Patient Information Leaflet

SUFENTANIL PIRAMAL 0.05 mg/ml injection solution

Sufentanil citrate
Please 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, pharmacist, or nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

What SUFENTANIL PIRAMAL is and what it is used for
What you need to know before using SUFENTANIL PIRAMAL
How to use SUFENTANIL PIRAMAL
Possible side effects
How to store SUFENTANIL PIRAMAL
Contents of the pack and other information

1. What SUFENTANIL PIRAMAL is and what it is used for

SUFENTANIL PIRAMAL contains sufentanil citrate, a medicine used to induce general anaesthesia (loss of sensation throughout the whole body) or local anaesthesia (loss of sensation in only one part of the body).
SUFENTANIL PIRAMAL can be administered by intravenous injection (intravenous administration) or into the back (epidural administration).

Adults

In intravenous administration, SUFENTANIL PIRAMAL is indicated:
- to induce and maintain general anaesthesia during surgical procedures;
- to prevent or relieve pain during surgical procedures.
In epidural administration, SUFENTANIL PIRAMAL is indicated:
- for postoperative pain management following general surgery;
- to prevent or relieve pain during labour and vaginal delivery, in combination with other medicinal products (bupivacaine).

Children and adolescents under 18 years of age

In intravenous administration, SUFENTANIL PIRAMAL is indicated in children over 1 month of age as an analgesic for the induction and maintenance of general anaesthesia.
In epidural administration, SUFENTANIL PIRAMAL is indicated in children over 1 year of age for postoperative pain management following surgical procedures.

2. What you should know before taking SUFENTANIL PIRAMAL

SUFENTANIL PIRAMAL will not be administered to you and/or your baby if:

you are allergic to sufentanil citrate or to any of the other ingredients of this medicine (listed in section 6)
you are allergic to medicines similar to sufentanil citrate (morphine-like medicines)
intravenous administration during labour or before clamping of the umbilical cord during caesarean section due to the risk of respiratory depression in the newborn (see section “Pregnancy and breastfeeding”)
intrathecal or epidural administration in case of:
severe bleeding or shock (reduced blood flow in the body and brain)
blood infection (septicaemia)
infection at the injection site
blood clotting disorders (such as thrombocytopenia and coagulopathy)
concomitant treatment with anticoagulants (medicines that make the blood thinner) or other drugs
clinical conditions that preclude this route of administration.

Warnings and precautions
This medicine is available only in hospital settings. Therefore, it will be administered to you only under close supervision by qualified medical personnel.
Before SUFENTANIL PIRAMAL is administered to you or your child, inform your doctor:

if you have recently experienced significant blood loss;
if you have brain disorders or diseases;
if you have been taking medicines similar to SUFENTANIL PIRAMAL (other opioid painkillers) for a long time or have previously abused them;
if you have reduced thyroid function and are not taking medication for it;
if you have lung problems or breathing difficulties;
if you have liver or kidney disease or a history of alcohol abuse;
if you or a family member has ever had alcohol, prescription medicine, or illegal substance abuse or dependence (“addiction”);
if you are a smoker;
if you have ever had mood disorders (depression, anxiety, or a personality disorder) or have been treated by a psychiatrist for other mental illnesses.

This medicine contains sufentanil, which is an opioid medicine. Repeated use of opioid analgesics may reduce the drug's effectiveness (tolerance develops). It may also lead to dependence and abuse, which can result in potentially fatal overdose. If you are concerned about developing dependence on SUFENTANIL PIRAMAL, it is important to consult your doctor.
Contact your doctor or nurse before treatment if:

you have unusually slow bowel movements;
you have a disease of the gallbladder or pancreas.

