Tomexa 2 mL/4 mL/10 mL Solution

TOMEXA is an alpha 2 adrenoreceptor agonist sedative with analgesic properties indicated for:

• Intensive Care Unit Sedation
  Sedation of intubated and mechanically ventilated adult post-surgical patients during treatment in an intensive care setting.
• Monitored Anaesthesia Care (MAC)/ Conscious sedation in a theatre or intensive care setting for
  Minor surgical procedures under local anaesthesia
  Fibreoptic intubation.

Efficacy and safety have not been studied in children under 18 years of age.

NOTE: TOMEXA should be administered only by health care professionals skilled in the management of patients in the intensive care setting. Continuous monitoring of vital signs, in particular blood pressure, heart rate and oxygen saturation is mandatory during infusion of TOMEXA.

In order to minimise undesirable pharmacologic side effects, bolus injections of TOMEXA should not be used. Clinically significant events of bradycardia and sinus arrest have been associated with dexmedetomidine hydrochloride as in TOMEXA administration in young healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of dexmedetomidine hydrochloride as in TOMEXA.

Fluid supplementation should be administered prior to and during administration of TOMEXA to ensure normovolaemia. TOMEXA has been administered to patients requiring mechanical ventilation as well as to patients breathing spontaneously after extubation. There is no respiratory depression associated with the administration of TOMEXA. TOMEXA has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post extubation. It is not necessary to discontinue TOMEXA prior to extubation.

Posology

Adults

ICU Sedation
TOMEXA dosage should be individualised and titrated to the desired clinical effect. Initiation: For adult patients, it is recommended to initiate TOMEXA with a loading dose of 1,0 microgram/kg over 10 minutes. Maintenance of ICU sedation: Adult patients will generally require a maintenance infusion in the range of 0,2 to 0,7 microgram/kg/hr. The rate of the maintenance infusion can be adjusted in order to achieve the desired clinical effect. Dosages as low as 0,05 microgram/kg/hr have been used.

A dose reduction for both the loading and the maintenance infusions should be considered in patients with impaired hepatic or renal function and in patients over 65 years of age (see section 4.3, 4.4 and 5.2).

Conscious Sedation
Monitored Anaesthesia Care (MAC) with an adequate nerve block and awake fibreoptic intubation (AFI). TOMEXA dosing should be individualised and titrated to the desired clinical effect. Initiation: For adult patients, TOMEXA is generally initiated with a loading infusion of 1 (one) microgram/kg over 10 minutes. For patients over 65 years of age or those undergoing less invasive procedures such as ophthalmic surgery, a loading infusion of 0,5 microgram/kg over 10 minutes may be suitable. Maintenance of conscious sedation: MAC: Following the load, maintenance dosing of TOMEXA should generally be initiated at 0,6 microgram/kg/hr and titrated to achieve desired clinical effect with doses ranging from 0,2 to 1 microgram/kg/hr for all procedures. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation. AFI: Following the load in awake fibreoptic intubation, a fixed maintenance dose of 0,7 microgram/kg/hr should be used.

Dosage adjustment
Due to possible pharmacodynamic interactions a reduction in dosage of TOMEXA or other concomitant anaesthetics, sedatives, hypnotics, or opioids may be required when co-administered (see section 4.5).

Special populations

Impaired hepatic function
Dosage reductions may need to be considered for patients with hepatic impairment, as TOMEXA is metabolised primarily in the liver.

Impaired renal function
Since the majority of metabolites are excreted in the urine, dosage reductions may need to be considered for patients with renal impairment.

Elderly
Since the elderly are more sensitive to the effects of TOMEXA dosage reductions may need to be considered.

Paediatric population
Safety and efficacy of TOMEXA has not been studied in children and adolescents and is therefore not recommended for patients under 18 years of age.

Method of administration
TOMEXA should be administered by continuous intravenous infusion. For instructions on preparation and dilution of the product before administration, see section 6.6.

• Hypersensitivity to dexmedetomidine or to any of the other excipients (see section 6.1).
• Patients with sepsis.
• Unstable trauma patients.
• Hypovolaemic patients.
• Heart block.
• Uncontrolled cardiac failure.
• Imminent hepatic failure.
• Acute cerebrovascular conditions.

