Zalviso 15microgram sublingual tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Sufentanil citrate
Available from:
Grunenthal Ltd
INN (International Name):
Sufentanil citrate
Pharmaceutical form:
Sublingual tablet
Administration route:
Schedule 2 (CD)
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04070200; GTIN: 4032129057814

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Package leaflet: Information for the patient

Zalviso 15 micrograms sublingual tablets


Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or nurse.

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet

What Zalviso is and what it is used for

What you need to know before you take Zalviso

How to take Zalviso

Possible side effects

How to store Zalviso

Contents of the pack and other information


What Zalviso is and what it is used for

The active substance of Zalviso is sufentanil, which belongs to a group of strong pain-relieving medicines

called opioids.

Zalviso is used to treat acute moderate to severe pain after an operation in adults.


What you need to know before you take Zalviso

Do not take Zalviso:

if you are allergic to sufentanil or any of the other ingredients of this medicine (listed in section 6).

if you have severe breathing problems.

Warnings and precautions

Talk to your doctor or nurse before taking Zalviso.

Tell your doctor or nurse before treatment if you:

are suffering from any condition that affects your breathing (such as asthma, wheezing, or shortness of

breath). As Zalviso may affect your breathing, your doctor or nurse will check your breathing during


have a head injury or brain tumour;

have problems with your heart and circulation, especially slow heart rate, irregular heart beats, low blood

volume or low blood pressure;

have moderate to severe liver or severe kidney problems, as these organs have an effect on the way in

which your body breaks down and eliminates the medicine;

have a history of medicine or alcoholabuse;

are regularly using a prescribed opioid medicine (e.g. codeine, fentanyl, hydromorphone, oxycodone);

have abnormally slow bowel movements;

have a disease of the gall bladder or pancreas.

Taking the sublingual tablets with the device

Before you start using Zalviso, your doctor or nurse will show you how to use the Zalviso administration

device. You will then be able to take a tablet as needed to relieve your pain. Follow the instructions

carefully. Talk to your doctor or nurse if you did not fully understand the instructions or are unsure about the

correct handling of the administration device.

Children and adolescents

Zalviso should not be used in children and adolescents below 18 years.

Other medicines and Zalviso

Tell your doctor if you are taking, have recently taken or might take any other medicines. In particular, tell

your doctor if you are taking any of the following:

Any medicines that might have an effect on the way in which your body breaks down Zalviso e.g.

ketoconazole, which is used for the treatment of fungal infections.

Any medicines which might make you sleepy (have a sedative effect), such as sleeping pills, medicines

to treat anxiety, tranquillisers or other opioid medicines, as they can increase the risk of severe breathing


Medicines for the treatment of severe depression (monoamine-oxidase (MAO) inhibitors), even if you

have taken them in the last 2

weeks. The use of MAO inhibitors must be stopped for at least 2


prior to use of Zalviso.

Other medicines which are also taken sublingually (medicines that are placed under the tongue where

they dissolve) or medicines which dilute or take effect in your mouth (e.g. nystatin, a liquid or pastilles

you hold in your mouth to treat fungus infections), as the effect on Zalviso has not been studied.

Zalviso with alcohol

Do not drink alcohol while using Zalviso. It can increase the risk of experiencing severe breathing problems.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor for advice before taking this medicine.

Zalviso should not be used during pregnancy or if you are a woman of childbearing potential not using


Sufentanil passes into breast milk and can cause side effects in the breast-fed child. Breastfeeding is not

recommended when you take Zalviso.

Driving and using machines

Zalviso affects your ability to drive or use machines as it may cause sleepiness, dizziness or visual

disturbances. You should not drive or operate machinery if you experience any of these symptoms whilst or

after being treated with Zalviso. You should only drive and use machines if sufficient time as elapsed after

your last dose of Zalviso.

Zalviso contains sunset yellow FCF Aluminium Lake (E110)

Zalviso contains the colouring agent sunset yellow FCF Aluminium Lake (E110), which may cause allergic



How to take Zalviso

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

The sublingual tablets are taken using the Zalviso administration device, which is a system that delivers a

single dose upon activation. After receiving a dose you will not be able to release another dose for

20 minutes and you will not be able to take more than 3 doses in one hour.

