Xomolix 2.5mg/Ml Solution For Injection

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Xomolix 2.5 mg/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each millilitre of the solution contains 2.5 mg droperidol.

Excipient: sodium < 23 mg per ml.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Clear colourless solution, free from visible particles.

The pH of droperidol solution for injection is 3.0 - 3.8 and has an osmolarity of approximately 300 milliosmol /kg water.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

■ Prevention and treatment of post-operative nausea and vomiting (PONV) in adults and, as second line, in children (2 to 11 years) and adolescents (12 to 18 years).

■ Prevention of nausea and vomiting induced by morphine and derivatives during postoperative patient controlled analgesia (PCA) in adults.

Certain precautions are required when administering droperidol: see sections 4.2, 4.3, and 4.4.

4.2 Posology and method of administration

Posology

For intravenous use.

Prevention and treatment of post-operative nausea and vomiting (PONV).

Adults: 0.625 mg to 1.25 mg (0.25 to 0.5 ml).

Elderly (over 65 years): 0.625 mg (0.25 ml)

Renal/hepatic impairment: 0.625 mg (0.25 ml)

Paediatric population

Children (2 to 11 years) and adolescents (12 to 18 years): 10 to 50 microgram/kg (up to a maximum of 1.25 mg).

Children (below the age of 2years): not recommended.

Administration of droperidol is recommended 30 minutes before the anticipated end of surgery. Repeat doses may be given every 6 hours as required.

The dosage should be adapted to each individual case. The factors to be considered here include age, body weight, use of other medicinal products, type of anaesthesia and surgical procedure.

Prevention of nausea and vomiting induced by morphine and derivatives during post-operative patient controlled analgesia (PCA).

Adults: 15 to 50 micrograms droperidol per mg of morphine, up to a maximum daily dose of 5 mg droperidol.

Elderly (over 65years), renal and hepatic impairment: no data in PCA available.

Paediatric population

Children (2 to 11 years) and adolescents (12 to 18 years): not indicated in PCA.

Continuous pulse oximetry should be performed in patients with identified or suspected risk of ventricular arrhythmia and should continue for 30 minutes following single i.v. administration.

For instructions on dilution of the product before administration, see section 6.6.

4.3 Contraindications

Droperidol is contraindicated in patients with:

■ Hypersensitivity to droperidol or to any of the excipients;

■ Hypersensitivity to butyrophenones;

■ Known or suspected prolonged QT interval (QTc of > 450 msec in females and

> 440 msec in males). This includes patients with congenitally long QT interval, patients who have a family history of congenital QT prolongation and those treated with medicinal products known to prolong the QT interval (see section 4.5);

■ Hypokalaemia or hypomagnesaemia;

■ Bradycardia (< 55 heartbeats per minute);

■ Known concomitant treatment leading to bradycardia;

■ Phaeochromocytoma;

■ Comatose states;

■ Parkinson’s Disease;

■ Severe depression.

4.4 Special warnings and precautions for use

Central Nervous System

Droperidol may enhance CNS depression produced by other CNS-depressant drugs. Any patient subjected to anaesthesia and receiving potent CNS depressant medicinal products or showing symptoms of CNS depression should be monitored closely.

Concomitant use of metoclopramide and other neuroleptics may lead to an increase in extrapyramidal symptoms and should be avoided (see section 4.5).

Use with caution in patients with epilepsy (or a history of epilepsy) and conditions predisposing to epilepsy or convulsions.

Cardiovascular

Mild to moderate hypotension and occasionally (reflex) tachycardia have been observed following the administration of droperidol. This reaction usually subsides spontaneously. However, should hypotension persist, the possibility of hypovolaemia should be considered and appropriate fluid replacement administered.

Patients with, or suspected of having, the following risk factors for cardiac arrhythmia should be carefully evaluated prior to administration of droperidol:

- a history of significant cardiac disease including serious ventricular arrhythmia, second or third degree atrio-ventricular block, sinus node dysfunction, congestive heart failure, ischemic heart disease and left ventricular hypertrophy;

- family history of sudden death;

- renal failure (particularly when on chronic dialysis);

- significant chronic obstructive pulmonary disease and respiratory failure;

- risk factors for electrolyte disturbances, as seen in patients taking laxatives, glucocorticoids, potassium-wasting diuretics, in association with the administration of insulin in acute settings, or in patients with prolonged vomiting and/or diarrhoea.

