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    Cyanocobalamin/Vitamin B12 and Analog Supplements
    Vitamin B Complex Supplement Combinations

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    Nasal/oral/parenteral B-vitamin found in a variety of foods such as fish, shellfish, meats, and dairy products. Equal in biologic activity to hydroxocobalamin. Used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test.

    COMMON BRAND NAMES

    B-12 Compliance Kit, B-12 Injection Kit, Cyomin, LA-12, Nascobal, Nutri-Twelve, Physicians EZ Use B-12, Primabalt

    HOW SUPPLIED

    B-12 Compliance Kit/B-12 Injection Kit/Cyanocobalamin (Vitamin B12)/Cyomin/LA-12/Nutri-Twelve/Physicians EZ Use B-12/Primabalt Intramuscular Inj Sol: 1mL, 1000mcg
    B-12 Compliance Kit/B-12 Injection Kit/Cyanocobalamin (Vitamin B12)/Cyomin/LA-12/Nutri-Twelve/Physicians EZ Use B-12/Primabalt Subcutaneous Inj Sol: 1mL, 1000mcg
    Cyanocobalamin (Vitamin B12) Oral Sol: 1mL, 3000mcg, 5000mcg
    Cyanocobalamin (Vitamin B12) Oral Tab ER: 1000mcg
    Cyanocobalamin (Vitamin B12)/Cyanocobalamin (Vitamin B12), Calcium Oral Tab: 50mcg, 100mcg, 250mcg, 500mcg, 1000mcg, 2000mcg, 100-79mg, 500-100mg, 500-54mg
    Cyanocobalamin (Vitamin B12)/Cyanocobalamin (Vitamin B12), Cobamamide Sublingual Tablet, SL: 500mcg, 1000mcg, 2500mcg, 3000mcg, 5000mcg, 5000-100mcg, 6000-100mcg
    Nascobal Nasal Spray Met: 0.1mL, 500mcg

    DOSAGE & INDICATIONS

    For nutritional supplementation.
    For the recommended dietary allowance (RDA) of cyanocobalamin in healthy individuals.
    NOTE: Adequate intakes (AI) and RDAs are established and updated via the IOM Food and Nutrition Board.
    Oral dosage
    Adults and Adolescent pregnant females

    2.6 mcg orally daily.

    Adults and Adolescent lactating females

    2.8 mcg orally daily.

    Adults and Adolescents >= 14 years

    2.4 mcg PO daily. NOTE: Due to malabsorption of food-bound vitamin B12, individuals older than age 50 years are advised to meet their recommended daily allowance mainly by taking vitamin B12-containing supplements or through foods fortified with vitamin B12.

    Children 9—13 years

    1.8 mcg PO daily.

    Children 4—8 years

    1.2 mcg PO daily.

    Children 1—3 years

    0.9 mcg PO daily.

    Infants 7—12 months

    0.5 mcg/day PO is the adequate intake. Recommended daily allowance has not been established.

    Infants 0—6 months

    0.4 mcg/day PO is the adequate intake. Recommended daily allowance has not been established.

    Intranasal dosage
    Adults and Adolescents

    500 mcg intranasally into 1 nostril once weekly. The intranasal route is for maintenance of adequate nutritional intake in patients who cannot absorb vitamin B12 via the oral route.

    For the treatment of vitamin B12 deficiency or for the treatment of vitamin B12 deficiency megaloblastic anemia or macrocytic anemia thought to be due to vitamin B12 deficiency.
    Oral dosage
    Adults†

    1,000 to 2,000 mcg/day PO for 1 to 2 weeks, followed by 500 to 1,000 mcg/day PO.

    Adolescents†

    1,000 to 2,000 mcg/day PO for 1 to 2 weeks, followed by 500 to 1,000 mcg/day PO.

    Intramuscular or Subcutaneous dosage
    Adults

    1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly until recovery is the usual dosage. 100 mcg IM/subcutaneously once daily for 6 or 7 days is the FDA-approved dosage. After clinical improvement and if a reticulocyte response is seen, give 100 mcg IM/subcutaneously on alternate days for 7 doses, then every 3 to 4 days for another 2 to 3 weeks, then 100 mcg IM/subcutaneously monthly. Administer with folic acid, if needed.

    Adolescents†

    1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly until recovery is the usual dosage.

    Children†

    Dosing is not well established in pediatric patients and should be guided by clinical response and laboratory measurements. 0.2 mcg/kg/dose IM/subcutaneously for 2 days, followed by 1000 mcg IM/subcutaneously daily for 2 to 7 days, then 100 mcg IM/subcutaneously weekly for 4 weeks, then monthly until recovery has been recommended and used in children. Older children may also receive the adult dosage (1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly).

    Infants†

    Dosing is not well established in pediatric patients and should be guided by clinical response and laboratory measurements. 250 to 1000 mcg IM daily for 4 to 10 days, followed by 100 to 1,000 mcg IM weekly or monthly until recovery, has been recommended and used in infants in case reports.

    Intranasal dosage
    Adults

    Initial dose is 500 mcg intranasally into 1 nostril once weekly.

