Prevention or Reduction of Drug Adverse Effect
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Consensus

Effect and Mechanism of Action

Aspirin's activity in inhibiting the effects of cyclooxygenase (COX) extends beyond those functions involved in inflammatory responses. In the stomach the enzyme's products build bicarbonate and mucus buffers against stomach acidity, without which the risk of ulceration can increase 20-fold. Gastrointestinal (GI) bleeding caused by aspirin results in iron loss, which can create a state of iron deficiency if aspirin is taken regularly. Iron supplementation can reverse iron depletion induced by aspirin-related blood loss.

Research

In a 1973 study involving 13 healthy subjects, Leonards et al. ⁴⁷ demonstrated that sodium salicylate tablets and aspirin tablets caused GI bleeding and that the blood loss in volunteers administered aspirin was appreciably greater (5.6 vs. 1.2 mL/day above control values). ⁴⁷ Subsequently, Palme and Koeppe ⁴⁸ compared the GI blood loss caused by the acetylsalicylic acid (ASA) and benorilate (4-acetamidophenyl-2-acetoxybenzoate, Benortan) in Wistar rats and human subjects by measuring the total body iron retention. Their findings indicate that the daily iron loss under ASA is significantly higher (almost doubled) than that under benorilate.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Chronic aspirin ingestion is a frequent cause of iron deficiency and anemia. Gastrointestinal bleeding is a universal and virtually unavoidable adverse effect associated with aspirin consumption. It can cause ulcerations, abdominal burning, pain, cramping, nausea, gastritis, and even serious GI bleeding and liver toxicity. Sometimes, stomach ulceration and bleeding can occur without abdominal pain. Black tarry stools, weakness, and dizziness on standing may be the only signs of internal bleeding. Often there are no externally observable symptoms or obvious blood in the stool.

Physicians prescribing aspirin, or working with patients who self-administer analgesics, are advised to be alert to signs of GI blood loss and iron depletion caused by aspirin intake. Likewise, it is essential to inform patients that aspirin, in any amount, causes gastric bleeding to some degree and to educate them regarding the associated risks. In general, iron supplementation should not be undertaken, and should be actively discouraged, unless iron deficiency has been clinically established. More broadly, patients may benefit from discussing the limitations of protracted palliative therapy for chronic pain and inflammation and engaging in the process of identifying and addressing the causes of pain within a more fundamental and proactive long-term therapeutic strategy.

Iron deficiency anemia (IDA) is readily identified by a low hemoglobin and serum ferritin concentration, although it is not excluded by a normal serum ferritin. Serum transferrin receptor measurements can provide a useful alternative for distinguishing IDA from the anemia of chronic disease because the serum receptor concentration is usually elevated in patients with IDA but normal in patients with anemia from inflammation or neoplasia. Screening for fecal occult blood is prudent with suspected GI blood loss, even when the suspicion of physiological IDA from other known risk factors is high. A gastric delivery system for oral iron that eliminates nausea and vomiting and improves iron absorption when given with food may be appropriate with patients who experience adverse effect from oral iron supplements.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Prevention or Reduction of Drug Adverse Effect
	Bimodal or Variable Interaction, with Professional Management
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Emerging

Effect and Mechanism of Action

Supplemental iron salts may diminish absorption and bioavailability of ACE inhibitors, and vice versa. The mechanism of this interaction has yet to be fully elucidated but is likely caused, at least in part, by binding within the intestines to form a poorly absorbed stable chelation complex. ⁴⁹ Dry cough, and resultant patient nonadherence, is the most common limiting factor of ACE inhibitors. The mechanism that induces ACE inhibitor–induced dry cough involves inhibition of the metabolism of inflammatory proteins known as kinins(e.g., bradykinin), but it has not yet been fully elucidated. Another contributing factor to ACE inhibitor–induced cough may be the increased generation of nitric oxide (NO), which acts as a proinflammatory substance on bronchial epithelial cells. Iron coadministration inhibits cough associated with ACE inhibitors, most likely by acting as an inhibitor of NO synthase activity in bronchial epithelial cells. The erythropoietin-lowering effects of enalapril treatment may also aggravate anemia in renal transplant recipients. Concomitant iron might reverse this adverse effect but can increase risks of oxidative stress if given without counterbalancing antioxidant support. However, ACE inhibitors may enhance the adverse effect and toxicity of iron salts, particularly administered parenterally. Outside the specific context of ACE inhibitor therapy, administration of intravenous (IV) iron to anemic patients on hemodialysis can lead to an “oversaturation” of transferrin, and as a result, non-transferrin-bound, redox-active iron can induce lipid peroxidation. ²⁰

