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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

OraVerse 400 micrograms/1.7 ml solution for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Phentolamine mesilate 400 micrograms in 1.7 ml (235 micrograms/ml). Excipients:

Sodium 0.5 mg in 1.7 ml.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless, isotonic, preservative free solution. The pH of the solution ranges from 3.5 to 4.5.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Reversal of soft tissue anaesthesia (lip and tongue), and the associated functional deficits, resulting from an intraoral submucosal injection of a local anaesthetic containing a catecholamine vasoconstrictor, such as epinephrine, following a routine dental procedure such as teeth cleaning, scaling and planing, cavity filling, crowns (see section 5.1).

OraVerse is indicated in adults and children 6 years of age and older and weighing at least 15 kg.

4.2 Posology and method of administration

Posology Adult patients

The recommended dose of OraVerse is based on the number of cartridges of local anaesthetic with vasoconstrictor administered:

Amount of local anaesthetic administered [cartridge(s)]	Amount of OraVerse to be administered [cartridge(s)]	Dose of OraVerse (phentolamine mesilate) [micrograms]
/	/	200
1	1	400
2	2	800

The maximum recommended dose is 2 cartridges of OraVerse (800 micrograms of phentolamine mesilate).

Paediatric patients

As for adult patients, the recommended dose of OraVerse in paediatric patients is based on the number of cartridges of local anaesthetic with vasoconstrictor administered.

The maximum dose to be administered should be determined based on the age and weight of the patient, as follows:

Age	Weight	Maximum amount of OraVerse [cartridge(s)]	Maximum dose of OraVerse (phentolamine mesilate) [micrograms]
6-11 years	15-30 kg	/	200
6-11 years	> 30 kg	1	400
> 12 years	> 30 kg	2	800

The efficacy of OraVerse in children less than 6 years of age has not yet been established. Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can be made.

Special populations

Patients with hepatic impairment:

OraVerse has not been studied in patients with hepatic impairment. Since phentolamine is metabolised principally in the liver, OraVerse should be used with caution in patients with hepatic impairment.

Patients with renal impairment:

OraVerse dose adjustment is not required in patients with renal impairment since phentolamine is metabolised principally in the liver, with less than 10% excreted unchanged in the urine.

Elderly patients:

OraVerse dose adjustment is not required in elderly patients.

Method of administration For dental use.

OraVerse should be administered by intraoral submucosal injection following the dental procedure using the same location(s) and technique(s) (infiltration or block injection) employed for the administration of the local anaesthetic. The Oraverse cartridge must be used in an appropriate syringe system that will permit aspiration before and during injection of solution. Each cartridge contains up to 0.2 ml overfill that allows aspiration prior to administration.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for use

Patients should be instructed not to eat or drink until normal oral sensation returns.

Do not administer OraVerse if the product is discoloured or contains particulate matter.

Use of OraVerse is not recommended in patients undergoing complex dental procedures where post-procedural pain or haemorrhage is anticipated.

There are limited data on the use of OraVerse in patients at increased risk of bleeding, including patients treated with anticoagulants. Caution should be exercised when using OraVerse in such patients due to the increased risk of injection site haemorrhage.

To minimize the likelihood of intravascular injection, aspiration should be performed before OraVerse is injected. If blood is aspirated, the needle must be repositioned until no return of blood can be elicited by aspiration.

Following the intravenous or intramuscular administration of phentolamine mesilate at doses higher than recommended for reversal of soft tissue anaesthesia, myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion, usually in association with marked hypotensive episodes, have been reported.

As hypotension, tachycardia and cardiac arrhythmias may occur with the use of phentolamine and other alpha-adrenergic blocking agents, clinicians should be alert to the signs and symptoms of these events. OraVerse is not recommended in patients with severe or uncontrolled cardiovascular disease.

4.5 Interaction with other medicinal products and other forms of interaction

There are no known clinical drug interactions with OraVerse.

