Phentermine HCl 5-HTP Complex Capsules

Phentermine

Phentermine is an oral sympathomimetic amine used as an adjunct for short-term (e.g., 8—12 weeks) treatment of exogenous obesity. The pharmacologic effects of phentermine are similar to amphetamines. Phentermine resin complex was approved by the FDA in 1959, but is no longer marketed in the US. Phentermine hydrochloride was FDA approved in 1973. In the mid-90s, there was renewed interest in phentermine in combination with another anorectic, fenfluramine, for the treatment of obesity and substance abuse, however, little scientific data support this practice. On July 8, 1997, the FDA issued a ‘Dear Health Care Professional’ letter warning physicians about the development of valvular heart disease and pulmonary hypertension in women receiving the combination of fenfluramine and phentermine; fenfluramine was subsequently withdrawn from the US market in fall of 1997. Use of phentermine with other anorectic agents for obesity has not been evaluated and is not recommended. In May 2011, the FDA approved a phentermine hydrochloride orally disintegrating tablet (Suprenza) for the treatment of exogenous obesity.

Dexpanthenol

Dexpanthenol is a synthetic derivative of pantothenic acid, a B complex vitamin that is widely distributed in plants and animals. Dexpanthenol is used parenterally as a gastrointestinal stimulant to treat and prevent ileus after GI surgery and in other conditions with impaired GI activity. Dexpanthenol was approved by the FDA in 1948.

Pyridoxine

Pyridoxine is a form of vitamin B6 – a water-soluble vitamin. Pyridoxine hydrochloride is the stable salt form of pyridoxine. Pyridoxine hydrochloride injection is prescribed when oral administration is not feasible, e.g., in case of gastric malabsorption syndromes, and pre-operative and post-operative conditions requiring parenteral nutrition.

Pyridoxine, or vitamin B6, is a naturally occurring vitamin found in food such as cereal grains, legumes, vegetables, liver, meat, and eggs. Pyridoxine is used to treat and prevent vitamin B6 deficiency; to prevent or treat toxicity from isoniazid, cycloserine, or hydralazine; and to treat sideroblastic anemia associated with elevated serum iron levels. It also has been used in pyridoxine-dependent neonates to treat seizures that are unresponsive to conventional therapy and in patients with metabolic disorders such as xanthurenic aciduria, primary hyperoxaluria, primary cystathioninuria, and primary homocystinuria. Pyridoxine hydrochloride has been commercially available since approval by the FDA in 1940.

Inside the body, pyridoxine is converted into its active form, the coenzyme pyridoxal 5’-phosphate. Pyridoxal 5’-phosphate is a versatile coenzyme participating in over 100 biochemical reactions mediating protein, carbohydrate, and lipid metabolism. It is crucial for the production of neurotransmitters, including dopamine, serotonin, norepinephrine, and GABA. It is also involved in regulating steroid hormone receptors and modulating the affinity of hemoglobin for oxygen.

Since humans lack the enzymes required for vitamin B6 (and pyridoxine) biosynthesis, it is an essential nutrient that needs to be procured through the diet. Dietary sources rich in vitamin B6 are fish, liver and other organ meats, potatoes and other starchy vegetables, and non-citrus fruits.3 Isolated vitamin B6 deficiency due to inadequate dietary intake is rare. Deficiency of vitamin B6 may occur in individuals with impaired renal function, genetic or autoimmune disorders, high alcohol intake, and with prolonged use of drugs including isoniazid, cycloserine, anti-epileptics, and oral contraceptives. In individuals with rheumatoid arthritis and inflammatory bowel disease, inflammatory cytokines cause low vitamin B6 levels, with greater deficiency associated with higher disease severity. People with celiac disease and other malabsorptive autoimmune disorders have vitamin B6 deficiency due to consuming a gluten-free diet low in essential vitamins. In people with alcohol dependence, the acetaldehyde produced from alcohol competes with the active form of pyridoxine for protein binding. Unbound pyridoxal 5’-phosphate – the active coenzyme form of pyridoxine – is rapidly hydrolyzed, resulting in vitamin B6 deficiency with high alcohol intake. Drugs like isoniazid and cycloserine interfere with enzymes that convert pyridoxine into pyridoxal-5-phosphate or enhance the catabolism and excretion of pyridoxine, resulting in vitamin B6 deficiency with prolonged use.

Vitamin B6 deficiency may produce symptoms such as electroencephalogram abnormalities, seizures, peripheral neuropathy, depression, confusion, dermatitis with scaling lips and cracks at the corners of the mouth, glossitis, microcytic anemia, and a weakened immune system. Low levels of vitamin B6 are associated with an increased risk of cardiovascular disorders, cognitive impairment, and certain types of cancer. However, more evidence is needed to conclusively demonstrate whether vitamin B6 supplementation reduces the risk or severity of these conditions.

Biotin

Biotin (vitamin H; coenzyme R; classified as a B vitamin) is a dietary component that is important for the metabolism of carbohydrates, fats, and amino acids. It is found primarily in liver, kidney, and muscle. Biotin functions as an essential cofactor for five carboxylases that catalyze steps in fatty acid, glucose, and amino acid metabolism. It is also an important factor in histone modifications, gene regulation, and cell signaling. Mammals must consume biotin to replenish stores. Sources of biotin include organ meats, eggs, fish, seeds, and nuts. As a dietary supplement, biotin has been promoted to be useful in the treatment of hair and nail problems, cradle cap (seborrheic dermatitis) in phenylketonuria patients, biotinidase deficiency, diabetes, peripheral neuropathy, candida infections, and high cholesterol. It has also been used in pregnancy, hemodialysis, and peritoneal dialysis, as biotin deficiency is more likely in these situations. Biotin is found in many cosmetics products. Radiolabeled biotin is used for pretargeted radioimmunotherapy of cancerous tumors.

Folic Acid

Folic acid is a water-soluble, B-complex vitamin that is available orally and parenterally. This vitamin is found in a variety of foods including liver, kidneys, yeast, and leafy, green vegetables. A deficiency in folic acid can cause a variety of hematologic complications including megaloblastic and macrocytic anemias. In addition to treating megaloblastic and macrocytic anemias as well as tropical sprue, this vitamin is also used as a diagnostic aid for folate deficiency. In recent years, it has been discovered that adequate folic acid intake can substantially decrease the risk of congenital neural tube defects. Unlike the folic acid derivative leucovorin, folic acid is not clinically useful in offsetting the action of folate reductase inhibitors because it requires the enzyme dihydrofolate reductase for activation. Folic acid is also ineffective in the treatment of aplastic and normocytic anemias. Prescription forms of folic acid were approved by the FDA in 1946. In 1998, the recommended dietary allowance for all women of child bearing age who are capable of becoming pregnant was increased to 400 mcg of folic acid daily. As of 1998, the FDA has required that all food manufacturers fortify enriched grain products with folic acid to reduce the risk of congenital neural tube defects.

Methylcobalamin

Methylcobalamin, or vitamin B12, is a B-vitamin. It is found in a variety of foods such as fish, shellfish, meats, and dairy products. Although methylcobalamin and vitamin B12 are terms used interchangeably, vitamin B12 is also available as hydroxocobalamin, a less commonly prescribed drug product (see Hydroxocobalamin monograph), and methylcobalamin. Methylcobalamin is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Vitamin B12 is an essential vitamin found in the foods such as meat, eggs, and dairy products. Deficiency in healthy individuals is rare; the elderly, strict vegetarians (i.e., vegan), and patients with malabsorption problems are more likely to become deficient. If vitamin B12 deficiency is not treated with a vitamin B12 supplement, then anemia, intestinal problems, and irreversible nerve damage may occur.

The most chemically complex of all the vitamins, methylcobalamin is a water-soluble, organometallic compound with a trivalent cobalt ion bound inside a corrin ring which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Methylcobalamin cannot be made by plants or by animals; the only type of organisms that have the enzymes required for the synthesis of methylcobalamin are bacteria and archaea. Higher plants do not concentrate methylcobalamin from the soil, making them a poor source of the substance as compared with animal tissues.

Ascorbic Acid

Ascorbic acid is a water-soluble vitamin found in fruits and vegetables such as citrus fruits and green peppers. It occurs as a white or slightly yellow crystal or powder with a slight acidic taste. It is an antiscorbutic product. On exposure to air and light it gradually darkens. In the dry state it is reasonably stable in air, but in solution it rapidly oxidizes. Ascorbic acid is a free radical, an antioxidant scavenger, and plays a major role in oxidation-reduction reactions. Ascorbic acid is a cofactor for enzymes involved in the biosynthesis of collagen (essential for tissue maintenance and repair), carnitine, and neurotransmitters. Humans cannot synthesize ascorbic acid endogenously and a lack of dietary intake can lead to scurvy. Vitamin C is most frequently used as a nutritional supplement. It also is used as an adjunct treatment of idiopathic methemoglobinemia and with deferoxamine in the treatment of chronic iron toxicity. Ascorbic acid has been used for a variety of ailments including the common cold, gum infections, acne, depression, fertility, and cancer; however, these claims have not been substantiated and vitamin C is not recommended for these purposes (see Mechanism of Action). Ascorbic acid was approved by the FDA in 1939.