Research and Reports

In a double-blind, placebo-controlled, crossover study involving seven healthy adult volunteers, Schaefer et al. ^49a observed that concomitant administration of captopril (25 mg) and ferrous sulphate (300 mg) resulted in a 37% decrease in area under the curve (AUC) plasma levels for unconjugated captopril compared with placebo. The authors suggested that the observed decrease could be caused by an interaction in the GI tract subsequent to simultaneous ingestion.

Dry cough has been reported to occur in 5% to 39% of patients undergoing ACE inhibitor therapy, and in most cases the drug needs to be discontinued because of this adverse effect. Lee et al. ⁵⁰ conducted a randomized, double-blind, placebo-controlled trial involving 19 patients who had developed ACE inhibitor–induced cough to determine if iron could ameliorate the cough, hypothetically by inhibiting NO-induced inflammation of bronchial epithelial cells. After an initial 2-week observation period, the subjects were randomized to a daily morning dose of 256 mg ferrous sulfate as a tablet or placebo for 4 weeks. The researchers evaluated data from cough diaries, scoring the daily severity of the symptom, as well as blood cell count and serum iron and ferritin concentration between the two periods. Mean daily cough scores during the observation and treatment periods showed a significant reduction in cough scores with iron coadministration but not with placebo. Three subjects in the iron group demonstrated almost complete cough abolition. Interestingly, the authors reported no significant changes in laboratory data in either group.

A bimodal pattern of interaction appears to occur with the administration of IV iron in patients being treated with ACE inhibitors, particularly in the context of hemodialysis. In several studies of hypertensive patients with renal failure (or transplant) on dialysis, mild exacerbation of anemia has been observed during treatment with enalapril. ^51-54 Gossmann et al. ⁵⁵ have suggested that ACE inhibitor–related anemia in renal transplant recipients seems to result from the erythropoietin-lowering effect of this group of drugs. However, administration of iron salts presents numerous risks in this patient population. During a 13-month period, Rolla et al. ⁵⁶ reported aggravated adverse effects, including erythema, abdominal cramps, nausea, vomiting, and hypotension, in three enalapril-treated patients after IV ferric gluconate administration. During that same period, 15 other patients, none of whom were undergoing ACE inhibitor therapy, demonstrated no similar adverse events while receiving IV ferric gluconate. The authors suggested that enalapril might exaggerate the known adverse effects of IV iron by inhibiting the degradation of bradykinin, substance P, or other presumed inflammatory mediators of such iron-related effects. Notably, coadministration of vitamin E may attenuate oxidative stress induced by IV iron in patients on hemodialysis. In a randomized crossover design involving 22 patients, Roob et al. ²⁰ investigated the effects on lipid peroxidation of 100 mg iron(III) hydroxide–sucrose complex, either with or without a single oral dose of 1200 IU of all-racemic alpha-tocopheryl acetate administered 6 hours before hemodialysis. They observed that vitamin E supplementation led to a 68% increase in plasma alpha-tocopherol concentrations and significantly reduced the AUC (0-180 minutes) of plasma malondialdehyde (MDA) to cholesterol and peroxides to cholesterol ratios. These findings suggest that an integrative strategy using several nutrients, such as ascorbic acid, folic acid, beta-carotene, and vitamin E, acting as an antioxidant network might serve to buffer potential adverse effects of IV iron salts and potentially enhance overall treatment outcomes in patients undergoing hemodialysis, particularly with concomitant ACE inhibitors. Further research in the form of well-designed clinical trials may be warranted to test these possible synergies.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing ACE inhibitors are advised to educate patients regarding the risk of adverse effects, including drug-induced cough and anemia, and to inform them that coadministration of an oral iron supplement may reduce such symptoms. However, to avoid absorption problems inhibiting bioavailability of both substances, patients should wait at least 2 hours after administration of the medication before taking iron.

Supplementation of any minerals by patients with renal failure or on dialysis can be dangerous and should only be done within the context of close medical supervision. Patients receiving ACE inhibitor therapy may experience an exaggeration of adverse effects often associated with IV administration of iron salts; monitor closely for adverse effects such as nausea, vomiting, and hypotension.

