4.1. Therapeutic indications

Dzuveo is indicated for the management of acute moderate to severe pain in adult patients.

4.2. Posology and method of administration

Dzuveo is to be administered by a healthcare professional in a medically monitored setting only. A medically monitored setting must have equipment and personnel trained to detect and manage hypoventilation, and availability of supplemental oxygen and opioid antagonists, such as naloxone. Dzuveo should only be prescribed and administered by healthcare professionals who are experienced in the management of opioid therapy; particularly opioid adverse reactions, such as respiratory depression (see section 4.4).

Posology

Dzuveo is provided in a disposable single-dose applicator, to be administered by a healthcare provider as needed by the individual patient, but no more than once every hour, resulting in a maximum dose of 720 micrograms /day. Patients with a higher pain intensity at one hour after sufentanil treatment was initiated required more frequent redosing compared to patients with lower pain intensity scores at one hour.

Dzuveo should not be used beyond 48 hours.

Elderly

No specific dose adjustment is required in elderly patients. However, elderly patients should be observed closely for adverse reactions of sufentanil (see section 5.2).

Hepatic or renal impairment

Sufentanil 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 sufentanil in children and adolescents below 18 years have not been established. No data are available.

Method of administration

For sublingual use only.

Dzuveo is to be administered by a healthcare professional from a disposable single- dose applicator (see section 6.6). The applicator is used as a placement aid for the healthcare professional to deliver the tablet under the tongue, on an as needed basis, per patient request, with a minimum of 1 hour between doses.

The dispensed sublingual tablet should dissolve under the tongue and should not be chewed or swallowed. If swallowed, the oral bioavailability of Dzuveo is only 9% which would result in a sub- therapeutic dose. Patients should not eat or drink and should minimise talking for 10 minutes after each dose of sufentanil 30 mcg sublingual tablet. In the case of an excessive dry mouth, patients may be given ice cubes. Some insoluble excipients of the tablet may remain in the mouth after dissolution is complete; this is normal and does not indicate lack of absorption of sufentanil from the tablet.

See section 6.6 for instructions regarding handling of the Dzuveo sublingual tablet and applicator.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Significant respiratory depression or pulmonary compromise.

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).

Risk from concomitant use of sedative medicines such as benzodiazepines or related medicinal products

Concomitant use of sufentanil and sedative medicines such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible, or when sufentanil is used in an emergency setting.

Intracranial pressure

Sufentanil should be used with caution in patients who may be particularly susceptible to the cerebral effects of CO2 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 sufentanil 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).

Tolerance and Opioid Use Disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids.

Abuse or intentional misuse of Dzuveo may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Gastrointestinal effects

Sufentanil as a μ-opioid receptor agonist may slow the gastrointestinal motility. Therefore, sufentanil 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, sufentanil should be used with caution in patients with biliary tract disease, including acute pancreatitis.

Opioid induced hyperalgesia

As with other opioids, in case of insufficient pain control in response to an increased dose of sufentanil, the possibility of opioid-induced hyperalgesia should be considered. A dose reduction or discontinuation of sufentanil treatment or treatment review may be indicated.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose- dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Excipients This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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 (Cmax) 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. itraconazole, ritonavir) cannot be excluded. Any change in efficacy/tolerability associated with the increased exposure would be compensated in practice by an increase in the amount of time between doses (see section 4.2).

Interaction with calcium channel and/or beta blockers

The incidence and degree of bradycardia and hypotension with sufentanil may be greater in patients on chronic calcium channel and/or beta blocker therapy.

Caution should be exercised in patients on these concomitant medicinal products and they should be closely monitored.

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 depression.

The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression and death.

When considering the use of sufentanil in a patient taking a CNS depressant, the duration of use of the CNS depressant and the patient's response should be assessed, including the degree of tolerance that has developed to CNS depression. If the decision to begin sufentanil is made, the patient should be closely monitored and a lower dose of the concomitant CNS depressant should be considered.

Co-administration of sufentanil with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), or Monoamine Oxidase Inhibitors (MAOIs), may increase the risk of serotonin syndrome, a potentially life threatening condition. Monoamine Oxidase Inhibitors must not be taken in the 2 weeks before or at the same time as Dzuveo is given.

Others

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

Pregnancy

There are no or limited amount of data from the use of sufentanil in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Sufentanil should not be used in pregnancy, because it crosses the placenta and the foetal respiratory center is sensitive to opiates. If sufentanil is administered to the mother during this time, an antidote for the child should be readily available. Following long- term treatment sufentanil may cause withdrawl symptoms in the newborn. Sufentanil is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Sufentanil is excreted in human milk to such an extent that effects on the breastfed newborns/infants are likely. A decision must be made whether to discontinue breast- feeding or to discontinue/abstain from sufentanil therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no clinical data on the effects of sufentanil on fertility. Studies in rats have revealed reduced fertility and enhanced embryo mortality (see section 5.3).