Chromium

Chromium, in its trivalent state (i.e., Cr3+), is an essential trace element that is required for proper carbohydrate, lipid, and nucleic acid metabolism in the human body. Dietary sources of chromium (Cr3+) include whole grains, egg yolks, brewer’s yeast, liver, meats, nuts, potatoes with skin, and beer. Overt signs and symptoms of chromium deficiency are usually only observed in adult patients eating diets high in refined foods or who are receiving long-term total parenteral nutrition without chromium supplementation. Clinically, overt deficiencies may be detected as the development of impaired glucose tolerance, glycosuria, and insulin resistance. Impaired protein and lipid metabolism, peripheral neuropathy, and encephalopathy secondary to chromium deficiency have also been reported. Chromium supplementation should only be expected to improve disorders that are due to chromium deficiency. Limited studies have reported that the addition of chromium picolinate supplements to the dietary regimens of patients with type 2 or steroid-induced diabetes mellitus may result in improvements in glycemic control and cholesterol in some patients, and may allow for the reduction of antidiabetic medication. However, these trials have studied few patients; the importance of chromium deficiency in the average patient with type 2 diabetes has not been established. Controversy exists concerning other claimed benefits of chromium supplementation. Among athletes, chromium is promoted as an alternative to anabolic steroids. Multiple studies have concluded that there is no evidence that chromium supplementation increases muscle mass to a level greater than that which is produced with a healthy diet and exercise alone. There also appears to be no basis for claims that chromium reduces body-fat or weight. Clinical studies of chromium intake have revealed no additional changes in body-fat percentages or weight loss in either obese females or young athletes following controlled diet and exercise regimens. Other claimed uses, such as the adjunctive treatment to medical therapy for gestational diabetes after the 1st trimester or the adjunctive treatment of dysthymic disorder, are not accepted at this time. In the US, sales of chromium picolinate supplements exceed 150-million dollars per year.

Phentermine

Limited data are available in reference texts regarding the mechanism of action of this drug. Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Thus, phentermine is classified as an indirect sympathomimetic. Other effects include a weak ability to dose-dependently raise serotonin levels, although the effect on serotonin occurs is less potent than that of methamphetamine itself. Clinical effects include CNS stimulation and elevation of blood pressure. Appetite suppression is believed to occur through direct stimulation of the satiety center in the hypothalamic and limbic region.

Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased.

Dexpanthenol

Dexpanthenol is a precursor needed for acetylcholine synthesis, which in turn causes parasympathetic activity to maintain normal GI activity. The exact mechanism is not known.

Pyridoxine

Vitamin B6 is composed of pyridoxine, pyridoxal, and pyridoxamine, and food usually contains all three forms. Pyridoxine is converted in erythrocytes to its active moiety, pyridoxal phosphate (requiring riboflavin for the conversion), while pyridoxamine is converted into pyridoxamine phosphate. These active forms act as coenzymes for no fewer than 60 metabolic processes including the metabolism of fat, protein, and carbohydrate. Their role in protein metabolism includes decarboxylation of amino acids, conversion of tryptophan to niacin or serotonin, deamination, and transamination of amino acids. In carbohydrate metabolism, it is necessary for the conversion of glycogen to glucose-1-phosphate. Pyridoxine is essential for synthesis of gamma aminobutyric acid (GABA) in the CNS and synthesis of heme.

Pyridoxine hydrochloride is used for the prophylaxis and treatment of vitamin B6 deficiency. Vitamin B6 is the collective term encompassing six closely-related compounds: pyridoxine, pyridoxal, and pyridoxamine, as well as their 5’-phosphate esters. Pyridoxal 5’-phosphate (PLP) and pyridoxamine 5’-phosphate (PMP) are the biologically active forms of vitamin B6.

PLP is the primary coenzyme used by pyridoxine-dependent enzymes. It catalyzes various transamination, decarboxylation, and racemization reactions in the body by acting as an electron sink. PLP-catalyzed transamination of amino acids to keto acids occurs during gluconeogenesis. PLP-mediated decarboxylation of L-amino acids yields biogenic amines that are precursors of neurotransmitters and hormones. PLP also acts as a coenzyme for the synthesis of nucleic acids, sphingomyelin, and heme precursors.

PLP plays a crucial role in the one-carbon unit generation and homocysteine metabolism. Therefore, pyridoxine is used in the management of B6-responsive homocystinuria. Homocystinuria is a genetic disorder caused by mutations in the gene encoding for the enzyme cystathionine β-synthase that converts methionine to cysteine. It is characterized by elevated plasma homocysteine and methionine levels.

Given its role in the synthesis of heme precursors, pyridoxine is used to treat congenital and acquired sideroblastic anemia. Sideroblastic anemia is characterized by iron overload and decreased production of mature red blood cells. Congenital sideroblastic anemia is caused by mutations in enzymes of the heme biosynthesis pathway. Acquired sideroblastic anemia is also linked to impaired heme biosynthesis due to excessive alcohol consumption, heavy metal toxicity, and prolonged use of certain medications.

Biotin

Biotin is a water-soluble B vitamin found naturally in some foods and used as a dietary supplement. It is important for the metabolism of carbohydrates, fats, and amino acids. It is found primarily in liver, kidney, and muscle. Biotin functions as an essential cofactor for five carboxylases that catalyze steps in fatty acid, glucose, and amino acid metabolism. It is mostly protein-bound in foods such as organ meats, eggs, nuts, and soybeans. Gastrointestinal enzymes break down ingested biotin via proteolysis. This creates biocytin, which is then cleaved by biotinidase into free biotin and lysine. Free biotin is then absorbed in the small intestine. Biotin can be used for metabolism issues such as biotinidase, holocarboxylase synthetase, and isolated carboxylase enzyme deficiencies due to its essential role in the metabolism of fatty acids, glucose, and amino acids.

Folic Acid

Folic acid, a biochemically inactive compound, is the precursor for tetrahydrofolic acid and methyltetrahydrofolate. Tetrahydrofolic acid, methyltetrahydrofolate, and other folic acid congeners are essential for the maintenance of normal erythropoiesis and are also required cofactors for the synthesis of purine and thymidylate nucleic acids. They are also necessary for the interconversion of amino acids such as the metabolism of histidine to glutamic acid and the interconversion of serine and glycine. Folic acid congeners are transported across cells by receptor-mediated endocytosis where they function and are stored. Other processes involving folate coenzymes include generation and use of formate and methylation of transfer RNA. Impaired thymidylate synthesis, which leads to faulty DNA synthesis, is responsible for megaloblastic and macrocytic anemias.

An important role of folic acid is the formation of methionine from homocysteine using vitamin B12 as a cofactor. Adequate folic acid intakes can normalize high homocysteine levels via increased remethylation of homocysteine to methionine via 5-methyltetrahydrofolate-homocysteine methyltransferase (a.k.a.; methionine synthetase). Reduced folic acid intake is associated with hyperhomocysteinemia. Hyperhomocysteinemia is recognized as an independent risk factor for artherosclerosis of the coronary, cerebral, and peripheral vasculature. There is mounting evidence that elevated plasma homocysteine (and therefore decreased serum methionine) contributes to congenital neural tube defects. High serum homocysteine levels may also be important in the pathogenesis of colon cancer, diabetic retinopathy, and other diseases.

Methylcobalamin

Vitamin B12 is used in the body in two forms, methylcobalamin and 5-deoxyadenosyl cobalamin. The enzyme methionine synthase needs methylcobalamin as a cofactor. This enzyme is involved in the conversion of the amino acid homocysteine into methionine which is, in turn, required for DNA methylation. The other form, 5-deoxyadenosylcobalamin, is a cofactor needed by the enzyme that converts L-methylmalonyl-CoA to succinyl-CoA. This conversion is an important step in the extraction of energy from proteins and fats. Furthermore, succinyl CoA is necessary for the production of hemoglobin, the substance that carries oxygen in red blood cells.

Vitamin B12, or methylcobalamin, is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for methylcobalamin. Vitamin B12 can be converted to coenzyme B12 in tissues; in this form it is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine (a reaction which also requires folate). In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage (which begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head). Vitamin B12 requires an intrinsic factor-mediated active transport for absorption, therefore, lack of or inhibition of intrinsic factor results in pernicious anemia.

Ascorbic Acid

Ascorbic acid is necessary for collagen formation (e.g., connective tissue, cartilage, tooth dentin, skin, and bone matrix) and tissue repair. It is reversibly oxidized to dehydroascorbic acid. Both forms are involved in oxidation-reduction reactions. Vitamin C is involved in the metabolism of tyrosine, carbohydrates, norepinephrine, histamine, and phenylalanine. Other processes that require ascorbic acid include biosynthesis of corticosteroids and aldosterone, proteins, neuropeptides, and carnitine; hydroxylation of serotonin; conversion of cholesterol to bile acids; maintenance of blood vessel integrity; and cellular respiration. Vitamin C may promote resistance to infection by the activation of leukocytes, production of interferon, and regulation of the inflammatory process. It reduces iron from the ferric to the ferrous state in the intestine to allow absorption, is involved in the transfer of iron from plasma transferrin to liver ferritin, and regulates iron distribution and storage by preventing the oxidation of tetrahydrofolate. Ascorbic acid enhances the chelating action of deferoxamine during treatment of chronic iron toxicity (see Interactions). Vitamin C may have a role in the regeneration of other biological antioxidants such as glutathione and α-tocopherol to their active state.