The device will work for 3 days (72 hours), which is also the maximum recommended duration of your


Zalviso is placed under the tongue using the Zalviso administration device. You can control your treatment

and should only activate the device when in need of pain relief.

The tablets dissolve under your tongue and should not be crushed, chewed, or swallowed. You should not eat

or drink and should talk as little as possible for 10 minutes after each dose.

Zalviso is only to be taken in a hospital setting. It is only prescribed by physicians who are experienced in

the use of strong pain killers like Zalviso and know the effects it may have on you, in particular on your

breathing (see “Warnings and precautions” above).

Do not use the device if any component is visibly damaged.

After your treatment the medical staff will take the Zalviso administration device and dispose of any unused

tablets accordingly. The device is constructed so that you will not be able to open it.

If you take more Zalviso than you should

The administration device will make you wait 20 minutes between doses to prevent you from taking more

Zalviso than you should. However, symptoms of overdose include severe breathing problems like slow and

shallow breathing, loss of conciousness, extreme low blood pressure, collapse and muscle rigidity. If these

start to develop, tell a doctor or nurse immediately.

If you have any further questions on the use of this medicine, ask your doctor or nurse.


Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The most serious side effects are severe breathing problems like slow and shallow breathing, which may even

lead to stopping breathing or inability to breathe.

In case you experience any of the above mentioned side effects, stop taking Zalviso and tell your doctor or

nurse immediately.

Very common side effects (may affect more than 1 in 10 people): nausea, vomiting, fever.

Common side effects (may affect up to 1 in 10 people):

confusion, dizziness, headache, drowsiness, increased heart rate, high blood pressure, low blood pressure,

constipation, indigestion, itching of the skin, involuntary muscle cramps, muscle twitching, difficulty passing


Uncommon side effects (may affect up to 1 in 100 people): allergic reactions, lack of interest or emotion,

nervousness, sleepiness, abnormal sensation of the skin, problems coordinating muscle movements, muscle

contractions, exaggeration of reflexes, vision disturbances, decreased heart rate, dry mouth, excessive

sweating, rash, dry skin, chills, weakness.

Frequency not known (frequency cannot be estimated from the available data): severe allergic reactions

(anaphylactic shock), convulsion (fits), coma, small pupil size, redness of the skin, withdrawal syndrome.

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in

this leaflet.

You can also report side effects directly via the national reporting system listed below.

By reporting side effects, you can help provide more information on the safety of this medicine.


HPRA Pharmacovigilance

Earlsfort Terrace

IRL – Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517



United Kingdom

Yellow Card Scheme



How to store Zalviso

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and sachet after EXP.

Store in the original package in order to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask the medical staff how to throw

away medicines you no longer use. These measures will help protect the environment.


Contents of the pack and other information

What Zalviso contains

The active substance is sufentanil. Each sublingual tablet contains 15 micrograms sufentanil (as citrate).

The other ingredients are mannitol (E421), calcium hydrogen phosphate (anhydrous), hypromellose,

croscarmellose sodium, stearic acid, magnesium stearate, sunset yellow FCF Aluminium Lake (E110)

(see section 2 “What you need to know before you take Zalviso”)

What Zalviso looks like and contents of the pack

Zalviso sublingual tablets are orange-coloured flat-faced tablets with rounded edges. The sublingual tablets

measure 3 mm in diameter.

The sublingual tablets are supplied in cartridges; each cartridge contains 40 sublingual tablets. One cartridge

is packed in a sachet including an oxygen absorber.

