EU PSUR Work Sharing

Sufenta/Sufenta Forte (sufentanil citrate)

PT/H/PSUR/0010/002
P-RMS Portugal

Invented name of the medicinal

Sufenta / Sufenta Forte
product(s)
INN (or common name) of the active
sufentanil citrate
substance(s)
MAHs whose PSURs were included in
Janssen Farmacutica Portugal, Lda.
this work-sharing
Pharmaco-therapeutic group (ATC
N01AH03
Code)
Intravenous sufentanil is indicated as an analgesic
adjunct during induction and maintenance of
balanced general anaesthesia, and as an anaesthetic
agent for induction and maintenance of anaesthesia
Indications authorised in the P-RMS for in patients undergoing major surgical procedures.
the product Epidural sufentanil is indicated for post-operative
management of pain following general surgery,
thoracic or orthopaedic procedures and caesarean
sections, and as an analgesic adjunct to epidural
bupivacaine during labour and vaginal deliveries.
Pharmaceutical form(s) and strength(s) solution for injection

PSUR Period
The period covered by this work sharing assessment was 01 December 2009 to 30 November
2012.

Final Conclusion
The major risks associated with sufentanil continue to be respiratory depression, muscle rigidity
and hypersensitivity reactions. There have been no new important identified or potential risks or
safety concerns for this product during the reporting period. Consequently, there has been no
change to the agreed core safety profile (CSP). The MAH is committed to continue to monitor
suspect adverse reactions in association with the use of sufentanil.
In conclusion, sufentanil continues to have a favourable benefit-risk profile as an analgesic and
anaesthetic agent in the approved indications.
The SmPC should be aligned with the last agreed CSP, see attachment.
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC
and published on the European medicines web-portal.

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In the light of the information provided in the reviewed PSUR, the P-RMS/CMDh considers there
were no new major findings affecting the overall safety profile of sufentanil citrate and the
benefit-risk profile of the medicinal product(s) remains favourable.

Recommendations:

Amendments to the Product Information

Sections 4.4, 4.5, 4.6 and 4.8 of the SmPC and the corresponding sections of the PL should be
amended/updated as specified below in order to update the safety-related information.

SmPC wording

4.4 Warnings and special precautions for use. The sentence Intravenous use in labour or
before clamping of the cord during caesarean section is not recommended due to the possibility
of respiratory depression in the newborn infant. This is in contrast to the epidural use in labour,
during which sufentanil in doses up to 30 g does not influence the condition of the mother or the
newborn. should be deleted from section 4.4 of the SmPC as it is already present in section 4.3
as a contraindication.
4.5 Interactions with other medicinal products and other forms of interaction. The sentence
However, several reports describe the uneventful use of fentanyl, a related opioid, during
surgical or anaesthetic procedures in patients on MAO-inhibitors should be deleted from the
SmPC as this information is not directly applicable to sufentanil and is not present in the CSP.
4.6. Fertility, pregnancy and lactation. The sentence Controlled clinical studies during labour
(...) but intravenous use is not recommended in labour. should be amended in section 4.6 of the
SmPC to Controlled clinical studies during labour (...) but intravenous use is contraindicated in
labour. as agreed in the last CSP.
4.8 Undesirable effects. The following undesirable effects Apnoea, Respiratory depression,
Pulmonary oedema, Laryngospasm should be deleted from SOC Cardiac Disorders in the
SmPC.

Agreed topics for close monitoring and review in the next PSUR are:

The following adverse events should be closely monitored by the MAHs having marketing
authorisation for products containing sufentanil citrate:
Respiratory depression
Muscle rigidity
Hypersensitivity reactions
Risks in labour
and report on these issues in the next PSUR.

Since generic PSURs are not requested, the generic companies are asked to report to NCAs and
to the P-RMS if a signal for any of these adverse events is strengthened.

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Core Safety Profile Sufentanil

4.3 Contraindications

Sufentanil is contraindicated in patients with known intolerance to any of its components

or to other morphinomimetics.

Intravenous use in labour or before clamping of the cord during caesarean section is not
recommended due to the possibility of respiratory depression in the newborn infant. This
is in contrast to the epidural use in labour, during which sufentanil in doses up to 30 g
does not influence the condition of the mother or the newborn (see section 4. 6).