	Prevention or Reduction of Drug Adverse Effect
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate

Emerging but Mixed

Effect and Mechanism of Action

The mechanisms proposed vary with the agent in question and the form of iron involved. All iron-antacid interactions are affected by the physiological premise that hydrochloric acid in the stomach reduces ferric iron to ferrous iron, the required form for absorption. By inhibiting acid secretion or neutralizing the normally acidic gastric environment, acid-suppressive agents will tend to reduce the absorption of dietary iron. Conversely, the iron status of patients with iron depletion due to internal bleeding from ulcers could also benefit from the therapeutic action of such medications. Finally, iron and some medications can bind to each other and inhibit absorption of both agents.

Scientific knowledge of the full set of factors and mechanisms involved in the various interactions in question is limited, inconsistent, and often of questionable relevance to clinical practice. In vitro experiments investigating the interactions of oral hematinics and antacid suspensions indicate that aluminum hydroxide can precipitate iron as hydroxide and ferric ions become intercalated into the aluminum hydroxide crystal lattice. ⁵⁷ Carbonates can interact with iron to form poorly soluble iron complexes. ⁵⁸ Ferrous sulfate can change into less easily absorbable salts, or its polymerization may increase, in the presence of magnesium trisilicate. ⁵⁹ Histamine (H ² ) receptor antagonists (H ² RAs) appear to be more problematic than other antacids, at least in light of currently available evidence. Cimetidine, and probably to a lesser extent ranitidine, can potentiate the action of oral anticoagulants of both coumarin and indanedione structure, through a dose-dependent, reversible inhibition of cytochrome P450, and if international normalized ratio (INR) is not closely monitored and adjusted appropriately, can cause hemorrhagic complications that further compromise iron status. ⁶⁰ Furthermore, H ² RAs are considered efficient chelators of Fe ²⁺ , and each agent will decrease absorption of the other by binding iron in the GI tract. ⁶¹ More recently, there has been concern that long-term use of proton pump inhibitors (PPIs) might impair the normal hematological process and result in iron deficiency by reducing stomach acid levels.

The adverse effect on absorption of food from iron, particularly ferric nonheme forms as found in plants and dairy products, is likely to be greater than from most iron contained in supplements, which is more often of the ferrous form and is readily absorbed without the need for acid. The degree and clinical significance of this interaction can be influenced by genetics, iron source, concomitant food constituents, timing of intake, duration of medication use, digestive health, aging, and other factors.

Research

A wide range of experimental and clinical studies in the scientific literature have reported that pharmacologically reducing the acidity of the gastric environment will inherently impair normal gastric function and inhibit absorption of iron and, to a lesser degree, zinc, calcium, and other minerals. ^62-67 Although the basic theme of impaired acidity underlies all permutations involved, the evidence cannot easily be analyzed as a coherent data set because of a variety of confounding factors, including significant variety in forms of iron used, iron doses ranging from minimal to relative overdoses, variable mechanism of action and dose of medications, initial iron status and medical conditions (or health) of subjects, the history and severity of any pathology present, lack of dietary consistency, and durations of treatment ranging from experimental single administrations to extended periods representative of clinical practice. Timing of intake and duration of use appear to influence the clinical significance of the interaction to the greatest degree.

Aluminum Hydroxide, Calcium Carbonate, Magnesium Hydroxide, Magnesium Trisilicate, Sodium Bicarbonate, and Combinations