    For the treatment of pernicious anemia.
    NOTE: Patients with pernicious anemia are 3 times more likely to develop carcinoma of the stomach than the general population, necessitating an appropriate work-up.
    For the treatment of pernicious anemia in patients who are in hematologic remission with no nervous system involvement .
    NOTE: A decline in serum concentrations of B12 after one month of therapy may indicate that the dose needs to be adjusted. Patients should be seen one month after each dosage adjustment. Continued low serum concentrations may indicate that the patient is not a candidate for this mode of administration.
    Intranasal dosage
    Adults

    Initial dose is 500 mcg intranasally into 1 nostril once weekly.

    Intramuscular or Subcutaneous dosage
    Adults

    1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly for life is the usual dosage. 100 mcg IM/subcutaneously once daily for 6 or 7 days is the FDA-approved dosage. After clinical improvement and if a reticulocyte response is seen, give 100 mcg IM/subcutaneously on alternate days for 7 doses, then every 3 to 4 days for another 2 to 3 weeks, then 100 mcg IM/subcutaneously monthly for life. Administer with folic acid, if needed.

    Adolescents†

    1,000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly for life is the usual dosage.

    Children†

    Dosing is not well established in pediatric patiens and should be guided by clinical response and laboratory measurements. 0.2 mcg/kg/dose IM/subcutaneously for 2 days, followed by 1000 mcg IM/subcutaneously daily for 2 to 7 days, then 100 mcg IM/subcutaneously weekly for 4 weeks, then monthly has been recommended and used in children. Older children may also receive the adult dosage (1000 mcg IM given daily or every other day for 1 week, then weekly for 4 to 8 weeks, then monthly for life). In case reports, a child as young as 3 years of age received the adult dosage.

    Infants†

    Dosing is not well established in pediatric patients and should be guided by clinical response and laboratory measurements. 250 to 1,000 mcg IM daily for 4 to 10 days, followed by 100 to 1000 mcg IM weekly or monthly, has been recommended and used in infants in case reports.

    Oral dosage
    Adults†

    1,000 to 2,000 mcg/day PO for life.

    Adolescents†

    1,000 to 2,000 mcg/day PO for life.

    For vitamin B12 deficiency diagnosis (Schilling test).
    Intramuscular dosage
    Adults, Adolescents and Children

    1,000 mcg intramuscularly as a single dose is the flushing dose for Schilling test for vitamin B12 malabsorption. However, the utility of the Schilling test is very limited and it is rarely done because it is complicated to perform, radiolabeled vitamin B12 is difficult to obtain, and the interpretation of the results can be difficult.

    For the treatment of methylmalonic aciduria†.
    Intramuscular dosage
    Neonates

    1,000 mcg intramuscularly once daily for 11 days with a protein-restricted diet.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Upper tolerable intake levels in healthy, non-vitamin deficient individuals are not determinable due to a lack of data.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
     
    Intermittent hemodialysis
    Specific guidelines are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Oral administration is useful only when treating nutritional deficiencies. Patients with malabsorption syndromes, small bowel disease, or gastric or ileal resections require intranasal or parenteral therapy.
    To increase oral absorption, administer with meals.

    Injectable Administration

    Administered intramuscularly or by deep subcutaneous injection; intravenous (IV) injection is not recommended as cyanocobalamin is excreted more readily following IV injection.
    Cyanocobalamin may be mixed with TPN solutions.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intramuscular Administration

    Inject deeply into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.

    Subcutaneous Administration

    Inject deeply into subcutaneous tissue taking care not to inject intradermally or into upper subcutaneous tissue.

    Inhalation Administration
    Intranasal Inhalation Administration

    Administer intranasally.
    To avoid the spread of infection, do not use the container for more than one person.
    Before using for the first time, the unit may have to be assembled. If so, screw the solution bottle and actuator unit together.
    The pump must be primed prior to first use. Pump the unit firmly and quickly until the first appearance of solution. For Nascobal, pump 2 additional times. For CaloMist, pump an additional 6 times for a total of 7 priming sprays.
    After priming, the metered-dose bottle of Nascobal delivers an average of 500 mcg of cyanocobalamin/actuation (0.1 mL/actuation); CaloMist delivers 25 mcg per spray (0.1 mL/actuation).
    Instruct patient on proper administration technique.
    Administer at least one hour before or after ingestion of foods or liquids that may cause nasal congestion or rhinorrhea.
    After administration, rinse the tip of the bottle with hot water, taking care not to suck water into the bottle, and dry with a clean tissue. Replace the cap immediately after cleaning.
    Re-Priming: For Nascobal, the spray must be re-primed before each use; prime the pump once immediately before each administration of doses 2 through 8. For CaloMist, if not used for 5 or more days, re-prime with 2 re-priming sprays.

    STORAGE

    Generic:
    - Protect from extreme heat
    - Protect from light
    - Protect from moisture
    - Store at room temperature (between 59 to 86 degrees F)
    B-12 Compliance Kit:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    B-12 Injection Kit:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    CaloMist:
    - Protect from freezing
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    - Store upright
    Cyomin:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    LA-12 :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Nascobal:
    - Protect from freezing
    - Store at room temperature (between 59 to 86 degrees F)
    Nutri-Twelve :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Physicians EZ Use B-12:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Primabalt:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Cyanocobalamin is contraindicated in patients with cyanocobalamin hypersensitivity or hypersensitivity to any of the medication components. Cyanocobalamin is also contraindicated in patients with cobalt hypersensitivity because cyanocobalamin 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 cyanocobalamin.
     
