Nicadan Zx (niacinamide/B6/folic acid/zinc/copper/astaxanthin/ubidecare)

Although pyridoxine was previously considered nontoxic even at high dosages, current evidence indicates that chronic administration of large dosages (e.g., 2 g daily) for the management of various conditions can cause severe adverse neurologic effects, and the risk to benefit of such dosages must be carefully weighed. (See Chronic Toxicity.)

Dosage of folic acid injection (sodium folate) is expressed in terms of folic acid. In general, although patient response to folic acid therapy depends on the degree and nature of the deficiency, once proper corrective measures are undertaken, folate-deficient patients generally respond rapidly. During the first 24 hours of treatment, the patient experiences an improved sense of well-being, and within 48 hours, the bone marrow begins to become normoblastic. Reticulocytosis generally begins within 2-5 days following initiation of folic acid therapy.

Pyridoxine hydrochloride is usually administered orally; however, the drug may be given by IM, IV, or subcutaneous injection when oral administration is not feasible. In infants with seizures, pyridoxine hydrochloride should be administered by IM or IV injection.

Folic acid is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered by deep IM, subcutaneous, or IV injection. However, most patients with malabsorption are able to absorb oral folic acid.

No dosing information is available for this tab.

No dosing information is available for this tab.

Pyridoxine hydrochloride reverses the therapeutic effects of levodopa by accelerating peripheral metabolism of levodopa. Concomitant administration of carbidopa with levodopa prevents the reversal by pyridoxine of levodopa's effects. Pyridoxine hydrochloride should not be administered in dosages greater than 5 mg daily to patients receiving levodopa alone.

In one study, 200 mg of pyridoxine hydrochloride daily for 1 month resulted in a 50% decrease in serum concentrations of phenobarbital and phenytoin.

Although isoniazid interferes with pyridoxine metabolism, the American Academy of Pediatrics (AAP) states that children receiving isoniazid do not need pyridoxine supplements unless they have or are likely to have nutritional deficiencies. The AAP currently recommends that children and adolescents receiving meat- and milk-deficient diets, those with nutritional deficiencies (including symptomatic children with human immunodeficiency virus (HIV) infection), infants who are breast-feeding and their mothers, and pregnant women receive pyridoxine supplements.

In folate-deficient patients, folic acid therapy may increase phenytoin metabolism, resulting in decreased phenytoin serum concentrations. Although this interaction is not usually clinically important, an increase in seizure frequency may occur in some patients.

It has been reported that concurrent administration of chloramphenicol and folic acid in folate-deficient patients may result in antagonism of the hematopoietic response to folic acid. Although the importance and mechanism of the interaction is unclear, the hematologic response to folic acid in patients receiving both drugs should be carefully monitored.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Aluminum & Magnesium Antacids;Polyvalent Cations/Raltegravir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aluminum and/or magnesium containing antacids may alter raltegravir absorption by altering gastric pH. Magnesium antacids and supplements containing polyvalent cations may bind to raltegravir in the GI tract, preventing its absorption.(1)

CLINICAL EFFECTS: Aluminum and/or magnesium containing antacids and supplements containing polyvalent cations may reduce levels and clinical effectiveness of raltegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of any formulation of raltegravir and aluminum and/or magnesium antacids is not recommended. Instruct patients not to use aluminum and/or magnesium containing antacids. Calcium carbonate may be used in place of aluminum and/or magnesium containing antacids in patients receiving raltegravir twice daily. Calcium carbonate is not recommended for patients receiving once daily raltegravir (1,200 mg daily).(1,2) The US HIV treatment guidelines state that if coadministration of other medications that contain polyvalent cations (e.g., Mg, Al, Fe, Ca, Zn, sucralfate) is necessary, administer raltegravir at least 2 hours before or at least 6 hours after polyvalent cations. Monitor for virologic response.(2)

DISCUSSION: Simultaneous administration of aluminum and magnesium hydroxide (20 ml) with raltegravir (400 mg BID) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 44%, 49%, and 63%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 51%, 51%, and 56%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%, 30%, and 57%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 4 hours before after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%, 19%, and 60%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 4 hours after after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 30%, 32%, and 62%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 6 hours before after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 10%, 13%, and 50%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 6 hours after after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 10%, 11%, and 49%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 12 hours after after raltegravir (1200 mg single dose) decreased raltegravir Cmax, AUC, and Cmin by 14%, 14%, and 58%, respectively.(1,3) Data from in vitro(3) and in vivo simulations(5) suggest that magnesium's effect on raltegravir may involve chelation as well as changes in pH.

