Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic group: Glucocorticoids
ATC Code: H02AB04
Pharmacotherapeutic group: Anaesthetics
ATC Code: N01BB02
Methylprednisolone acetate is a synthetic glucocorticoid with the actions and use of natural corticosteroids. Methylprednisolone is a potent anti-inflammatory steroid. It has greater anti-inflammatory potency than prednisolone and less tendency than prednisolone to induce sodium and water retention. However the slower metabolism of the synthetic corticosteroid with their lower protein-bonding affinity, may account for their increased potency compared with the natural corticosteroids.
Lidocaine has the actions of a local anaesthetic which reversibly blocks nerve conduction near the site of application or injection.
No pharmacokinetic studies have been performed with the combination product of methylprednisolone and lidocaine, however, data are provided from pharmacokinetic studies performed with the individual product components methylprednisolone and lidocaine.
One in-house study of eight volunteers determined the pharmacokinetics of a single 40 mg intramuscular dose of methylprednisolone acetate. The average of the individual peak plasma concentrations was 14.8 ± 8.6 ng/mL, the average of the individual peak times was 7.25 ± 1.04 hours, and the average area under the curve (AUC) was 1354.2 ± 424.1 ng/mL x hrs (Day 1-21).
Pharmacokinetics of lidocaine after synovial absorption following intra-articular bolus injection in patients with knee joint arthroscopy was studied with different maximum concentration (Cmax) values reported. The Cmax values are 2.18 microg/mL at 1 hour (serum) and 0.63 microg/mL at 0.5 hour (plasma) following administration of lidocaine doses of 7 mg/kgand 400 mg, respectively. Other reported serum Cmax values are 0.69 microg/mL at 5 minutes and 0.278 microg/mL at 2 hours following administration of lidocaine doses of 25 mL of 1% and 20 mL of 1.5%, respectively.
Pharmacokinetic data of lidocaine after intra-bursa and intra-cyst administrations for local effect are not available.
Methylprednisolone is widely distributed into the tissues, crosses the blood-brain barrier, and is secreted in breast milk. Its apparent volume of distribution is approximately 1.4 L/kg. The plasma protein binding of methylprednisolone in humans is approximately 77%.
The plasma protein binding of lidocaine is concentration-dependent, and binding decreases as concentration increases. At concentrations of 1 to 5 microg/mL, 60%-80% lidocaine is protein bound. Binding is also dependent on the plasma concentration of the α1-acid glycoprotein.
Lidocaine has a volume of distribution at steady state of 91 L.
Lidocaine readily crosses the placenta, and equilibrium of unbound drug concentration is rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus.
In humans, methylprednisolone is metabolized in the liver to inactive metabolites; the major ones are 20α-hydroxymethylprednisolone and 20β-hydroxymethylprednisolone. Metabolism in the liver occurs primarily via the CYP3A4. (For a list of drug interactions based on CYP3A4-mediated metabolism, see section 4.5.)
Methylprednisolone, like many CYP3A4 substrates, may also be a substrate for the ATP-binding cassette (ABC) transport protein p-glycoprotein, influencing tissue distribution and interactions with other medicines.
Lidocaine is mainly metabolized by the liver. The main metabolites of lidocaine are monoethylglycine xylidide, glycinexylidide, 2,6-dimethylaniline, and 4-hydroxy-2,6-dimethylaniline. The lidocaine N-dealkylation to monoethylglycine xylidide is considered to be mediated by both CYP1A2 and CYP3A4. The metabolite 2,6-dimethylaniline is converted to 4-hydroxy-2,6-dimethylaniline by CYP2A6 and CYP2E1.
The mean elimination half-life for total methylprednisolone is in the range of 1.8 to 5.2 hours. Total clearance is approximately 5 to 6 ml/min/kg.
The clearance of lidocaine in plasma following intravenous bolus administration is 9 to 10 ml/min/kg.
The elimination half-life of lidocaine following intravenous bolus injection is typically 1.5 to 2 hours.
The pharmacological actions of monoethylglycine xylidide and glycinexylidide are similar to but less potent than those of lidocaine. Monoethylglycine xylidide has a half-life of approximately 2.3 hours and glycinexylidide has a half-life of about 10 hours and may accumulate after long-term administration.
Only 3% of lidocaine is excreted unchanged by the kidneys. About 73% of lidocaine appears in the urine as 4-hydorxy-2,6-dimethylaniline metabolite.
No pharmacokinetic studies have been performed for methylprednisolone in special populations.