Patients at risk for cardiac arrhythmia should have serum electrolytes and creatinine levels assessed and the presence of QT prolongation excluded prior to administration of droperidol.

Continuous pulse oximetry should be performed in patients with identified or suspected risk of ventricular arrhythmia and should continue for 30 minutes following single i.v. administration.

General

To prevent QT prolongation, caution is necessary when patients are taking medicinal products likely to induce electrolyte imbalance (hypokalaemia and/or hypomagnesaemia) e.g. potassium-wasting diuretics, laxatives and glucocorticoids.

Patients who have, or are suspected of having, a history of alcohol abuse or recent high intakes, should be thoroughly assessed before droperidol is administered.

In case of unexplained hyperthermia, it is essential to discontinue treatment, since this sign may be one of the elements of malignant syndrome reported with neuroleptics.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Xomolix and preventive measures undertaken.

The dose should be reduced in the elderly and those with impaired renal and hepatic function (see section 4.2).

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml, i.e. essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Contraindicated for concomitant use

Medicinal products known to cause torsades de pointes through QT prolongation should not be concomitantly administered with droperidol. Examples include Examples include:

- Class IA antiarrhythmics e.g. quinidine, disopyramide, procainamide

- Class III antiarrhythmics e.g. amiodarone, sotalol

- macrolide antibiotics e.g. erythromycin, clarithromycin

- fluoroquinolone antibiotics e.g. sparfloxacin

- antihistamines e.g. astemizole, terfenadine

- certain antipsychotic medications e.g. chlorpromazine, haloperidol, pimozide, thioridazine

- anti-malaria agents e.g. chloroquine, halofantrine

- cisapride, domperidone, methadone, pentamidine.

Concomitant use of medicinal products that induce extrapyramidal symptoms, e.g. metoclopramide and other neuroleptics, may lead to an increased incidence of these symptoms and should therefore be avoided.

Consumption of alcoholic beverages and medicines should be avoided.

Caution is advised for concomitant use

To reduce the risk of QT prolongation, caution is necessary when patients are taking medicinal products likely to induce electrolyte imbalance (hypokalaemia and/or hypomagnesaemia) e.g. potassium-wasting diuretics, laxatives and glucocorticoids.

Droperidol may potentiate the action of sedatives (barbiturates, benzodiazepines, morphine derivatives). The same applies to antihypertensive agents, so that orthostatic hypotension may ensue.

Like other sedatives, droperidol may potentiate respiratory depression caused by opioids.

Since droperidol blocks dopamine receptors, it may inhibit the action of dopamine agonists, such as bromocriptine, lisuride, and of L-dopa.

Substances inhibiting the activity of cytochrome P450 iso-enzymes (CYP) CYP1A2, CYP3A4 or both could decrease the rate at which droperidol is metabolised and prolong its pharmacological action. Hence, caution is advised if droperidol is given concomitantly with CYP1A2 inhibitors (e.g. ciprofloxacin, ticlopidine), CYP3A4 inhibitors (e.g. diltiazem, erythromycin, fluconazole, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, verapamil) or both (e.g. cimetidine, mibefradil).

4.6 Fertility, pregnancy and lactation

Fertility

There were no effects on fertility in studies conducted in male and female rats (see section 5.3). The clinical effect of droperidol on fertility has not been established.

Pregnancy

A limited amount of clinical data have shown no increase of malformative risk.

Droperidol has not been shown to be teratogenic in rats. Animal studies are insufficient with respect to the effects on pregnancy and embryonal/foetal, parturition and postnatal development.

In newborn babies from mothers under long-term treatment and high doses of neuroleptics, temporary neurological disturbances of extrapyramidal nature have been described.

In practice, as a precautionary measure, it is preferable not to administer droperidol during pregnancy. In late pregnancy, if its administration is necessary, monitoring of the newborn’s neurological functions is recommended.

Breastfeeding

Neuroleptics of the butyrophenone type are known to be excreted in breast milk; treatment with droperidol should be limited to a single administration. Repeat administration is not recommended.

4.7 Effects on ability to drive and use machines

Droperidol has major influence on the ability to drive and use machines. Patients should not drive or operate a machine for 24 hours after droperidol administration.