Folic Acid/Fluorouracil & Fluorouracil Prodrugs

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Folic acid has been shown to enhance both the therapeutic and toxic effects of fluoropyrimidines, such as 5-fluorouracil (5-FU) and fluorouracil prodrugs.(1-3) Fluorouracil prodrugs include capecitabine and tegafur.

CLINICAL EFFECTS: Folic acid, when used concurrently with 5-FU or fluorouracil prodrugs, has been shown to increase side effects of 5-FU.(1-3)

PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3)

PATIENT MANAGEMENT: Folic acid or folate analog-containing products should not be used concurrently with fluorouracil or fluorouracil prodrugs unless directed by the healthcare provider.(1-3) Fluorouracil prodrugs include capecitabine and tegafur.

DISCUSSION: Due to increased toxic effects, stomatitis and diarrhea are observed more commonly, may be more severe, and may occur for a prolonged duration when compared to therapy with 5-FU alone. It is postulated that the lower standard dose of 5-FU in the US versus other regions may be due to increased folic acid supplementation within the US food supply.(2) In a cohort study in 290 patients, the use of dietary supplements with folic acid during treatment compared to nonuse increased the risk of capecitabine toxicities (HR 1.81, 95%CI: 1.15,2.85). The detection of folic acid in plasma also increased the risk of capecitabine toxicities (HR 2.09, 95%CI: 1.24,3.52 and HR 2.31, 95%CI: 1.29,4.13 at diagnosis and during treatment, respectively).(4) In a cohort study of 9 patients, patients taking folate-containing supplements and higher serum folate levels had an increased risk of grade >=2 toxicity. The risk of grade >=2 toxicity increased by 9% for every increase in serum folate level by 10 nmol/L. Patients with grade >=2 toxicity had higher serum folate levels than patients with grade <= 1 toxicity (28 nmol/L [range, 13.2-45.4] vs. 20 nmol/L [range, 12.8-45.4]; p=0.001).(5) In two case reports, patients developed capecitabine toxicity while taking supplements containing folic acid 400-500 mcg.(6) In a case report, a woman developed grade 4 diarrhea, grade 3 vomiting, and grade 3 hand-foot syndrome 8 days after the addition of capecitabine (2500 mg/m2/day) to high-dose folic acid supplementation. She developed necrotic colitis and died, despite the discontinuation of folic acid and capecitabine.(7) There are two other reports of excessive fluorouracil toxicity in patients treated with folic acid.(8)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Aluminum, Iron, Zinc/Deferiprone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Deferiprone chelates polyvalent cations such as aluminum, iron, and zinc.(1)

CLINICAL EFFECTS: Deferiprone chelation with oral aluminum, iron or zinc containing products in the gastrointestinal tract may decrease the amount of free deferiprone available for systemic iron chelation. Zinc supplements prescribed to counteract deferiprone-induced zinc deficiency may not be effective if taken near time of deferiprone administration.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer recommends at least a four hour interval between deferiprone dose and administration of aluminum, iron or zinc containing medications or supplements.(1) Avoid use of iron-containing vitamins or nutritional supplements in patients who require chelation therapy for iron overload.

DISCUSSION: The US manufacturer has not studied this interaction. The recommendation to separate deferiprone and polyvalent cation doses by at least four hours is based upon the deferiprone mechanism of action.(1)

Antacids And Selected Minerals/Oral Iron Supplements

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Some antacids may bind to iron, preventing its absorption. Alterations in gastric pH by antacids may also play a role. Iron may bind to other minerals such as calcium, manganese, tin, and zinc in the GI tract.

CLINICAL EFFECTS: Simultaneous administration of an antacid or minerals may decrease the absorption of orally administered iron.

PREDISPOSING FACTORS: The interaction with some combinations may be affected by the presence or absence of food.