Hepatic impairment:
Following intravenous administration, the half-life of lidocaine has approximately 3-fold increase in patients with liver impairment.Pharmacokinetic data of lidocaine after intra-articular, intra-bursa and intra-cyst administrations for local effect are not available in hepatic impairment.
Renal impairment:
Mild to moderate renal impairment (CLcr 30-60 ml/min) does not affect lidocaine pharmacokinetics but may increase the accumulation of glycinexylidide metabolite following intravenous administration. However, lidocaine clearance decreases about half and its half-life is approximately doubled with increased accumulation of glycinexylidide metabolite in patients with severe renal impairment (CLcr <30 ml/min).
The pharmacokinetics of lidocaine and its main metabolite of monoethylglycine xylidide are not altered significantly in haemodialysis patients who receive an intravenous dose of lidocaine.
Pharmacokinetic data of lidocaine after intra-articular, intra-bursa and intra-cyst administrations for local effect are not available in renal impairment.
Based on conventional studies of safety pharmacology and repeat-dose toxicity studies, no unexpected hazards were identified. The toxicities seen in the repeat-dose studies are those expected to occur with continued exposure to exogenous adrenocortical steroids.
Methylprednisolone has not been formally evaluated in rodent carcinogenicity studies. Variable results have been obtained with other glucocorticoids tested for carcinogenicity in mice and rats. However, published data indicate that several related glucocorticoids including budesonide, prednisolone, and triamcinolone acetonide can increase the incidence of hepatocellular adenomas and carcinomas after oral administration in drinking water to male rats. These tumorigenic effects occurred at doses which were less than the typical clinical doses on a mg/m² basis.
Methylprednisolone has not been formally evaluated for genotoxicity. However, methylprednisolone sulfonate, which is structurally similar to methylprednisolone, was not mutagenic with or without metabolic activation in Salmonella typhimurium at 250 to 2,000 µg/plate, or in a mammalian cell gene mutation assay using Chinese hamster ovary cells at 2,000 to 10,000 µg/ml. Methylprednisolone suleptanate did not induce unscheduled DNA synthesis in primary rat hepatocytes at 5 to 1,000 µg/ml. Moreover, a review of published data indicates that prednisolone farnesylate (PNF), which is structurally similar to methylprednisolone, was not mutagenic with or without metabolic activation in Salmonella typhimurium and Escherichia coli strains at 312 to 5,000 µg/plate. In a Chinese hamster fibroblast cell line, PNF produced a slight increase in the incidence of structural chromosomal aberrations with metabolic activation at the highest concentration tested 1,500 µg/ml.
Corticosteroids have been shown to reduce fertility when administered to rats. Male rats were administered corticosterone at doses of 0, 10, and 25 mg/kg/day by subcutaneous injection once daily for 6 weeks and mated with untreated females. The high dose was reduced to 20 mg/kg/day after Day 15. Decreased copulatory plugs were observed, which may have been secondary to decreased accessory organ weight. The numbers of implantations and live fetuses were reduced.
In reproductive studies, glucorticoids such as methylprednisolone were shown to increase the incidence of malformations (clef palate, central nervous system and skeletal anomalies) and embryo‑foetal lethality (e.g., increase in resorptions) in many species. The relevance of these findings to the risk of malformations in human infants born to mothers treated with methylprednisolone early in pregnancy is unknown.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of lidocaine. A metabolite of lidocaine, 2,6-xylidine, has been shown to be carcinogenic in rats with unknown clinical relevance in relation to short-term/intermittent use of lidocaine as a local anaesthetic.
Genotoxicity tests with lidocaine showed no evidence of mutagenic potential. A metabolite of lidocaine, 2,6-xylidine, showed weak genotoxic potential in vitro and in vivo. Reproductive toxicity: A study was conducted on male and female rats administered orally 30 mg/kg bw of lidocaine daily for 8 months. During that period, 3 matings were conducted and reproductive parameters were analysed for each gestation, as well as offspring development up to weaning. No effects could be detected.
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Non-clinical data based on acute and sub-acute toxicity studies revealed no findings other than those attributable to either methylprednisolone or lidocaine alone.
Genotoxicity studies have not been conducted with the combination of methylprednisolone and lidocaine (see above for genotoxicity as it pertains to the individual drugs).
Reproductive toxicity studies have not been conducted with the combination of methylprednisolone and lidocaine (see above for reproductive toxicity as it pertains to the individual drugs).
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