Sleep-related breathing disorders
SUFENTANIL PIRAMAL may cause sleep-related breathing disorders such as sleep apnoea
(pauses in breathing during sleep) and sleep-related hypoxemia (low blood oxygen levels). Symptoms may include breathing pauses during sleep, nocturnal awakenings due to breathlessness, difficulty maintaining sleep, or excessive daytime sleepiness.
If you or someone else observes these symptoms, contact your doctor. The doctor may consider reducing the dose.
Inform your doctor if you are pregnant, think you might be pregnant, or are breastfeeding (for further information, see section “Pregnancy”).
If you experience pain or increased sensitivity to pain (hyperalgesia) that does not respond to an increase in dose as prescribed by your doctor, inform your doctor or pharmacist. The doctor will assess whether to adjust the dose or discontinue administration.

For athletes
Using this medicine without a therapeutic need constitutes doping and may result in a positive anti-doping test.

Other medicines and SUFENTANIL PIRAMAL
Inform your doctor, nurse, or pharmacist if you/your child are taking, have recently taken, or might take any other medicines.
In particular, inform your doctor if you/your child are taking the following medicines.

Medicines that increase the effect of SUFENTANIL PIRAMAL
Taking the following medicines together with SUFENTANIL PIRAMAL may enhance the effects of SUFENTANIL PIRAMAL and thereby increase the risk of adverse effects, especially respiratory depression:

Medicines used to treat depression known as monoamine oxidase inhibitors (MAOIs). These medicines must not be taken within 2 weeks before or during treatment with SUFENTANIL PIRAMAL.
Medicines used to treat depression known as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Concomitant use of these medicines with SUFENTANIL PIRAMAL is not recommended.
Medicines that reduce/block the activity of the Central Nervous System, such as:
barbiturates (medicines that induce physical and mental relaxation and sleep, and may be used to treat epilepsy)
benzodiazepines (medicines used to treat anxiety and insomnia)
neuroleptics (medicines used for mental disorders such as schizophrenia)
halogenated anaesthetic gases (a class of anaesthetics). Your doctor will reduce the dose of SUFENTANIL PIRAMAL during surgery and may also reduce the dose of the other medicines listed above.
Other medicines affecting the metabolism of SUFENTANIL PIRAMAL, for example:
ketoconazole, itraconazole (medicines used to treat fungal infections)
ritonavir (a medicine used to treat HIV)
erythromycin (an antibiotic). Your doctor will provide special care and monitor you/your child closely and may reduce the dose of SUFENTANIL PIRAMAL during surgery.

Concomitant use of SUFENTANIL PIRAMAL and sedative medicines such as benzodiazepines or related drugs increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and can be life-threatening. Therefore, concomitant use should only be considered when no other treatment options are available.
However, if your doctor prescribes SUFENTANIL PIRAMAL together with sedative medicines, the dose and duration of concomitant treatment should be limited.
Inform your doctor about all sedative medicines you are taking and strictly follow their dosage recommendations. It may be helpful to inform friends and relatives to watch for the symptoms listed above. Contact your doctor if these symptoms occur.
Concomitant use of opioids and medicines used to treat epilepsy, neuralgia, or anxiety (gabapentin and pregabalin) increases the risk of opioid overdose and respiratory depression, which can be potentially fatal.

SUFENTANIL PIRAMAL and alcohol
Taking SUFENTANIL PIRAMAL with alcoholic beverages may enhance the effect of SUFENTANIL PIRAMAL and cause respiratory depression.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning pregnancy, or are breastfeeding, inform your doctor before this medicine is administered.
SUFENTANIL PIRAMAL must not be administered intravenously during pregnancy and labour or before clamping of the umbilical cord during caesarean section, as it may cause respiratory problems in the newborn.
Newborns of women who receive this medicine during pregnancy are at risk of developing neonatal abstinence syndrome (NAS).

Driving and using machines
SUFENTANIL PIRAMAL affects your ability to drive or operate machinery for a certain period of time.
Therefore, your doctor will decide when you/your child can resume driving or using machinery after surgery.
Your doctor will also assess whether you should be accompanied when leaving the hospital.