TOMEXA should be administered only by health care professionals skilled in the management of patients in the intensive care setting and who have received complete training in the use of TOMEXA in the ICU setting. Safety and efficacy of TOMEXA in non-surgical intensive care patients have not been established.

Clinical events of bradycardia and sinus arrest have been associated with TOMEXA administration in some young, healthy volunteers with high vagal tone, or with different routes of administration including rapid intravenous or bolus administration of TOMEXA. Bolus injections of TOMEXA should not be used, in order to minimise undesirable pharmacological side effects.

Elderly
The elderly are more prone to cardiovascular adverse events e.g., hypotension and bradycardia and the dose must be carefully titrated to obtain the desired effect. Close CVS monitoring is required. Elderly patients (over 65 years) often require lower doses of TOMEXA.

Special precautions

NOTE: TOMEXA should be administered only by health care providers skilled in the management of patients in the intensive care setting. Continuous electrocardiogram (ECG), blood pressure and oxygen saturation monitoring are mandatory during infusion of TOMEXA.

Caution should be exercised in patients with pre-existing severe bradycardia disorders (e.g. advanced heart block), or patients with pre-existing severe ventricular dysfunction (e.g., ejection fraction < 30 %) including congestive heart failure and cardiac failure in whom sympathetic tone is critical for maintaining haemodynamic balance (see section 4.3).

Hypotension, bradycardia, and sinus arrest
See boxed warning above. Decreased blood pressure and/or heart rate may occur with the administration of TOMEXA. Based on clinical experience with TOMEXA, if medical intervention is required, treatment may include decreasing or stopping the infusion of TOMEXA, increasing the rate of intravenous fluid administration, elevation of the lower extremities and use of pressor medicines. Because TOMEXA has the potential to augment bradycardia induced by vagal stimuli, health care professionals should be prepared to intervene. The intravenous administration of anticholinergic medicines should be considered to modify vagal tone. Atropine and glycopyrrolate were effective in the treatment of most episodes of TOMEXA-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

TOMEXA decreases sympathetic nervous activity and therefore, these effects may be expected to be most pronounced in patients with desensitised autonomic nervous system control (e.g. elderly, diabetes, chronic hypertension, severe cardiac disease).

Prevention of hypotension and bradycardia should take into consideration the haemodynamic stability of the patient and normovolaemia must be ensured prior to the administration of TOMEXA. Patients who are hypovolaemic may become hypotensive under TOMEXA therapy. Therefore, fluid supplementation should be administered prior to and during the administration of TOMEXA.

Additionally, in situations where other vasodilators or negative chronotropic medicines are administered, co-administration of TOMEXA could have an additive pharmacodynamics effect and should be administered with caution and careful titration (see section 4.5).

Clinical events of bradycardia or hypotension may be potentiated when TOMEXA is used concurrently with propofol or midazolam. Therefore, consider a dose reduction of propofol or midazolam (see section 4.5).

Caution is advised when administering TOMEXA together with spinal or epidural anaesthesia due to possible increased risk of hypotension or bradycardia.

Transient hypertension
Transient hypertension has been observed primarily during the loading infusion, associated with initial peripheral vasoconstrictive effects of TOMEXA and relatively higher plasma concentrations achieved during the loading infusion. If intervention is necessary, reduction of the loading infusion rate may be considered. Following the loading infusion, the central effects of TOMEXA dominate and the blood pressure usually decreases.

Hyperthermia and lacrimation
TOMEXA may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medicines. Discontinue TOMEXA if medicine-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes. TOMEXA treatment is not recommended for use in malignant hyperthermia-sensitive patients. TOMEXA may cause reduced lacrimation. Lubrication of the patientu2019s eyes may be considered when administering TOMEXA to avoid corneal dryness.