4.8 Undesirable effects

The most frequently reported events during clinical experience are incidents of drowsiness and sedation. In addition, less frequent reports of hypotension, cardiac arrhythmias, neuroleptic malignant syndrome (NMS) and symptoms associated with NMS, plus movement disorders, such as dyskinesias, plus incidents of anxiety or agitation have occurred.

System Organ Class	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)
Blood and lymphatic systems disorders				Blood dyscrasias
Immune system disorders			Anaphylactic reaction; Angioneuroti c oedema; Hypersensitivity
Metabolism					Inappropriate

and nutrition disorders					anti-diuretic hormone secretion
Psychiatric disorders		Anxiety; Restlessness/ Akathisia;	Confusional states; Agitation	Dysphoria	Hallucinatio ns
Nervous system disorders	Drowsiness	Dystonia; Oculogyratio n		Extra pyramidal disorder; Convulsions; Tremor	Epileptic fits; Parkinson’s disease; Psychomotor hyperactivity ; Coma
Cardiac disorders		Tachycardia; Dizziness	Cardiac arrhythmias, including ventricular arrhythmias	Cardiac arrest; Torsades de pointes; Electrogram QT prolonged
Vascular disorders	Hypotension				Syncope
Respiratory, thoracic and mediastinal disorders					Broncho- spasm; Laryngospas m
Skin and subcutaneous system disorders			Rash
General disorders and administratio n site conditions			Neuroleptic malignant syndrome (Nms)	Sudden death

Symptoms potentially associated with NMS have occasionally been reported i.e. changes in body temperature, stiffness and fever. An alteration in mental status with confusion or agitation and altered consciousness, have been seen. Autonomic instability may manifest as tachycardia, fluctuating blood pressure, excessive sweating/salivation and tremor. In extreme cases NMS may lead to coma, or renal and/or hepato-biliary problems.

Isolated cases of amenorrhoea, galactorrhoea, gynaecomastia, hyperprolactinaemia, and oligomenorrhoea have been associated with prolonged exposure in psychiatric indications.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic medicinal products -frequency unknown.

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 Yellow Card Scheme, www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

The manifestations of droperidol overdose are an extension of its pharmacologic actions.

Symptoms of accidental overdose are psychic indifference with a transition to sleep, sometimes in association with lowered blood pressure.

At higher doses or in sensitive patients, extrapyramidal disorders may occur (salivation, abnormal movements, sometimes muscle rigidity). Convulsions may occur at toxic doses.

Cases of QT-interval prolongation, ventricular arrhythmias and sudden death have been reported rarely.

Treatment

No specific antidote is known. However, when extrapyramidal reactions occur, an anticholinergic should be administered.

Patients with droperidol overdose should be closely monitored for signs of QT interval prolongation.

Factors which predispose to torsades de pointes, e.g. electrolyte disturbances (especially hypokalaemia or hypomagnesaemia) and bradycardia should be taken into consideration.

Pronounced hypotension should be treated by boosting circulation volume and taking other appropriate measures. Clear airways and adequate oxygenation should be maintained; an oropharyngeal airway or endotracheal tube might be indicated.

If required, the patient should be observed carefully for 24 hours or longer; body warmth and adequate fluid intake should be maintained.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: application pending. ATC code: application pending.

Droperidol is a butyrophenone neuroleptic. Its pharmacologic profile is characterised mainly by dopamine-blocking and weak a₁-adrenolytic effects. Droperidol is devoid of anticholinergic and antihistaminic activity.

Droperidol’s inhibitory action on dopaminergic receptors in the chemotrigger zone in the area postrema, gives it a potent antiemetic effect, especially useful for the prevention and treatment of postoperative nausea and vomiting and/or induced by opioid analgesics.

At a dose of 0.15 mg/kg, droperidol induces a fall in mean blood pressure (MBP), due to a decrease in cardiac output in a first phase, and then subsequently due to a decrease in preload. These changes occur independently of any alteration in myocardial contractility or vascular resistance. Droperidol does not affect myocardial contractility or heart rate, therefore has no negative inotropic effect. Its weak ^-adrenergic blockade can cause a modest hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may also reduce the incidence of epinephrine-induced arrhythmia, but it does not prevent other forms of cardiac arrhythmia.