    Intranasal formulations of cyanocobalamin are not suitable for vitamin B12 absorption test (Schilling Test).

    Hereditary optic nerve atrophy (Leber's disease)

    Cyanocobalamin should not be used in patients with early hereditary optic nerve atrophy (Leber's disease). Optic nerve atrophy can worsen in patients whose cyanocobalamin levels are already elevated. Hydroxocobalamin is the preferred agent in this patient population.

    Benzyl alcohol hypersensitivity, neonates

    Most formulations of cyanocobalamin injection contain benzyl alcohol as a preservative. Benzyl alcohol may cause allergic reactions. Cyanocobalamin injections should be used cautiously in those patients with benzyl alcohol hypersensitivity. Cyanocobalamin, 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.

    Polycythemia vera

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

    Anemia, iron-deficiency anemia

    Folic Acid, vitamin B9 is not a substitute for cyanocobalamin, 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 cyanocobalamin, 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 cyanocobalamin intranasal formulations. Concurrent iron-deficiency anemia and folic acid deficiency may result in a blunted or impeded response to cyanocobalamin therapy.

    Bone marrow suppression, infection, renal failure, uremia

    Certain conditions may blunt or impede therapeutic response to cyanocobalamin 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 cyanocobalamin.

    Respiratory infection, rhinorrhea

    Patients with rhinorrhea (rhinitis) who are receiving the intranasal formulations of cyanocobalamin may experience decreased medication absorption secondary to nasal discharge. These patients may experience a blunted or impeded response to the intranasal medication. Treatment with intranasal cyanocobalamin should be delayed until symptoms resolve in patients with nasal congestion, allergic rhinitis, and upper respiratory infection. Intranasal cyanocobalamin therapy is not ideal for patients with chronic nasal symptoms or significant nasal pathology. If used in these patients, more frequent monitoring is required because of the potential for erratic or blunted absorption.

    Pregnancy

    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 breast-fed 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 cyanocobalamin, vitamin B12 either through dietary intake or supplementation should be taken during pregnancy.

    Breast-feeding

    Cyanocobalamin is distributed into breast milk in amounts similar to those in maternal plasma, and distribution in breast milk allows for adequate intakes of cyanocobalamin by breast-feeding 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 cyanocobalamin, vitamin B12 for lactating women should be taken maternally during breast-feeding. The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Studies of intranasal cyanocobalamin did not include sufficient numbers of geriatric patients aged >= 65 years to determine whether the clinical response differs from that of younger patients. Other 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.

    ADVERSE REACTIONS

    Severe

    anaphylactic shock / Rapid / Incidence not known
    heart failure / Delayed / Incidence not known
    pulmonary edema / Early / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    ataxia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    polycythemia / Delayed / Incidence not known