When OraVerse was administered as an intraoral submucosal injection 30 minutes after injection of a local anaesthetic containing 2% lidocaine HCl with 1:100,000 epinephrine, the lidocaine plasma concentration increased

immediately after OraVerse intraoral injection. Lidocaine AUC and Cmax values were not affected significantly by administration of OraVerse. OraVerse administration did not affect the pharmacokinetics of epinephrine.

4.6 Fertility, Pregnancy and lactation

Pregnancy

There are limited data from the use of phentolamine mesilate in pregnant women. Despite the fact that this active substance did not reveal a teratogenic potential, animal studies are insufficient with respect to reproductive toxicity (see section 5.3). OraVerse is not recommended during pregnancy.

Breast-feeding

It is unknown whether phentolamine is excreted in human milk. The excretion of phentolamine in milk has not been studied in animals. A decision to discontinue breast-feeding temporarily in favour of a treatment with OraVerse should be made taking into account the benefit of breast-feeding to the child and the benefit of OraVerse therapy to the woman.

Fertility

The effect of OraVerse on human fertility is unknown.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

Summary of the safety profile

In clinical trials, the most frequently reported adverse reactions with OraVerse were post procedural pain and injection site pain, occurring in 6.0% and 5.3% of patients, respectively. The majority of adverse reactions were mild and resolved within 24 hours.

List of adverse reactions

Adverse reactions, based on experience from 418 dental patients enrolled in clinical trials, are listed in the table below. Within the system organ classes, adverse reactions are listed under headings of frequency using the following categories: common (>1/100 to <1/10) and uncommon (>1/1,000 to <1/100).

System Organ Class	Common	Uncommon
Nervous system disorders	Headache	Paraesthesia

Cardiac disorders	Tachycardia, bradycardia
Vascular disorders	Hypertension/blood pressure increased
Gastrointestinal disorders	Oral pain	Abdominal pain upper, diarrhoea, vomiting
Skin and subcutaneous tissue disorders		Pruritus, swelling face
Musculoskeletal and connective tissue disorders		Pain in jaw
General disorders and administration site conditions	Injection site pain	Injection site reaction, tenderness
Injury, poisoning and procedural complications	Post procedural pain

The few reports of paraesthesia were mild and transient and resolved during the 48-hour observation period.

Paediatric population

In 154 dental patients 3 to 17 years of age, common (>1/100 to <1/10) adverse reactions consisted of tachycardia, bradycardia, blood pressure increased, and oral pain.

4.9 Overdose

Overdosage with parenterally administered phentolamine mesilate is characterised chiefly by cardiovascular disturbances such as arterial hypotension, reflex tachycardia, cardiac stimulation, arrhythmia, increase of systemic venous capacity, and possibly shock. These effects may be accompanied by headache, hyperexcitability and disturbances of vision, sweating, increased gastric motility, vomiting and diarrhoea, hypoglycaemia.

There is no specific antidote; treatment consists of appropriate monitoring and supportive care. Substantial decreases in blood pressure or other evidence of shock-like conditions should be treated vigorously and promptly.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Imidazoline derivatives, ATC code V03AB36.

Mechanism of action

Phentolamine is a competitive non-selective a1 and a2-adrenergic receptor blocker of relatively short duration. When applied to vascular smooth muscle, it produces an a-adrenergic block resulting in vasodilatation. However, the mechanism by which OraVerse accelerates reversal of soft-tissue anaesthesia and the associated functional deficits is not fully understood. In an animal model, OraVerse increased local blood flow in submucosal tissue of the dog when given after an intraoral injection of lidocaine 2% with 1:100,000 epinephrine. Phentolamine is not an antidote to local anaesthetics.

Clinical efficacy and safety

The safety and efficacy of OraVerse were evaluated in double-blinded, randomised, multicentre, controlled studies in patients undergoing dental restorative or periodontal maintenance procedures. In these studies, 484 patients were randomised to local anesthetic/vasoconstrictor combinations based on a 6:1:1:1 allocation ratio (lidocaine/epinephrine 1:100,000 (66%), articaine/epinephrine 1:100,000 (11%), prilocaine/epinephrine 1:200,000 (11%), and mepivacaine/levonordefrin 1:20,000 (11%)) prior to the dental procedure. The primary endpoint was time to normal lip sensation as measured by patient reported responses to lip palpation. The control group consisted of patients receiving a sham injection.