Ascorbate deficiency lowers the activity of microsomal drug-metabolizing enzymes and cytochrome P-450 electron transport. In the absence of vitamin C, impaired collagen formation occurs due to a deficiency in the hydroxylation of procollagen and collagen. Non-hydroxylated collagen is unstable, and the normal processes of tissue repair cannot occur. This results in the various features of scurvy including capillary fragility manifested as hemorrhagic processes, delayed wound healing, and bony abnormalities.

Currently, the use and dosage regimen of vitamin C in the prevention and treatment of diseases, other than scurvy, is unclear. Although further study is needed to recommend vitamin C therapy for the following ailments, recent data indicate a positive role for vitamin C for: overall increased mortality; the prevention of coronary heart disease (especially in women); management of diabetes mellitus; reducing the risk of stroke; management of atherosclerosis in combination with other antioxidants; osteoporosis prevention; reducing the risk of Alzheimer disease in combination with vitamin E; and the prevention of cataracts. In humans, an exogenous source of ascorbic acid is required for collagen formation and tissue repair.

Chromium

Chromium, in its trivalent state (i.e., Cr3+), is an essential trace element that is required for proper carbohydrate, lipid, and nucleic acid metabolism in the human body. Dietary sources of chromium (Cr3+) include whole grains, egg yolks, brewer’s yeast, liver, meats, nuts, potatoes with skin, and beer. Overt signs and symptoms of chromium deficiency are usually only observed in adult patients eating diets high in refined foods or who are receiving long-term total parenteral nutrition without chromium supplementation. Clinically, overt deficiencies may be detected as the development of impaired glucose tolerance, glycosuria, and insulin resistance. Impaired protein and lipid metabolism, peripheral neuropathy, and encephalopathy secondary to chromium deficiency have also been reported. Chromium supplementation should only be expected to improve disorders that are due to chromium deficiency. Limited studies have reported that the addition of chromium picolinate supplements to the dietary regimens of patients with type 2 or steroid-induced diabetes mellitus may result in improvements in glycemic control and cholesterol in some patients, and may allow for the reduction of antidiabetic medication. However, these trials have studied few patients; the importance of chromium deficiency in the average patient with type 2 diabetes has not been established. Controversy exists concerning other claimed benefits of chromium supplementation. Among athletes, chromium is promoted as an alternative to anabolic steroids. Multiple studies have concluded that there is no evidence that chromium supplementation increases muscle mass to a level greater than that which is produced with a healthy diet and exercise alone. There also appears to be no basis for claims that chromium reduces body-fat or weight. Clinical studies of chromium intake have revealed no additional changes in body-fat percentages or weight loss in either obese females or young athletes following controlled diet and exercise regimens. Other claimed uses, such as the adjunctive treatment to medical therapy for gestational diabetes after the 1st trimester or the adjunctive treatment of dysthymic disorder, are not accepted at this time. In the US, sales of chromium picolinate supplements exceed 150-million dollars per year.

Phentermine

Phentermine is administered orally. The rate and extent of phentermine exposure under fasting conditions is equivalent regardless of oral formulation administered.

Limited data exist on the pharmacokinetics of phentermine. Phentermine is primarily excreted by the kidneys. The elimination half-life ranges 19—24 hours and is influenced by urinary pH. Because the pKa of phentermine is 9.84, the elimination half-life decreases to about 7—8 hours under acidic urinary conditions.

Route-Specific Pharmacokinetics:

Oral Route: Following oral administration, most absorption of phentermine occurs from the small intestine. The duration of action following administration of the 8 mg capsules or tablets is about 4 hours and 12—14 hours after administration of the 30 mg capsules or the 37.5 mg tablets.

Phentermine oral disintegrating tablet (ODT) reaches peak concentrations (Cmax) 3—4.4 hours post-administration. Water ingestion prior to swallowing the ODT did not affect the AUC. Despite a decrease in the Cmax (approximately 5%) and AUC (approximately 12%) when phentermine ODT was administered after a high fat/high calorie breakfast, phentermine ODT can be administered with or without food. The Cmax and AUC were decreased by approximately 7% and 8%, respectively, when the ODT was swallowed without prior disintegration.

Special Populations:

Renal Impairment: Use with caution in patients with renal impairment. Cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions is 62—85%, and exposure increases can be expected in patients with renal impairment.

Dexpanthenol

Dexpanthenol is administered via IM or IV injection. Per the manufacturer, the pharmacokinetics of dexpanthenol in humans are not known.

Pyridoxine

Pyridoxine is administered orally and by intramuscular or intravenous injection. Vitamin B6 is stored in the liver, with small amounts in the brain and muscles. The total body storage for adults is between 16—27 mg. Pyridoxal crosses the placenta, with fetal concentrations five times that of maternal plasma concentrations. Pyridoxal and pyridoxal phosphate are the primary forms of vitamin B6 in the blood. Pyridoxal phosphate is 100% protein-bound. The half-life of pyridoxine is 15—20 days. Conversion of pyridoxine to pyridoxal phosphate, and pyridoxamine to pyridoxamine phosphate takes place in erythrocytes. Pyridoxine is also phosphorylated in the liver. Pyridoxal is oxidized in the liver to produce 4-pyridoxic acid, which is excreted in the urine.

All forms of orally administered vitamin B6 are absorbed in the small intestine, mainly in the upper jejunum. Orally administered pyridoxine has a bioavailability of 61% to 81%. Pyridoxine is rapidly taken up by mucosal cells lining the small intestine via active transport and diffusion. Once inside the cell, pyridoxine is phosphorylated by ATP-dependent pyridoxine kinase into pyridoxal 5-phosphate (PLP), preventing its transport out of the cell. PLP needs to be dephosphorylated in order to be transported across the basolateral membrane of mucosal cells and into the bloodstream. In circulation, PLP binds to albumin and is concentrated in red blood cells by binding to hemoglobin. PLP is mainly metabolized in the liver to 4-pyridoxic acid, which is then excreted through urine. In adults, the half-life of pyridoxine is 15 to 20 days.

Bioavailability of parenterally administered pyridoxine was greater than oral administration. Intravenously infused pyridoxine is not protein-bound and easily penetrates cell membranes. When administered as an IV infusion of 100 mg pyridoxine hydrochloride over 6 hours, pyridoxine rapidly reached steady-state concentration in the plasma. High amounts of PLP were detected in plasma and concentrated in erythrocytes. Approximately 63% of the infused dose was excreted in urine as 4-pyridoxic acid, while less than 7% was excreted unchanged as pyridoxine.

Biotin

The mechanism of biotin transport is not fully understood. An acid anion carrier is thought to be the primary transporter of biotin into liver cells. It is known that biotin is taken up by the placenta and transported to the fetus, with no harm to the fetus. About half of the biotin consumed is metabolized into bisnorbiotin and biotin sulfoxide before being excreted. The urinary excretion and serum concentrations of biotin and its metabolites increase in about the same proportion whether biotin is given orally or intravenously.

Folic Acid

Folic acid is administered orally and parenterally. Folic acid congeners are extensively bound to plasma proteins and are distributed throughout the body including the CSF. They also appear in breast milk. After administration of small doses, reduction and methylation of folic acid to methyltetrahydrofolate occurs in the liver. Following large doses, folic acid may appear unchanged in the plasma. Active forms of folic acid are reabsorbed through enterohepatic recirculation. Folic acid is eliminated primarily renally as metabolites. When body stores become saturated, excess folic acid is excreted unchanged in the urine.

Methylcobalamin

Methylcobalamin is administered intranasally, orally, and parenterally, while hydroxocobalamin is administered only parenterally. Once absorbed, vitamin B12 is highly bound to transcobalamin II, a specific B-globulin carrier protein and is distributed and stored primarily in the liver as coenzyme B12. The bone marrow also stores a significant amount of the absorbed vitamin B12. This vitamin crosses the placenta and is distributed into breast milk. Enterohepatic recirculation conserves systemic stores. The half-life is about 6 days (400 days in the liver). Elimination is primarily through the bile; however, excess methylcobalamin is excreted unchanged in the urine.

Intramuscular Route Specific Pharmacokinetics: Bioavailability of the nasal gel and spray forms relative to an IM injection are about 9% and 6%, respectively. Because the intranasal forms have lower absorption than the IM dosage form, intranasal B12 forms are administered once weekly. After 1 month of treatment in pernicious anemia patients, the once weekly dosing of 500 mcg B12 intranasal gel resulted in a statistically significant increase in B12 levels when compared to a once monthly 100 mcg IM dose.

Route-Specific Pharmacokinetics:

Intravenous Route: Peak plasma levels of cyanocobalamin are attained within 1 hour for parenteral doses.

Ascorbic Acid

Vitamin C is administered orally and by intramuscular, subcutaneous, or intravenous injection. The bioavailabilities of vitamin C from foods and supplements are similar; however, the bioavailability of vitamin C in foods is variable as it is easily degraded with cooking, processing, or the addition of preservatives (e.g., sodium bicarbonate). Approximately 70—90% of the usual dietary intake of ascorbic acid (30—180 mg/day) is absorbed, although absorption falls to <= 50% with doses above 1 g/day or in patients with GI disease (e.g., short bowel syndrome). Due to homeostatic regulation, the biological half-life of ascorbate varies widely from 8—40 days and is inversely related to body stores. Total body stores are approximately 1.5 g of ascorbic acid, with a daily turnover of 30—45 mg. Scurvy symptoms are associated with total body stores of < 300 mg and 3—5 months of deficient vitamin C intake. High levels of ascorbate are maintained in the pituitary and adrenal glands, leukocytes, eye tissues and humors, and the brain. Vitamin C crosses the placenta and is distributed into breast milk (see Contraindications).