    Mild

    dizziness / Early / 12.0
    fever / Early / 4.0
    rhinorrhea / Early / 12.0
    epistaxis / Delayed / 4.0
    back pain / Delayed / 4.0
    cough / Delayed / 4.0
    malaise / Early / 4.0
    arthralgia / Delayed / 12.0
    sinusitis / Delayed / 4.0
    rash (unspecified) / Early / 8.0
    paresthesias / Delayed / Incidence not known
    nausea / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    anxiety / Delayed / Incidence not known
    headache / Early / Incidence not known
    diarrhea / Early / Incidence not known
    infection / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain either magnesium or aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Alendronate; Cholecalciferol: (Major) High intake of phosphates concomitantly with vitamin D or vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Alogliptin; Metformin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Aluminum Hydroxide: (Moderate) The oral absorption of phosphorus is reduced by ingestion of aluminum-containing antacids (e.g., aluminum hydroxide). If the patient requires treatment with aluminum-containing antacids, it may be wise to separate the administration of phosphorus salts from the antacid. In some instances the administration of an aluminum hydroxide product is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of these drugs in these settings, assuming hypophosphatemia is not present.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Phosphate may bind magnesium salts and magnesium-containing antacids (e.g., magnesium carbonate, magnesium hydroxide) may limit phosphorus absorption or phosphorus may limit magnesium absorption. If the patient requires magnesium supplements or a magnesium-containing antacid, it may be wise to separate the administration of phosphates from magnesium-containing products. (Moderate) The oral absorption of phosphorus is reduced by ingestion of aluminum-containing antacids (e.g., aluminum hydroxide). If the patient requires treatment with aluminum-containing antacids, it may be wise to separate the administration of phosphorus salts from the antacid. In some instances the administration of an aluminum hydroxide product is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of these drugs in these settings, assuming hypophosphatemia is not present.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Phosphate may bind magnesium salts and magnesium-containing antacids (e.g., magnesium carbonate, magnesium hydroxide) may limit phosphorus absorption or phosphorus may limit magnesium absorption. If the patient requires magnesium supplements or a magnesium-containing antacid, it may be wise to separate the administration of phosphates from magnesium-containing products. (Moderate) The oral absorption of phosphorus is reduced by ingestion of aluminum-containing antacids (e.g., aluminum hydroxide). If the patient requires treatment with aluminum-containing antacids, it may be wise to separate the administration of phosphorus salts from the antacid. In some instances the administration of an aluminum hydroxide product is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of these drugs in these settings, assuming hypophosphatemia is not present.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Phosphate may bind magnesium salts and magnesium-containing antacids (e.g., magnesium carbonate, magnesium hydroxide) may limit phosphorus absorption or phosphorus may limit magnesium absorption. If the patient requires magnesium supplements or a magnesium-containing antacid, it may be wise to separate the administration of phosphates from magnesium-containing products. (Moderate) The oral absorption of phosphorus is reduced by ingestion of aluminum-containing antacids (e.g., aluminum hydroxide). If the patient requires treatment with aluminum-containing antacids, it may be wise to separate the administration of phosphorus salts from the antacid. In some instances the administration of an aluminum hydroxide product is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of these drugs in these settings, assuming hypophosphatemia is not present.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) The oral absorption of phosphorus is reduced by ingestion of aluminum-containing antacids (e.g., aluminum hydroxide). If the patient requires treatment with aluminum-containing antacids, it may be wise to separate the administration of phosphorus salts from the antacid. In some instances the administration of an aluminum hydroxide product is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of these drugs in these settings, assuming hypophosphatemia is not present.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Aspirin, ASA: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Aspirin, ASA; Carisoprodol: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Aspirin, ASA; Dipyridamole: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Aspirin, ASA; Omeprazole: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels. (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Aspirin, ASA; Oxycodone: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Aspirin, ASA; Pravastatin: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Atenolol: (Minor) Calcium antacids (e.g., calcium carbonate) and supplements (e.g., other oral calcium salts) have been reported to reduce the mean peak concentrations by 51% and the AUC of atenolol by 32%. In another study, antacids reduced the AUC of atenolol by 33%. Separate doses of atenolol and calcium-containing antacids or supplements by at least 2 hours to minimize this potential interaction,. However, most clinicians consider the interaction of atenolol with antacids to be of minor clinical significance, since clinical efficacy (heart rate and blood pressure parameters) appear to be unchanged under usual intermittent clinical use.
    Atenolol; Chlorthalidone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended. (Minor) Calcium antacids (e.g., calcium carbonate) and supplements (e.g., other oral calcium salts) have been reported to reduce the mean peak concentrations by 51% and the AUC of atenolol by 32%. In another study, antacids reduced the AUC of atenolol by 33%. Separate doses of atenolol and calcium-containing antacids or supplements by at least 2 hours to minimize this potential interaction,. However, most clinicians consider the interaction of atenolol with antacids to be of minor clinical significance, since clinical efficacy (heart rate and blood pressure parameters) appear to be unchanged under usual intermittent clinical use.
    Atracurium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Moderate) It has been reported that high intakes of phosphates, such as are found in dietary supplements or food additives, can interfere with absorption of trace nutrients such as iron, copper, and zinc. The magnitude of the effect may be small, and the interactions require further study to judge clinical significance. The theorized mechanism is the formation of insoluble complexes within the gut. Until more data are available, it may be helpful to separate administration times of phosphorus salts by as much as possible from the oral administration of iron (e.g., iron salts or polysaccharide-iron complex), copper salts, or zinc salts to limit any potential interactions. (Minor) It has been reported that high intakes of phosphates, such as are found in dietary supplements or food additives, can interfere with absorption of trace nutrients such as iron, copper, and zinc. The magnitude of the effect may be small, and the interactions require further study to judge clinical significance. The theorized mechanism is the formation of insoluble complexes within the gut. Until more data are available, it may be helpful to separate administration times of potassium phosphate; sodium phosphateby as much as possible from the oral administration of iron (e.g., iron salts or polysaccharide-iron complex), copper salts, or zinc salts to limit any potential interactions.
    Azilsartan; Chlorthalidone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Bendroflumethiazide; Nadolol: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Beta-Carotene: (Minor) Doses in excess of 1,500 to 2,000 mcg per day of Vitamin A may lead to bone loss and will counteract the effects of supplementation with calcium salts.
    Betamethasone; Calcipotriene: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