PATIENT MANAGEMENT: Iron supplements should not be taken within 1 hour before or 2 hours after antacids, calcium, manganese, or zinc.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Magnesium hydroxide has been shown to inhibit the absorption of elemental iron,(2) although other studies have shown conflicting results.(3,4) Sodium bicarbonate has been shown to decrease the absorption of iron by 50%.(3) In a study in 61 healthy subjects, calcium citrate, calcium carbonate, and calcium phosphate inhibited iron absorption when taken with food. However, in the fasted state, calcium carbonate had no effect on iron absorption. In the fasted state, calcium citrate and calcium phosphate decreased iron absorption by 49% and 62%, respectively,(6) In a study in 23 healthy subjects, calcium acetate and calcium carbonate decreased the area-under-curve (AUC) of elemental iron (65 mg) by 27% and 19%, respectively.(7) In a study, manganese decreased iron absorption. A ratio of 5:1 of zinc:iron decreased iron absorption by 56%.(8) In a study, inorganic iron decreased zinc absorption.(9) In another study, ferrous sulfate decreased the absorption of zinc sulfate in a concentration dependent manner; however, heme chloride had no effect on zinc sulfate.(10) In a study in premature infants, administration of liquid zinc and iron supplements between feedings decreased iron uptake; however, no effect was seen when the supplements were mixed with feedings.(11) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Di-; Trivalent Cations/Chloroquine; Hydroxychloroquine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Di- and trivalent cations such as aluminum, calcium, lanthanum, and magnesium may adsorb chloroquine and hydroxychloroquine; preventing their absorption.(1-5) The adsorption may also limit the effectiveness of the di- or trivalent cation.(1)

CLINICAL EFFECTS: Simultaneous administration of di- or trivalent cations may result in decreased levels and effectiveness of chloroquine and hydroxychloroquine(2-5) and decreased effectiveness of the di- or trivalent cation.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to separate the administration times of these medicines by 2 to 4 hours.(2,3)

DISCUSSION: Adsorption of chloroquine by magnesium trisilicate was found to decrease hydrochloric acid uptake and decrease the amount of magnesium released in an acidic environment.(1) In a study, calcium carbonate, kaolin, and magnesium trisilicate were found to decrease the absorption of chloroquine by 52.8%, 46.5%, and 31.3%, respectively.(3) Magnesium trisilicate and magnesium oxide have been shown to decrease the release of chloroquine from tablets and to adsorb chloroquine after its release.(4) In a study in 6 subjects, magnesium trisilicate and kaolin decreased the area-under-curve (AUC) of chloroquine by 18.2% and 28.6%, respectively.(5)

Divalent & Trivalent Cations/Tetracyclines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Di- and trivalent cations may form chelation complexes with tetracyclines, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of di- or trivalent cations may result in decreased levels of and therapeutics effects from tetracyclines.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer tetracyclines at least two hours before or after the di- or trivalent cations. When used for the treatment of H. pylori infection, tetracyclines and bismuth should be given simultaneously. The US manufacturer of omadacycline states to fast for at least four hours, administer omadacycline, and then wait four hours before taking di- or trivalent cations.(21) The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours.(22)

DISCUSSION: Concurrent administration of aluminum hydroxide or divalent cations (such as calcium, magnesium, or zinc) has been shown to significantly decrease the gastrointestinal absorption of tetracycline.(3-5) Concurrent administration of tetracycline and magnesium-aluminum hydroxide gel has been shown to decrease the tetracycline area-under-curve (AUC) by 90%.(6) Magnesium-aluminum silicate has been shown to decrease the AUC of tetracycline by 27%.(7) Demeclocycline(8,9) methacycline,(10) chlortetracycline,(11) and oxytetracycline(10,12) have been shown to interact with aluminum hydroxide and/or dairy products. Doxycycline has been reported to interact with aluminum hydroxide gel.(13) Aluminum magnesium hydroxide has been shown to decrease doxycycline absorption by 84%.(14) Minocycline absorption has been shown to be impaired by aluminum, calcium, and magnesium.(15) Bismuth subsalicylate has been shown to decrease absorption of doxycycline and tetracycline by 37%(16) and 34%,(17) respectively. Since sucralfate is an aluminum salt of a sulfated disaccharide, it may also prevent absorption of tetracyclines. This complex has been used to provide site-specific delivery of tetracycline to gastric ulcers in the treatment of Helicobacter pylori gastric ulcer disease and may be useful in some indications.(18) Quinapril tablets contain a high percentage of magnesium and have been shown to decrease the absorption of tetracycline by 28-37%.(19) Lanthanum is expected to interact with tetracyclines as well.(20)

Folic Acid/Pafolacianine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Folate, folic acid, and folate-containing supplements may reduce binding of pafolacianine to folate receptors expressed on ovarian cancer cells.

CLINICAL EFFECTS: Folate, folic acid, and folate-containing supplements could reduce the detection of malignant lesions with pafolacianine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid administration of folate, folic acid, or folate-containing supplements within 48 hours before administration of pafolacianine.

DISCUSSION: Folate, folic acid, and folate-containing supplements may reduce binding of pafolacianine to folate receptors expressed on cancer cells, which could result in reduced detection of malignant lesions with pafolacianine.