Most ascorbic acid is reversibly oxidized to dehydroascorbic acid. The remainder is metabolized to the inactive metabolites (ascorbic acid-2-sulfate and oxalic acid) which are excreted in the urine. Unmetabolized ascorbate is not excreted with normal dietary intake (<= 80 mg/day); however, renal excretion increases proportionately with higher intake. When body stores become saturated, excess ascorbic acid is excreted unchanged in the urine; this is the basis for the ascorbic acid saturation test for vitamin C nutritional status. With large oral doses, unabsorbed ascorbate is degraded in the intestine, which may be the cause of diarrhea and intestinal discomfort.

Of note, tobacco smoking increases oxidative stress and metabolic turnover of vitamin C, thereby increasing the suggested daily intake of vitamin C in smokers.

Chromium

Chromium is administered intravenously as chromic chloride after dilution with compatible intravenous fluids and orally as trivalent chromium (Cr3+) formulated as the picolinate and nicotinate salts. Intestinal absorption of trivalent chromium from the diet is normally low (i.e., 0.5—10% of food chromium content). Atomic absorption spectrometry can accurately assess chromium levels in blood, urine, or hair, but results cannot be related to the amount of total chromium in tissue stores. Chromium appears to be distributed throughout body tissues. The metabolism of chromium in the body is still poorly understood. Diurnal variations in serum chromium occur secondary to the ingestion of meals and the subsequent increase in insulin secretion. Most chromium ingested in the diet or as supplements is excreted renally via glomerular filtration or via a low-molecular-weight organic transport system; the exact route of renal excretion is not clear but appears to approximate a two-compartment model. Normal renal excretion of chromium is < 1 mcg/24 hours. However, urinary excretion may be increased to 3—50 mcg/24 hour with chromium supplementation above dietary intake. Small amounts of chromium are excreted in the bile and small intestine.

Route-Specific Pharmacokinetics

Oral Route: Oral supplements of trivalent chromium (Cr3+) are formulated as the picolinate and nicotinate salts to improve bioavailability (i.e., roughly 10—50% bioavailable).

Phentermine

Phentermine is contraindicated for use in any patient with a prior history of sympathomimetic amine hypersensitivity.

According to the manufactures of phentermine capsules and tablets, its products are contraindicated in patients with cardiac disease, advanced arteriosclerosis, moderate to severe hypertension, agitated states, or glaucoma. Likewise, orally disintegrating tablets, are contraindicated in patients with a history of cardiac disease including coronary artery disease, stroke, cardiac arrhythmias, heart failure, and uncontrolled hypertension. Valvular heart disease has been reported in women receiving the combination of fenfluramine and phentermine; the safety and efficacy of combination therapy with phentermine and any other drug products for weight loss, including selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of these drug products for weight loss is not recommended. Further, primary pulmonary hypertension (PPH) has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between the use of phentermine alone and PPH or valvular heart disease cannot be ruled out. The initial symptom of PPH is usually dyspnea. Other initial symptoms include: angina pectoris, syncope, or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or lower extremity edema.

Because phentermine is a sympathomimetic agent, it is contraindicated in patients with hyperthyroidism. It should also be used with caution in patients with thyroid disease.

Phentermine is contraindicated for use during or within 14 days following the use of MAOI therapy or other drugs with MAO-inhibiting activity. Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine.

Phentermine is contraindicated in patients with agitated states.aggravate these effects or cause an adverse drug reaction. Symptoms of chronic intoxication include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from other psychotic disorders, like schizophrenia. Phentermine could aggravate certain mental conditions, such as those patients who exhibit highly nervous or agitated behavior, including psychosis, mania, or severe anxiety.

The use of phentermine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Advise patients to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and/or motor performance. In general, ethanol ingestion may aggravate these effects or cause an adverse drug reaction. Advise patients to avoid alcohol while taking phentermine.

Use phentermine cautiously in patients with diabetes mellitus. Insulin or other antidiabetic medication requirements may be altered in these patients when using phentermine during weight loss and due to altered dietary regimens. Patients should monitor their blood glucose regularly and follow the recommendations of their health care provider.

Appetite suppressant therapy is not recommend for use in those patients with a history of anorexia nervosa or other eating disorders. Use of phentermine is contraindicated in patients with a known history of drug or substance abuse. Phentermine is chemically and pharmacologically related to the amphetamines which have been extensively abused. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion.

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy. Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.

Abrupt discontinuation of phentermine after prolonged high doses may result in severe mental depression or extreme fatigue; sleep EEG changes have also been noted. Gradual withdrawal of therapy is recommended. If immediate discontinuation is medically necessary, careful monitoring and symptom management is warranted.

Phentermine is contraindicated during breastfeeding. It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breastfeeding while taking phentermine is not recommended.

Safety and effectiveness of phentermine in children have not been established. Phentermine is not recommended for children or adolescents 16 years of age and under. There is no established use of phentermine in infants or neonates.

The debilitated or geriatric patient may be more susceptible to the CNS and sympathomimetic side effects of phentermine; use with caution in elderly patients. Patients with renal impairment may also be more susceptible to side effects. Exposure increases can be expected in patients with renal impairment or renal failure. Use caution when administering phentermine to patients with renal impairment.

The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of sympathomimetic drugs. Because of this, and its effects on blood pressure, in general, phentermine should be discontinued several days prior to surgery. Avoid abrupt discontinuation.

Dexpanthenol

Some rare cases of allergic reactions have been reported when taking dexpanthenol injection in combination with drugs such as antibiotics, narcotics, and barbiturates.

Use dexpanthenol only if clearly needing during pregnancy; animal reproductive studies have not been conducted. Dexpanthenol is a FDA pregnancy risk category C drug.

It is not known whether dexpanthenol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dexpanthenol is administered to a woman who is breastfeeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Use caution in the management of adynamic ileus which may include the correction of any fluid and electrolyte imbalance (especially hypokalemia), anemia and hypoproteinemia, treatment of infection, and avoidance of drugs which are known to decrease gastrointestinal motility.

If the ileus is secondary to a mechanical GI obstruction, primary attention should be directed to treating the obstruction.

Pyridoxine

This medication is contraindicated in individuals with hypersensitivity to pyridoxine or any inactive ingredients in the parenteral formulation.

Parenteral pyridoxine solutions contain varying concentrations of aluminum. Patients with renal impairment, especially as seen in premature neonates, are at risk of aluminum accumulation which may result in toxicity. Limit intravenous pyridoxine therapy and consider the cumulative aluminum content among all therapies under administration in patients with renal impairment. It is noted that 4—5 mcg/kg/day of IV aluminum leads to accumulation at concentrations associated with CNS and bone toxicity; further, aluminum tissue loading is possible at lesser, but undefined, daily administration rates.  Aluminum concentration in parenteral solutions can be obtained by direct manufacturer inquiry.

Pyridoxine may reduce the efficacy of levodopa by accelerating its metabolism. However, it may be used concurrently in patients receiving combination carbidopa and levodopa therapy. Pyridoxine may also inhibit the effectiveness or duration of action of altretamine, barbiturates, and anticonvulsant medications.

Pyridoxine hydrochloride injection may be administered via intravenous (IV) or intramuscular (IM) routes. Administer as a direct IV injection or as an intermittent IV infusion in a standard IV solution. For IM administration, inject into a large muscle and rotate injection sites to avoid injury or discomfort upon repeated use.

Biotin

Biotin in blood or other samples taken from patients who are ingesting higher biotin dosages (i.e., doses of 10 to 300 mg biotin/day) in dietary supplements, including multivitamins, prenatal vitamins, and supplements for hair, skin, and nail growth, can cause clinically significant incorrect lab test results (falsely high or falsely low results) in assays that use biotin-streptavidin technology. Adverse events, including one death, related to biotin interference with lab tests have been reported. Specifically, biotin lab interference has caused falsely low troponin results, which may lead to missed diagnosis and potentially serious clinical implications. One patient taking high levels of biotin died following falsely low troponin test results when a troponin test known to have biotin interference was used. Some lab test developers have been successful at mitigating the biotin interference in their assays, while others may have not addressed this. Health care providers should be aware that many lab tests, including but not limited to, cardiovascular diagnostic tests and hormone tests that use biotin technology, may be affected. Discuss dietary supplement intake, particularly those that may contain biotin, with patients and communicate to the lab conducting testing if the patient reports taking biotin containing supplements. Consider laboratory test interference from biotin as a possible source of error if the lab test result does not match the clinical presentation of the patient and report any adverse events thought to be due to biotin interference to the lab test manufacturer and the FDA. One patient reportedly had abnormal thyroid function tests (TFTs) that did not match the clinical context after starting biotin. Within 3 days of stopping supplementation with biotin, repeated TFTs were normal. Then, biotin was reintroduced to the same patient, and TFTs taken 16 hours after the last dose and after an overnight fast showed further evidence of biotin immunoassay interference.

Biotin during pregnancy at the recommended adequate intake (AI) is recommended. Supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed and no deficiency has been diagnosed.

Breastfeeding females may consume biotin within the recommended adequate intake (AI) parameters. Supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed and no deficiency has been diagnosed.