Monitoring
The time to recovery after the use of TOMEXA was reported to be approximately one hour. When used in an outpatient setting close monitoring should continue for at least one hour (or longer based on the patient condition), with medical supervision continued for at least one further hour to ensure the safety of the patient. When TOMEXA is used in an outpatient setting patients should normally be discharged into the care of a suitable third party. Patients should be advised to refrain from driving or other hazardous tasks and where possible to avoid the use of other medicines that may sedate (e.g. benzodiazepines, opioids, alcohol) for a suitable period of time based on observed effects of dexmedetomidine, the procedure, concomitant medications, the age and the condition of the patient.

General precautions
TOMEXA should not be given as a bolus dose and in the ICU a loading dose is not recommended. Users should therefore be ready to use an alternative sedative for acute control of agitation or during procedures, especially during the first few hours of treatment. During procedural sedation, a small bolus of another sedative may be used if a rapid increase in sedation level is required. Some patients receiving TOMEXA have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms. TOMEXA normally does not cause deep sedation, and patients may be easily roused. TOMEXA is therefore not suitable in patients who will not tolerate this profile of effects, for example those requiring continuous deep sedation. TOMEXA should not be used as a general anaesthetic induction medicine for intubation or to provide sedation during muscle relaxant use. Dexmedetomidine as in TOMEXA lacks the anticonvulsant action of some other sedatives and so will not suppress underlying seizure activity. Patients with impaired peripheral autonomic activity (e.g. due to spinal cord injury) may have more pronounced haemodynamic changes after starting TOMEXA and so should be treated with care.

Patients with hepatic impairment
Care should be taken in severe hepatic impairment as excessive dosing may increase the risk of adverse reactions, over-sedation, or prolonged effect as a result of reduced dexmedetomidine clearance (see section 4.2).

Patients with neurological disorders
Experience of dexmedetomidine as in TOMEXA in severe neurological disorders such as head injury and after neurosurgery is limited and it should be used with caution here, especially if deep sedation is required. Dexmedetomidine as in TOMEXA may reduce cerebral blood flow and intracranial pressure and this should be considered when selecting therapy.

Withdrawal reactions
Alpha 2 agonists have rarely been associated with withdrawal reactions when stopped abruptly after prolonged use. This possibility should be considered if the patient develops agitation and hypertension shortly after stopping dexmedetomidine as in TOMEXA (see section 4.8).

Mortality in ICU patients u2264 65 years old
It is documented that in critically ill adult ICU patients there was no overall difference in 90-day mortality between the dexmedetomidine as in TOMEXA and usual care group (mortality 29,1 % in both groups), but a heterogeneity of effect from age on mortality was observed. Dexmedetomidine was associated with an increased mortality in the age-group u2264 65 years (odds ratio 1,26; 95 % credibility interval 1,02 to 1,56) compared to alternative sedatives. While the mechanism is unclear, this heterogeneity of effect on mortality from age was most prominent in cases with early use of dexmedetomidine in high dose to achieve deep sedation in patients admitted for other reasons than postoperative care and increased with increasing APACHE II scores. The effect on mortality was not detectable when dexmedetomidine was used for light sedation. These findings should be weighed against the expected clinical benefit of TOMEXA compared to alternative sedatives in younger patients.

Diabetes insipidus
Diabetes insipidus has been reported in association with dexmedetomidine treatment. If polyuria occurs, it is recommended to stop dexmedetomidine and check serum sodium level and urine osmolality.

Excipients with known effect
TOMEXA contains less than 1 mmol sodium (23 mg) per mL that is to say essentially u201csodium freeu2019u2019.

Cytochrome P-450
In vitro studies indicate that clinically relevant cytochrome P450 mediated interactions are unlikely.

Anaesthetics/ sedatives/ hypnotics/ opioids
Co-administration of TOMEXA is likely to lead to an enhancement of effects with anaesthetics, sedatives, hypnotics, and opioids. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine as in TOMEXA and isoflurane, propofol, alfentanil, and midazolam were demonstrated. However, due to pharmacodynamics effects, when co-administered with TOMEXA a reduction in dosage of these medicines may be required.

Neuromuscular blockers
No clinically meaningful increases in the magnitude of neuromuscular blockade and no pharmacokinetic interactions were observed with TOMEXA and rocuronium administration.