Oral Multivalent Cations/Oral Bisphosphonates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Multivalent cations may bind to and inhibit the absorption of oral bisphosphonates.(1-6)

CLINICAL EFFECTS: Simultaneous administration of products containing multivalent cations may result in decreased levels of and clinical effects from oral bisphosphonates.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to separate the administration times of products containing multivalent cations and oral bisphosphonates. Manufacturer recommendations regarding the separation of administration times of oral bisphosphonates and multivalent cations vary. Do NOT give multivalent cation-containing products: - until at least 30 minutes after taking alendronate(1) - within 2 hours of etidronate(2) - until at least 1 hour after taking ibandronate(3) - until at least 30 minutes after taking risedronate(4) - within 2 hours of tiludronate(5)

DISCUSSION: Multivalent cations may bind to and inhibit the absorption of oral bisphosphonates, resulting in decreased levels of and clinical effects from these agents.(1-6) Administration of aluminum- or magnesium-containing antacids 1 hour before tiludronate decreased the bioavailability of tiludronate by 60%.(5)

Polyvalent Cations And Phosphate Binders/Vadadustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat may form a chelate with iron supplements, phosphate binders, and other medicinal products whose primary component consists of polyvalent cations such as aluminum, calcium, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of vadadustat and polyvalent cations and phosphate binders decreases the exposure and effectiveness of vadadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of vadadustat states that it should be administered at least 1 hour before or 2 hours after any medications or products whose primary component consists of iron, phosphate binders and polyvalent cations.(1)

DISCUSSION: Two studies evaluating the pharmacokinetics, safety, and tolerability of a single oral dose of vadadustat coadministered with a phosphate binder or iron supplement were conducted in healthy adult participants. Vadadustat exposure was reduced by coadministration with sevelamer carbonate, calcium acetate, ferric citrate, and ferrous sulfate. Geometric least squares mean ratios for area under the concentration-time curve (AUC) were reduced 37% to 55% by phosphate binders and 46% by ferrous sulfate. However, when vadadustat was administered 1 hour before phosphate binders, 90% confidence intervals for vadadustat exposure were within the no-effect boundaries of +50% to -33%, indicating that drug-drug interactions can be reduced by administering vadadustat 1 hour before phosphate binders.(2)

Polyvalent Cations/Baloxavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, magnesium, selenium, and zinc may form chelation compounds with baloxavir.(1)

CLINICAL EFFECTS: Simultaneous administration of products containing aluminum, calcium, iron, magnesium, selenium, and zinc may result in decreased levels of and clinical effects from baloxavir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of baloxavir with cation-containing products.(1)

DISCUSSION: A significant decrease in baloxavir exposure was observed when baloxavir was coadministered with calcium, aluminum, magnesium, or iron in monkeys. No studies have been conducted in humans.(1)

Polyvalent Cations/Cabotegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cabotegravir chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of cabotegravir and polyvalent cations may decrease the absorption and clinical effects of cabotegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cabotegravir states that it should be administered at least 4 hours before or 2 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: Clinical studies have not been conducted. Prescribing information states cabotegravir levels may be decreased when coadministered with antacids containing polyvalent cations (examples include aluminum or magnesium hydroxide, calcium carbonate) suggesting cabotegravir is susceptible to chelation.(1)

Polyvalent Cations/Eltrombopag

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Eltrombopag chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of eltrombopag and polyvalent cations may decrease the absorption and clinical effects of eltrombopag.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eltrombopag states that it should be administered at least 2 hours before or 4 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: In a crossover study in 25 healthy subjects, administration of eltrombopag with an antacid (1524 mg aluminum hydroxide/1425 mg magnesium carbonate/sodium alginate) decreased eltrombopag levels by 70%.(1,2)

Polyvalent Cations/Penicillamine, Oral

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Penicillamine chelates with polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc in the GI tract reducing the absorption of the penicillamine.

CLINICAL EFFECTS: Reduced (to 30% of fasting) bioavailability of penicillamine with decreased pharmacologic response.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In order to assure systemic absorption and maximal effectiveness from penicillamine, counsel patient to separate penicillamine by at least 1 hour before or 1 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements. Monitor clinical status for decreased effectiveness and adjust the penicillamine dose if necessary.

DISCUSSION: Clinical studies with polyvalent cations have not been conducted. Multivitamins with low doses of cations including iron and zinc may decrease penicillamine absorption so insure patient is aware of the risks.