SUFENTANIL PIRAMAL contains sodium
20 ml vial: this medicine contains 70.84 mg of sodium (a key component of table salt) per vial. This corresponds to 3.54% of the maximum daily dietary intake recommended for an adult.
1 ml vial and 5 ml vial: this medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e., essentially 'sodium-free'.

3. How to take SUFENTANIL PIRAMAL

This medicine is available only in a hospital setting. Therefore, this medicine will be administered exclusively under the close supervision of qualified medical personnel.
The appropriate dose for you or the child will be determined by the doctor/anesthesiologist based on age, body weight, general condition, underlying disease, concomitant use of other medicines you/the child may be taking, type of surgical procedure, and type of anesthesia.
SUFENTANIL PIRAMAL will be administered to you and/or the child either by injection into a vein (intravenous administration) or into the back (epidural administration).
If SUFENTANIL PIRAMAL is administered intravenously, the doctor/anesthesiologist may first administer other medicines to prevent the occurrence of adverse effects due to SUFENTANIL PIRAMAL, such as bradycardia (reduced heart rate, i.e. number of heartbeats per minute), nausea, or vomiting.
If you and/or the child are given more SUFENTANIL PIRAMAL than prescribed
If an excessive dose of SUFENTANIL PIRAMAL is administered, you may experience breathing difficulties up to respiratory depression, which may be associated with muscle rigidity and low blood pressure (hypotension).
In case an excessive dose of SUFENTANIL PIRAMAL is administered, the doctor will implement appropriate supportive therapy.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The frequency, type and severity of side effects expected in children are the same as those expected in adults.
Based on safety data from clinical studies, the most commonly reported adverse reactions included sedation (19.5%), pruritus (15.2%), nausea (9.8%), and vomiting (5.7%).

The following side effects may occur during treatment with SUFENTANIL PIRAMAL:

Very common (may affect up to 1 in 10 people)

physical and mental relaxation (sedation)
itching (pruritus)

Common (may affect up to 1 in 100 people)

tremor in the newborn
dizziness (vertigo)
headache (cephalalgia)
increased heart rate, i.e. number of heartbeats per minute (tachycardia)
increased blood pressure (hypertension)
decreased blood pressure (hypotension)
pallor
bluish discoloration of the newborn's skin due to respiratory problems (neonatal cyanosis)
skin discoloration
involuntary muscle contractions
inability to completely empty the bladder (urinary retention)
involuntary loss of urine (urinary incontinence)
fever (pyrexia)
nausea, vomiting

Uncommon (may affect up to 1 in 1,000 people)

infection and inflammation of the nose (rhinitis)
hypersensitivity
reduced or absent emotional response to situations (apathy)
nervousness
loss of coordination of muscles and movements (ataxia)
movement difficulties in the newborn (neonatal dyskinesia)
movement disorder causing abnormal postures due to muscle contractions (dystonia)
exaggerated reflexes (hyperreflexia)
increased muscle tone (hypertonia)
reduced movement in the newborn (neonatal hypokinesia)
drowsiness
visual disturbances
disturbances in the heart's electrical conduction (atrioventricular block)
bluish discoloration of the skin due to respiratory problems (cyanosis)
reduced heart rate, i.e. number of heartbeats per minute (bradycardia)
alteration in the heart's beat rhythm (arrhythmia). This occurred during intravenous administration of SUFENTANIL PIRAMAL
abnormal electrocardiogram
breathing difficulty due to reduced airflow (bronchospasm)
reduced airflow to the lungs (hypoventilation)
difficulty producing voice (dysphonia)
cough
hiccups
respiratory disorders
allergic skin eruptions (allergic dermatitis). These occurred during intravenous administration of SUFENTANIL PIRAMAL
increased sweating (hyperhidrosis)
skin rash, including in newborns (rash, neonatal rash)
dry skin
back pain
decreased muscle tone in the newborn (neonatal hypotonia)
muscle rigidity. This occurred during intravenous administration of SUFENTANIL PIRAMAL
decreased body temperature (hypothermia)
increased body temperature (hyperthermia)
chills
reaction at the injection site
pain at the injection site. This occurred during intravenous administration of SUFENTANIL PIRAMAL
pain

