Doxylamine Succinate 10 mg, Folic Acid 2.5 mg, Pyridoxine 10 mg Tablets

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.

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.

The mechanism of action of doxylamine succinate and pyridoxine hydrochloride is unknown.

The pharmacokinetics of doxylamine succinate and pyridoxine hydrochloride has been characterized in healthy non-pregnant adult women. Pharmacokinetic results for doxylamine and pyridoxine, including its vitamin B6 metabolites, pyridoxal, pyridoxal 5’-phosphate, pyridoxamine and pyridoxamine 5’-phosphate, are summarized in Tables 2 to 5.

Absorption — A single-dose (two tablets) and multiple-dose (four tablets daily), open-label study was conducted to assess the safety and pharmacokinetic profile of doxylamine succinate and pyridoxine hydrochloride administered in healthy non-pregnant adult women. Single-doses (two tablets at bedtime) were administered on Days 1 and 2. Multiple-doses (one tablet in the morning, one tablet in the afternoon and two tablets at bedtime) were administered on Days 3-18.

Blood samples for pharmacokinetic analysis were collected pre-and post-dose on Days 2 and 18 as well as pre-dose prior to bedtime dose only (trough) on Days 9, 10, 11, 16, 17, and 18.

Doxylamine and pyridoxine are absorbed in the gastrointestinal tract, mainly in the jejunum.

The Cmax of doxylamine and pyridoxine are achieved within 7.5 and 5.5 hours, respectively (see Table 2).

Multiple-dose administration of doxylamine succinate and pyridoxine hydrochloride results in increased concentrations of doxylamine as well as increases in doxylamine Cmax and AUC0-last of absorption. The time to reach the maximum concentration is not affected by multiple doses. The mean accumulation index is more than 1.0 suggesting that doxylamine accumulates following multiple dosing (see Table 3).

Although no accumulation was observed for pyridoxine, the mean accumulation index for each metabolite (pyridoxal, pyridoxal 5’-phosphate, and pyridoxamine 5’-phosphate) is more than 1.0 following multiple-dose administration of doxylamine succinate and pyridoxine hydrochloride. The time to reach the maximum concentration is not affected by multiple doses (see Table 2).

Food Effect — The administration of food delays the absorption of both doxylamine and pyridoxine. This delay is associated with a lower peak concentration of doxylamine, but the extent of absorption is not affected (see Table 4).

The effect of food on the peak concentration and the extent of absorption of the pyridoxine component is more complex because the pyridoxal, pyridoxamine, pyridoxal 5’-phosphate and pyridoxamine 5’-phosphate metabolites also contribute to the biological activity. Food significantly reduces the bioavailability of pyridoxine, lowering its Cmax and AUC by approximately 50% compared to fasting conditions. Similarly, food significantly reduces pyridoxal AUC and reduces its Cmax by 50% compared to fasting conditions. In contrast, food slightly increases pyridoxal 5’-phosphate Cmax and extent of absorption. As for pyridoxamine and pyridoxamine 5’-phosphate, the rate and extent of absorption seem to decrease under fed conditions.

Distribution — Pyridoxine is highly protein bound, primarily to albumin. Its main active metabolite, pyridoxal 5’-phosphate (PLP) accounts for at least 60% of circulating vitamin B6 concentrations.

Metabolism — Doxylamine is biotransformed in the liver by N-dealkylation to its principle metabolites N-desmethyl-doxylamine and N, N-didesmethyldoxylamine.

Pyridoxine is a prodrug primarily metabolized in the liver.

Excretion — The principle metabolites of doxylamine, N-desmethyl-doxylamine and N, N-didesmethyldoxylamine, are excreted by the kidney.

The terminal elimination half-life of doxylamine and pyridoxine are 12.5 hours and 0.5 hours, respectively (see Table 5).

Use in Specific Populations — Race: No pharmacokinetic studies have been conducted related to race.

Hepatic Impairment: No pharmacokinetic studies have been conducted in hepatic impaired patients.

Renal Impairment: No pharmacokinetic studies have been conducted in renal impaired patients.