CLOROTEKAL Solution for injection Ref.[28062] Active ingredients: Chloroprocaine

Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, with toxic blood concentrations myocardial contractility may be depressed and peripheral vasodilation may occur, leading to decreased cardiac output and arterial blood pressure.

Following systemic absorption, toxic blood concentrations of local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation may be manifested as restlessness, tremors and shivering, which may progress to convulsions. Depression and coma may occur, possibly progressing ultimately to respiratory arrest.

However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior stage of central nervous system stimulation.

The rate of systemic absorption of local anesthetic drugs is dependent upon the total dose concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic injection.

The onset of action with chloroprocaine is rapid (usually 6 to 12 minutes), and the duration of anesthesia, depending upon the amount used and the route of administration.

Local anesthetics appear to cross the placenta by passive diffusion. However, the rate and degree of diffusion varies considerably among the different drugs as governed by: (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility.

Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, since only the free, unbound drug is available for placental transfer. Thus, drugs with the highest protein binding capacity may have the lowest fetal/maternal ratios. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.

Distribution

Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of administration, and the age of the patient.

Chloroprocaine plasma half-life in vitro is about 25 seconds, whereas the apparent half-life in vivo was found to be 3.1±1.6 min (range 1.5 to 6.4 min) in maternal plasma after intrapartum epidural anesthesia.

Metabolism

Chloroprocaine is rapidly metabolized in plasma by hydrolysis of the ester linkage by pseudocholinesterase. The hydrolysis of chloroprocaine results in the production of ß-diethylaminoethanol and 2-chloro-4-aminobenzoic acid, which inhibits the action of the sulfonamides [see Drug Interactions (7)].

Excretion

The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH.

Pharmacokinetic after intrathecal administration

Plasma concentrations of chloroprocaine and 2-chloro-4-aminobenzoic acid (ACBA) after intrathecal administration of 50 mg dose of CLOROTEKAL are reported in Table 3.

Table 3. PK Variables: Plasma Concentrations (ng/mL) of chloroprocaine and ACBA:

Specific Populations

Renal Impairment

Chloroprocaine is known to be substantially excreted by the kidney [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Carcinogenesis

Long-term studies in animals to evaluate carcinogenic potential of chloroprocaine have not been conducted.

Mutagenesis

2-chloroprocaine and the main metabolite, ACBA, were negative in the in vitro bacterial reverse mutation test (Ames assay) and the in vitro chromosome aberrations assay.

Impairment of Fertility

Studies in animals to evaluate the impairment of fertility have not been conducted with chloroprocaine.

14.1 Study 1

A Phase 2 single-center, prospective, randomized, observer-blind study evaluated the efficacy and the tolerability of chloroprocaine 30, 40, and 50 mg after spinal injection in 45 patients (27 males and 18 females) undergoing short duration (< 40 minutes) lower limb surgery. The mean age was 41 years (range 19 to 63).

Efficacy was determined by proportion of patients who were able to complete the surgical procedure without the need for supplementary intravenous analgesic or sedation drugs.

Efficacy results

Neither rescue anesthesia nor rescue analgesia was required for subjects randomized to chloroprocaine 50 mg. Three subjects in the 30 mg dose group and three subjects in the 40 mg dose group required intraoperative rescue medications. Duration data such as time from injection to surgery end, etc., for the chloroprocaine 50 mg-administered subjects follow:

Table 4. Duration Data for Chloroprocaine 50 mg Subjects in Minutes (N = 15):

The maximum surgical duration in the 50 mg dose group was 40 minutes and 93% (14 of 15) of the 50 mg dose group had surgical procedures ≤ 30 minutes.

14.2 Study 2

A Phase 3, multicenter, prospective, randomized, observer-blind study evaluated the safety and the efficacy of 50 mg of chloroprocaine 10 mg/mL in intrathecal anesthesia versus 10 mg of bupivacaine 0.5%, in 130 patients (69 males and 61 females) undergoing short duration (< 40 minutes) low abdominal surgery (gynecological or urological) and lower limb surgery that required T10 metameric level of sensory block and identical anesthesia procedures.

The mean age was 45 years (range 18 to 78) in the chloroprocaine group and 51 years (range 20 to 79) in the bupivacaine group. Each patient received a single dose of anesthetic (50 mg of chloroprocaine or 10 mg of bupivacaine) according to the randomization plan. Sixty-six subjects were randomized to the chloroprocaine group. Sixty-four subjects were randomized to the bupivacaine group.

Efficacy was determined by proportion of patients who were able to complete the surgical procedure without the need for rescue intravenous analgesic or sedation drugs.

Efficacy results

Six of 66 subjects (9%) in the chloroprocaine group required rescue compared to 6 of 64 (9%) in the bupivacaine group. Duration data such as time from injection to surgery end, etc., for the chloroprocaine-administered subjects follow:

Table 5. Duration Data in Minutes (N = 66):

Only two subjects had surgical procedures lasting over 60 minutes, and both required intraoperative rescue medications.