Regulatory Decision Summary for Clorotekal

This New Drug Submission was filed to obtain market authorization for Clorotekal, a 10 milligrams per millilitre (mg/mL) chloroprocaine hydrochloride solution for intrathecal administration. The proposed and approved indication was for use in spinal anesthesia in adults for procedures lasting 40 minutes or less.

The efficacy of Clorotekal in patients was supported by one Phase 3 pivotal trial and two supporting Phase 2 dose-finding trials sponsored by the applicant as well as third-party published literature. The Phase 3 trial was a prospective, observer -blinded, randomized clinical study that compared the efficacy and safety of 50 milligrams (mg) of chloroprocaine 1% (CP-2) with 10 mg bupivacaine 0.5% (BP). Patients underwent elective short-duration (less than 40 minutes [min]) in low abdominal surgery (gynecology and urology disciplines) that required T10 metameric level of sensory block and identical anesthesia procedures. The trial included 130 patients (66 in chloroprocaine group, 64 in bupivacaine group). The patient population was 63.63% male and 92.4% white, with a mean age of 45.2 (± 15.9) years (range 18-78), and a mean body weight of 71.4 (± 11.9) kilograms (kg).

Two (out of 66) patients in the CP-2 group and seven (out of 64) in the BP group had treatment failures requiring general anesthesia or supplemental analgesia or sedation and were removed from the Per Protocol (PP) population. The primary endpoint was non-inferiority of CP-2 versus BP in terms of onset time of sensory block at T10 metameric level in minutes, with a non-inferiority margin of 4 minutes. Mean time (± SD) to achievement of sensory block to T10 was 7.9 min (± 6.0) in the CP-2 group and 9.4 min (± 6.5) in the BP group. Non inferiority of CP-2 vs BP was demonstrated (Confidence Interval [CI] 95% -3; 1) by non-parametric Wilcoxon rank sum test. In the CP-2 group, the time to end of aesthesia was 109 (± 25.7) minutes, the time to unassisted ambulation was 163.3 (± 74.8) minutes and time to home discharge was 190 (± 95.4) minutes. In the PP population, 4/64 CP-2 and 1/57 BP administered patients were given intraoperative rescue medication for anxiety or analgesia. Two Phase 2, dose response studies (CHL1/02-2004 and CHL1/02-2014) evaluated three doses of chloroprocaine (30 mg, 40 mg and 50 mg) in 45 patients each (15 per treatment arm) enrolled for short-duration (less than 60 and less than 40 minutes, respectively) lower abdominal surgery. The results of the Phase 2 studies were supportive of the pivotal trial.

The safety of Clorotekal was assessed in the controlled clinical trials and is further supported by 10 years of foreign post-market experience. In the clinical trials, a total of 548 patients were exposed to doses of 30 to 70 mg of chloroprocaine 1% for spinal anesthesia. In addition, a Phase 4 observational prospective safety study with a focus on neurological adverse events such as transient neurological symptoms and cauda equina syndrome, enrolled 393 patients. Overall, Clorotekal was well-tolerated. The most common adverse events (AEs) observed in the clinical trials were related to the cardiovascular system (hypotension, bradycardia), nervous system (paresthesia, hypotonia) or the procedure (injection site pain, anesthetic complication). There were no deaths, serious or unexpected AEs reported.

The application included five Periodic Safety Update Reports (PSURs) spanning March 2012 and March 2022, where it was estimated that 958,260 patients worldwide have been exposed to chloroprocaine 1%. As of the cut-off date, there had been 141 serious and 159 non-serious AEs reported from spontaneous sources and 43 serious AEs reported from non-spontaneous sources, such as clinical trials. The most common AEs involved procedural complications, nervous system disorders, and cardiovascular disorders. There have been serious AEs, such as cardiac arrest and neurological injury (cauda equina syndrome and transient neurological symptoms), reported post-market. As these events were infrequent and consistent with the known safety profile of local anesthetics and spinal anesthesia, they did not preclude approval and the risk is being mitigated through labelling in the Serious Warnings and Precautions box.

Clorotekal pharmacokinetics and pharmacodynamics in humans is largely supported by literature and foreign product labels. Plasma concentrations of chloroprocaine and its metabolite 2-chloro-4-aminobenzoic acid (ACBA), along with urinary ACBA excretion were investigated as secondary end-points of the Phase 2 dose-finding, safety and pharmacokinetic study CHL1/02-2014. Due to its short half-life, Chloroprocaine was not quantifiable in plasma after the spinal injection, whereas the metabolite ACBA was quantifiable in most plasma samples (5, 10, 30 and 60 minutes). ACBA concentrations increased in plasma after the spinal injection of the parent compound and reached a peak 30 min post-dose. Plasma ACBA concentrations showed dose-proportionality across the doses studied. The percent of ACBA excreted was approximately 1.70% with all 3 doses. The sponsor did not conduct studies using intrathecal chloroprocaine on individuals with renal impairment, hepatic impairment, cardiac conditions or other disorders that may impact safety/efficacy such as pseudocholinesterase deficiency. This information is reflected in the Product Monograph (PM).

Based on the totality of clinical evidence, which includes the clinical trial program and 10 years of foreign market experience, the benefit of Clorotekal for use in spinal anesthesia for short-duration procedures has been demonstrated. The identified risks related to cardiovascular and neurological toxicity are consistent with the well-established safety profile of chloroprocaine and have been mitigated through labelling and adequate post-market pharmacovigilance activities.

A Risk Management Plan for Clorotekal was submitted to Health Canada by the sponsor, and following review by the Marketed Health Products Directorate was considered to be acceptable.

The chemistry and manufacturing information submitted for Clorotekal has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications

Following review and requested revisions, the final labelling and PM were considered to be acceptable

Overall, the benefit-harm-uncertainty profile was favourable for Clorotekal 10 mg/mL for the approved indication when used under the conditions of use recommended in the approved PM. Therefore, a Notice of Compliance was recommended.

For further details about Clorotekal, please refer to the PM, approved by Health Canada and available through the Drug Product Database.