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 sufentanil. Patients should only drive and use machines if sufficient time has elapsed after the last administration of sufentanil.

Driving in the UK:

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

- The medicine has been prescribed to treat a medical or dental problem and

- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

- It was not affecting your ability to drive safely

4.8. Undesirable effects

Summary of the safety profile

The most serious adverse reaction of sufentanil is respiratory depression, which occurred at a rate of 0.6% in sufentanil clinical trials.

The most commonly reported adverse reactions seen in clinical trials and from post marketing experience with sufentanil containing products were nausea, vomiting and pyrexia (≥1/10 patients) (see section 4.4).

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 as:

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

not known

cannot be estimated from the available data.

MedDRA system organ class

Very common

Common

Uncommon

Not known

Infections and infestations

Bronchitis

Conjunctivitis infective

Pharyngitis

Neoplasm benign, malignant and unspecified (including cysts and polyps)

Lipoma

Blood and lymphatic system disorders

Anaemia

Leukocytosis

Thrombocytopenia

Immune system disorders

Hypersensitivity

Anaphylactic shock

Metabolism and nutrition disorders

Hypocalcaemia Hypoalbuminaemia Hypokalaemia Hyponatraemia

Hypomagnesaemia

Hypoproteinaemia

Hyperkalaemia

Diabetes mellitus

Hyperglycaemia

Hyperlipidaemia

Hypophosphataemia

Hypovolaemia

Psychiatric disorders

Insomnia

Anxiety

Confusional state

Agitation

Apathy

Conversion disorder

Disorientation

Euphoric mood

Hallucination

Mental status changes

Nervousness

Nervous system disorders

Headache

Dizziness

Somnolence

Sedation

Tremor

Ataxia

Dystonia

Hyperreflexia

Tremor

Burning sensation

Presyncope

Paraesthesia

Hypoaesthesia

Lethargy

Memory impairment

Migraine

Tension headache

Convulsions

Coma

Eye disorders

Eye pain

Visual disturbance

Miosis

Cardiac disorders

Tachycardia

Sinus tachycardia

Bradycardia

Angina pectoris

Atrial fibrillation

Ventricular extrasystoles

Vascular disorders

Hypotension

Hypertension

Orthostatic hypertension

Flushing

Diastolic hypotension

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Hypoxia

Pharyngolaryngeal pain

Respiratory

Depression

Bradypnoea

Epistaxis

Hiccups

Apnoea

Atelectasis

Hypoventilation

Pulmonary embolism

Pulmonary oedema

Respiratory distress

Respiratory failure

Wheezing

Respiratory arrest

Gastrointestinal disorders

Nausea

Vomiting

Constipation

Dyspepsia

Flatulence

Dry Mouth

Diarrhoea

Eructation

Retching

Abdominal discomfort

Abdominal distension

Abdominal Pain upper

Epigastric discomfort

Gastritis

Gastroesophageal reflux disease

Hypoaesthesia oral

Hepatobilary disorders

Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Pruritus

Hyperhidrosis

Hypoaesthesia facial

Pruritus generalized

Blister

Rash

Dry Skin

Erythema

Musculoskeletal and connective tissue disorders

Muscle spasms

Muscle twitching

Back Pain

Musculoskeletal pain

Musculoskeletal chest pain

Pain in extremity

Renal and urinary disorders

Urinary retention

Urinary hesitation

Oliguria

Renal failure

Urinary tract pain

General disorders and administration site conditions

Pyrexia

Feeling hot

Fatigue

Asthenia

Chills

Local swelling

Non-cardiac chest pain

Chest discomfort

Drug withdrawal syndrome

Investigations

Oxygen saturation decreased

Body temperature increased

Blood pressure increased

Respiratory rate decreased

Blood glucose increased

Blood bilirubin increased

Urine output decreased

Aspartate aminotransferase increased

Blood urea increased

Electrocardiogram T wave abnormal

Electrocardiogram abnormal

Hepatic enzyme increased

Liver function test abnormal

Injury, poisoning and procedural complications

Anaemia postoperative

Procedural nausea

Postoperative ileus

Procedural vomiting

Gastrointestinal stoma complication

Procedural pain

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 the national reporting system:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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

Management of sufentanil 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 that of sufentanil should be taken into account. In that case, the opioid antagonist can be administered repeatedly or by infusion.