Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2021 Publisher: Pfizer New Zealand Ltd, PO Box 3998, Auckland, NEW ZEALAND, Toll Free Number: 0800 736 363
Methylprednisolone is a potent anti-inflammatory steroid. It has a greater anti-inflammatory potency than prednisolone and even less tendency than prednisolone to induce sodium and water retention.
Methylprednisolone sodium succinate has the same metabolic and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The relative potency of SOLU-MEDROL sterile powder (methylprednisolone sodium succinate) and hydrocortisone sodium succinate, as indicated by depression of eosinophil count, following intravenous administration, is at least four to one. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone.
Methylprednisolone sodium succinate has been investigated for acute spinal cord injury in two randomised, double-blind, comparative National Acute Spinal Cord Injury Studies (NASCIS 2 and 3). The effect of high dose methylprednisolone sodium succinate given as initial bolus of 30 mg/kg by IV for 15 minutes followed 45 minutes later by a continuous infusion of 5.4 mg/kg/hour for 24 hours was significant on neurologic recovery when given to patients within 8 hours from injury (NASCIS 2) and motor recovery was higher for those patients initiated within 3 to 8 hours from injury and treated with the same regimen for 48 hours (NASCIS 3).
Methylprednisolone pharmacokinetics is linear, independent of route of administration.
After an intravenous infusion of SOLU-MEDROL, 30 mg/kg over a 20-minute period or 1 g over 30 to 60 minutes, peak methylprednisolone plasma concentrations of approximately 20 mcg/mL were achieved. Peak methylprednisolone levels of 42-47 mcg/100 mL were reported following a single 40 mg IV bolus injection to six adult male volunteers.
Peak methylprednisolone plasma levels of 33.67 mcg/100 mL were achieved in two hours after a single 40 mg IM injection to 22 adult male volunteers.
Although with intramuscular (IM) injection lower peak levels are obtained than with intravenous (IV) injection, the plasma levels persist longer such that the extent of methylprednisolone absorption is equivalent with either route of administration.
Methylprednisolone is widely distributed throughout the body and is described by a two-compartment model. Its apparent volume of distribution is approximately 1.4 L/kg and its total clearance is approximately 5 to 6 mL/min/kg.
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.
SOLU-MEDROL readily crosses the blood-brain barrier into the central nervous system with peak CSF levels being 5-6% of the corresponding plasma levels. Methylprednisolone peak CSF levels occurred within five minutes to one hour after IV administration of a 500 mg dose to patients with lupus cerebritis.
Methylprednisolone and the sodium succinate salt crosses the placental barrier. Although there is no data regarding methylprednisolone passage into breast milk of humans, it is present in breast milk of animals.
SOLU-MEDROL, the sodium succinate ester of methylprednisolone, is rapidly and extensively hydrolysed in vivo by cholinesterases to free methylprednisolone.
In humans, methylprednisolone is metabolised in the liver to inactive metabolites, the major ones being 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).
The mean elimination half-life ranges for total methylprednisolone is in the range of 1.8 to 5.2 hours.
The plasma protein binding of methylprednisolone in humans is approximately 77%.
Total body clearance following intravenous or intramuscular injection of methylprednisolone to healthy adult volunteers is approximately 15-16 L/hr. In adult volunteers receiving 40 mg SOLU-MEDROL, either IM or IV, renal clearance is 0.61-0.83 L/hr. Methylprednisolone clearance is altered by concurrent administration of troleandomycin, erythromycin, rifampicin, anticonvulsants, and theophylline.
Following IV administration of radiolabelled 6α-methylprednisolone to six cancer patients, 75% of total reactivity was recovered in the urine after 96 hours and 9% in the faeces after five days. Twenty percent of the total dose was excreted in the bile, but the time course was not cited.
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 colistrains 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.
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.
In animal studies for embryotoxic effects of methylprednisolone, no teratogenic effect was observed in mice or rats at daily intraperitoneal doses of 125 mg/kg/day or 100 mg/kg/day, respectively. In rats, methylprednisolone was teratogenic when administered subcutaneously at a dose of 20 mg/kg/day. Methylprednisolone aceponate was teratogenic when given subcutaneously to rats at a dose of 1.0 mg/kg/day. 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.
Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. In animal reproduction studies, glucocorticoids such as methylprednisolone have been shown to increase the incidence of malformations (cleft palate, skeletal malformations), embryo-fetal lethality (e.g., increase in resorptions), and intra-uterine growth retardation.
Based on conventional studies of safety pharmacology, repeated dose toxicity in mice, rats, rabbits, and dogs using intravenous, intraperitoneal, subcutaneous, intramuscular, and oral routes of administration, no unexpected hazards were identified. Methylprednisolone is a potent steroid, with pharmacological activity consistent with that of glucocorticoids, including effects on carbohydrate metabolism, electrolyte and water balance, formed elements of the blood, lymphoid tissue, and protein metabolism leading to decreased or lack of body weight gain, lymphopenia, atrophy of spleen, thymus, lymph nodes, adrenal cortex and testes, as well as fatty changes of the liver and enlargement of pancreatic islet cells. A 30-day reversibility study conducted with methylprednisolone-treated rats indicated that within approximately 1 month of drug withdrawal, normal organ function was resumed. Many parameters returned to normal after a 9-week reversibility period following 52 weeks of treatment of methylprednisolone suleptanate in rats. The toxicities seen in the repeated-dose studies are those expected to occur with continued exposure to exogenous adrenocortical steroids.
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