Zalviso sublingual tablets are available in pack sizes of 1, 10 and 20 cartridges and in multipacks containing

40 (2 packs of 20), 60 (3 packs of 20) and 100 (5 packs of 20) cartridges, equivalent to 40, 400, 800, 1,600,

2,400 and 4,000 sublingual tablets, respectively.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Grünenthal GmbH

Zieglerstraße 6

52078 Aachen


Tel.: +49-241-569-0

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:


Grünenthal Denmark ApS

Arne Jacobsens Allé 7

2300 København S

Tlf: +45 88883200


Grünenthal Norway AS

C.J. Hambros Plass 2C

0164 Oslo

Tlf: +47 22996054


Grünenthal Pharma Ltd

4045 Kingswood Road,

Citywest Business Park

IRL – Citywest Co., Dublin

Tel: +44 (0)870 351 8960

United Kingdom

Grünenthal Ltd

1 Stokenchurch Business Park

Ibstone Road, HP14 3FE – UK

Tel: +44 (0)870 351 8960

This leaflet was last revised in 09/2015

Detailed information on this medicine is available on the European Medicines Agency web site:

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Object 1

Zalviso 15 micrograms sublingual tablets

Summary of Product Characteristics Updated 04-Apr-2016 | Grunenthal Ltd

1. Name of the medicinal product

Zalviso 15 micrograms sublingual tablets

2. Qualitative and quantitative composition

Each sublingual tablet contains 15 micrograms sufentanil (as citrate).

Excipient(s) with known effect:

Each sublingual tablet contains 0.074 mg sunset yellow FCF Aluminium Lake (E110).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Sublingual tablet.

Zalviso sublingual tablets of 3 mm diameter are orange-coloured flat-faced tablets with rounded edges.

4. Clinical particulars

4.1 Therapeutic indications

Zalviso is indicated for the management of acute moderate to severe post-operative pain in adult patients.

4.2 Posology and method of administration

Zalviso is to be administered in a hospital setting only. Zalviso should only be prescribed by physicians

who are experienced in the management of opioid therapy, particularly opioid adverse reactions such as

respiratory depression (see section 4.4).


Zalviso sublingual tablets are to be self-administered by the patient in response to pain using the Zalviso

administration device. The Zalviso administration device is designed to deliver a single sufentanil 15

micrograms sublingual tablet, on a patient-controlled as needed basis, with a minimum of 20 minutes

(lockout interval) between doses, over a period of up to 72 hours, which is the maximum recommended

treatment duration. See section “Method of administration“.


No special population studies were performed using sufentanil sublingual tablets in elderly patients. In

clinical trials approximately 30 % of enrolled patients were 65 to 75 years of age. The safety and efficacy

in elderly patients was similar to that observed in younger adults (see section 5.2).

Hepatic or renal impairment

No special population studies were performed using sufentanil sublingual tablets in hepatic and renal

impaired patients. Only limited data are available for the use of sufentanil in such patients. Zalviso should

be administered with caution to patients with moderate to severe hepatic or severe renal impairment (see

section 4.4).

Paediatric population

The safety and efficacy of Zalviso in children aged below 18 years have not been established. No data are


Method of administration

For sublingual use only.

The Zalviso sublingual tablets are to be self-administered using the Zalviso administration device which

should only be actuated by the patient in response to pain (see section 6.6).

The dispensed sublingual tablet should dissolve under the tongue and should not be crushed, chewed, or

swallowed. Patients should not eat or drink and minimize talking for 10 minutes after each dose of


The maximum amount of sublingual sufentanil that can be delivered via the Zalviso administration device

over an hour is 45 micrograms (3 doses).

In the event of repeated maximal usage by the patient, one cartridge will last for a period of 13 hours 20

minutes. Additional Zalviso cartridges may be utilized if needed.

For instructions on the setup and handling of the Zalviso administration device before administration, see

section 6.6.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Significant respiratory depression.

4.4 Special warnings and precautions for use

Respiratory depression

Sufentanil may cause respiratory depression, for which the degree/severity is dose related. The respiratory

effects of sufentanil should be assessed by clinical monitoring, e. g. respiratory rate, sedation level and

oxygen saturation. Patients at higher risk are those with respiratory impairment or reduced respiratory

reserve. Respiratory depression caused by sufentanil can be reversed by opioid antagonists. Repeat

antagonist administration may be required as the duration of respiratory depression may last longer than

the duration of the effect of the antagonist (see section 4.9).

