Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Gedeon Richter Plc, Gyömroi út 19-21, H-1103, Budapest, Hungary
Pharmacotherapeutic group: Anaesthetics; Anaesthetics, local
ATC code: N01BB02
Lidocaine is a local anaesthetic of the amide type. Lidocaine reversibly stabilises neuronal membranes and prevents initiation and conduction of nerve impulses, thus providing local anaesthesia. At high plasma concentrations, lidocaine may also decrease conduction of excitatory neural membranes in the brain and in heart muscle.
Lidbree is a thermogelling, preservative-free local anaesthetic viscous liquid. The formulation forms a gel when temperature increases to body temperature, and thereby remains adhered to the mucosal tissues in the cervical canal and the uterus (minimising leakage that would occur with a liquid formulation). The thermogelling formulation limits dilution with the mucus secretion and the local anaesthetic works as a buffering system.
Anaesthetic onset time of Lidbree after topical application to genital cervical mucous membranes is 2 minutes. Local anaesthesia of the corpus uteri for intrauterine procedures is achieved within 5 minutes after administration into the uterine cavity. The duration of effect is at least 30 minutes, while no effect on post-procedural pain compared to placebo gel remains after 60 minutes.
Visibility during hysteroscopy is not impaired.
The efficacy and safety of Lidbree as a topical anaesthetic for cervical and intrauterine procedures was demonstrated in a pain model: a placebo-controlled multicentre study in 218 nulliparous women requesting the placement of an intrauterine contraceptive device (IUD). This pain model is representative of the pain experienced from intrauterine procedures such as diagnostic hysteroscopy, and cervical and endometrial biopsies, which involve the same painful stimuli (grasping of the cervix with a tenaculum, cervical manipulation and uterine distension). In the placebo-controlled study gel was applied to the portio, into the cervical canal, and into the corpus uteri that was filled with gel 5 minutes before placement of IUD. The full volume of 8.5 mL could not be administered in 72 out of 218 women, nulliparous women often having a smaller uterus. The maximum pain intensity experienced during and within 10 minutes after the start of IUD placement, as rated on a 100 mm visual analogue scale (VAS), was significantly lower in women given Lidbree (p<0.0001) with an estimated effect size of 16 mm (mean difference) corresponding to a 36% lower mean VAS pain score, compared to women given placebo gel. The proportion of patients in the Lidbree and placebo group with close to pain-free scores (0-10), and the proportion with high scores indicating moderate or severe pain (51-100), was 31% vs. 9.7%, and 18% vs. 40%, respectively. The proportion of patients with pain scores indicating severe pain (71-100) was 9.4% vs. 19.4%. The need for analgesics during the first hour after completion of the IUD placement was 15.4% and 30.5% in the Lidbree and placebo group, respectively. The proportion of patients in the Lidbree and placebo group with close to pain-free scores (VAS 0-10) after 30 min was 34.5% and 16.1% (p<0.01), and after 60 min 38.7% and 32.4%, respectively.
In no case was uterine perforation observed on ultrasound examination. There were no serious adverse events.
Lidbree has not been studied in paediatric patients below 18 years of age. Lidocaine is known to be an effective local anaesthetic in children, adolescents and adults. Posology for adolescents is provided based on the adult efficacy study (see Section 4.2). Administration of Lidbree to mucous membranes of infants and children below 15 years of age is not indicated (see Section 4.2) and may result in local anaesthetic systemic toxicity in individuals with body weight below 30 kg if the applied dose of lidocaine is larger than the maximum recommended parenteral dose (6 mg/kg bodyweight lidocaine hydrochloride, corresponding to 5.2 mg/kg lidocaine base in Lidbree, i.e. 1.2 mL Lidbree per 10 kg).
The systemic absorption of lidocaine from Lidbree is dependent upon dose applied. In non-clinical studies plasma concentrations following intrauterine administration demonstrated less than dose proportional increases in peak concentration. The high lidocaine concentration can temporarily increase the pH in the mucus secretion at the application site, which will increase the rate of absorption of the local anaesthetic.