    Bismuth Subsalicylate: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Bisphosphonates: (Moderate) Separating times of administration of the oral bisphosphonate from calcium-containing supplements and medications will maximize absorption and clinical benefit. Calcium will interfere with the absorption of the orally administered bisphosphonates alendronate, etidronate, ibandronate, risedronate, and tiludronate. At least 30 minutes should elapse after the oral administration of alendronate before taking any calcium containing product. At least 1 hour should elapse after the oral administration of ibandronate before taking any calcium containing product. At least 2 hours should elapse after the oral administration of etidronate, risedronate, or tiludronate before administering any calcium containing product.
    Calcipotriene: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
    Calcitonin: (Moderate) Calcitonin is given to hypercalcemic patients to reduce serum calcium concentrations. For the treatment of hypercalcemia, calcium supplements should be avoided. Calcium salts, including calcium carbonate, can elevate serum calcium concentrations and antagonize the effects of the calcitonin for this condition. For the treatment of osteoporosis adequate intake of calcium salts are necessary in conjunction with calcitonin. An increase in serum calcium concentrations helps to reduce bone resorption and loss of bone mass, and offsets the effect of calcitonin in lowering serum calcium levels.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Phosphate may bind magnesium salts and magnesium-containing antacids (e.g., magnesium carbonate, magnesium hydroxide) may limit phosphorus absorption or phosphorus may limit magnesium absorption. If the patient requires magnesium supplements or a magnesium-containing antacid, it may be wise to separate the administration of phosphates from magnesium-containing products.
    Calcium Phosphate, Supersaturated: (Moderate) The concomitant use of oral sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous preparations in conjunction with antacids containing calcium (e.g., calcium carbonate, calcium salts) may bind the phosphate in the stomach and reduce its absorption. If the patient requires multiple mineral supplements or concurrent use of antacids, it is prudent to separate the administration of sodium phosphate salts from calcium containing products by at least one hour.
    Calcium: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Calcium; Vitamin D: (Major) High intake of phosphates concomitantly with vitamin D or vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Canagliflozin; Metformin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Carbetapentane; Guaifenesin; Phenylephrine: (Minor) It has been reported that high intakes of phosphates, such as are found in dietary supplements or food additives, can interfere with absorption of trace nutrients such as iron, copper, and zinc. The magnitude of the effect may be small, and the interactions require further study to judge clinical significance. The theorized mechanism is the formation of insoluble complexes within the gut. Until more data are available, it may be helpful to separate administration times of potassium phosphate; sodium phosphateby as much as possible from the oral administration of iron (e.g., iron salts or polysaccharide-iron complex), copper salts, or zinc salts to limit any potential interactions.
    Carbetapentane; Phenylephrine: (Minor) It has been reported that high intakes of phosphates, such as are found in dietary supplements or food additives, can interfere with absorption of trace nutrients such as iron, copper, and zinc. The magnitude of the effect may be small, and the interactions require further study to judge clinical significance. The theorized mechanism is the formation of insoluble complexes within the gut. Until more data are available, it may be helpful to separate administration times of potassium phosphate; sodium phosphateby as much as possible from the oral administration of iron (e.g., iron salts or polysaccharide-iron complex), copper salts, or zinc salts to limit any potential interactions.
    Cardiac glycosides: (Major) Calcium salts augment the actions of digoxin. In addition, when calcium is administered via rapid intravenous injection, the risk of serious arrhythmias in digitalized patients is increased. It is recommended that serum calcium be monitored regularly in patients receiving digoxin.
    Chlorothiazide: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Chlorpheniramine; Pseudoephedrine: (Minor) It has been reported that high intakes of phosphates, such as are found in dietary supplements or food additives, can interfere with absorption of trace nutrients such as iron, copper, and zinc. The magnitude of the effect may be small, and the interactions require further study to judge clinical significance. The theorized mechanism is the formation of insoluble complexes within the gut. Until more data are available, it may be helpful to separate administration times of potassium phosphate; sodium phosphateby as much as possible from the oral administration of iron (e.g., iron salts or polysaccharide-iron complex), copper salts, or zinc salts to limit any potential interactions.
    Chlorthalidone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Chlorthalidone; Clonidine: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Cholecalciferol, Vitamin D3: (Major) High intake of phosphates concomitantly with vitamin D or vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Ciprofloxacin: (Major) Administer oral ciprofloxacin at least 2 hours before or 6 hours after oral products that contain calcium. Ciprofloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Cisatracurium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Cod Liver Oil: (Major) Concurrent administration of phosphorus salts and cod liver oil may lead to ergocalciferol-induced increases in serum phosphorus levels. (Major) High intake of phosphates concomitantly with vitamin D or vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. (Moderate) Concomitant cod liver oil and calcium supplementation should be undertaken with caution. The vitamin D contained within cod liver oil can increase serum calcium concentrations; the combination may result in hypercalcemia. Additionally, doses in excess of 1,500 to 2,000 mcg/day of vitamin A may lead to bone loss and can counteract the effects of supplementation with calcium salts. (Minor) Doses in excess of 1,500 to 2,000 mcg per day of Vitamin A may lead to bone loss and will counteract the effects of supplementation with calcium salts.
    Colchicine: (Minor) Colchicine has been shown to induce reversible malabsorption of vitamin B12. Patients receiving these agents concurrently should be monitored for the desired therapeutic response to vitamin B12.
    Colesevelam: (Moderate) It is not known if colesevelam can reduce the absorption of oral vitamin supplements including fat soluble vitamins A, D, E, and K. To minimize potential interactions, administer vitamins at least 4 hours before colesevelam.
    Colestipol: (Moderate) Colestipol may interfere with the oral absorption of phosphorus salts. According to the manufacturer, administer other drugs at least 1 hour before or at least 4-6 hours after the administration of colestipol. The manufacturer also recommends that the interval between the administration of colestipol and other drugs should be as long as possible.
    Conjugated Estrogens: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Dapagliflozin; Metformin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Delafloxacin: (Major) Administer oral delafloxacin at least 2 hours before or 6 hours after oral products that contain calcium. Delafloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with fluoroquinolone bioavailability include antacids and multivitamins that contain calcium.
    Dexlansoprazole: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Dienogest; Estradiol valerate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Diethylstilbestrol, DES: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Diflunisal: (Moderate) Agents that acidify the urine, like phosphate salts, should be avoided in patients receiving high-dose salicylates. Urine acidifying agents may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels.
    Dolutegravir: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain either magnesium or aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
    Doxacurium: (Moderate) Calcium salts may antagonize the neuromuscular blocking effects of doxacurium.