Most experiments have assessed short-term pharmacokinetic effects of simultaneous iron and antacid administration. In an experiment involving iron-replete healthy subjects, Benjamin et al. ⁵⁸ (1967) and Rastogi et al. ⁶⁸ (1976) observed poor absorption of iron in the presence of sodium bicarbonate or aluminum hydroxide, respectively. Ekenved et al. ⁶⁹ found that an antacid containing aluminum and magnesium hydroxides along with magnesium carbonate reduced absorption of ferrous sulfate and ferrous fumarate (both containing 100 mg ferrous iron) by 37% and 31%, respectively. Hall and Davis ⁵⁹ administered magnesium trisilicate (35 g) to nine subjects, who were given 5 mg of isotopically labeled ferrous sulfate (5 mg), and observed a reduction in iron from 30% to 12% on average but from 67% to 5% in one individual. In 1986, O’Neil-Cutting and Crosby ⁷⁰ published findings from a small-dose iron tolerance test involving 22 mildly iron-deficient (menstruation or blood donation) but healthy subjects to compare absorption of iron with and without various antacids. They found that sodium bicarbonate (1 g) and calcium carbonate (500 mg) caused the plasma iron increase to decline by 50% and 37% compared with the controls, respectively, except when the calcium carbonate was present in a tableted multivitamin-mineral formulation. The authors suggested that the competitive binding of iron by ascorbic acid in the multivitamin-mineral tablet facilitated uninhibited absorption of the iron. In contrast, they observed that 1 teaspoonful of a magnesium hydroxide/aluminum hydroxide antacid did not significantly decrease absorption at 2 hours of simultaneously ingested iron (10 or 20 mg ferrous sulfate). In a prospective, unblinded, randomized trial involving 16 healthy, fasting male subjects, Snyder and Clark ⁷¹ investigated the effect of administering magnesium hydroxide, in a 5:1 MgOH/Fe ratio, on a supratherapeutic dose of ferrous sulfate, containing a 10-mg/kg dose of elemental iron, ingested 30 minutes later, by measuring serum iron levels at hourly intervals for 6 or 7 hours. The mean peak serum iron level was 300.8 µg/dL in the control group and 272.5 µg/dL in the experimental group, but mean serum iron levels at each time point and peak serum iron levels did not differ significantly between groups. This experiment was subsequently criticized in a letter by Wallace et al. ⁷² on the basis that iron absorption was not measured for an adequate period to rule out a reduction in iron absorption.

Histamine (H ² ) Receptor Antagonists

The inhibition of gastric secretion by the H ² RAs alters the stomach environment for significantly longer periods than simple antacids and can cause malabsorption of dietary iron (and cobalamin), although not necessarily of iron in supplemental form, such as ferrous sulfate. Furthermore, patients with internal bleeding from ulcers demonstrate improved iron status as a result of the intended therapeutic action of the medications. Lastly, evidence from multiple sources indicates that H ² RAs can act as efficient chelators of Fe ²⁺ such that coadministration might result in binding and reduced bioavailability of both substances. Macdougall et al. ⁷³ conducted a controlled clinical trial investigating the prevention of bleeding from gastric erosions in patients with fulminant hepatic failure using antacids and H ² blockers. They found that intragastric pH recordings taken at 2-hour intervals in the treated group could be consistently maintained above 5.0 with the H ² RAs metiamide and cimetidine, as opposed to patients receiving antacids. In the group receiving H ² blockers only, 1 of 26 patients bled, compared with 13 (54%) of the controls, a highly significant difference. Blood transfusion requirements were significantly less in those treated with H ² RAs. Campbell et al. ⁶¹ performed experiments in vitro and in vivo using isolated perfused rat jejunal tissue to examine the binding of iron and cimetidine. They used a dose of cimetidine paralleling a human dose of 300 mg, with the ferrous sulfate doses equivalent to 150- and 300-mg doses. They observed complete inhibition of cimetidine absorption with the higher ferrous sulfate dose, whereas the lower dose of ferrous sulfate caused a 63% reduction in cimetidine absorption. Furthermore, in vitro iron in its ferrous form rapidly oxidized to the ferric form, which then binds to cimetidine. In a prospective, open, multicenter clinical trial, Bianchi et al. ⁷⁴ studied the effects of concurrent use of famotidine, nizatidine, or ranitidine on response to administration of iron succinyl–protein complex (2400 mg, equivalent to 60 mg iron, twice daily) in a group of patients with iron deficiency or iron deficiency anemia. These researchers observed no significant alteration in iron absorption at the end of 60 days. In this situation the healing of the ulcers, and attendant decreased blood loss, may have improved the iron status of treated individuals.

Partlow and two teams of researchers conducted two studies on the effects of H ² blockers on absorption of ferrous sulfate. In an in vitro experiment, they found that cimetidine and famotidine bind with iron and that ranitidine did so to a much lesser degree. ⁷⁵ In a second study, Partlow et al. ⁷⁶ conducted a series of three experiments investigating the interaction between ferrous sulfate and H ² blockers and the potential impairment of absorption (of both agents) caused by binding. They observed that the reductions in the AUC and the maximum serum levels (C ^max ) of cimetidine were small (<16%) when healthy subjects were administered ferrous sulfate, 300 mg, either as a tablet or in solution. Similarly, they observed very small (<10%) reductions in the AUC and C ^max of famotidine when 40 mg was administered concurrently with 300 mg ferrous sulfate, as a tablet. Overall, these experiments of short duration have tended to show minimal adverse effects on iron absorption and status as well as on drug availability. Thus, Stockley's review ⁷⁷ of the subject concludes that evidence is inadequate to confirm a clinically significant reduction of supplemental iron by H ² blockers. However, extended or repetitive use of H ² RAs may contribute to the occurrence of iron (and/or cobalamin) deficiency anemia. ⁶⁰