As with other opioids administered epidurally, sufentanil should not be given in the
presence of: severe haemorrhage or shock; septicaemia; infection at the injection site;
disturbances in haemostasis such as thrombocytopenia and coagulopathy; or in the
presence of anticoagulant therapy or of other concomitant drug therapy or medical
conditions which could contraindicate the technique of epidural administration.

4.4. Special warnings and special precautions for use

As with all potent opioids:

Respiratory depression is dose related and can be reversed by specific narcotic

antagonists (naloxone), but a repeated dose of the latter may be necessary because the
respiratory depression may last longer than the duration of action of the opioid
antagonist. Marked respiratory depression accompanies profound analgesia. It can
persist in the postoperative period, and if sufentanil has been given intravenously it can
even recur. Therefore, patients should remain under appropriate surveillance.
Resuscitation equipment and narcotic antagonists should be readily available.
Hyperventilation during anaesthesia may alter the patients responses to CO2, thus
affecting respiration postoperatively.

Induction of muscle rigidity, which may also involve the thoracic respiratory muscles,
can occur, but can be avoided by the following measures: slow I.V. injection (ordinarily
sufficient for lower doses), premedication with benzodiazepines and the use of muscle
relaxants.

Non-epileptic (myo)clonic movements can occur.

Bradycardia and possibly cardiac arrest can occur if the patient has received an
insufficient amount of anticholinergic or when sufentanil is combined with non-
vagolytic muscle relaxants. Bradycardia can be treated with atropine.

Opioids may induce hypotension, especially in hypovolemic patients. Appropriate

measures to maintain a stable arterial pressure should be taken.

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 The use of rapid bolus injections of opioids should be avoided in patients with
compromised intracerebral compliance; in such patients the transient decrease in the
mean arterial pressure has occasionally been accompanied by a short-lasting reduction of
the cerebral perfusion pressure.

Patients on chronic opioid therapy or with a history of opioid abuse may require higher
doses.

It is recommended to reduce the dosage in the elderly and in debilitated patients. Opioids
should be titrated with caution in patients with any of the following conditions:
uncontrolled hypothyroidism; pulmonary disease; decreased respiratory reserve;
alcoholism; impaired hepatic or renal function. Such patients also require prolonged
post-operative monitoring.

With epidural administration, caution should be exercised in the presence of respiratory

depression or compromised respiratory function and in the presence of foetal distress.
The patient should be closely monitored for at least 1 hour after each dose, as early
respiratory depression may occur.

4.5. Interaction with other medicaments and other forms of interaction

Drugs such as barbiturates, benzodiazepines, neuroleptics, halogenic gases and other,

non-selective CNS depressants (e.g. alcohol) may potentiate the respiratory depression
of narcotics.

When patients have received such drugs, the dose of sufentanil required will be less than
usual. Likewise, following the administration of sufentanil, the dose of other CNS-
depressant drugs should be reduced.

Sufentanil is metabolised mainly via the human cytochrome P450 3A4 enzyme.
However, no in vivo inhibition by erythromycin (a known cytochrome P450 3A4
enzyme inhibitor) has been observed. Although clinical data are lacking, in vitro data
suggest that other potent cytochrome P450 3A4 enzyme inhibitors (e.g. ketoconazole,
itraconazole, ritonavir) may inhibit the metabolism of sufentanil. This could increase the
risk of prolonged or delayed respiratory depression. The concomitant use of such drugs
requires special patient care and observation; in particular, it may be necessary to lower
the dose of sufentanil.

It is usually recommended to discontinue MAO-inhibitors 2 weeks prior to any surgical

or anaesthetic procedure.

4.6. Pregnancy and lactation

Safety of intravenous sufentanil in human pregnancy has not been established although
studies in animals have not demonstrated any teratogenic effects. As with other drugs,
risk should be weighed against potential benefit to the patient.

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 Controlled clinical studies during labour have shown that sufentanil added to epidural
bupivacaine in total doses up to 30 g has no detrimental effect on the mother or the
newborn, but intravenous use is contraindicated in labour. Sufentanil crosses the
placenta. After epidural administration of a total dose not exceeding 30 g, average
plasma concentrations of 0.016 ng/mL were detected in the umbilical vein.

An antidote for the child should always be at hand.

Sufentanil is excreted in breast milk. Caution should be exercised when sufentanil is

administered to a nursing woman.