    Drospirenone; Estradiol: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Drospirenone; Ethinyl Estradiol: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Edetate Calcium Disodium, Calcium EDTA: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Edetate Disodium, Disodium EDTA: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Eltrombopag: (Major) Eltrombopag chelates polyvalent cations (e.g., calcium, aluminum, and magnesium) in food, mineral supplements, and antacids. In a clinical study, systemic exposure to eltrombopag was decreased by 70% when it was administered with a polyvalent cation-containing antacid. Administer eltrombopag at least 2 hours before or 4 hours after any oral products containing polyvalent cations, such as aluminum salts, (like aluminum hydroxide), calcium salts, (including calcium carbonate), and magnesium salts.
    Empagliflozin; Metformin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Ergocalciferol, Vitamin D2: (Major) High intake of phosphates concomitantly with vitamin D or vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Esomeprazole: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Esomeprazole; Naproxen: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Esterified Estrogens: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol; Levonorgestrel: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol; Norethindrone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estradiol; Norgestimate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estramustine: (Major) Administration of estramustine with calcium impairs the oral absorption of estramustine significantly, due to formation of a calcium-phosphate complex. Calcium-containing drugs must not be taken simultaneously with estramustine. Patients should be instructed to take estramustine with water at least 1 hour before or 2 hours after calcium supplements.
    Estrogens: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Estropipate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethanol: (Moderate) Excessive ethanol (e.g., alcoholism) may result in increased urinary excretion of magnesium. Avoid high intakes of ethanol while taking magnesium salts. (Minor) The heavy consumption of ethanol for greater than 2 weeks has been reported to reduce the absorption of cyanocobalamin, 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.
    Ethinyl Estradiol: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Desogestrel: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Etonogestrel: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Levonorgestrel: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norelgestromin: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norethindrone Acetate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norethindrone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norgestimate: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethinyl Estradiol; Norgestrel: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Ethotoin: (Major) Oral absorption of phenytoin can be reduced by calcium salts. Calcium salts can form complexes that are nonabsorbable. Separating the administration of phenytoin and calcium salts by at least 2 hours to help avoid this interaction. A similar interaction may occur with ethotoin.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Major) High intake of phosphates concomitantly with vitamin D or vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Food: (Moderate) Food or medicines containing a high potassium content such as salt substitutes could increase the risk of complications of potassium excess when given with potassium-based phosphorous salts. (Moderate) Foods containing oxalates (found in vegetables like rhubarb, tomatoes, celery, and spinach; as well as berries, beans, nuts and chocolate) or phytates (found in bran and whole-grain cereals) may reduce the absorption of phosphorus by forming complexes with the phosphorus salt. (Minor) The intranasal forms of cyanocobalamin, vitamin B12, should be administered at least one hour before or one hour after ingestion of hot foods 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 cyanocobalamin are not expected.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Gallium: (Moderate) Concurrent administration products containing calcium salts may antagonize the effects of gallium nitrate.
    Gemifloxacin: (Major) Administer oral products that contain calcium at least 2 hours before or 2 hours after gemifloxacin. Gemifloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Glipizide; Metformin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Glyburide; Metformin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Phosphate may bind magnesium salts and magnesium-containing antacids (e.g., magnesium carbonate, magnesium hydroxide) may limit phosphorus absorption or phosphorus may limit magnesium absorption. If the patient requires magnesium supplements or a magnesium-containing antacid, it may be wise to separate the administration of phosphates from magnesium-containing products.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Ibritumomab Tiuxetan: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Iron: (Moderate) It has been reported that high intakes of phosphates, such as are found in dietary supplements or food additives, can interfere with absorption of trace nutrients such as iron, copper, and zinc. The magnitude of the effect may be small, and the interactions require further study to judge clinical significance. The theorized mechanism is the formation of insoluble complexes within the gut. Until more data are available, it may be helpful to separate administration times of phosphates by as much as possible from the oral administration of iron (e.g., iron salts or polysaccharide-iron complex), copper salts, or zinc salts to limit any potential interactions.
    Lansoprazole: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Lansoprazole; Naproxen: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Levofloxacin: (Major) Administer oral products that contain calcium at least 2 hours before or 2 hours after orally administered levofloxacin. Levofloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Chelation of divalent cations with levofloxacin is less than with other quinolones. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Linagliptin; Metformin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Magnesium Hydroxide: (Moderate) Phosphate may bind magnesium salts and magnesium-containing antacids (e.g., magnesium carbonate, magnesium hydroxide) may limit phosphorus absorption or phosphorus may limit magnesium absorption. If the patient requires magnesium supplements or a magnesium-containing antacid, it may be wise to separate the administration of phosphates from magnesium-containing products.
    Magnesium Salts: (Moderate) Phosphate may bind magnesium salts and magnesium-containing antacids (e.g., magnesium carbonate, magnesium hydroxide) may limit phosphorus absorption or phosphorus may limit magnesium absorption. If the patient requires magnesium supplements or a magnesium-containing antacid, it may be wise to separate the administration of phosphates from magnesium-containing products.
    Magnesium: (Moderate) Phosphate may bind magnesium salts and magnesium-containing antacids (e.g., magnesium carbonate, magnesium hydroxide) may limit phosphorus absorption or phosphorus may limit magnesium absorption. If the patient requires magnesium supplements or a magnesium-containing antacid, it may be wise to separate the administration of phosphates from magnesium-containing products.
    Mestranol; Norethindrone: (Minor) Estrogens can increase calcium absorption. Use caution in patients predisposed to hypercalcemia or nephrolithiasis.
    Metformin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Metformin; Pioglitazone: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Metformin; Repaglinide: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Metformin; Rosiglitazone: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Metformin; Saxagliptin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Metformin; Sitagliptin: (Minor) 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. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.
    Methyclothiazide: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Metolazone: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Mivacurium: (Moderate) Calcium salts may antagonize the neuromuscular blocking effects of mivacurium.
    Moxifloxacin: (Major) Administer oral moxifloxacin at least 4 hours before or 8 hours after oral products that contain calcium. Moxifloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Neomycin: (Minor) Oral neomycin has been shown to inhibit the gastrointestinal absorption of cyanocobalamin, Vitamin B12. Caution is warranted with concomitant use.
