuntary eye movements (nystagmus) may occur. Other symptoms may include lack of reflexes (areflexia), difficulty breathing (apnoea), low blood pressure (hypotension), heart problems (cardiovascular depression), and, in rare cases, coma.
If you think you have been given too much of this medicine, contact your doctor or nurse immediately.
If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, Midazolam Bioindustria L.I.M. can cause side effects, although not everyone experiences them. The following side effects have been reported (frequency not known, as it cannot be estimated from the available data).

Immune system disorders: allergic reactions, even severe (skin reactions, reactions affecting the heart and circulatory system, bronchospasm, anaphylactic shock), swelling due to fluid accumulation in the face, larynx, tongue, hands (angioedema)
Psychiatric disorders: confusion, euphoria (an excessive feeling of well-being), hallucinations, inappropriate behaviour (agitation, hostility, rage attacks, aggressiveness, excitement)* Physical dependence (i.e. the need to continue taking the medicine) and withdrawal syndrome, abuse
Nervous system disorders: drowsiness and sedation (prolonged and postoperative), reduced alertness, lethargy, headache, dizziness, difficulty in muscle coordination (ataxia), memory loss (anterograde amnesia) which may persist even after treatment has ended and in isolated cases may last for prolonged periods, involuntary movements (including tonic/clonic movements and muscle tremors)*, hyperactivity*, seizures due to withdrawal syndrome
Cardiac disorders: serious events have occurred, such as heart attacks (cardiac arrest), decreased heart rate (bradycardia).
Vascular disorders: reduction in blood pressure (hypotension), vasodilation, circulatory problems (thrombophlebitis, thrombosis)
Respiratory disorders: serious events have occurred, such as respiratory complications, which sometimes led to respiratory arrest, apnoea, shortness of breath (dyspnoea), sudden blockage of the airways (laryngospasm), hiccups.
Potentially fatal incidents are more likely to occur in adults over 60 years of age and in individuals who already have respiratory difficulties or heart problems, especially when the medicine is injected too rapidly or at a high dosage (see section 2, paragraph "MIDAZOLAM BIOINDUSTRIA L.I.M. will be administered to you with great caution if").
Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth.
Skin disorders: skin irritation (skin rash, urticaria, pruritus).
General disorders and administration site conditions: fatigue, redness (erythema), pain at the injection site (erythema)
Injury, poisoning and procedural complications: falls and fractures, particularly in elderly patients and in individuals taking substances such as alcohol that have sedative effects.
Social circumstances: aggression*

*These reactions have been reported particularly in children and elderly patients (see section 2 Warnings and precautions).
Dependence: The use of midazolam – even at therapeutic doses – may lead to the development of physical dependence. After prolonged intravenous administration, discontinuation of the product, especially if abrupt, may be accompanied by withdrawal symptoms including seizures (see section 2). Cases of abuse have been reported.
Additional side effects in premature infants and newborns
Frequency not known (frequency cannot be estimated from the available data)

Involuntary muscle contractions (seizures).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at the following website:
http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store MIDAZOLAM BIOINDUSTRIA L.I.M.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after the wording
“EXPIRY”. The expiry date refers to the last day of that month and applies to the product in
intact packaging and properly stored. Do not use this medicine if you notice any visible signs
of deterioration.
Keep the vial in the outer packaging to protect the medicine from light.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Pack contents and other information

What MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/ml injectable solution contains
The active substance is midazolam. Each 1 ml vial of solution contains: 5 mg of midazolam (equivalent
to 5.6 mg of midazolam hydrochloride).
The other components are: sodium chloride, hydrochloric acid (E 507)/sodium hydroxide (E 524), water for
injectable preparations.

What MIDAZOLAM BIOINDUSTRIA L.I.M. 15 mg/3 ml injectable solution contains
The active substance is midazolam. Each 3 ml vial of solution contains: 15 mg of midazolam (equivalent
to 16.8 mg of midazolam hydrochloride).
The other components are: sodium chloride, hydrochloric acid (E 507)/sodium hydroxide (E 524), water for
injectable preparations.

What MIDAZOLAM BIOINDUSTRIA L.I.M. 50 mg/10 ml injectable solution contains
The active substance is midazolam. Each 10 ml vial of solution contains: 50 mg of midazolam (equivalent
to 56 mg of midazolam hydrochloride).
The other components are: sodium chloride, hydrochloric acid (E 507)/sodium hydroxide (E 524), water for
injectable preparations.

What MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/5 ml injectable solution contains
The active substance is midazolam. Each 5 ml vial of solution contains: 5 mg of midazolam (equivalent
to 5.6 mg of midazolam hydrochloride).
The other components are: sodium chloride, hydrochloric acid (E 507)/sodium hydroxide (E 524), water for
injectable preparations.

Description of the appearance of MIDAZOLAM BIOINDUSTRIA L.I.M. and contents of the pack
MIDAZOLAM BIOINDUSTRIA L.I.M. is a clear, colourless solution.

MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/ml injectable solution: 1 ml vials. Pack of 10 vials.
MIDAZOLAM BIOINDUSTRIA L.I.M. 15 mg/3 ml injectable solution: 3 ml vials. Pack of 5 vials.
MIDAZOLAM BIOINDUSTRIA L.I.M. 50 mg/10 ml injectable solution: 10 ml vials. Pack of 10 vials.
MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/5 ml injectable solution: 5 ml vials. Pack of 5 vials.