CYP enzymes
Inhibition of CYP enzymes including CYP2B6 by dexmedetomidine as in TOMEXA has been studied in human liver microsome incubations. In vitro study suggests that interaction potential in vivo exists between dexmedetomidine and substrates with dominant CYP2B6 metabolism. Induction in vitro of dexmedetomidine as in TOMEXA was observed on CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A4, and induction in vivo cannot be excluded. The clinical significance is unknown.

Medicines enhancing hypotensive and bradycardic effects
The possibility of enhanced hypotensive and bradycardic effects should be considered in patients receiving other medicines causing these effects, for example beta blockers, although additional effects in an interaction study with esmolol were modest.

Pregnancy
The use of TOMEXA is not recommended in pregnancy. Available data indicates that dexmedetomidine as in TOMEXA crosses the placenta. Animal studies have shown toxicity.

Labour and delivery
The safety of TOMEXA in labour and delivery has not been studied and it is therefore not recommended for obstetrics, including caesarean section deliveries.

Breastfeeding
There is no information regarding the effects of TOMEXA on the breastfed infant or the effects on milk production. Dexmedetomidine as in TOMEXA is excreted in human milk, however levels will be below the limit of detection by 24 hours following treatment discontinuation. A risk to the infant cannot be excluded. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the motheru2019s clinical need for TOMEXA and any potential adverse effects on the breastfed infant from TOMEXA or from the underlying condition.

Fertility
In the rat fertility study, dexmedetomidine as in TOMEXA had no effect on male or female fertility. No human data on fertility are available.

The patient should not drive or operate machinery or make legal decisions until 24 hours after recovery from a surgical procedure in which TOMEXA was used.

a. Summary of the safety profile
Sedation of adult ICU (Intensive Care Unit) patients. The most frequently reported adverse reactions with dexmedetomidine as in TOMEXA in ICU setting are hypotension, hypertension, and bradycardia.

Procedural/awake sedation
The most frequently reported adverse reactions with dexmedetomidine as in TOMEXA in procedural sedation are listed below.

b. Tabulated summary of adverse reactions
The table below shows all adverse drug reactions (ADRs) observed during clinical trials and post-marketing spontaneous reports with dexmedetomidine.

System organ class Frequency Adverse reactions

Blood and lymphatic system disorders Less frequent Anaemia

Frequency unknown Coagulation disorders, disseminated intravascular coagulation, haematoma, abnormal platelets, decreased prothrombin, thrombocytopenia, leukocytosis

Endocrine disorders Frequency unknown Diabetes insipidus

Metabolism and nutrition disorders Frequent Hypovolaemia, hyperglycaemia

Less frequent Hypocalcaemia, acidosis

Frequency unknown Lactic acidosis, respiratory acidosis, diabetes mellitus, hypoglycaemia, hypokalaemia, hyperkalaemia, hypoproteinaemia, increased alkaline, phosphatase, increased non-protein nitrogen (NPN)

Psychiatric disorders Frequent Agitation

Less frequent Hallucination

Frequency unknown Anxiety, confusion, delirium, depression, illusion, nervousness

Nervous system disorders Frequency unknown Convulsion, dizziness, headache, neuralgia, neuritis, neuropathy, paraesthesia, paralysis, paresis, speech disorder

Eye disorders Frequency unknown Diplopia, photopsia, abnormal vision

Cardiac disorders Frequent Myocardial ischaemia or infarction, bradycardia, atrial fibrillation, tachycardia

Less frequent Atrioventricular block, cardiac output decreased, cardiac arrest, sinus tachycardia, ventricular tachycardia

Frequency unknown Angina pectoris, abnormal ECG, heart disorder, dysrhythmia, atrial dysrhythmia, atrial fibrillation, AV block, bundle branch block, extrasystoles, heart block, supraventricular tachycardia, T- wave inversion, ventricular dysrhythmia

Vascular disorders Frequent Hypotension, hypertension

Frequency unknown Blood pressure fluctuation, circulatory failure, cyanosis, aggravated hypertension, postural hypotension, pulmonary hypertension, haemorrhage, cerebral haemorrhage, peripheral ischaemia, vascular disorder, vasodilation