4.7. Effects on ability to drive and use machines

Patients should drive or operate a machine only if sufficient time has elapsed after the
administration of sufentanil.

4.8. Undesirable effects

The safety of sufentanil was evaluated in 650 sufentanil-treated subjects who

participated in 6 clinical trials. Of these, 78 subjects participated in 2 trials of sufentanil
administered intravenously as an anaesthetic agent for induction and maintenance of
anaesthesia in subjects undergoing major surgical procedures (coronary artery bypass or
open- heart). The remaining 572 subjects participated in 4 trials of epidural sufentanil
administered as a postoperative analgesic, or as an analgesic adjunct to epidural
bupivacaine during labour and vaginal deliveries. These subjects took at least 1 dose of
sufentanil and provided safety data. Based on pooled safety data from these clinical
trials, the most commonly reported ( 5% incidence) ADRs were (with % incidence):
sedation (19.5); pruritus (15.2); nausea (9.8); and vomiting (5.7).

Including the above-mentioned adverse drug reactions (ADRs), the following table
displays ADRs that have been reported with the use of sufentanil from either clinical
trial or post-marketing experiences. The displayed frequency categories use the
following convention:

Very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100);

rare (1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated
form the available clinical trial data).

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System Organ Adverse Drug Reactions
Class Frequency Category
Very Com Common Uncommon Rare Not Known
mon ( 1/100 ( 1/1,000 ( 1/10,00
( 1/10) to < 1/10) to < 1/100) 0
to
<1/1,000)
Infection and Rhinitis
Infestation
Immune Hypersensitivity Anaphylactic
System shock,
Disorders Anaphylactic
reaction,
Anaphylactoi
d reaction
Psychiatric Apathy,
Disorders Nervousness
Nervous Sedation Tremor Ataxia, Coma,
System neonatal, Dyskinesia Convulsion,
Disorders Dizziness, neonatal, Muscle
Headache Dystonia, contractions
Hyperreflexia, involuntary
Hypertonia,
Hypokinesia
neonatal,
Somnolence
Eye Disorders Visual Miosis
Disturbance
Cardiac Tachycardia Atrioventricular Cardiac arrest
Disorders block,
Cyanosis,
Bradycardia,
Arrhythmia,
Electrocardiogra
m
abnormal
Vascular Hypertensio Shock
Disorders n,
Hypotension
, Pallor
Respiratory, Cyanosis Bronchospasm, Respiratory
Thoracic and neonatal Hypoventilation, arrest,
Mediastinal Dysphonia, Apnoea,
Disorders Cough, Respiratory
Hiccups, depression,
Respiratory Pulmonary
disorder oedema,
Laryngospas
m

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Gastrointestina Vomiting,
l Disorders Nausea
Skin and Pruritus Skin Dermatitis Erythema
Subcutaneous discolouratio allergic,
Tissue n Hyperhidrosis,
Disorders Rash,
Rash neonatal,
Dry skin
Musculoskeleta Muscle Back pain, Muscle
l and twitching Hypotonia spasms
Connective neonatal, Muscle
Tissue rigidity
Disorders
Renal and Urinary
Urinary retention,
Disorders Urinary
incontinence
General Pyrexia Hypothermia,
Disorders and Body
Administration temperature
Site decreased,
Conditions Body temperature
increased, Chills,
Injection site
reaction,
Injection site
pain, Pain

4.9 Overdose

Signs and Symptoms

An overdosage of sufentanil manifests itself as an extension of its pharmacologic

actions. Depending on the individual sensitivity, the clinical picture is determined
primarily by the degree of respiratory depression, which varies from bradypnoea to
apnoea.

Treatment

In the presence of hypoventilation or apnoea, oxygen should be administered and

respiration should be assisted or controlled as indicated. A specific narcotic antagonist,
such as naloxone, should be used as indicated to control respiratory depression. This
does not preclude the use of more immediate countermeasures. The respiratory
depression may last longer than the effect of the antagonist; additional doses of the latter
may therefore be required.

If depressed respiration is associated with muscular rigidity, an intravenous

neuromuscular blocking agent might be required to facilitate assisted or controlled
respiration.

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The patient should be carefully observed; body warmth and adequate fluid intake should
be maintained. If hypotension is severe or if it persists, the possibility of hypervolemia
should be considered, and if present, it should be controlled with appropriate parenteral
fluid administration.

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