Additionally, the following side effects may occur for which the frequency is unknown:

Effects related to the body's defence system

severe allergic reactions (anaphylactic reactions, anaphylactic shock, anaphylactoid reactions)

Effects related to the nervous system

coma
seizures
involuntary contraction of one or more muscles

Effects related to the eye

reduced pupil diameter (miosis)

Effects related to the heart and blood vessels

cardiac arrest (cardiac arrest)
condition of severe reduction in blood circulation (shock)

Effects related to the respiratory system

cessation of breathing (respiratory arrest)
interruption of breathing (apnoea)
reduced breathing (respiratory depression)
accumulation of fluid in the lung (pulmonary oedema)
narrowing of the larynx (laryngospasm)

Effects related to the skin

redness of the skin (erythema)

Effects related to the muscles

involuntary muscle contractions (muscle spasms)

Reporting of side effects
If you/your child experience any side effect, including those not listed in this leaflet, please contact your doctor. You may also report side effects directly via the national reporting system at the website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store SUFENTANIL PIRAMAL

Keep this medicine out of sight and reach of children.
Do not use this medicine after the expiry date which is stated on the packaging after Exp. The
expiry date refers to the last day of the month.
Store in the original packaging to protect the medicine from light.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What SUFENTANIL PIRAMAL contains

The active substance is: sufentanil citrate. Each 5 ml vial contains 0.375 mg of sufentanil citrate, equivalent to 0.250 mg of sufentanil. Each 1 ml vial contains 0.075 mg of sufentanil citrate, equivalent to 0.05 mg of sufentanil. Each 20 ml vial contains 1.50 mg of sufentanil citrate, equivalent to 1.00 mg of sufentanil.
The other components are: sodium chloride (see section “SUFENTANIL PIRAMAL contains sodium”), water for injections.

Description of the appearance of SUFENTANIL PIRAMAL
SUFENTANIL PIRAMAL is a sterile aqueous solution for administration via intravenous injection (intravenous administration) or into the back (epidural administration). The solution is supplied in 1 ml or 2 ml vials containing 1 ml of solution, 5 ml vials containing 5 ml of solution, and 20 ml vials containing 20 ml of solution, packaged in cartons containing 5 vials.

Marketing Authorization Holder
Piramal Critical Care Italia S.p.A,
Legal address Via XXIV Maggio, 62/a
37057 San Giovanni Lupatoto
Verona, Italy

Manufacturer
Piramal Critical Care BV
Rouboslaan 32
2252 TR Voorschoten
The Netherlands

The following information is intended exclusively for doctors or healthcare professionals

SPECIAL WARNINGS
As with all potent opioids:
respiratory depression is dose-dependent and can be reversed by specific opioid antagonists, but repeated doses of these antagonists may be necessary because respiratory depression may last longer than the action of the opioid antagonist. Marked respiratory depression is associated with profound analgesia. It may persist in the postoperative period and may recur if SUFENTANIL PIRAMAL is administered intravenously. For these reasons, careful patient monitoring is essential, and resuscitation equipment and opioid antagonist drugs must always be readily available.
Hyperventilation during anesthesia may alter the patient's sensitivity to CO₂ and thus affect postoperative respiration.
Muscle rigidity may occur, which may also involve the thoracic muscles, but can be avoided by the following measures: slow intravenous injection of the drug (usually sufficient for lower doses), premedication with benzodiazepines, and use of muscle relaxants.
Non-epileptic myoclonic movements may occur.
If the patient receives an insufficient dose of anticholinergic agent or if SUFENTANIL PIRAMAL is combined with non-vagolytic muscle relaxants, bradycardia and even cardiac arrest may occur. Bradycardia can be treated with atropine.
Opioids may cause arterial hypotension, especially in hypovolemic patients; therefore, appropriate measures should be taken to maintain stable blood pressure.
Rapid bolus administration of opioids should be avoided in patients with compromised intracranial conditions; in such patients, the transient decrease in mean arterial pressure may occasionally be accompanied by a short-lived reduction in cerebral perfusion pressure.
Patients on chronic opioid therapy or with a history of narcotic dependence may require higher doses.
The dosage of SUFENTANIL PIRAMAL should be reduced in debilitated patients and in the elderly. Opioids should be titrated cautiously in patients with any of the following conditions: uncontrolled hypothyroidism, pulmonary disease, reduced respiratory reserve, alcoholism, or impaired hepatic or renal function. These patients also require prolonged postoperative monitoring.
With epidural administration, caution is required in the presence of respiratory depression or compromised respiratory function and in cases of fetal distress. The patient must be closely monitored for at least one hour after each dose, as respiratory depression may occur rapidly.