Despite long-standing knowledge of the intimate and essential role that gastric pH plays in the conversion of ferric to ferrous iron and subsequent bioavailability and absorption, controversy has continued unabated as to whether the suppression of gastric acid is likely to induce a clinically significant effect on iron nutriture and risk of iron depletion and deficiency. In part, this results from the predominant study of ferrous sulfate as a form of medicinal iron rather than a study of food sources, and a methodological emphasis on studies that often last only 1 day, sometimes as long as 2 months, but rarely reflect the extended duration of medication use common in clinical practice. Likewise, the body of available evidence indicates that any reduction in the serum levels of cimetidine and famotidine due to iron are small and clinically irrelevant. Remarkably, given the widespread use of such agents over extended periods, the issue of iron supplementation in individuals receiving acid-suppressive therapies has been the subject of only limited human research.

Reports

An unconfirmed report published by Esposito ⁷⁸ briefly described a reduction in clinical response to ferrous sulfate (600 mg/day) in three patients taking cimetidine (1 g) and attributed it to the “prolonged periods” of elevated intragastric pH after cimetidine, as previously reported by Macdougall et al. ⁷³ After 2 months’ treatment, anemia and altered iron metabolism persisted, even though the ulcers resolved. In a subsequent letter, Rosner ⁷⁹ noted that the proposed mechanism involved was unconvincing because the iron in ferrous sulfate is Fe ²⁺ , not ferric Fe ³⁺ , and thus not needing an acidic environment for absorption.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The clinical implications of the interaction between gastric acid–suppressive therapies and iron intake and function operate at two levels. The most immediate and probable pharmacokinetic issue of chelation and decreased absorption and bioavailability affects both iron and pharmaceutical agents. The longer-term and more variable issues of decreased iron absorption and bioavailability, potentially leading to depletion and deficiency, are subject to more variability in terms of occurrence, severity, and consequences. The former is easily avoided through education regarding the timing of intake. The latter may be offset through iron supplementation or alteration in dietary sources of iron intake, but may only partially address the potential adverse effects of chronic suppression of gastric acid activity.

Stabilization of iron status is central among the many benefits of medical treatment of gastric bleeding, and subsequent enhancement of iron intake may be appropriate in select cases. Anemia due to blood loss is common among the users of antacids and gastric acid–suppressive medications because many have ulcers. Proper medical evaluation of blood and tissue iron status and presence of internal blood loss from GI bleeding are necessary preliminaries to consideration of iron supplementation. Professional supervision and regular monitoring are appropriate once it has been determined that iron administration is appropriate. It is important to inform patients of limitations and risks of acid suppression on an extended basis, including increased susceptibility to Helicobacter pyloriand other infections, impaired protein digestion and other adverse effects of hypochlorhydria, and disruption of normal GI ecology. ^80-86 In clinical practice, complementary approaches for supporting renewal of gastric mucosa typically include deglycyrrhizinated licorice (DGL), zinc carnosine, cabbage leaf (Brassica oleracea),cranesbill root (Geranium maculatum),marshmallow root (Althaea officinalis),and slippery elm bark (Ulmus rubra). Ultimately, changes in causative and exacerbating factors underlying dyspepsia and reflux need to be addressed through education about the importance of thorough chewing and relaxing while eating; the inherent risks of excessive portion size and eating late in the evening; the value of paying attention to individual responses to particular foods, food combinations, and eating patterns; potential roles of H. pylori;and the influence of stress. Overall, the adverse effect on absorption of iron from food, particularly ferric forms as found in plants, is likely to be greater than on ferrous forms, as found in many iron supplements. Thus, the initial action of these medications in providing a gastric environment more suitable toward healing of ulcerations and resolution of internal bleeding may tend to result in minimal adverse effect on iron status. This situation could, however, change as the continued elevation of gastric pH results in decreased iron absorption from some food sources, particularly ferric iron.