Marketing Authorisation Holder and Manufacturer
Bioindustria LIM S.p.A. - Via De Ambrosiis n. 2 - 15067 Novi Ligure (Alessandria)

Package leaflet: information for the physician

MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/ml injectable solution

MIDAZOLAM BIOINDUSTRIA L.I.M. 15 mg/3 ml injectable solution
MIDAZOLAM BIOINDUSTRIA L.I.M. 50 mg/10 ml injectable solution
MIDAZOLAM BIOINDUSTRIA L.I.M. 5 mg/5 ml injectable solution
Midazolam
Generic medicine
The following information is intended exclusively for physicians or healthcare professionals
CLINICAL INFORMATION
Instructions for use

MIDAZOLAM BIOINDUSTRIA L.I.M. is compatible with the following infusion solutions:

0.9% sodium chloride, 5% glucose, 10% glucose, Lactated Ringer's solution.
Do not dilute the solution from MIDAZOLAM BIOINDUSTRIA L.I.M. vials with Macrodex 6%
in dextrose. Do not mix the solution from the MIDAZOLAM BIOINDUSTRIA L.I.M. vial with
alkaline injectable solutions. Midazolam precipitates in the presence of sodium bicarbonate. To avoid
potential incompatibility with other solutions, the solution from the MIDAZOLAM
BIOINDUSTRIA L.I.M. vial must not be mixed with any solutions other than those listed above.
Dosage and method of administration
Midazolam is a potent sedative agent requiring dose adjustment and slow administration. Dose
adjustment is strongly recommended to safely achieve the desired level of sedation according to clinical need, physical condition, age, and concomitant administration of other drugs.
In adults over 60 years of age, debilitated patients, patients with chronic diseases, and pediatric patients, the dose should be determined cautiously, taking into account individual risk factors for each patient.
Standard dosages are reported in the following table.

Indications	Adults < 60 years	Adults ≥ 60 years / debilitated or with chronic diseases	Children
Conscious sedation	e.v. Initial dose: 2–2.5 mg Additional doses: 1 mg Total dose: 3.5–7.5 mg	e.v. Initial dose: 0.5–1 mg Additional doses: 0.5–1 mg Total dose: <3.5 mg	e.v. (in patients aged between 6 months and 5 years) Initial dose: 0.05–0.1 mg/kg Total dose: <6 mg e.v. (in patients aged between 6 and 12 years) Initial dose: 0.025–0.05 mg/kg Total dose: <10 mg Rectal (in patients older than 6 months): 0.3–0.5 mg/kg i.m. (in patients aged between 1 and 15 years): 0.05–0.15 mg/kg
Pre-anesthetic medication	e.v. 1–2 mg repeated i.m. 0.07–0.1 mg/kg	e.v. Initial dose: 0.5 mg, gradually increased as needed i.m.	Rectal (in patients older than 6 months): 0.3–0.5 mg/kg i.m. (in patients aged between 1 and 15 years)
		0.025–0.05 mg/kg	0.08–0.2 mg/kg
Induction of anesthesia	e.v. 0.15–0.2 mg/kg (0.3–0.35 without premedication)	e.v. 0.05–0.15 mg/kg (0.15–0.3 without premedication)
Sedative component in combined anesthesia	e.v. Intermittent doses of 0.03–0.1 mg/kg or continuous infusion of 0.03–0.1 mg/kg/h	e.v. Lower doses than those recommended for adults < 60 years
Sedation in intensive care	e.v. Loading dose: 0.03–0.3 mg/kg with increments of 1–2.5 mg Maintenance dose: 0.03–0.2 mg/kg/h		e.v. (in neonates < 32 weeks gestational age): 0.03 mg/kg/h e.v. (in neonates > 32 weeks and children up to 6 months): 0.06 mg/kg/h e.v. (in patients older than 6 months) Loading dose: 0.05–0.2 mg/kg Maintenance dose: 0.06–0.12 mg/kg/h

Use in specific patient populations

Renal impairment: (creatinine clearance <10 ml/min) the mean duration of sedative effect in patients with renal insufficiency was considerably longer, most likely due to accumulation of α-hydroxymidazolam glucuronide.
Hepatic impairment: impaired hepatic function reduces the clearance of intravenous midazolam, resulting in a prolonged terminal half-life.
Paediatric population: see table above and section “preterm infants and neonates”.

Overdose
Patients receiving doses higher than those recommended must be closely monitored.
Management of overdose consists of monitoring vital signs and implementing supportive measures according to the patient's clinical condition. In particular, patients may require symptomatic treatment for cardiovascular, respiratory or central nervous system effects.
In case of oral administration, further absorption should be prevented by appropriate means, such as administration of activated charcoal within 1–2 hours. When using activated charcoal, airway protection is mandatory in drowsy patients.
In cases of mixed ingestion, gastric lavage may be considered, although it is not a routine procedure.
In the event of severe CNS depression, consider the use of flumazenil, a benzodiazepine antagonist. Flumazenil should be administered only under strictly controlled conditions.

Special precautions for storage
MIDAZOLAM BIOINDUSTRIA L.I.M. vials are for single use only. Any unused solution must be discarded. Before use, examine the solution visually; only clear solutions without particulate matter should be used.

For further information, consult the Summary of Product Characteristics.