Polyvalent Cations/Roxadustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Roxadustat chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of roxadustat and polyvalent cations may decrease the absorption and clinical effects of roxadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of roxadustat states that it should be administered at least 1 hour before or 1 hour after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: Clinical studies with polyvalent cations have not been conducted. In a study in health subjects, concurrent use of roxadustat with sevelamer carbonate or calcium acetate decreased roxadustat area-under-curve (AUC) by 67% and 46% and concentration maximum (Cmax) by 66% and 52%, respectively.(1)

Polyvalent Cations; Lanthanum; Sucralfate/Bictegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Polyvalent cations, lanthanum, and sucralfate may bind to bictegravir in the GI tract, preventing its absorption.(1)

CLINICAL EFFECTS: Polyvalent cations, lanthanum and sucralfate may reduce levels and clinical effectiveness of bictegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Bictegravir must be taken 2 hours before or 6 hours after polyvalent cations, lanthanum or sucralfate. Medicines containing calcium can be taken together with bictegravir if taken with food.(1) Some vitamin preparations may contain sufficient quantities of polyvalent cations to interact as well.

DISCUSSION: Simultaneous administration of aluminum and magnesium hydroxide (20 ml) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 79%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax and AUC by 7% and 13%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax and AUC by 58% and 52%, respectively.(1) Simultaneous administration of aluminum and magnesium hydroxide (20 ml) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 49% and 47%, respectively.(1) Simultaneous administration of calcium carbonate (1200 mg single dose) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 42% and 33%, respectively.(1) Simultaneous administration of calcium carbonate (1200 mg single dose) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax by 10% and increased AUC 3%, respectively.(1) Simultaneous administration of ferrous fumarate (324 mg single dose) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 71% and 63%, respectively.(1) Simultaneous administration of ferrous fumarate (324 mg single dose) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 25% and 16%, respectively.(1)

Sel Oral Cations; Antacids; H2 Antag/Dolutegravir-Rilpivirin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may form chelation compounds with dolutegravir.(1) Rilpivirine requires an acidic medium for absorption. Antacid or H2 antagonist induced decrease in gastric pH may result in decrease in rilpivirine absorption.(1)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate close to the administration time of dolutegravir may result in decreased absorption and clinical effectiveness of dolutegravir.(1) Simultaneous administration of an antacid or a H2 antagonist may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with dolutegravir-rilpivirine and cation-containing products. If it is necessary to use these agents concurrently, dolutegravir-rilpivirine should be administered 4 hours before or 6 hours after taking these medications.(1) Alternatively, dolutegravir-rilpivirine and supplements containing calcium or iron can be taken together with food.(1) In patients maintained on dolutegravir-rilpivirine, administer dolutegravir-rilpivirine at least 4 hours before or 6 hours after antacids .(1) In patients maintained on dolutegravir-rilpivirine, administer dolutegravir-rilpivirine at least 4 hours before or 12 hours after H2 antagonists.(1) Concurrent use of proton pump inhibitors will dolutegravir-rilpivirine is contraindicated.(1)

DISCUSSION: In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir (50 mg single dose) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 72%, 74%, and 74%, respectively.(1) In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%, respectively.(1) In a study in 16 subjects, the administration of a multiple vitamin (One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1) In a study in 16 subjects, omeprazole (20 mg daily) decreased the Cmax, AUC, and Cmin of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours before a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)

Selected Minerals, Oral/Trientine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Mineral supplements may bind to trientine and block its absorption.

CLINICAL EFFECTS: The levels and clinical effects of trientine may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of trientine states that mineral supplements should not be given with trientine. If concomitant therapy is necessary, take trientine on an empty stomach and separate administration at least one hour apart from any other drug. Monitor clinical status for decreased effectiveness and adjust the trientine dose if necessary.

DISCUSSION: Multivitamins with minerals may decrease trientine absorption so ensure patient is aware of the risks and counsel on instructions for concurrent use.

Selected Oral Cations/Dolutegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may form chelation compounds with dolutegravir.(1)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate close to the administration time of dolutegravir may result in decreased absorption and clinical effectiveness of dolutegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with dolutegravir and cation-containing products. If it is necessary to use these agents concurrently, dolutegravir should be administered 2 hours before or 6 hours after taking these medications.(1) Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food.(1)

DISCUSSION: In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir (50 mg single dose) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 72%, 74%, and 74%, respectively.(1) In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%, respectively.(1) In a study in 16 subjects, the administration of a multiple vitamin (One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1)

Selected Oral Cations/Elvitegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may bind to elvitegravir in GI tract.