In the event that iron administration is determined to be necessary, a typical adult dose is 100 mg of elemental iron daily. Iron preparations should be taken at least 2 hours before or after antacid medications, particularly cimetidine, sodium bicarbonate, or calcium, to avoid interference with iron absorption (and in some cases drug absorption). In general, gastric acidity is not required for absorption of supplements containing ferrous iron. However, because carbonyl iron requires adequate stomach acid for absorption, concomitant use of PPIs may suppress its absorption. Ferrous fumarate and iron-EDTA may be more bioavailable than ferrous sulfate, particularly in individuals with low (or impaired) gastric acidity. Simultaneous intake of vitamin A and C (>200 mg/day) may enhance absorption. Increased intake of plant foods and herbs rich in iron and other minerals may be more appropriate than iron supplements for some individuals because of tolerance, compliance, and bioavailability factors. Furthermore, because iron levels in the body are regulated by absorption, rather than by excretion, individuals with low body iron levels, including iron deficiency, can demonstrate increased absorption efficiency, often in the range of 10% to 20%.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Emerging but Mixed

Effect and Mechanism of Action

When ingested together, iron and cholestyramine or colestipol can bind to form a chelation complex that is poorly absorbable. ^63,87 In the process of sequestering intestinal bile acids, these agents may contribute to iron depletion and potential deficiency with long-term use. ^88,89 Impaired absorption and resultant decreased bioavailability of the drug could reduce its therapeutic activity.

Research

The body of research regarding the pattern of interactions between iron and bile acid sequestrants is limited, potentially contradictory, and sometimes not focused on key questions of clinical relevance. Using a rat model, Thomas et al. ⁹⁰ observed that cholestyramine reduced intestinal absorption of a single 100-µg dose of ferrous sulfate by half. Subsequently, this same team extended their research by demonstrating diminished iron stores after prolonged cholestyramine administration. ⁹¹ Several years later, in vitro experiments by Leonard et al. ⁸⁷ demonstrated that cholestyramine and colestipol can both bind iron citrate. The amount of iron citrate bound by colestipol ranged from 95% to 98%. Cholestyramine bound 24% to 97% of the iron citrate in a pH-dependent manner. In another animal study, Watkins et al. ⁸⁸ found that cholestyramine-fed rats had a net negative balance for calcium and a lower net positive balance for iron, magnesium, and zinc than the controls. These researchers attributed the reported disturbance in iron balance to diminished iron absorption caused by resin binding. Schlierf et al. ⁹² investigated the availability of minerals and vitamins in young patients with familial hypercholesterolemia administered colestipol over a 5-year period. They reported a lack of significant alterations in plasma levels of iron (as well as of calcium, sodium, parathyroid hormone, and water-soluble and fat-soluble vitamins, except for changes in carotenoid and vitamin E levels paralleling lipoprotein concentrations). The researchers’ observation that the treatment was effective in lowering cholesterol levels by 19% indicates that any mutual binding that might have occurred did not significantly impair drug activity.

Notably, no human trials have examined the effect of the observed pharmacokinetic interactions on long-term patterns of depletion in tissue iron stores (as opposed to plasma levels), the influence of intake timing, or the variable responses in patients with preexisting iron depletion or anemia. In a review of cholesterol-lowering agents, Torkos ⁸⁹ suggested that an iron deficiency can result from long-term use of colestipol.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing bile acid sequestrants are advised to inform patients of the probable pharmacokinetic interaction between iron and these agents and to recommend separating oral intake by at least 2 hours. Such measures usually allow concurrent use of both agents without interfering with the intended therapeutic activity of either. Despite the lack of solid evidence, many practitioners of nutritional therapeutics recommend regular use of a multivitamin-mineral formula to patients on long-term bile acid sequestrant therapy as a preventive measure in light of the diverse body of evidence indicating significant probability of associated, multiple nutrient deficiency patterns, particularly with fat-soluble vitamins. Such safe and low-cost measures appear judicious pending the emergence of more conclusive evidence based on well-designed, long-term clinical trials.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Consensus

Effect and Mechanism of Action

Absorption of bisphosphonates occurs through passive diffusion in the stomach and upper small intestine and is very low and variable (1%-10%). Simultaneous ingestion of cations such as iron (or calcium/magnesium) can result in chelation that significantly reduces absorption and bioavailability of both substances. ⁹³

Research

Evidence from clinical trials specifically investigating the interaction between iron and bisphosphonates is lacking. Nevertheless, this interaction represents the consensus position within the standard pharmacological literature. ^93,94

No research or case reports were found focusing on potential iron depletion resulting from simultaneous intake of these substances over an extended period.