Intracranial pressure

Sufentanil should be used with caution in patients who may be particularly susceptible to the cerebral

effects of CO

retention, such as those with evidence of increased intracranial pressure or impaired

consciousness. Sufentanil may obscure the clinical course of patients with head injury. Sufentanil should

be used with caution in patients with brain tumours.

Cardiovascular effects

Sufentanil may produce bradycardia. Therefore, it should be used with caution in patients with previous

or pre-existing bradyarrhythmias.

Sufentanil may cause hypotension, especially in hypovolemic patients. Appropriate measures should be

taken to maintain stable arterial pressure.

Impaired hepatic or renal function

Sufentanil is primarily metabolised in the liver and excreted in the urine and faeces. The duration of

activity may be prolonged in patients with severe hepatic and renal impairment. Only limited data are

available for the use of Zalviso in such patients. Patients with moderate to severe hepatic or severe renal

impairment should be monitored carefully for symptoms of sufentanil overdose (see section 4.9).

Abuse potential and tolerance

Sufentanil has potential for abuse. This should be considered when prescribing or administering

sufentanil where there is concern about an increased risk of misuse, abuse or diversion.

Patients on chronic opioid therapy or opioid addicts may require higher analgesic doses than the Zalviso

administration device can deliver.

Gastrointestinal effects

Sufentanil as a µ-opioid receptor agonist may slow the gastrointestinal motility. Therefore, Zalviso should

be used with caution in patients at risk of ileus.

Sufentanil as a µ-opioid receptor agonist may cause spasm of the sphincter of Oddi. Therefore, Zalviso

should be used with caution in patients with biliary tract disease, including acute pancreatitis.


Before use, the health-care professional should ensure that the patients have been appropriately instructed

on how to operate the Zalviso administration device to self-administer tablets as needed to manage their

pain post-operatively. Only patients who are able to understand and follow the instructions to operate the

administration device should use Zalviso. The health-care professional should take into consideration the

ability (e. g. visual or cognitive) of the patient to use the device appropriately.


Zalviso sublingual tablets contain the azo colouring agent sunset yellow FCF Aluminium Lake (E110),

which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Interaction with cytochrome P450-3A4 enzyme

Sufentanil is primarily metabolised by the human cytochrome P450-3A4 enzyme. Ketoconazole, a potent

CYP3A4 inhibitor, can significantly increase the systemic exposure to sublingual sufentanil (maximal

plasma levels (C

) increase of 19 %, overall exposure to the active substance (AUC) increase of 77 %)

and prolong the time to reach maximum concentration by 41 %. Similar effects with other potent

CYP3A4 inhibitors (e. g. itraconazol, ritonavir) cannot be excluded. Any change in efficacy/tolerability

associated with the increased exposure would be compensated in practice by an alteration in dosing

frequency (see section 4.2).

Central nervous system (CNS) depressants

The concomitant use of CNS depressants including barbiturates, benzodiazepines, neuroleptics or other

opioids, halogen gases or other non-selective CNS depressants (e.g. alcohol) may enhance respiratory


Monoamine oxidase (MAO) inhibitors

Discontinuation of MAO inhibitors is generally recommended 2 weeks before treatment with Zalviso,

because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid



Interaction with other sublingually administered products or products intended to dilute/establish an effect

in the oral cavity were not evaluated and simultaneous administration should be avoided.

4.6 Fertility, pregnancy and lactation


There is insufficient data on the use of sufentanil during human pregnancy to evaluate its potential

harmful effects. There are no indications to date that the use of sufentanil during pregnancy increases the

risk of congenital abnormalities.

Sufentanil crosses the placenta.

Reproductive toxicity has been shown in animal studies (see section 5.3).

Zalviso is not recommended during pregnancy and in women of childbearing potential not using



Sufentanil is excreted in human milk when applied intravenously; therefore caution is advised when

Zalviso is administered to breast-feeding women. Breastfeeding is not recommended when sufentanil is

administered, due to the risk of opioid effects or toxicity in the breastfed newborns/infants (see section



There are no data on the effects of sufentanil on fertility in women or men.