Droperidol has a specific antiarrhythmic effect at a dose of 0.2 mg/kg by an effect on myocardial contractility (prolongation of the refractory period) and a decrease in blood pressure.

Two studies (one placebo-controlled and one comparative active treatment-controlled) performed in the general anaesthesia setting and designed to better identify the QTc changes associated with postoperative nausea and vomiting treatment by small dose of droperidol (0.625 and 1.25 mg intravenous, and 0.75 mg intravenous, respectively) identified a QT interval prolongation at 3-6 min after administration of 0.625 and 1.25 mg droperidol (respectively 15 ± 40 and 22 ± 41 ms), but these changes did not differ significantly from that seen with saline (12 ± 35 ms). There were no statistically significant differences amongst the droperidol and saline groups in the number of patients with greater than 10% prolongation in QTc versus baseline. There was no evidence of droperidol-induced QTc prolongation after surgery.

No ectopic heartbeats were reported from the electrocardiographic records or 12-lead recordings during the perioperative period. The comparative active-treatment study with 0.75 mg intravenous droperidol identified a significant QTc interval prolongation (maximal of 17 ± 9 ms at the second minute after droperidol injection when compared with pre-treatment QTc measurement), with the QTc interval significantly lower after the 90^th minute.

5.2 Pharmacokinetic properties

The action of a single intravenous dose commences 2-3 minutes following administration.

The tranquillising and sedative effects tend to persist for 2 to 4 hours, although alertness may be affected for up to 12 hours.

Distribution

Following intravenous administration, plasma concentrations fall rapidly during the first 15 minutes. Plasma protein binding amounts to 85 - 90 %. The distribution volume is approximately 1.5 l/kg.

Metabolism

Droperidol is extensively metabolised in the liver, and undergoes oxidation, dealkylation, demethylation and hydroxylation by cytochrome P450 isoenzymes 1A2 and 3A4, and to a lesser extent by 2C19. The metabolites are devoid of neuroleptic activity.

Elimination

Elimination occurs mainly through metabolism; 75% is excreted via the kidneys. Only 1% of the active substance is excreted unchanged with urine, and 11% with faeces. Plasma clearance is 0.8 (0.4 - 1.8) l/min. The elimination half-life (t/^) is 134 ± 13 min.

Paediatric Population

In a study of 12 children (age 3.5 to 12 years), the values for distribution volume and clearance reported were lower than those found in the adult population

(0.58 ± 0.29 l/kg and 4.66 ± 2.28 ml/kg*min respectively) and decrease in parallel.

The elimination half-life (101.5 ± 26.4 min) was similar to that found in adults.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxic or carcinogenic potential, and reproductive toxicity.

Electrophysiological in vitro and in vivo studies indicate an overall risk of droperidol to prolong the QT interval in humans.

In humans, the free peak plasma concentration is approximately 4-fold higher to 25fold lower than the droperidol concentrations affecting the endpoints examined in the different in vitro and in vivo test systems used to assess the impact of this drug on cardiac repolarisation. Plasma levels fall by about one order of magnitude over the first twenty minutes after administration.

Environmental Risk Assessment (ERA)

This product is unlikely to represent a risk to the environment following its prescribed use in patients.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol Tartaric acid

Sodium hydroxide (for pH adjustment) Water for injections.

6.2 Incompatibilities

Incompatible with barbiturates. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened: 3 years.

After first opening: For immediate use.

Following dilution: Compatibility of droperidol with morphine sulphate in 0.9% sodium chloride (14 days at room temperature) has been demonstrated in plastic syringes. From a microbiological point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in the original package.

For storage conditions after dilution, and first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I amber glass ampoules containing 1 ml solution for injection, in packs of 10 ampoules.

6.6 Special precautions for disposal and other handling

For single use only. Any unused solution should be discarded.

The solution should be inspected visually prior to use. Only clear and colourless solutions free from visible particles should be used.

For use in PCA: Draw droperidol and morphine into a syringe and make up the volume with 0.9% sodium chloride for injection.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

ProStrakan Ltd Galabank Business Park Galashiels TD11QH United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 16508/0036

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/09/2012

10 DATE OF REVISION OF THE TEXT

08/03/2015