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate may result in decreased levels and effectiveness of elvitegravir, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration of elvitegravir and products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate by at least 2 hours.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Administration of an antacid (exact formulation not stated) 2 hours before elvitegravir (50 mg) decreased the maximum concentration (Cmax), area-under-curve (AUC), or minimum concentration (Cmin) of elvitegravir by 18%, 15%, and 10%, respectively.(1) Administration of an antacid 2 hours after elvitegravir (50 mg) decreased the Cmax, AUC, or Cmin of elvitegravir by 21%, 20%, and 20%, respectively.(1) Administration of an antacid 4 hours before elvitegravir (50 mg) decreased the Cmax and AUC of elvitegravir by 5%, and 4%, respectively.(1) Administration of an antacid 4 hours before elvitegravir (50 mg) decreased both the Cmax and AUC of elvitegravir by 2%.(1)

Selected Oral Cations/Selected Oral Quinolones

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, and zinc may form chelation compounds with the quinolones.(1-40) MECHANISM OF ACTION: Aluminum, iron, lanthanum, magnesium, and zinc may form chelation compounds with the quinolones.(1-23)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or zinc close to the administration time of an oral quinolone may result in decreased absorption and clinical effectiveness of the quinolone. CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, iron, lanthanum, magnesium, and/or zinc close to the administration time of an oral quinolone may result in decreased absorption and clinical effectiveness of the quinolone

PREDISPOSING FACTORS: None determined. PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with quinolones and cation-containing products. If it is necessary to administer these agents concurrently, follow the manufacturers' recommendations regarding timing of administration of the quinolone and cation-containing products. Manufacturer recommendations regarding the separation of administration times of quinolones and products containing aluminum, calcium, iron, lanthanum, magnesium, and/or zinc vary: ---Do not give ciprofloxacin for at least 2 hours before or 6 hours after oral cations.(1) ---Do not give delafloxacin for at least 2 hours before or 6 hours after oral cations.(2) ---Do not give enoxacin for at least 2 hours before or 8 hours after oral cations.(3) ---Do not give levofloxacin for at least 2 hours before or 2 hours after oral cations.(4) ---Do not give nalidixic acid for at least 2 hours before or 2 hours after oral cations.(5) ---Do not give norfloxacin for at least 2 hours before or 2 hours after oral cations.(6) ---Do not give ofloxacin for at least 2 hours before or 2 hours after oral cations.(7) ---Do not give sparfloxacin for at least 4 hours before oral cations.(8) ---Do not give sitafloxacin for at least 2 hours before or 2 hours after oral cations.(9) The US manufacturer of lanthanum recommends that quinolones be taken at least 1 hour before or 4 hours after lanthanum;(10) however, it would be prudent to follow the specific quinolone manufacturers' recommendations regarding concurrent administration of cations. The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours. For quinolones not listed above, separate their administration from oral cations by as much time as feasible. PATIENT MANAGEMENT: If possible, avoid concurrent therapy with quinolones and cation-containing products. If it is necessary to administer these agents concurrently, follow the manufacturers' recommendations regarding timing of administration of the quinolone and cation-containing products. Manufacturer recommendations regarding the separation of administration times of quinolones and products containing aluminum, iron, lanthanum, magnesium, and/or zinc vary: ---Do not give gatifloxacin for at least 4 hours before oral cations(1) ---Do not give gemifloxacin for at least 2 hours before or 3 hours after oral cations.(2) ---Do not give lomefloxacin for at least 2 hours before or 4 hours after oral cations.(3) ---Do not give moxifloxacin for at least 4 hours before or 8 hours after oral cations.(4) ---Do not give trovafloxacin for at least 2 hours before or after oral cations.(5) ---Do not give prulifloxacin for at least 2 hours before or 4 hours after oral cations.(23) The US manufacturer of lanthanum recommends that quinolones be taken at least 1 hour before or 4 hours after lanthanum;(6) however, it would be prudent to follow the specific quinolone manufacturers' recommendations regarding concurrent administration of cations. The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours. For quinolones not listed above, separate their administration from oral cations by as much time as feasible.