Folic Acid

Folic acid is contraindicated for use in patients with folic acid hypersensitivity.

Folic acid should be used with extreme caution in patients with undiagnosed anemia. Folic acid corrects the hematologic manifestations of pernicious anemia, while the neurologic complications progress, potentially causing irreversible central nervous system effects. Doses greater than 0.4 mg/day should be avoided until the diagnosis of pernicious anemia is ruled out.

Many formulations of folic acid injection contain benzyl alcohol as a preservative. Benzyl alcohol may cause allergic reactions. Folic acid injections should be used cautiously in those patients with benzyl alcohol hypersensitivity. Injectable folic acid preparations containing benzyl alcohol should be avoided in neonates because benzyl alcohol has been associated with ‘gasping syndrome,’ a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction. Additionally, the injection products may contain aluminum which may reach toxic concentrations with prolonged administration in patients with impaired renal function or in premature neonates with immature kidneys. Premature neonates may also be at particular risk because they may require large amounts of calcium and phosphate solutions, which also contain aluminum.

Appropriate maternal folic acid intake is essential to the fetus during pregnancy, and no problems with maternal supplementation to achieve adequate intake goals are known. There is significant evidence that fetal neural tube defects can be prevented if folic acid therapy is initiated before pregnancy and continued during pregnancy. Based on evidence from clinical studies, the USPHS, AAP, and ACOG recommend a folic acid intake of 0.4 mg/day PO from food and/or supplements in females during the child-bearing years, and 0.6 mg PO daily throughout pregnancy. Additionally, data indicate that women with previous neural tube defect (NTD) affected pregnancies should increase their folic acid intake to 4 mg/day PO during the period of greatest risk (1 month before and the 3 months after conception). An optimum dosage has not been established; the lowest effective dose for preventing recurrent NTDs is unknown.

Appropriate maternal folic acid intake is important during lactation, and no problems have been identified with supplementation to achieve adequate intake goals during breastfeeding. The American Academy of Pediatrics (AAP) considers folic acid supplementation compatible with breastfeeding.

The folic acid injection products may contain aluminum which may reach toxic concentrations with prolonged administration in patients with renal failure, renal disease, renal impairment, or in premature neonates with immature kidneys.

Methylcobalamin

Who should not take this medication? Patients with early hereditary optic nerve atrophy, cyanocobalmin hypersensitivity, and those who are pregnant. Your health care provider needs to know if you have any of these conditions: kidney disease; Leber’s disease; megaloblastic anemia; an unusual or allergic reaction to methylcobalamin, cobalt, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breastfeeding.

Methylcobalamin is contraindicated in patients with methylcobalamin hypersensitivity or hypersensitivity to any of the medication components. Methylcobalamin is also contraindicated in patients with cobalt hypersensitivity because methylcobalamin contains cobalt. In the case of suspected cobalt hypersensitivity, an intradermal test dose should be administered because anaphylactic shock and death have followed parenteral administration of methylcobalamin.

Methylcobalamin should not be used in patients with early hereditary optic nerve atrophy (Leber’s disease). Optic nerve atrophy can worsen in patients whose methylcobalamin levels are already elevated. Hydroxocobalamin is the preferred agent in this patient population (see separate monograph in Less Common Drugs).

Most formulations of methylcobalamin injection contain benzyl alcohol as a preservative. Benzyl alcohol may cause allergic reactions. Methylcobalamin injections should be used cautiously in those patients with benzyl alcohol hypersensitivity. Methylcobalamin, vitamin B12 preparations containing benzyl alcohol should be avoided in premature neonates because benzyl alcohol has been associated with ‘gasping syndrome,’ a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction.

Vitamin B12 deficiency can suppress the symptoms of polycythemia vera. Treatment with methylcobalamin or hydroxocobalamin may unmask this condition.

Folic Acid, vitamin B9 is not a substitute for methylcobalamin, vitamin B12 deficiency, although it may improve vitamin B12 megaloblastic anemia. However, exclusive use of folic acid in treating vitamin B12 deficient megaloblastic anemia could result in progressive and irreversible neurologic damage. Before receiving folic acid or methylcobalamin, patients should be assessed for deficiency and appropriate therapy started concurrently. The intranasal formulations are not approved to treat acute B12 deficiency; all hematologic parameters should be normal before beginning the methylcobalamin intranasal formulations. Concurrent iron-deficiency anemia and folic acid deficiency may result in a blunted or impeded response to methylcobalamin therapy.

Certain conditions may blunt or impede therapeutic response to methylcobalamin therapy. These include serious infection, uremia or renal failure, drugs with bone marrow suppression properties (e.g., chloramphenicol), or concurrent undiagnosed folic acid or iron deficiency anemia. The mechanism appears to be interference with erythropoiesis. Patients with vitamin B12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of methylcobalamin.

Clinical reports have not identified differences in responses between elderly and younger patients. Generally, dose selection for elderly patients should be done with caution. Elderly patients tend to have a greater frequency of decreased hepatic, renal, or cardiac function, and also have concomitant disease or receiving other drug therapy. Start with doses at the lower end of the dosing range.

Ascorbic Acid

Ascorbic acid should not be ingested 48—72 hours before amine-dependent stool occult blood tests are conducted because false negatives may occur.

Chronic, excessive doses of ascorbic acid can cause an increase in its own metabolism, which can cause scurvy if normal and supplemental intake are significantly reduced or discontinued. Large doses can also increase the likelihood of oxalate stones in the urinary tract in patients with a history of nephrolithiasis, hyperoxaluria, or oxalosis.

Large IV or oral doses of ascorbic acid have caused hemolytic anemia in some patients with G6PD deficiency (glucose-6-phosphate dehydrogenase deficiency).

High doses of ascorbic acid may interfere with urinary glucose determinations using the glucose oxidase method. Patients with diabetes mellitus should be made aware of the possibility of falsely decreased glucose concentrations with these tests.

Ascorbic acid may increase the risk of iron toxicity in patients with hemochromatosis, therefore, patients with hemochromatosis should limit their intake of ascorbic acid to no more than 500 mg/day. Rarely, ingestion of large quantities of ascorbic acid have been associated with fatal cardiac arrhythmias in patients with iron overload.

Patients with anemia (e.g., sideroblastic anemia, thalassemia) may experience decreased iron absorption during high dose ascorbic acid therapy. High doses of ascorbic acid may precipitate a crisis in patients with sickle cell anemia.

Chromium

Some chromium products are not for human use or ingestion. Chromium products labeled for industrial or craft use can be very toxic. A case of mistaken ingestion of a chromium-containing leather tanning solution by a patient has been reported. Patients should not take chromium products that are not labeled for use as nutritional supplements. If accidental exposure to such a product occurs, the patient should be instructed to contact a local poison control center and health care professional immediately.
Parenteral chromium products must be diluted prior to intravenous administration. Direct intravenous injection or intramuscular administration is contraindicated, as the acidic pH of the parenteral chromium solution may cause considerable tissue necrosis.

Some parenteral chromium and trace element products contain benzyl alcohol and should be avoided in patients with a history of benzyl alcohol hypersensitivity. Because benzyl alcohol has been associated with a ‘gasping syndrome’ in neonates, excessive exposure to benzyl alcohol containing products should be avoided.

Patients with diabetes mellitus should pursue chromium supplementation with products such as chromium picolinate only under the supervision and advice of a qualified health care professional. Chromium supplementation may influence serum blood glucose concentrations and hemoglobin A(1c) levels; medications used for the treatment of diabetes may need dosages adjusted during chromium use. Frequent monitoring of blood sugar and other clinical parameters is recommended. Patients with diabetes should be well-versed in the detection and management of hypoglycemia.
Chromium elimination may be decreased in patients with renal disease or renal impairment. Dosage reductions in supplemental parenteral or oral doses may be needed. Since chromium is primarily excreted via the renal route, supplementation should be approached with caution, particularly in patients maintained on dialysis or with renal failure.
There is insufficient clinical data to promote chromium’s role in obesity treatment at this time. In limited but controlled clinical trials, chromium does not appear to induce significant effects on body-fat composition or weight loss.

The use of oral chromium supplements in children, like chromium picolinate, is not recommended. If dietary intakes of chromium are judged to be insufficient, the use of a general multivitamin and mineral supplement formulated for children should provide the needed nutritional supplementation (i.e., the estimated adequate intake or AI). Chromium supplementation has only been established for children receiving maintenance nutrition with parenteral nutritional formulas (TPN) to prevent or treat chromium deficiency.

Use of chromium within the recommended daily dietary intake for lactating women is generally recognized as safe. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Parenteral chromium injections are classified in FDA pregnancy category C. The use of chromium in pregnancy is only established for the prevention of chromium deficiency in patients maintained on parenteral nutritional formulas (TPN). Other claimed uses for chromium, such as the use of chromium picolinate for the adjunctive treatment of gestational diabetes, are not recommended; safety and efficacy have not been established in these patients at this time. Currently available studies have not been well controlled and have not established the safety or efficacy of chromium intake in excess of the estimated adequate intake (AI) during pregnancy. Adverse effects have not been reported with the normal daily intake of chromium within the recommended dietary daily intakes for a pregnant female. The use of chromium in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.

Phentermine

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy. Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.

Dexpanthenol

Use dexpanthenol only if clearly needing during pregnancy; animal reproductive studies have not been conducted. Dexpanthenol is a FDA pregnancy risk category C drug.