4.7 Effects on ability to drive and use machines

Sufentanil has major influence on the ability to drive and use machines. Patients should be advised not to

drive or operate machinery if they experience somnolence, dizziness, or visual disturbance while taking

or after the treatment with Zalviso. Patients should only drive and use machines if sufficient time has

elapsed after the last administration of Zalviso.

4.8 Undesirable effects

Summary of the safety profile

The most serious adverse reaction of sufentanil is respiratory depression, potentially leading to apnoea

and respiratory arrest (see section 4.4).

Based on the combined safety data from these clinical studies, nausea and vomiting were the most

frequently reported adverse reactions (≥1/10 frequency).

Tabulated list of adverse reactions

Adverse reactions identified either from clinical studies or from post-marketing experience with other

medicinal products containing sufentanil are summarised in the table below. The frequencies are defined

Very common



≥1/100 and <1/10


≥1/1,000 and <1/100


≥1/10,000 and <1/1,000

Very rare


Not known

Cannot be estimated from the available data

MedDRA system

organ class

Very common



Not known

Immune system



Anaphylactic shock



Confusional state



Nervous system












Eye disorders

Vision disturbances


Cardiac disorders

Heart rate increased

Heart rate


Vascular disorders

Blood pressure


Blood pressure



thoracic and






Respiratory arrest







Dry mouth

Skin and


tissue disorders




Dry skin*



and connective

tissue disorders

Involuntary muscle


Muscle twitching*

Renal and urinary


Urinary retention

General disorders

and administration

site conditions




Drug Withdrawal


* see “Description of selected adverse reactions“

Description of selected adverse reactions

After prolonged use of other substances with µ-opioid receptor activity, symptoms of withdrawal were

observed after abrupt interruption of the treatment.

Some adverse reactions were not observed in the clinical trials with Zalviso. Their frequencies were

established based on data from intravenous administration of sufentanil: common “ muscle twitching;

uncommon “ hypersensitivity, apathy, nervousness, ataxia, dystonia, hyperreflexia, heart rate decreased

and dry skin.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme



HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517


e-mail: [email


4.9 Overdose

Signs and symptoms

Sufentanil overdose is manifested by an exaggeration of its pharmacological effects. Depending on

individual sensitivity, the clinical picture is determined by the degree of respiratory depression. This may

range from hypoventilation to respiratory arrest. Other symptoms that may occur are loss of

consciousness, coma, cardiovascular shock and muscle rigidity.


Management of overdose should be focused on treating symptoms of µ-opioid receptor agonism

including administration of oxygen. Primary attention should be given to obstruction of airways and the

necessity of assisted or controlled ventilation.

An opiate antagonist (e.g. naloxone) should be administered in the event of respiratory depression. This

does not rule out more direct countermeasures. The shorter duration of activity of the opiate antagonist

compared to sufentanil should be taken into account. In that case, the opioid antagonist can be

administered repeatedly or by infusion.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, opioids, ATC Code: N01AH03

Mechanism of action

Sufentanil is a synthetic, potent opioid with highly selective binding to µ-opioid receptors. Sufentanil acts

as a full agonist in µ-opioid receptors.

Sufentanil does not induce histamine release. All effects of sufentanil can immediately and completely be

blocked by administration of a specific antagonist such as naloxone.

Primary pharmacodynamics effects


Analgesia induced by sufentanil is thought to be mediated via activation of µ-opioid receptors primarily

within the CNS to alter processes affecting both the perception of and the response to pain. In humans the

potency is 7 to 10-fold higher than fentanyl and 500 to 1,000-fold higher than morphine (per oral). The

high lipophilicity of sufentanil allows it to be administered sublingually and achieve a rapid onset of

analgesic effect.

Secondary pharmacodynamics effects

Respiratory depression

Sufentanil may cause respiratory depression (see section 4.4) and also suppresses the cough reflex.