DISCUSSION: Aluminum, calcium, iron, magnesium, and zinc products have been shown to form chelation compounds with quinolone antibiotics, resulting in decreased absorption of the quinolone.(1-40) Treatment failures have been reported.(11-12) In a study in 12 healthy subjects, simultaneous administration of didanosine chewable tablets, which contain aluminum and magnesium, decreased ciprofloxacin area-under-curve (AUC) and maximum concentration (Cmax) by 92% and 98%, respectively.(14) The administration of ciprofloxacin 2 hours prior to Videx chewable/dispersible tablets decreased ciprofloxacin concentrations by 26%.(15,16) In a study in healthy subjects, pretreatment with an antacid containing aluminum-magnesium hydroxide at 5-10 minutes, 2 hours, and 4 hours before a single dose of ciprofloxacin decreased ciprofloxacin AUC by 84.9%, 76.8%, and 30%, respectively. There was no effect when the antacid was administered 6 hours before or 2 hours after.(17) In a study in 12 healthy subjects, aluminum hydroxide decreased ciprofloxacin AUC by 85%.(18) In a study in patients on continuous ambulatory peritoneal dialysis, peak levels of ciprofloxacin were decreased by 67% to 92% in patients receiving aluminum-containing antacids.(19) In a study in 15 healthy subjects, simultaneous administration of calcium acetate decreased the bioavailability of ciprofloxacin by 51%.(20) In a study in 6 healthy males, simultaneous administration of calcium carbonate decreased ciprofloxacin Cmax and AUC by 40% and 43%, respectively.(21) In a study in 12 healthy subjects, calcium carbonate decreased ciprofloxacin AUC by 40%.(18) In a study in 13 healthy males, calcium carbonate had no effect on ciprofloxacin bioavailability when administered 2 hours prior to the antibiotic.(22,23) In a study in healthy males, simultaneous administration of calcium polycarbophil decreased ciprofloxacin AUC by 50%.(24) In a study in 8 healthy males, simultaneous administration of ferrous fumarate (200 mg) decreased ciprofloxacin AUC by 70%.(25) In a study in healthy subjects, ferrous gluconate decreased ciprofloxacin bioavailability by 50%; however, no significant effects were seen with iron-ovotransferrin.(26) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered ciprofloxacin by 54% and 57%, respectively.(27) In a study in 8 healthy subjects, administration of ferrous sulfate decreased the Cmax and AUC of ciprofloxacin by 33% and 46%, respectively. Administration of ferrous gluconate decreased the Cmax and AUC of ciprofloxacin by 57% and 67%, respectively. Administration of a multivitamin product containing calcium, copper, iron, magnesium, manganese, and zinc decreased the Cmax and AUC of ciprofloxacin by 53% and 56%, respectively.(28) In a study in 12 healthy males, ferrous sulfate decreased ciprofloxacin AUC by 63%.(29) In a study in 12 healthy subjects, lanthanum carbonate decreased the area-under-curve (AUC) and maximum concentration (Cmax) of concurrently administered ciprofloxacin by 54% and 56%, respectively.(30) In a study in 12 healthy males, a multivitamin containing zinc decreased ciprofloxacin AUC by 22%.(29) In a study in 12 healthy subjects, an antacid containing aluminum-magnesium hydroxide had no effect on the pharmacokinetics of intravenous enoxacin.(31) In a study in 10 healthy subjects, administration of an aluminum-magnesium hydroxide antacid 0.5 hours or 2 hours before oral enoxacin (400 mg single dose) decreased the AUC of enoxacin by 73% and 43%, respectively. There were no significant effects on enoxacin AUC when the antacid was administered 8 hours before or 2 hours after enoxacin.(32) In a study in 9 healthy subjects, colloidal aluminum phosphate had no effect on the amount of enoxacin absorbed; however, ferrous sulfate (1050 mg) decreased the amount of enoxacin absorption by 10%.(33) In a study in 5 healthy subjects and 5 patients with cystic fibrosis, separation of levofloxacin (750 mg) and calcium carbonate (500 mg 3 times daily with meals) by 2 hours resulted in no interaction in healthy subjects; however, levofloxacin levels were not bioequivalent in patients with cystic fibrosis.(34) Concurrent magnesium-aluminum hydroxide or calcium have been shown to decrease the bioavailability of norfloxacin by 91.0% and 63.5%, respectively.(35) Concurrent zinc has been shown to decrease the bioavailability of norfloxacin.(36) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered norfloxacin by 75% and 73%, respectively.(27) Simultaneous aluminum phosphate was found to decrease the rate, but not the extent, of absorption of ofloxacin.(37) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered norfloxacin by 36% and 25%, respectively.