Clinical Implications and Adaptations

Oral iron preparations need to be taken at least 2 hours away from the bisphosphonate to avoid pharmacokinetic interference. It is generally recommended that oral bisphosphonates be taken with a full glass (6-8 ounces) of plain water on an empty stomach, avoiding the recumbent position for at least 30 minutes to prevent potential severe esophageal irritation associated with incomplete transfer of the tablet to the stomach.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Consensus

Effect and Mechanism of Action

Iron, especially ferric iron, can bind strongly to carbidopa or levodopa, and the resulting insoluble chelation complexes can significantly reduce absorption and bioavailability of both substances. ^49,95-97

Ferrous iron, such as ferrous sulfate, is formed from ferric iron when it is reduced under the influence of the acidic pH of the GI environment. However, ferrous iron undergoes autooxidation to the ferric form in the presence of methyldopa and levodopa. The formation of these complexes is rapid at high pH (i.e., pH 9), and the rate slows considerably as the pH is lowered (e.g., pH 4). A variety of iron-methyldopa complexes can be formed between pH 4 and 9. Complexation is absent below pH 2. Together these processes can result in both catechol oxidation and production of the toxic hydroxyl radical. ⁹⁶

Research

The pioneering research done by Campbell, Hasinoff, and Greene has established the basis for consensus regarding these issues within the pharmacological literature. In a rat model, Campbell et al. ⁹⁸ observed that ferrous sulfate significantly reduced L-dopa absorption by 22.6% in the duodenum and 23.9% in the jejunum, on average. Furthermore, the authors noted a tendency for ferrous sulfate to cause a greater reduction in L-dopa absorption as the buffer pH increased. They concluded that “the combined results are compatible with the chemical model of increased L-dopa–iron binding as pH increases.” Chelation was investigated as a mechanism in iron-induced reduction in levodopa bioavailability in a study involving eight healthy subjects who were administered a single dose of levodopa (250 mg), with and without a single dose of ferrous sulfate (325 mg). When the serum levodopa levels were measured, these researchers observed a 55% decline in peak serum levodopa levels (from 3.6 to 1.6 nmol/L) and a reduction in the AUC by 51% (from 257 to 125 nmol.min/mL). Notably, subjects who had demonstrated the highest peak levels and greatest absorption demonstrated the largest reductions in the presence of ferrous sulfate. ⁹⁵ Similarly, in a study involving nine patients with Parkinson's disease being treated with Sinemet (100/25 tablet), Campbell et al. ⁹⁷ found that coadministration of a single dose of ferrous sulfate resulted in a decrease in the AUC of carbidopa by more than 75% and of levodopa by 30%. However, despite an apparently strong relationship observed between reductions in levodopa AUC and reductions in Sinemet efficacy, the average reduction in Sinemet efficacy associated with ferrous sulfate did not achieve statistical significance. Thus, these authors reported that some patients manifested a worsening of their Parkinson's symptomatology and concluded that the effect on Sinemet availability, when taken concurrently with ferrous sulfate, appears to be clinically significant in some, but not all, patients. ⁹⁷

More broadly, an emerging pattern of evidence indicates that chronic iron intake may be contraindicated in patients who would typically be prescribed these medications. Diverse findings suggest that glutathione depletion, oxidative stress, and possibly other factors resulting from iron excess may play a significant role in the pathophysiology of Parkinson's and other neurodegenerative diseases. ^42,45,99,100 As noted by Gotz et al. ⁴⁵ : “Glial iron is mainly stored as ferric iron in ferritin, while neuronal iron is predominantly bound to neuromelanin. Iron overload may induce progressive degeneration of nigrostriatal neurons by facilitating the formation of reactive biological intermediates, including reactive oxygen species, and the formation of cytotoxic protein aggregates.” Thus, apart from short-term response in cases involving confirmed comorbid depleted iron stores or iron deficiency anemia, a more appropriate therapeutic strategy might invoke iron chelators in the prevention or treatment of Parkinson's disease in individuals with iron overload, or even with physiological iron stores in the higher ranges of normal. ^46,101,102

Clinical Implications and Adaptations

Despite a relatively consistent body of evidence, the clinical significance of the interaction between iron preparations and levodopa or carbidopa is not fully known. Physicians prescribing levodopa or carbidopa are advised to caution these patients against taking iron supplements outside the context of medical supervision and monitoring. Simultaneous intake can decrease absorption and bioavailability of both substances, which may result in impaired control of Parkinson's symptomatology and interfere with medically appropriate iron support.