Other CNS effects

High doses of intravenously administered sufentanil are known to cause muscle rigidity, probably as a

result of an effect on the substantia nigra and the striate nucleus. Hypnotic activity can be demonstrated

by EEG alterations.

Gastrointestinal effects

Analgesic plasma concentrations of sufentanil may provoke nausea and vomiting by irritation of the

chemoreceptor trigger zone.

Gastrointestinal effects of sufentanil comprise decreased propulsive motility, reduced secretion and

increased muscle tone (up to spasms) of the sphincters of the gastrointestinal tract (see section 4.4).

Cardiovascular effects

Low doses of intravenous sufentanil associated with likely vagal (cholinergic) activity cause mild

bradycardia and mildly reduced systemic vascular resistance without significantly lowering blood

pressure (see section 4.4).

Cardiovascular stability is also the result of minimal effects on cardiac preload, cardiac flow rate and

myocardial oxygen consumption. Direct effects of sufentanil on myocardial function were not observed.

Clinical efficacy and safety


Efficacy of Zalviso for patient-controlled analgesia was demonstrated in 3 Phase III clinical trials in acute

post-surgical nociceptive and visceral pain (post-surgical pain following major abdominal or orthopaedic

surgery): 2 trials were double-blind placebo-controlled (Zalviso N = 430 patients; placebo N = 161

patients) and 1 was an open-label active-controlled (Zalviso N = 177 patients; morphine N = 180 patients)


Patients were treated using the Zalviso dosing regimen of 15 micrograms sufentanil sublingually as

needed with a minimum 20 minute lock-out interval over a period of 72 hours.

Superiority over placebo was demonstrated in the Phase III placebo-controlled trials for the primary

endpoint time-weighted sum of pain intensity difference from baseline over 48 hours (SPID48; P ≤0.001),

and the secondary endpoints, time-weighted SPID (P ≤0.004), total pain relief (TOTPAR; P ≤0.004), and

patients global assessment (P ≤0.007) over 24, 48 and 72 hours. After 48 hours more than half of the

subjects in the Zalviso group had a relevant pain reduction (30 % responder rate) in these trials (visceral

pain 60 %, nociceptive pain 54.9 %).

A significantly higher proportion of patients (78.5 %) rated the method of pain control as “good“ or

“excellent“ with Zalviso than with intravenous morphine patient-controlled analgesia method (65.5 %)

(primary endpoint at 48 hours; P = 0.007). Patients reported in all the 3 Phase III trials a clinically

meaningful pain relief within the first hour of treatment with Zalviso (pain intensity difference to baseline

and total pain response >1 NRS). Zalviso was also considered to be easier to use by health-care

professionals (P = 0.017).

As demonstrated in the active-controlled trial, the average time between Zalviso doses was approximately

double as long as compared to intravenous morphine patient-controlled analgesia (approximately 80

minutes compared to approximately 45 minutes) over the first 48 hours.

Patients who were treated with Zalviso between 48 and 72 hours in the three controlled trials used a wide

range of the available 216 doses, with a mean of 49 doses/patient (range of 8-153 doses) with the majority

of patients (69.7 %) using between 24 to 72 doses.

Respiratory depression

Analgesic doses of Zalviso resulted in respiratory depressive effects in some patients in the clinical trials.

In the Phase III active-controlled trial, the magnitude of decrease in oxygen saturation was comparable

between Zalviso and i.v. patient-controlled morphine groups. However, there was a statistically

significant lower percentage of patients who experienced oxygen desaturation episodes following the

administration of Zalviso sublingual tablets (19.8 %) with the administration device than in the IV PCA

morphine group (30.0 %). Clinical trials have shown that sufentanil administered intravenously causes

less respiratory depression when compared with equianalgesic doses of fentanyl.

5.2 Pharmacokinetic properties


The pharmacokinetics of sufentanil after sublingual administration can be described as a three-

compartment model with first-order absorption. This route of administration results in higher absolute

bioavailability by avoiding intestinal and first-pass liver 3A4 enzyme metabolism.