(27) In an in vitro study, ferrous sulfate, aluminum hydroxide, and calcium carbonate decreased ofloxacin availability by 32.6%, 30.7%, and 26.2%, respectively. However, in vivo tests showed a significant effect with only aluminum hydroxide.(38) In a study in 9 healthy subjects, simultaneous administration colloidal aluminum phosphate had no effect on ofloxacin (200 mg) absorption; however, ferrous sulfate (1050 mg) decreased the ofloxacin fraction of dose absorbed by 10.85%.(33) In a study in 16 subjects, administration of either aluminum-magnesium hydroxide or calcium carbonate at least 2 hours before or after ofloxacin administration had no significant effects on ofloxacin levels.(39) The administration of an antacid containing aluminum hydroxide and magnesium hydroxide 2 hours before, 2 hours after, and 4 hours after sparfloxacin decreased sparfloxacin levels by 23%, 17%, and 5%, respectively.(40) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. DISCUSSION: Magnesium and aluminum compounds have been shown to form chelation compounds with quinolone antibiotics, resulting in decreased absorption of the quinolone.(1-22) Treatment failures during concurrent use of cations and gatifloxacin(7) and pefloxacin(8) have been reported. In a study in 24 healthy subjects, administration of an aluminum-magnesium hydroxide antacid simultaneously, 2 hours before, or 2 hours after decreased the area-under-curve (AUC) of a single dose of gatifloxacin (400 mg) by 42%, 64%, or 18%, respectively. There were no affects on gatifloxacin AUC when the antacid was administered 4 hours after gatifloxacin.(9) In a study in 16 healthy males, administration of an aluminum-magnesium hydroxide antacid 10 minutes before or 3 hours after a single dose of gemifloxacin (320 mg) decreased the gemifloxacin AUC by 85% and 15%, respectively. There was no affect when the antacid was administered 2 hours after gemifloxacin.(10) In a study in 16 subjects, simultaneous administration of calcium carbonate decreased the maximum concentration (Cmax) and AUC of a single dose of gemifloxacin (320 mg) by 17% and 21%, respectively. There was no effect of calcium carbonate when administered either 2 hours before or after gemifloxacin.(11) In a study in 27 healthy males, the administration of ferrous sulfate (325 mg) 3 hours before a single dose of gemifloxacin (320 mg) decreased the Cmax and AUC of gemifloxacin by 20% and 11%, respectively. There were no effects when ferrous sulfate was administered 2 hours after gemifloxacin.(12) In a study in 8 healthy subjects, ferrous sulfate (100 mg elemental iron) decreased the Cmax and AUC of a single dose of lomefloxacin by 26% and 13%, respectively. There were no effects with concurrent calcium carbonate (500 mg calcium).(13) Magnesium- and aluminum-containing antacids have been shown to decrease the bioavailability of lomefloxacin by 40%.(14) Administration of moxifloxacin 2 hours before, simultaneously, or 4 hours after a magnesium- and aluminum-containing antacid decreased moxifloxacin AUC by 26%, 60%, and 23%, respectively.(15) Simultaneous administration of moxifloxacin and ferrous sulfate (100 mg) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of moxifloxacin by 39% and 59%, respectively.(16) Concurrent administration of calcium had no affect on moxifloxacin pharmacokinetics.(17) In a study in 10 healthy subjects, an aluminum-magnesium hydroxide antacid decreased the bioavailability of pefloxacin (400 mg) by 44.4%.(18) The administration of an antacid containing aluminum hydroxide and magnesium hydroxide 5 minutes before rufloxacin decreased rufloxacin levels by 36%. Administration of the antacid 4 hours after rufloxacin decreased rufloxacin levels by 13%.(19) Magnesium- and aluminum-containing antacids have been shown to decrease the bioavailability of temafloxacin by 40%.(20) Aluminum hydroxide has been shown to decrease the bioavailability of tosufloxacin by 31.6%.(21) Administration of an antacid containing aluminum hydroxide and magnesium hydroxide 30 minutes before trovafloxacin decreased trovafloxacin levels by 66%.(22) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

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There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• Biliary obstruction
• Disease of liver
• Hypotension

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Rare or Very Rare

• Bronchospastic pulmonary disease
• Concentration difficulty

Rare or Very Rare

• Abdominal distension
• Abnormal hepatic function tests
• Acute cognitive impairment
• Anorexia
• Anorexia
• Depression
• Diarrhea
• Dysgeusia
• Erythema
• Excitement
• Flatulence
• Gastrointestinal irritation
• Irritability
• Malaise
• Nausea
• Nausea
• Pruritus of skin
• Skin rash
• Sleep disorder

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