Alpha Lipoic Acid 100 mg, Folic Acid 1.5 mg, Methylcobalamin 750 mcg, Pregabalin 75 mg, Pyridoxine 3 mg Hard-gelatin capsules

Pregabalin binds with high affinity to the alpha 2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha 2-delta subunit may be involved in pregabalin’s anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha 2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.

While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA A, GABA B, or benzodiazepine receptors, does not augment GABA Aresponses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.

Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about 6 hours.

Absorption and Distribution — Following oral administration of pregabalin capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is greater than or equal to 90% and is independent of dose. Following single-(25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, maximum plasma concentrations (C max) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.

The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in C maxof approximately 25% to 30% and an increase in T maxto approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.

Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.

Metabolism and Elimination — Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin

(S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CLcr) [see Dosage and Administration ( 2.7)].

Race — In population pharmacokinetic analyses of the clinical studies in various populations, the pharmacokinetics of pregabalin were not significantly affected by race (Caucasians, Blacks, and Hispanics).

Gender — Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and pregabalin drug exposure is similar between genders.

Renal Impairment and Hemodialysis — Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified [ see Dosage and Administration( 2.7)].

Elderly — Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function [ see Dosage and Administration ( 2.7)].

Folic acid acts on megaloblastic bone marrow to produce a normoblastic marrow.

In man, an exogenous source of folate is required for nucleoprotein synthesis and the maintenance of normal erythropoiesis. Folic acid is the precursor of tetrahydrofolic acid, which is involved as a cofactor for transformylation reactions in the biosynthesis of purines and thymidylates of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective deoxyribonucleic acid (DNA) synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias.

Absorption — Folic acid is absorbed from the small intestine, primarily from the proximal portion. Folic acid appears in the plasma approximately 15 to 30 minutes after an oral dose; peak levels are generally reached within 1 hour.

Distribution — Folic acid as well as its physiologically active metabolite, L-5-methyl tetrahydro folate (L-5-MTHF), can be bound to plasma proteins when entering the systemic circulation. The fraction of folic acid bound to plasma proteins, particularly albumin, ranges between ~50% to 64%. The volume of distribution of L-5-MTHF is estimated to be 32.0 L. Tetrahydrofolic acid derivatives are distributed to all body tissues but are stored primarily in the liver. Cerebrospinal fluid levels of folic acid are several times greater than serum levels of the drug.

Metabolism — The first step in the metabolism of folic acid is its reduction to dihydrofolate via dihydrofolate reductase. Subsequently, dihydrofolate is further reduced to tetrahydrofolate (THF). THF is further converted to methylene-THF by serine-hydroxymethyltransferase and reduced to physiologically active L-5-MTHF via methylenetetrahydrofolate reductase (MTHFR).

Elimination — After intravenous administration, folic acid is rapidly cleared from the plasma. Following oral administration, majority of the dose was recovered in the urine. A majority of the metabolic products appeared in the urine after 6 hours; excretion was generally complete within 24 hours. Small amounts of orally administered folic acid have also been recovered in the feces.

Vitamin B12 supplies cofactors for methionine synthase and methylmalonyl-CoA mutase. These reactions support methionine formation and conversion of methylmalonyl-CoA to succinyl-CoA. B12 is involved in DNA synthesis, red-cell formation and nervous-system function.

Free B12 combines with intrinsic factor and is taken up in the distal ileum. Absorption becomes less efficient as the dose exceeds intrinsic-factor capacity; the NIH review reports about 2% absorption at 500 micrograms and 1.3% at 1,000 micrograms. Cyanocobalamin and hydroxocobalamin are converted into active cobalamin forms. These are oral nutrient data, not injectable-product pharmacokinetics.

Pyridoxal phosphate and pyridoxamine phosphate are active vitamin B6 coenzymes involved in amino-acid metabolism. B6 also contributes to neurotransmitter synthesis, glycogen metabolism and hemoglobin formation.

Vitamin B6 is absorbed in the jejunum. Phosphorylated forms are dephosphorylated before free B6 enters by passive diffusion. The NIH review describes similar absorption from foods and supplements; much of a large pharmacological dose is rapidly eliminated in urine. This physiology does not supply a measured half-life for this formulation.

Alpha-lipoic acid is a coenzyme in mitochondrial multienzyme complexes. The reference also describes antioxidant biochemical effects and experimental findings in diabetic nerve models; these do not establish that every supplement or combination produces the same clinical benefit.

After a 600 mg oral tablet, the reference reports rapid absorption, a peak at approximately 0.3–0.5 hours and a plasma half-life of 20–30 minutes. Metabolism includes oxidative chain shortening and sulfur methylation. Only small quantities of unchanged substance appear in human urine. The high urinary recovery percentages reported in animal experiments are not presented here as human elimination data.