Mean absolute bioavailability after a single sublingual administration of Zalviso relative to a one-minute

intravenous sufentanil infusion of 15 micrograms was 59 %. This compares to a substantially lower

bioavailability of 9 % after oral intake (swallowed). In clinical trials during repeated administrations the

bioavailability decreased to 37.6 %.

Buccal administration study showed an increased bioavailability of 78 % when the tablets were placed in

front of the front lower teeth.

Maximum concentrations of sufentanil are achieved approximately 50 minutes after a single dose; this is

shortened to approximately 20 minutes following repeat dosing. When Zalviso was administered every 20

minutes, steady state plasma concentrations were achieved after 13 doses.


The central volume of distribution after intravenous application of sufentanil is approximately 14 litres

and the volume of distribution at steady state is approximately 350 litres.


Biotransformation takes place primarily in the liver and the small intestine. Sufentanil is mainly

metabolised in humans by the cytochrome P450-3A4 enzyme system (see section 4.5). Sufentanil is

rapidly metabolised to a number of inactive metabolites, with oxidative N- and O-dealkylation being the

major routes of elimination.


The total plasma clearance after single intravenous administration is about 917 l/min.

Approximately 80 % of the intravenously administered dose of sufentanil is excreted within 24 hours.

Only 2 % of the dose is excreted in unchanged form. Clearance is not affected by race, sex, renal

parameters, hepatic parameters, or concomitant CYP3A4 substrates.

Clinically relevant plasma levels are largely determined by the time for the sufentanil plasma

concentration to drop from C

to 50 % of C

after discontinuation of dosing (context sensitive half-

time or CST½) rather than by the terminal half-life. After a single dose, the median CST½ was 2.2 hours,

increasing to a median value of 2.5 h after multiple dosing: the sublingual delivery route thus

substantially extends the duration of action associated with intravenous sufentanil administration (CST½

of 0.14 hours). Similar CST½ values were observed following both single and repeated administration

demonstrating that there is a predictable and consistent duration of action after multiple dosing of the

sublingual tablet.

After single administration of a 15 micrograms sufentanil sublingual tablet, mean terminal phase half-

lives in the range of 6 to 10 hours have been observed. After multiple administrations, a longer mean

terminal half-life of up to 18 hours was determined, owing to the higher plasma concentrations of

sufentanil achieved after repeated dosing and due to the possibility to quantify these concentrations over a

longer time period.

Special populations

Renal impairment

A population pharmacokinetic analysis of plasma sufentanil concentrations following usage of Zalviso in

patients and healthy volunteers (N = 700), which included 75 patients with moderate and 7 patients with

severe renal impairment, did not identify renal function as a significant covariate for clearance. However,

due to the limited number of patients with severe renal impairment studied, Zalviso should be used with

caution in such patients (see section 4.4).

Hepatic impairment

Based on the population pharmacokinetic analysis for Zalviso in patients and healthy volunteers (N =

700), which included 13 patients with moderate and 6 patients with severe hepatic impairment, hepatic

function was not identified as a significant covariate for clearance. Due to the limited number of patients

with moderate to severe hepatic impairment, a potential effect of hepatic dysfunction as covariate on

clearance may not have been detected. Therefore, Zalviso should be used with caution in such patients

(see section 4.4).

Paediatric population

No pharmacokinetic data exist for the Zalviso in paediatric patients.

There is limited pharmacokinetic data available in children after intravenous sufentanil administration.


No special population studies were performed using Zalviso in the elderly. Pharmacokinetic data from

intravenous sufentanil administration did not reveal age related differences. In the placebo-controlled

Phase 3 trials, approximately 20 % of enrolled patients were elderly (≥ 75 years of age) and

approximately 30 % of enrolled patients were 65 to 75 years of age. The population pharmacokinetic

analysis showed an effect of age with a 27 % decrease in clearance in the elderly people (above 65 years

of age). Since this decrease related to age is smaller than the observed inter-subject variability of 30-40 %

in exposure parameters for sufentanil, this effect is not considered to be of clinical relevance, particularly

given that Zalviso is only used on an 'as-needed' basis.