The absorption of lidocaine was studied after a single cervical and intrauterine administration of 8.5 mL Lidbree in fifteen women 20 to 36 years of age, several in their menstrual cycle days 1 to 6, before placement of IUD. In all patients lidocaine was detected in plasma within 5 to 10 minutes after intrauterine administration of gel. Maximum plasma concentrations were observed at 30 to 180, mean 68 minutes. The mean (SD) peak plasma concentration (Cmax) was 351 (205) ng/mL with a range of 65 to 725 ng/mL. Symptoms of local anaesthetic toxicity become increasingly apparent at increasing plasma concentration from 5,000 to 10,000 ng/mL and the observed mean Cmax is less than 10% of the ceiling for initial signs of CNS toxicity. At 3 hours concentrations had decreased to 30-50% of maximal values in most patients.
The major elimination pathway of lidocaine is via hepatic metabolism involving CYP 1A2 and 3A4 forming monoetylglycinxylidid (MEGX) which has pharmacological activity similar to lidocaine. MEGX is further metabolised by CYP2A6 and the resulting metabolites are renally excreted. Following IV administration the systemic clearance of lidocaine is 10 to 20 mL/min/kg and the elimination half-life 1.5 to 2 hours. However, the rate of metabolism and elimination of the local anaesthetic after topical application of Lidbree are governed by the rate of absorption. Therefore, a decrease in clearance, such as in patients with severely impaired liver function, has limited effects on the systemic plasma concentrations after a single dose.
The clearance of lidocaine after epidural administration is decreased by approximately 40% in women with a mean age of 77 years as compared to women with a mean age of 42 years, whereas there are no significant differences in plasma concentrations of lidocaine. As the rate of metabolism and elimination of the local anaesthetic after topical application of Lidbree are governed by the rate of absorption, a decrease in clearance has limited effects on the plasma concentrations after a single dose.
No pharmacokinetic data is available on the intrauterine and cervical use of lidocaine in postmenopausal women. Safety data did not indicate an increased risk after a single dose of cervical and intrauterine lidocaine in postmenopausal women.
Local and systemic toxicity of Lidbree containing 40 or 50 mg/mL of lidocaine were investigated up to the maximal intrauterine dose volume of 1mL/kg in female beagle dogs for up to 28 days. Due to the presence of macrogolglycerol ricinoleate in the formulation and minor changes indicating peripheral neuropathy in the 28-day study, a single dose study of Lidbree evaluating peripheral nerves was conducted at the maximal volume of 1 mL/kg of Lidbree. The dose of lidocaine at 40 or 50 mg/kg was 7 to 10 times the dose in humans at therapeutic use. Intrauterine application of Lidbree to female beagle dogs indicated rapid systemic uptake of lidocaine. There were no findings indicating systemic lidocaine toxicity or local reactions in vaginal, cervical or uterine membranes at this dose of Lidbree. No findings in the single dose study of 40 mg/kg lidocaine demonstrated a risk for systemic toxicity or peripheral nerurotoxicity following single dose in humans
No non-clinical studies on fertility, embryo-foetal development or pre- and postnatal toxicity have been conducted with Lidbree. In studies of lidocaine an impairment of the fertility of male or female rats was not observed.
Lidocaine crosses the placental barrier by means of simple diffusion. Embryotoxic or foetotoxic effects of lidocaine were detected in the rabbit, but only at maternally toxic doses which are higher than the clinical dose.
Studies on genotoxicity or carcinogenicity have not been conducted with Lidbree. Genotoxicity tests with lidocaine showed no evidence of mutagenic potential. A metabolite of lidocaine, 2,6‑dimethylaniline, showed weak evidence of activity in some genotoxicity tests. The metabolite 2,6‑dimethylaniline has been shown to have carcinogenicity potential in preclinical toxicological studies evaluating chronic exposure. Risk assessments comparing the calculated maximum human exposure from intermittent use of lidocaine, with the exposure used in preclinical studies, indicate a wide margin of safety for clinical use. Cancer studies have not been performed with lidocaine, due to the area and duration of therapeutic use for this drug.
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