Pyridoxine

Appropriate maternal pyridoxine intake is encouraged during pregnancy (FDA pregnancy risk category A), and the requirement for pyridoxine appears to be increased during pregnancy. Pyridoxine (up to 40 mg/day) in combination with doxylamine is FDA-approved for the treatment of pregnancy-induced nausea and vomiting. No increased risk for malformations from first trimester exposures to doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride was noted in a meta-analysis. Further, no statistically significant relationships between fetal abnormalities and the first trimester use of the combination doxylamine succinate and pyridoxine hydrochloride with or without dicyclomine hydrochloride were noted in a separate meta-analysis.

The requirement for vitamin B6 increases during pregnancy and lactation. The use of vitamin B6 supplements to reduce nausea and vomiting in pregnant women has yielded mixed results. Two randomized controlled trials reported that 30 to 75 mg oral pyridoxine per day significantly reduced nausea in pregnant women. However, a systematic review of 27 studies found limited evidence to support the benefits of pyridoxine for treating morning sickness. Greater benefits have been observed with an oral combination of vitamin B6 and doxylamine. Nonetheless, the American Congress of Obstetrics and Gynecology recommends starting with a daily dose of 10 to 25 mg of pyridoxine three to four times a day, and only adding doxylamine if monotherapy fails to confer any benefits.

Biotin

Biotin during pregnancy at the recommended adequate intake (AI) is recommended. Supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed and no deficiency has been diagnosed.

Folic Acid

Appropriate maternal folic acid intake is essential to the fetus during pregnancy, and no problems with maternal supplementation to achieve adequate intake goals are known. There is significant evidence that fetal neural tube defects can be prevented if folic acid therapy is initiated before pregnancy and continued during pregnancy. Based on evidence from clinical studies, the USPHS, AAP, and ACOG recommend a folic acid intake of 0.4 mg/day PO from food and/or supplements in females during the child-bearing years, and 0.6 mg PO daily throughout pregnancy. Additionally, data indicate that women with previous neural tube defect (NTD) affected pregnancies should increase their folic acid intake to 4 mg/day PO during the period of greatest risk (1 month before and the 3 months after conception). An optimum dosage has not been established; the lowest effective dose for preventing recurrent NTDs is unknown.

Methylcobalamin

Parenteral methylcobalamin is classified as pregnancy category C. Adequate studies in humans have not been conducted; however, no maternal or fetal complications have been associated with doses that are recommended during pregnancy, and appropriate treatment should not be withheld from pregnant women with vitamin B12 responsive anemias. Conversely, pernicious anemia resulting from vitamin B12 deficiency may cause infertility or poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breastfed infants of vegetarian mothers whose diets contain no animal products (e.g., eggs, dairy), even though the mothers had no symptoms of deficiency at the time. Maternal requirements for vitamin B12 increase during pregnancy. The usual daily recommended amounts of methylcobalamin, vitamin B12 either through dietary intake or supplementation should be taken during pregnancy.

Ascorbic Acid

Ascorbic acid, vitamin C is classified as pregnancy category C. Umbilical cord blood concentrations are 2—4 times higher than those of maternal plasma levels. Adverse effects have not been reported with the normal daily intake of ascorbic acid, vitamin C within the recommended dietary daily intakes for a pregnant female. The use of ascorbic acid, vitamin C in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.

Chromium

Parenteral chromium injections are classified in FDA pregnancy category C. The use of chromium in pregnancy is only established for the prevention of chromium deficiency in patients maintained on parenteral nutritional formulas (TPN). Other claimed uses for chromium, such as the use of chromium picolinate for the adjunctive treatment of gestational diabetes, are not recommended; safety and efficacy have not been established in these patients at this time. Currently available studies have not been well controlled and have not established the safety or efficacy of chromium intake in excess of the estimated adequate intake (AI) during pregnancy. Adverse effects have not been reported with the normal daily intake of chromium within the recommended dietary daily intakes for a pregnant female. The use of chromium in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits in a specific, unique case outweigh the significant hazards involved.

Phentermine

Phentermine is contraindicated during breastfeeding. It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breastfeeding while taking phentermine is not recommended.

Dexpanthenol

It is not known whether dexpanthenol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dexpanthenol is administered to a woman who is breastfeeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Pyridoxine

Pyridoxine is excreted in human milk. Appropriate maternal intake of pyridoxine (vitamin B6) is important during lactation, and no problems have been identified with maternal supplementation to achieve adequate intake goals during breastfeeding. The American Academy of Pediatrics (AAP) has considered the use of pyridoxine compatible with breastfeeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Whether high doses of pyridoxine are effective in suppressing post-partum lactation has been tested. A systematic review of seven studies administered 450 to 600 mg pyridoxine orally for up to a week found the evidence inconclusive. Studies assessing pyridoxine safety found no untoward side effects. Pyridoxine levels in breast milk are associated with maternal pyridoxine intake. Pyridoxine supplementation during the first trimester of pregnancy was not associated with teratogenic effects in neonates.

Biotin

Breastfeeding females may consume biotin within the recommended adequate intake (AI) parameters. Supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed and no deficiency has been diagnosed.

Folic Acid

Appropriate maternal folic acid intake is important during lactation, and no problems have been identified with supplementation to achieve adequate intake goals during breastfeeding. The American Academy of Pediatrics (AAP) considers folic acid supplementation compatible with breastfeeding.

Methylcobalamin

Methylcobalamin is distributed into breast milk in amounts similar to those in maternal plasma, and distribution in breast milk allows for adequate intakes of methylcobalamin by breastfeeding infants. Adequate maternal intake is important for both the mother and infant during nursing, and maternal requirements for vitamin B12 increase during lactation. According to the manufacturer, the usual daily recommended amounts of methylcobalamin, vitamin B12 for lactating women should be taken maternally during breastfeeding (see Dosage). The American Academy of Pediatrics considers vitamin B12 to be compatible with breastfeeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Ascorbic Acid

Ascorbic acid, vitamin C is distributed into breast milk. Use of ascorbic acid, vitamin C within the recommended daily dietary intake for lactating women is generally recognized as safe. In mothers not taking vitamin C supplements, vitamin C in human milk in the first 6 months of lactation varied from 34—83 mg/L. In mothers taking vitamin C supplements ranging from 45 to > 1,000 mg/day, vitamin C content of human milk varied from 45—115 mg/L. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Chromium

Use of chromium within the recommended daily dietary intake for lactating women is generally recognized as safe. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Phentermine

The safety of phentermine when used with other anorexiant agents such as amphetamine, benzphetamine, dexfenfluramine, dextroamphetamine, diethylpropion, ephedrine, fenfluramine, and sibutramine is controversial and concurrent use should be avoided. The role of phentermine in the production of cardiac valvulopathy when combined with dexfenfluramine, fenfluramine, or other medications for weight loss is uncertain. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias. Similarly, because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics or psychostimulants for weight loss, including OTC preparations, and herbal products that may contain ephedra alkaloids or Ma huang.

Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.

Concurrent use of bromocriptine and some sympathomimetics such as phentermine should be approached with caution. One case report documented worsening headache, hypertension, premature ventricular complexes, and ventricular tachycardia in a post-partum patient receiving bromocriptine for lactation suppression who was subsequently prescribed acetaminophen; dichloralphenazone; isometheptene for a headache. A second case involved a post-partum patient receiving bromocriptine who was later prescribed phenylpropanolamine; guaifenesin and subsequently developed hypertension, tachycardia, seizures, and cerebral vasospasm.

In theory, an interaction is possible between cabergoline, an ergot derivative, and some sympathomimetic agents such as phentermine. Use of the ergot derivative bromocriptine for lactation suppression in conjunction with a sympathomimetic (i.e., isometheptene or phenylpropanolamine) for other therapeutic uses has resulted in adverse effects such as worsening headache, hypertension, ventricular tachycardia, seizures, sudden loss of vision, and cerebral vasospasm.

Concurrent use of dronabinol, THC or nabilone with sympathomimetics may result in additive hypertension, tachycardia, and possibly cardiotoxicity.

Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone, linezolid, or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine. Phenelzine and tranylcypromine appear to produce the greatest risk since these two MAOIs also have intrinsic amphetamine-like activity. In the presence of MAOIs, phentermine and other drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. It is unclear if selegiline, an inhibitor of MAO type B, can also predispose to this reaction. Phentermine should not be administered during or within 14 days following the use of most MAOIs or drugs with MAO-inhibiting activity. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious reactions with sympathomimetics are not ordinarily expected. However, because a case of elevated blood pressure occurred during use of rasagiline and a sympathomimetic ophthalmic preparation, caution is advised when rasagiline is administered with sympathomimetics.

The pressor response to some sympathomimetics is exaggerated in patients currently receiving tricyclic antidepressants. Concomitant use of tricyclic antidepressants with sympathomimetics, including phentermine, should be avoided whenever possible.

Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as guanadrel, guanethidine, methyldopa or reserpine. Phentermine may displace guanethidine from the neuron and antagonize the neuronal blockade caused by guanethidine. Concomitant use of phentermine with methyldopa or reserpine may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.

Use caution in combining phentermine with antidiabetic agents. Phentermine exhibits sympathomimetic activity. Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Diabetic patients may have decreased requirements of insulins, sulfonylureas, or other antidiabetic agents in association with the use of phentermine and the concomitant dietary regimen and weight loss. As long as blood glucose is carefully monitored to avoid hypoglycemia or hyperglycemia, it appears that phentermine can be used concurrently.

Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.

Concurrent use of phentermine and phenothiazines may antagonize the anorectic effects of phentermine. In addition, psychostimulants can aggravate psychotic states.

Although not studied, the concomitant use of ethanol and phentermine may result in an adverse reaction and should be avoided.

Phentermine, like other sympathomimetics, is contraindicated in selected patients with thyroid disease; caution should be used if coadministering thyroid hormones with phentermine.

Atomoxetine has been reported to increase blood pressure and heart rate, probably via inhibition of norepinephrine reuptake. Due to an additive pharmacodynamic effect, phentermine and atomoxetine should be used together cautiously, particular in patients with a history of cardiac disease. Consider monitoring heart rate and blood pressure at baseline and regularly throughout treatment if these agents must be used together.

Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, such as phentermine or the combination of phentermine; topiramate, may be associated with an increased seizure risk; therefore, seizures may be more likely to occur in patients receiving these weight loss aides with bupropion or bupropion-containing combinations. Other side effects might also occur, such as dizziness, blood pressure changes, or other side effects. Patients should be closely monitored if this combination is necessary. Do not combine therapy with phentermine or phentermine-combinations and bupropion; naltrexone due to this risk and the duplication of therapy for weight loss.

Due to the pharmacology of salmeterol, caution and close observation should also be used when fluticasone; salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects based on the pharmacology of salmeterol.

Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine’s effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.

Use phentermine and vortioxetine together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and the antidepressant fluoxetine. However, recent data suggest that phentermine’s effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.

Dexpanthenol

Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Acetaminophen; Codeine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Acetaminophen; Hydrocodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Acetaminophen; Oxycodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Acetaminophen; Propoxyphene: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Alfentanil: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Aspirin, ASA; Oxycodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Belladonna; Opium: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Chlorpheniramine; Codeine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Chlorpheniramine; Hydrocodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Codeine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of `dexpanthenol.

Codeine; Guaifenesin: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Codeine; Phenylephrine; Promethazine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Codeine; Promethazine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Fentanyl: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Guaifenesin; Hydrocodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Homatropine; Hydrocodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Hydrocodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Hydrocodone; Ibuprofen: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Hydrocodone; Phenylephrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Hydrocodone; Pseudoephedrine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Hydromorphone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Ibuprofen; Oxycodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Levorphanol: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Meperidine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Meperidine; Promethazine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Methadone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Morphine: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Morphine; Naltrexone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Opiate Agonists: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Oxycodone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Oxymorphone: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Propoxyphene: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Remifentanil: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Succinylcholine: (Minor) The effects of succinylcholine may be prolonged with dexpanthenol administration. It is recommended to separate doses of dexpanthenol and succinylcholine by at least 1 hour to decrease the potential for this effect.

Sufentanil: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.

Biotin

Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Phenobarbital use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like phenobarbital, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.

Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Phenobarbital use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like phenobarbital, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.

Carbamazepine: (Moderate) Carbamazepine use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like carbamazepine, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.

Ethanol: (Moderate) Excessive ethanol (e.g., alcoholism) may result in increased urinary excretion of magnesium. Avoid high intakes of ethanol while taking magnesium salts.

Food: (Minor) Dietary avidin, a glycoprotein in raw egg whites (food), binds tightly to dietary biotin and prevents its absorption in the gastrointestinal tract. Cooking denatures the avidin, disabling it from interfering with biotin absorption.

Fosphenytoin: (Moderate) Fosphenytoin use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like fosphenytoin, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.

Phenobarbital: (Moderate) Phenobarbital use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like phenobarbital, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.

Phenytoin: (Moderate) Phenytoin use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like phenytoin, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.

Primidone: (Moderate) Primidone use for greater than one year while taking biotin can lead to decreased concentrations of biotin. Anticonvulsants that are potent CYP3A4 inducers, like primidone, are thought to increase biotin metabolism, leading to reduced biotin status and inhibition of intestinal biotin absorption. This can result in decreased efficacy of biotin. Discuss biotin status with patients taking these medications concomitantly.

Methylcobalamin

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Several drugs, including para-aminosalicylic acid, have been reported to reduce the absorption of methylcobalamin, vitamin B12. Monitor for the desired therapeutic response to vitamin B12.

The heavy consumption of ethanol for greater than 2 weeks has been reported to reduce the absorption of Methylcobalamin, vitamin B12. Patients should be aware that heavy, chronic ethanol use may counteract the therapeutic effects of vitamin B12; such patients with regular and chronic ethanol consumption be monitored for the desired therapeutic response to vitamin B12.

Several drugs, including colchicine, have been reported to reduce the absorption of methylcobalamin, vitamin B12. Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. Although further study of these interactions is necessary, patients receiving these agents concurrently should be monitored for the desired therapeutic response to vitamin B12.

In a study of 10 healthy male volunteers, omeprazole, in doses of 20 mg—40 mg per day, caused a significant decrease in the oral absorption of methylcobalamin, vitamin B12. Theoretically this interaction is possible with other proton pump inhibitors (PPIs), although specific clinical data are lacking. Patients receiving long-term therapy with omeprazole or other proton pump inhibitors (PPIs) should be monitored for signs of B12deficiency.

Chloramphenicol can antagonize the hematopoietic response to Methylcobalamin, vitamin B12 through interference with erythrocyte maturation. Chloramphenicol is known to cause bone marrow suppression, especially when serum concentrations exceed 25 mcg/ml. Chloramphenicol should be discontinued if anemia attributable to chloramphenicol is noted during periodic blood studies, which should be done approximately every 2 days during chloramphenicol receipt. Aplastic anemia and hypoplastic anemia are known to occur after chloramphenicol administration. Peripherally, pancytopenia is most often observed, but only 1—2 of the major cell types (erythrocytes, leukocytes, platelets) may be depressed in some cases.

Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with Methylcobalamin, vitamin B12 supplementation. Certain individuals may be predisposed to this interaction. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.

Medications know to cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) may result in a blunted or impeded response to methylcobalamin, vitamin B12 therapy. Antineoplastics that are antimetabolites for the vitamin may induce inadequate utilization of vitamin B12. However, cancer patients usually benefit from vitamin B12 supplementation. The use of methotrexate may additionally invalidate diagnostic assays for folic acid and vitamin B12; however, this is a diagnostic laboratory test interference and not a drug interaction.

The intranasal forms of methylcobalamin, vitamin B12, should be administered at least 1 hour before or 1 hour after ingestion of hot food or liquids. Hot foods may cause nasal secretions and a resulting loss of medication or medication efficacy. Interactions between foods and oral or injectable forms of methylcobalamin are not expected.

Depressed levels of methylcobalamin, vitamin B12, and abnormal Schilling’s test have been reported in patients receiving octreotide.

The use of anti-infective agents or pyrimethamine may invalidate diagnostic assays for folic acid and vitamin B12; however, these are diagnostic laboratory test interferences and not true drug interactions.

Ascorbic Acid

Ascorbic acid is necessary for many physiologic functions, including the metabolism of iron. The absorption of nonheme iron (primarily from plant sources) from the intestinal tract depends on iron being in its reduced form. (Heme iron, found in meat, fish, and poultry, appears to be absorbed intact.) Ascorbic acid, by maintaining iron in the ferrous state, can enhance the absorption of oral iron, however, the magnitude of this increase is in the range of 10% and only occurs with doses of ascorbic acid, vitamin C of 500 mg or greater. Healthy individuals usually absorb iron supplements (e.g., iron salts or polysaccharide-iron complex) adequately from the GI tract, but some patients may benefit from receiving supplemental ascorbic acid with each oral iron dose.

Patients should be advised not to take ascorbic acid, vitamin C supplements along with deferoxamine chelation therapy unless such supplements are prescribed with the approval of their health care professional. Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. Vitamin C can be a beneficial adjunct in iron chelation therapy because it facilitates iron chelation and iron complex excretion. As an adjuvant to iron chelation therapy (e.g., deferoxamine), vitamin C (in doses up to 200 mg/day for adults, 50 mg/day in children < 10 years of age or 100 mg/day in older children) may be given in divided doses, starting after an initial month of regular treatment with deferoxamine. However, higher doses of ascorbic acid, vitamin C can facilitate iron deposition, particularly in the heart tissue, causing cardiac decompensation. In patients with severe chronic iron overload, the concomitant use of deferoxamine with > 500 mg/day PO of vitamin C in adults has lead to impairment of cardiac function; the dysfunction was reversible when vitamin C was discontinued. The manufacturer of deferoxamine recommends certain precautions for the coadministration of vitamin C with deferoxamine. First, vitamin C supplements should not be given concurrently with deferoxamine in patients with heart failure. Secondly, in other patients, such supplementation should not be started until 1 month of regular treatment with deferoxamine, and should be given only to patients receiving regular deferoxamine treatments. Do not exceed vitamin C doses of 200 mg/day for adults, 50 mg/day in children < 10 years of age, or 100 mg/day in older children, given in divided doses. Clinically monitor all patients, especially the elderly, for signs or symptoms of decreased cardiac function.