OraVerse reduced the median time to recovery of normal sensation in the lower lip by 85 minutes (55%) compared to control (p < 0.0001). The median time to recovery of normal lip sensation in the upper lip was reduced by 83 minutes (62%) compared to control (p < 0.0001). Within 1 hour after administration of OraVerse, 41% of patients reported normal lower lip sensation as compared to 7% in the control group, and 59% of patients in the OraVerse group reported normal upper lip sensation as compared to 12% in the control group. There was a significant reduction (p < 0.0001) in the time to return to normal oral function (speaking, smiling, drinking, and lack of drooling) and to normal perception in the OraVerse group compared to control.

The potential benefit of OraVerse concerning the reduction of self-inflicted injuries has not been studied during the clinical trials.

Before administering OraVerse, the majority of patients included in the clinical studies were treated with a local anaesthetic and a vasoconstrictor (eg. epinephrine) at 1:100000 concentration.

Limited data have been submitted to support the efficacy of OraVerse when a local anaesthetic and a vasoconstrictor (eg. epinephrine) at concentration less than 1:100000 is administered.

Paediatric population

In clinical studies, paediatric patients between the ages of 3 and 17 years received OraVerse. The safety, but not the efficacy, of OraVerse has been evaluated in patients 3 to 5 years of age. The median time to normal lip sensation in patients 6 to 11 years of age was reduced by 75 minutes (56%) compared to control (p < 0.0001). Within 1 hour after administration of OraVerse, 44 patients (61%) reported normal lip sensation, while only 9 patients (21%) in the control group reported normal lip sensation.

Elderly patients:

In clinical studies of OraVerse, 55 patients were 65 years of age and over, while 21 patients were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients.

5.2 Pharmacokinetic properties

Following OraVerse administration, phentolamine is 100% available from the submucosal intraoral injection site and peak concentrations are achieved 10 to 20 minutes after injection. Phentolamine systemic exposure increased linearly after 800 micrograms compared to 400 micrograms OraVerse intraoral submucosal injection. The terminal elimination half-life of phentolamine in the blood was approximately 2 to 3 hours.

Paediatric population:

Following OraVerse administration, the phentolamine Cmax was higher in children who weighed between 15 and 30 kg than in children who weighed more than 30 kg. However, phentolamine AUC was similar between the two groups. It is recommended that in children weighing 15 to 30 kg, the maximum dose of OraVerse should be limited to ^ cartridge (200 micrograms) (see section 4.2).

The pharmacokinetics of OraVerse in adults and in children who weighed more than 30 kg are similar after intraoral submucosal injection.

OraVerse has not been studied in children under 3 years of age or weighing less than 15 kg. The pharmacokinetics of OraVerse after administration of more than 1 cartridge (400 micrograms) has not been studied in children.

5.3 Preclinical safety data

According to the experimental data available, phentolamine did not reveal either a mutagenic or a teratogenic potential. Carcinogenicity studies with OraVerse have not been conducted.

At doses up to 150 mg/kg (143 times human therapeutic exposure levels at the Cmax), phentolamine mesilate was shown to have no adverse effects on male fertility in the rat.

6.1 List of excipients

Mannitol (E 421)

Disodium edetate Sodium acetate trihydrate (E 262i) Acetic acid (E 260) (for pH adjustment) Sodium hydroxide (for pH adjustment) Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life 24 months.

6.4 Special precautions for storage

Do not store above 25°C.

Do not refrigerate or freeze.

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

6.5 Nature and contents of container

1.7 ml solution in a glass cartridge (type 1 colourless glass) with a standard plunger (bromobutyl rubber) and a blue flanged cap (aluminium) with a stopper (bromobutyl rubber).

Pack-sizes of 10 or 50 cartridges. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Septodont Holding 58 rue du Pont de Creteil 94100 Saint-Maur-des-Fosses