Respiratory, thoracic, and mediastinal disorders Frequent Respiratory depression, atelectasis, pleural effusion, hypoxia, bradypnoea

Less frequent Dyspnoea, apnoea, pulmonary oedema, wheezing

Frequency unknown Adult respiratory distress syndrome, bronchospasm, coughing, emphysema, haemoptysis, hypercapnia, hypoventilation, pharyngitis, pleurisy, pneumonia, pneumothorax, pulmonary congestion, respiratory disorder, respiratory insufficiency, increased sputum, stridor

Gastrointestinal disorders Frequent Nausea, dry mouth, vomiting

Less frequent Abdominal distension

Frequency unknown Abdominal pain, diarrhoea, eructation, mucosal ulceration

Hepato-biliary disorders Frequency unknown Increased AG ratio, increased GGT, abnormal hepatic function, hyperbilirubinaemia, increased aspartate transaminase (AST), increased alanine transaminase (ALT), jaundice

Skin and subcutaneous tissue disorders Frequency unknown Rash erythematous, increased sweating

Musculoskeletal, connective tissue and bone disorders Frequency unknown Muscle weakness

Renal and urinary disorders Frequency unknown Haematuria, acute renal failure, abnormal renal function, urinary retention, increased blood urea

General disorders and administration site conditions Frequent Withdrawal syndrome, hyperthermia, pyrexia, chills,

Less frequent Medicine ineffective, thirst, peripheral oedema

Frequency unknown Allergic reaction, ascites, hyperpyrexia, light anaesthesia, oedema, pain, syncope, rigors

Investigations Less frequent Decreased urine output

Injury, poisoning and procedural complications Frequent Post-procedural haemorrhage

Infections and Infestations Frequency unknown Infection, fungal infection, sepsis

c. Description of selected adverse reactions
Withdrawal ICU sedation: Although not specifically studied, withdrawal symptoms similar to those reported for another alpha 2 adrenergic medicine (clonidine) may result when TOMEXA is administered in excess of 24 hours and stopped abruptly. These symptoms include nervousness, agitation and headache accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. Conscious sedation: Withdrawal symptoms were not seen after discontinuation of short-term infusions of TOMEXA (< 6 hours).

Hypotension or bradycardia
Clinically significant hypotension or bradycardia should be treated as described in section 4.4. In relatively healthy non-ICU subjects treated with dexmedetomidine, bradycardia has occasionally led to sinus arrest or pause. The symptoms responded to leg raising and anticholinergics such as atropine or glycopyrrolate. In isolated cases bradycardia has progressed to periods of asystole in patients with pre-existing bradycardia. Also, cases of cardiac arrest, often preceded by bradycardia or atrioventricular block, have been reported.

Hypertension
Hypertension has been associated with the use of a loading dose and this reaction can be reduced by avoiding such a loading dose or reducing the infusion rate or size of the loading dose.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of TOMEXA is important. It allows continued monitoring of the benefit/risk balance of TOMEXA. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on the SAHPRA website. In addition, side effects can also be reported to [email protected].

Symptoms
Several cases of dexmedetomidine overdose have been reported both in the clinical trial and the post-marketing data. The reported highest infusion rates of dexmedetomidine as in TOMEXA in these cases have reached up to 60 micrograms/kg/h for 36 minutes and 30 micrograms/kg/h for 15 minutes in a 20-month-old child and in an adult, respectively. The most common adverse reactions reported in conjunction with overdose include bradycardia, hypotension, hypertension, oversedation, respiratory depression and cardiac arrest.

Management
In cases of overdose with clinical symptoms, TOMEXA infusion should be reduced or stopped. Expected effects are primarily cardiovascular and should be treated as clinically indicated (see section 4.4). At high concentration hypertension may be more prominent than hypotension. In clinical studies, cases of sinus arrest reversed spontaneously or responded to treatment with atropine and glycopyrrolate. Resuscitation was required in isolated cases of severe overdose resulting in cardiac arrest.