Phentermine

This medicine may be habit-forming with long-term use. Check medicines with healthcare provider. This medicine may not mix well with other medicines. Limit caffeine (for example, tea, coffee, cola) and chocolate intake. Use with this medicine may cause nervousness, shakiness, and fast heartbeat. Use birth control that you can trust to prevent pregnancy while taking this medicine.

Primary pulmonary hypertension, a rare and serious lung disease, has developed in patients who received a combination of phentermine along with fenfluramine or dexfenfluramine. Phentermine may cause this lung disease. This medicine may be habit-forming; avoid long-term use. Tell healthcare provider if you have a history of drug or alcohol abuse. May cause serious heart-related side effects. Tell healthcare provider if you have any heart disease.

If you suspect an overdose, call your local poison control center or emergency department immediately.Signs of a life-threatening reaction. These include wheezing; chest tightness; fever; itching; bad cough; blue skin color; fits; or swelling of face, lips, tongue, or throat. Severe behavioral problems. Chest pain or pressure or fast heartbeat. Severe dizziness or passing out. Very nervous and excitable. Severe headache. Any rash. No improvement in condition or feeling worse.

Phentermine

Central nervous system adverse reactions that have been reported in patients receiving phentermine include dizziness, dysphoria, euphoria, headache, insomnia, overstimulation, restlessness, and tremor. Psychosis at recommended doses may occur rarely in some patients.

Primary pulmonary hypertension (PPH) and cardiac valvulopathy (regurgitant cardiac valvular disease) have been reported with phentermine. The initial symptom of PPH is usually dyspnea; other initial symptoms include: angina pectoris, syncope, or peripheral edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or peripheral edema. Other cardiovascular adverse effects that have been reported include hypertension, ischemic events, palpitations, and sinus tachycardia.

Reported adverse gastrointestinal effects of phentermine include constipation, diarrhea, dysgeusia, nausea, and xerostomia.

Impotence (erectile dysfunction), libido increase, and libido decrease have been reported in patients receiving phentermine.

Urticaria has been reported in patients receiving phentermine.

Phentermine has not been systematically studied for its potential to produce dependence in obese patients treated with usual recommended dose ranges. Phentermine is related chemically and pharmacologically to the amphetamines, and these stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including this drug product as part of a weight reduction program. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with intense psychological dependence and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times than recommended. Physical dependence (physiological dependence) is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Limited data are available for phentermine. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram. Thus, in situations where rapid withdrawal is required, appropriate medical monitoring is recommended. Evidence-based data from the literature are relatively limited, and some experts suggest that long-term phentermine pharmacotherapy for obesity does not induce abuse or psychological dependence (addiction), drug craving, and that abrupt treatment cessation within the normal prescription dose range does not induce amphetamine-like withdrawal. More data are needed to confirm the dependence potential of phentermine-containing obesity products.

Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased. The maximum recommended dose should not be exceeded.

Dexpanthenol

There was a case report of respiratory depression following dexpanthenol administration.

Two patients experienced vomiting and diarrhea in the days following surgery and dexpanthenol administration.

There are minimal case reports of allergic reactions such as pruritus, urticaria, rash (unspecified), tingling, and difficulty breathing. If this occurs, dexpanthenol should be discontinued.

Pyridoxine

High doses of pyridoxine hydrochloride injection may cause adverse effects due to aluminum in the parenteral formulation. In patients with impaired kidney function and premature neonates, aluminum in the formulation may reach toxic levels upon prolonged parenteral administration. Severe sensory neuropathy has been reported in patients treated with 1 to 6 g/day of pyridoxine hydrochloride. The lowest dose at which sensory neuropathy has been observed is 500 mg/day. Therefore, the Food and Nutrition Board has set a safe upper limit of 100 mg/day of pyridoxine for adults. These upper limits do not apply to individuals administered pyridoxine for medical treatment under the supervision of a physician. Common adverse events at low doses of pyridoxine include indigestion, nausea, breast tenderness, photosensitivity, and vesicular dermatoses.

Pyridoxine is considered nontoxic in regular doses; however, nausea/vomiting, headache, paresthesias, hyperesthesia, somnolence, and low serum folic acid levels have been reported. Excessive, chronic dosages of pyridoxine (2—6 grams/day) have been associated with a severe sensory peripheral neuropathy or neuronopathy syndrome. This may result from neuron susceptibility in the dorsal root ganglia. One patient who consumed 5 g/day developed pseudoathetosis of the outstretched arms, ataxia, and absent limb reflexes. Seven months after discontinuation of high-dose pyridoxine, she felt much improved, could walk steadily without a cane, could stand with her eyes closed, but still had shooting pains in her calves and shins. Other patients who took several g/day for several months developed unstable gait, perioral numbness, and a “stocking-glove” sensory loss. Seizures have occurred following large IV doses of pyridoxine. Seizures in neonates have occurred following the use of large doses of pyridoxine during pregnancy. Adverse neurologic reactions with lower dosages have been reported less frequently.

A transient worsening of metabolic acidosis, which is frequently present in patients with seizures, may occur after rapid infusion of large pyridoxine doses. Pyridoxine injection is acidic (pH 2—3.8). In a randomized, controlled crossover trial of 5 adult patients, 5000 mg of pyridoxine administered over 5 minutes induced a significant but transient increase in the base deficit; mean maximal increase in base deficit was 2.74 mEq/L at 3 minutes after infusion. Resolution occurred 30 minutes after the infusion.

Biotin

Biotin has been very rarely associated with any adverse effects, even with high doses. There is one case report of life-threatening eosinophilic pleuro-pericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid for two months.

Folic Acid

Folic acid is relatively nontoxic in man. In rare instances, allergic or anaphylactoid reactions have been reported with folic acid use; other allergic reactions that have been reported include erythema, skin rash (unspecified), pruritus, general malaise, and respiratory difficulty due to bronchospasm.

Anorexia, nausea, abdominal distention, flatulence, and bitter or bad taste/dysgeusia have been reported in patients receiving 15mg of folic acid daily for 1 month.

Altered sleep patterns, difficulty concentrating, irritability, overactivity, excitability, mental depression, confusion and impaired judgement have all been reported in patients receiving 15 mg of folic acid daily for 1 month. Prolonged folic acid therapy may result in decreased vitamin B12 serum levels.

Methylcobalamin

In most cases, methylcobalamin is nontoxic, even in large doses. Adverse reactions reported following methylcobalamin administration include headache, infection, nausea/vomiting, paresthesias, and rhinitis. Adverse reactions following intramuscular (IM) injection have included anxiety, mild transient diarrhea, ataxia, nervousness, pruritus, transitory exanthema, and a feeling of swelling of the entire body. Some patients have also experienced a hypersensitivity reaction following intramuscular injection that has resulted in anaphylactic shock and death. In cases of suspected cobalt hypersensitivity, an intradermal test dose should be administered.

During the initial treatment period with methylcobalamin, pulmonary edema and congestive heart failure have reportedly occurred early in treatment with parenteral methylcobalamin. This is believed to result from the increased blood volume induced by methylcobalamin. Peripheral vascular thrombosis has also occurred. In post-marketing experience, angioedema and angioedema-like reactions were reported with parenteral methylcobalamin.

Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with methylcobalamin therapy. Therefore, monitoring of the platelet count and serum potassium concentrations are recommended during therapy. Polycythemia vera has also been reported with parenteral methylcobalamin.

Diarrhea and headache.

Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, swollen painful area on the leg.

Ascorbic Acid

Oxalate, urate, or cystine renal stones causing renal tubular obstruction, characterized by costovertebral pain or lower back pain, can occur following large doses of ascorbic acid. Hyperoxaluria develops in 5% of patients taking large doses. Patients at an increased risk are those with renal disease, on hemodialysis, or with a history of nephrolithiasis.

Ascorbic acid is generally nontoxic. Adverse reactions that have been reported include flushing, headache, nausea/vomiting, and abdominal cramps. Diarrhea has resulted from oral dosages of more than 1 gram daily. Dizziness and faintness can result from rapid administration of IV ascorbic acid.

Hemolytic anemia due to hemolysis has been observed in some patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency after receiving large IV or oral doses of ascorbic acid. In rare cases, sickle-cell crisis has occurred in patients with sickle cell disease because of decreased blood pH.

Excessive use of chewable ascorbic acid formulations can lead to dental caries or sensitivity from the breakdown of dental enamel.

Chromium

In a case report, rhabdomyolysis has been associated with ingestion of 1200 mcg of chromium for 2 days by an otherwise healthy body-builder. This above the recommended adequate oral intake (AI) of 200 mcg per day. Reported symptoms included dehydration, musculoskeletal pain, muscular weakness, and bilateral leg muscle cramps.

There is some initial evidence that picolinic acid, as part of the chromium picolinate salt, may generate hydroxy-radicals upon entry into cells and induce chromosomal changes. Further trials are needed to determine the safety of chromium picolinate. The clastogenesis of picolinic acid suggests the potential for the development of tumors.

Although chromium picolinate is thought to be safe, case reports of nephrotoxicity from oral supplementation have appeared in the medical literature. All subjects consumed doses well above the recommended adequate oral intake (AI) of 200 mcg per day. A dose of 600 mcg PO per day for 6 weeks reportedly resulted in chronic renal insufficiency and interstitial nephritis in one patient according to the case report. Acute renal failure (unspecified) and renal tubular necrosis have been reported secondary to chromium intake of 1200—2400 mcg PO per day for 4—5 months in another patient. Renal function returned to normal following medical treatment.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

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