    Norfloxacin: (Major) Administer oral products that contain calcium at least 2 hours before or 2 hours after norfloxacin. Norfloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Octreotide: (Minor) Depressed levels of cyanocobalamin, vitamin B12, and abnormal Schilling's test have been reported in patients receiving octreotide.
    Ofloxacin: (Major) Administer oral products that contain calcium at least 2 hours before or 2 hours after ofloxacin. Ofloxacin absorption may be reduced as quinolone antibiotics can chelate with divalent or trivalent cations. Examples of compounds that may interfere with quinolone bioavailability include antacids and multivitamins that contain calcium.
    Omeprazole: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Omeprazole; Sodium Bicarbonate: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency. (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Pancuronium: (Moderate) Calcium salts usually reverse the effects of nondepolarizing neuromuscular blocking agents such as pancuronium.
    Pantoprazole: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Phenicol Derivatives: (Minor) Chloramphenicol can antagonize the hematopoietic response to cyanocobalamin, vitamin B12 through interference with erythrocyte maturation.
    Phosphorated Carbohydrate Solution: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Phosphorus Salts: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Phosphorus: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Potassium Phosphate; Sodium Phosphate: (Moderate) The oral absorption of phosphorus is reduced by ingestion of pharmacologic doses of calcium carbonate or other phosphate-lowering calcium salts (e.g., calcium acetate). There is, however, no significant interference with phosphorus absorption by oral dietary calcium at intakes within the typical adult range. If the patient requires multiple calcium supplements or a calcium-containing antacid, it may be wise to separate the administration of phosphorus salts from calcium-containing products. In some instances the administration of calcium salts or calcium carbonate is used therapeutically (e.g., uremia) to decrease serum phosphorus levels, so the administration of phosphorus supplements would dynamically counteract the intended use of calcium in these settings, assuming hypophosphatemia is not present. Appropriate calcium-phosphorus ratios in vivo are important for proper calcium homeostasis in tissues and bone; if the serum ionized calcium concentration is elevated, the concomitant use of calcium salts and phosphorus salts may increase the risk of calcium deposition in soft tissue.
    Proton pump inhibitors: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Rabeprazole: (Moderate) Proton pump inhibitors may cause a decrease in the oral absorption of cyanocobalamin, vitamin B12. Patients receiving long-term therapy with proton pump inhibitors should be monitored for signs of B12 deficiency.
    Rocuronium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers, such as rocuronium.
    Sevelamer: (Severe) Pharmacologically, sevelamer decreases serum phosphate concentrations. Therefore, phosphate salts would be expected to counteract the pharmacological benefits of sevelamer. It would be illogical to administer phosphate or phosphorus salts to patients who require sevelamer.
    Sodium Bicarbonate: (Minor) Prolonged use of sodium bicarbonate along with calcium carbonate may result in milk-alkali syndrome.
    Sodium Fluoride: (Moderate) Absorption of sodium fluoride may be reduced by concomitant use of antacids that contain magnesium, aluminum, or calcium. An interval of at least 2 hours is advisable between administration of sodium fluoride and antacids.
    Sodium Phosphate Monobasic Monohydrate; Sodium Phosphate Dibasic Anhydrous: (Moderate) The concomitant use of oral sodium phosphate monobasic monohydrate; sodium phosphate dibasic anhydrous preparations in conjunction with antacids containing calcium (e.g., calcium carbonate, calcium salts) may bind the phosphate in the stomach and reduce its absorption. If the patient requires multiple mineral supplements or concurrent use of antacids, it is prudent to separate the administration of sodium phosphate salts from calcium containing products by at least one hour.
    Succinylcholine: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Sucralfate: (Moderate) Serum phosphorus should be checked routinely in patients treated chronically with sucralfate; sucralfate may cause hypophosphatemia and some patients may require phosphorus repletion. This nutrient interaction should be considered in patients receiving phosphates for dietary supplementation. It appears that sucralfate chelates phosphorus in the gut, forming nonabsorbable complexes. Because of sucralfate's therapeutic effect, this interaction may not be prevented by separating times of oral administration.
    Tetracyclines: (Major) Divalent or trivalent cations readily chelate with tetracycline antibiotics, forming insoluble compounds. The oral absorption of these antibiotics will be significantly reduced by other orally administered compounds that contain calcium salts, particularly if the time of administration is within 60 minutes of each other. Calcium salts and tetracyclines should not be administered within 1 to 2 hours of each other, although doxycycline chelates less with calcium than other tetracyclines.
    Thiazide diuretics: (Moderate) The simultaneous administration of thiazide diuretics and calcium salts or calcium carbonate may lead to hypercalcemia. Thiazides cause a decrease in renal tubular excretion of calcium as well as increase in distal tubular reabsorption. Moderate increases in serum calcium have been seen during the treatment with thiazides; if calcium salts are used concomitantly, careful monitoring of serum calcium in recommended.
    Thyroid hormones: (Major) Calcium salts have been reported to chelate oral thyroid hormones within the GI tract when administered simultaneously, leading to decreased thyroid hormone absorption. Some case reports have described clinical hypothyroidism resulting from coadministration of thyroid hormones with oral calcium supplements. To avoid the interaction, thyroid hormones should be administered at least 4 hours before or after ingestion of oral calcium supplements.
    Trientine: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of trientine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and trientine each inhibit oral absorption of the other, 2 hours should elapse between administration of trientine and iron doses.
    Tubocurarine: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Vecuronium: (Moderate) Calcium salts may antagonize the effects of nondepolarizing neuromuscular blockers.
    Vitamin A: (Minor) Doses in excess of 1,500 to 2,000 mcg per day of Vitamin A may lead to bone loss and will counteract the effects of supplementation with calcium salts.
    Vitamin D analogs: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    Vitamin D: (Major) High intake of phosphates concomitantly with vitamin D or vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
    Zinc Salts: (Minor) It has been reported that high intakes of phosphates, such as are found in dietary supplements or food additives, can interfere with absorption of trace nutrients such as iron, copper, and zinc. The magnitude of the effect may be small, and the interactions require further study to judge clinical significance. The theorized mechanism is the formation of insoluble complexes within the gut. Until more data are available, it may be helpful to separate administration times of potassium phosphate; sodium phosphateby as much as possible from the oral administration of iron (e.g., iron salts or polysaccharide-iron complex), copper salts, or zinc salts to limit any potential interactions.
    Zinc: (Minor) It has been reported that high intakes of phosphates, such as are found in dietary supplements or food additives, can interfere with absorption of trace nutrients such as iron, copper, and zinc. The magnitude of the effect may be small, and the interactions require further study to judge clinical significance. The theorized mechanism is the formation of insoluble complexes within the gut. Until more data are available, it may be helpful to separate administration times of potassium phosphate; sodium phosphateby as much as possible from the oral administration of iron (e.g., iron salts or polysaccharide-iron complex), copper salts, or zinc salts to limit any potential interactions.