DOSAGE, METHOD, AND TIMING OF ADMINISTRATION
The dosage of SUFENTANIL PIRAMAL must be individually determined based on age, body weight, general condition of the patient, underlying pathological condition, concomitant medications, type of surgical procedure, and type of anesthesia. The effect of the initial dose should be taken into account when determining supplemental doses.

INTRAVENOUS ADMINISTRATION
To avoid bradycardia, a small intravenous (I.V.) dose of an anticholinergic agent may be administered just before induction of anesthesia.

Use as an analgesic adjuvant
In patients undergoing general surgery, doses of SUFENTANIL PIRAMAL of 0.5–5 µg/kg provide profound analgesia, reducing the sympathetic response to surgical stimulation and maintaining cardiovascular stability. Duration of action is dose-related. A dose of 0.5 µg/kg has an expected duration of 50 minutes. Supplemental doses of 10–25 µg should be adjusted according to individual patient needs and the remaining duration of the surgical procedure.

Use as an anesthetic agent
When used in doses ≥8 µg/kg, SUFENTANIL PIRAMAL induces sleep and maintains a deep, dose-dependent level of analgesia without the need for additional anesthetics. In addition, sympathetic and hormonal responses to surgical stimuli are attenuated.
Supplemental doses of 25–50 µg are generally sufficient to maintain cardiovascular stability during anesthesia.

P
Elderly patients (≥ 65 years of age)
As with other opioids, dosage must be reduced in elderly and debilitated patients.

Paediatric population
Infants ≤ 1 month (neonates)
Due to the variability of pharmacokinetic parameters in neonates, a safe dose cannot be established (see also sections 4.4 and 5.2).

Children > 1 month
Premedication with an anticholinergic agent such as atropine is recommended for all dosage regimens, unless specifically contraindicated.

Induction of anesthesia
SUFENTANIL PIRAMAL may be administered by slow infusion of 0.2–0.5 µg/kg over 30 seconds or over a longer period, in combination with an anesthetic-inducing agent. For major procedures (e.g., cardiac surgery), doses up to 1 µg/kg may be administered.

Maintenance of anesthesia in ventilated patients
SUFENTANIL PIRAMAL may be administered as part of balanced anesthesia. Dosage depends on the dose of concomitant anesthetic agents, type and duration of surgery. An initial dose of 0.3–2 µg/kg administered by slow infusion over more than 30 seconds may be followed by additional doses of 0.1–1 µg/kg as needed, up to a total maximum of 5 µg/kg in cardiac surgery.

EPIDURAL ADMINISTRATION
Before injecting SUFENTANIL PIRAMAL, correct placement of a needle or catheter in the epidural space must be confirmed.

Use for postoperative pain control
An initial dose of 30–50 µg is expected to provide adequate pain relief for 4–6 hours. If analgesic effect decreases, additional bolus doses of 25 µg may be administered.