Population pharmacokinetics

When patients titrated themselves to analgesic effect with Zalviso, plasma sufentanil concentrations

averaged 60-100 pg/ml over two days of use, with no effect based on age or body mass index (BMI), or

mild to moderate renal or liver impairment.

Patients with BMI > 30 kg/m

Population pharmacokinetic analysis with a BMI as covariate showed that patients with a BMI > 30


dosed more frequently.

5.3 Preclinical safety data

Repeat-dose toxicity

Sufentanil has been shown to induce opioid-like effects in a variety of laboratory animals (dogs, rats,

guinea pigs, hamsters) at doses above those inducing analgesia and in two repeat-dose studies with

sufentanil sublingual tablets administered buccally in Golden Syrian hamster.

Reproductive toxicity

Sufentanil was not teratogenic in rats and rabbits. Sufentanil caused embryolethality in rats and rabbits

who were treated for 10-30 days during pregnancy with 2.5 times the maximum human dose by

intravenous administration. The embryolethal effect was considered secondary to the toxicity for the

mother animal.

No negative effects were observed in another study in rats that were treated with 20times the maximum

human dose in the period of organogenesis. The preclinical effects were only observed following

administrations of levels significantly above the maximum human dose, which are therefore of little

relevance for clinical use.


The Ames test revealed no mutagenic activity of sufentanil. In the micronucleus test in female rats, single

intravenous doses of sufentanil as high as 80 µg/kg (approximately 2.5 times the upper human

intravenous dose) produced no structural chromosome mutations.


Carcinogenicity studies have not been conducted on sufentanil.

Local tolerance

Two local tolerance studies were conducted in the hamster cheek pouch with the sufentanil sublingual

tablets. It was concluded from these studies that Zalviso sublingual tablets have no or minimal potential

for local irritation.

6. Pharmaceutical particulars

6.1 List of excipients

Mannitol (E421)

Calcium hydrogen phosphate, anhydrous


Croscarmellose sodium

Stearic acid

Magnesium stearate

Sunset yellow FCF Aluminium Lake (E110)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Zalviso is provided in a polycarbonate cartridge, each of which contains 40 sublingual tablets and is

packed in a polyester film/LDPE/aluminium foil/LDPE sachet with an oxygen absorber. Zalviso is

available in pack sizes of 1 and 10, 20 cartridges and multipacks containing 40 (2 packs of 20), 60 (3

packs of 20) and 100 (5 packs of 20) cartridges, equivalent to 40, 400, 800, 1,600, 2,400 and 4,000

sublingual tablets, respectively.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The cartridge should be used only with the Zalviso administration device, consisting of a controller and a

dispenser to ensure the proper use of this system.

After removing from the sachet, the cartridge should be placed into the Zalviso administration device


The device should be used as recommended in the information provided by the device manufacturer.

The instructions for setting up the Zalviso administration device by a healthcare professional must be

followed carefully.

The Zalviso administration device should not be used if any component is visibly damaged.

The fully charged Zalviso administration device will operate without recharging for up to 72 hours.

After treatment discontinuation the health-care professional has to remove the cartridge from the device

and any unused and/or not completely empty cartridges have to be disposed by the health-care

professional in accordance with local laws and requirements for controlled substances. Any other waste

material must be discarded in accordance to the institutional policies and local requirements.

7. Marketing authorisation holder

Grünenthal GmbH

Zieglerstr. 6

52078 Aachen


Tel.: +49-241-569-0

8. Marketing authorisation number(s)







9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 18.09.2015

10. Date of revision of the text


Detailed information on this medicinal product is available on the website of the European Medicines


Company Contact Details

Grunenthal Ltd


Units 1 and 2 Stokenchurch Business Park, Ibstone Road, Stokenchurch, Buckinghamshire, HP14 3FE,

Medical Information Direct Line

+44 (0)870 351 8960

Medical Information Fax

+44 (0)1494 486298

Medical Information e-mail



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