    PREGNANCY AND LACTATION

    Pregnancy

    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 breast-fed 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 cyanocobalamin, vitamin B12 either through dietary intake or supplementation should be taken during pregnancy.

    Cyanocobalamin is distributed into breast milk in amounts similar to those in maternal plasma, and distribution in breast milk allows for adequate intakes of cyanocobalamin by breast-feeding 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 cyanocobalamin, vitamin B12 for lactating women should be taken maternally during breast-feeding. The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Vitamin B12, or cyanocolbalamin, 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 cyanocobalamin. 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.

    PHARMACOKINETICS

    Cyanocobalamin 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 cyanocobalamin is excreted unchanged in the urine.

    Oral Route

    Oral absorption of vitamin B12 from the GI tract depends on the presence of adequate intrinsic factor, which is secreted from gastric mucosa. Drugs like the proton pump inhibitors (PPIs) (e.g., omeprazole and lansoprazole) have the potential for interfering with B12 absorption, presumably by impairing gastric acid and pepsin secretion, which are thought to be necessary for releasing B12 from its protein-binding sites in food. A vitamin B12-intrinsic factor complex is formed in the stomach following removal of cobalamin from dietary sources. This complex passes to the small intestine where attachment to receptor sites occurs on the ileal mucosa, and vitamin B12 is actively transported to portal plasma. Calcium and a pH greater than 6 are required for attachment to the receptor sites. When the receptor sites become saturated, absorption through passive diffusion occurs. Initially, oral doses of B12 and intrinsic factor (IF) will increase cobalamin levels in patients with pernicious anemia; however, 50% of patients develop intestinal antibodies to IF. Peak plasma levels are attained for oral in 8—12 hours.

    Intravenous Route

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

    Intramuscular Route

    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.

    Other Route(s)

    Intranasal Route
    Cyanocobalamin is passively absorbed though the highly vascular nasal mucosa. Both intranasal forms (gel and spray) achieve peak serum concentrations within 1—2 hours of administration. Administration of the nasal gel and spray forms produce highly variable average peak serum concentration (Cmax) ranging from 411—2417 pg/ml and 225—1289 pg/ml, respectively. Bioavailability of the nasal gel and spray forms relative to an IM injection are about 9% and 6%, respectively. The bioavailability of the cyanocobalamin intranasal gel was found to be 10% greater than the spray. 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.