Use as an analgesic adjuvant during labor and vaginal delivery
The addition of 10 µg of SUFENTANIL PIRAMAL to epidural bupivacaine (0.125%–0.25%) provides longer-lasting and higher-quality analgesia. If necessary, two consecutive doses of this combination may be administered. It is recommended not to exceed a total dose of 30 µg of sufentanil.

P
Elderly patients (≥ 65 years of age)
As with other opioids, dosage must be reduced in elderly and debilitated patients.

Paediatric population
SUFENTANIL PIRAMAL should be administered epidurally to children only by anesthesiologists specialized in pediatric epidural anesthesia and in the management of opioid-induced respiratory depression.
Appropriate resuscitation equipment, including airway safety devices and an opioid antagonist, must be immediately available.
Paediatric patients must be monitored for respiratory function for at least 2 hours after epidural administration of SUFENTANIL PIRAMAL.
The epidural use of SUFENTANIL PIRAMAL in the paediatric population has been documented in only a limited number of cases.

Children < 1 year:
No data are available for epidural administration of SUFENTANIL PIRAMAL in neonates and infants under 3 months of age.
Limited data are available for children aged between 3 months and 1 year (see section 5.1).
Safety and efficacy in children under 1 year of age have not been established (see also sections 4.4 and 5.1). Therefore, no recommended doses can be administered to children in this age group.

Children > 1 year:
A single dose of 0.25–0.75 µg/kg of SUFENTANIL PIRAMAL administered during surgery provides pain relief for a duration ranging from 1 to 12 hours.
The actual duration of analgesia is influenced by the type of surgery and the concomitant use of an epidural amide local anesthetic.

PREGNANCY AND LACTATION
PREGNANCY
Although animal studies have not shown any teratogenic effects, the safety of intravenous sufentanil in pregnant women has not yet been sufficiently documented.
As with other drugs, risks must be weighed against potential benefits for the patient.
Chronic use of opioids during pregnancy may lead to neonatal dependence and cause neonatal withdrawal syndrome. If prolonged opioid use during pregnancy is necessary, the patient should be informed of the risk of neonatal withdrawal syndrome. Controlled clinical studies conducted during labor have shown that SUFENTANIL PIRAMAL, when combined with epidural bupivacaine in total doses up to 30 µg, has no harmful effects on mother or neonate; however, intravenous use during labor is not recommended.
Sufentanil crosses the placenta. After epidural administration of a total dose not exceeding 30 µg, a mean plasma concentration of 0.016 ng/ml was detected in the umbilical vein.
Assisted ventilation equipment should be available, if needed, for both mother and baby. An opioid antagonist must always be available for the baby.

LACTATION
Sufentanil is excreted in breast milk. Caution should be exercised when administering sufentanil to nursing women.

OVERDOSE
Signs and symptoms
An overdose of SUFENTANIL PIRAMAL manifests as an extension of its pharmacological effects. Depending on individual sensitivity, the clinical picture is primarily characterized by the degree of respiratory depression, ranging from bradypnea to apnea.

Treatment
In the presence of hypoventilation or apnea, oxygen should be administered and respiration must be assisted and controlled as indicated. To reverse pharmacological depression, a specific opioid antagonist such as naloxone should be used according to its indications. This does not preclude the use of more immediate countermeasures. The duration of respiratory depression may exceed the duration of action of the opioid antagonist, and therefore additional doses of the antagonist may be required.
If respiratory depression is associated with muscle rigidity, administration of a neuromuscular blocker is recommended to facilitate controlled or assisted ventilation.
The patient must be closely monitored. Body temperature and adequate fluid intake must be maintained. If hypotension is severe or persistent, hypovolemia should be considered and, if present, corrected with appropriate parenteral fluid administration.
In case of accidental ingestion/uptake of an excessive dose of SUFENTANIL PIRAMAL, contact a physician immediately or go to the nearest hospital.

Sufentanil Piramal

Patient Information Leaflet