In cases where a comprehensive strategy calls for inclusion of both agents as medically necessary and appropriate, intake should be separated by at least 2 hours to avoid impairing their activity. Otherwise, conservative principles of practice suggest that coadministration be discouraged pending substantive research clearly defining mechanisms of action, parameters of effect, and respective risks and benefits.

Impaired Drug Absorption and Bioavailability, Precautions Appropriate

Emerging, treated as Consensus

Effect and Mechanism of Action

Supplemental iron salts may diminish absorption and bioavailability of cefdinir and related cephalosporin antibiotics, and vice versa. The mechanism of this interaction has yet to be fully elucidated but is likely caused, at least in part, by binding within the GI tract to form a poorly absorbed, stable chelation complex. ^77,103,104

Research

In a randomized three-way crossover study involving healthy male volunteers, Ueno et al. ¹⁰³ compared the effects on concentration curve [AUC (0-12)] of cefdinir (200 mg) alone, ingested simultaneously with two tablets of iron ion, and followed 3 hours later by two tablets of iron ion preparation. They observed that the AUC (0-12) of cefdinir with concurrent iron and the AUC (3-12) with delayed iron were both significantly smaller than that with cefdinir alone. However, there were no differences in AUC (0-3) between cefdinir alone and with delayed iron. These researchers interpreted their findings to suggest that the impaired absorption of cefdinir was caused by formation of a chelation complex.

More recently, in an in vitro experiment comparing the effects of calcium polycarbophil granules and iron(III) citrate on cefdinir, Kato et al. ¹⁰⁵ found that, in contrast to the calcium compound, “the release of cefdinir from the cellulose membrane in the presence of iron ions was slower than in the absence of iron ions.”

Clinical Implications and Adaptations

Physicians prescribing cefdinir or related oral cephalosporin antibiotics are advised to caution these patients against taking iron supplements within 3 hours of the medication. A general caution regarding iron supplementation outside the context of medical supervision and monitoring may also be appropriate with some patients. Simultaneous intake can decrease absorption and bioavailability of the antibiotic, which may impair its antimicrobial activity.

Clinically significant iron depletion caused by simultaneous intake of these substances is improbable over the limited time such medications are typically administered.

	Prevention or Reduction of Drug Adverse Effect
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Consensus

Effect and Mechanism of Action

At serum levels of 25 µg/mL or more, chloramphenicol can inhibit protein synthesis and cause a reversible bone marrow depression. Although much milder than the irreversible form, in which chloramphenicol can cause aplastic anemia, this more common and possibly unrelated adverse effect can interfere with the activity of iron (or vitamin B ¹² ) in the treatment of anemia.

Research and Reports

The adverse effects of chloramphenicol on erythropoiesis and red blood cell (RBC) maturation have been well documented for more than 50 years. In 1954, Rigdon et al. ¹⁰⁶ first documented anemia produced by chloramphenicol in the duck. In their study of the effect of chloramphenicol on erythropoiesis, Saidi et al. ¹⁰⁷ observed that 10 of 22 patients being treated with iron dextran for iron deficiency anemia failed to demonstrate the expected hematological response when coadministered chloramphenicol. Likewise, four patients being treated with vitamin B ¹² for pernicious anemia were refractory to therapy until chloramphenicol was discontinued. McCurdy ¹⁰⁸ reported bone marrow toxicity in series of patients with liver disease after exposure to chloramphenicol. Jiji et al. ¹⁰⁹ (1963) published a report of reversible erythropoietic toxicity in healthy volunteers associated with chloramphenicol and its sulfamoyl analog. Two years later, Scott et al. ¹¹⁰ conducted a controlled double-blind study of the hematological toxicity of chloramphenicol and, based on their findings, suggested that drug dosage levels of 25 to 30 mg/kg are usually sufficient for effectively treating infections while minimizing the risk of elevating serum levels to 25 µg/ml or greater, at which bone marrow suppression occurs.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Chloramphenicol may impair the therapeutic effects of iron administration. A decline in the reticulocyte count will indicate inadequate RBC maturation. As recommended by Scott et al., ¹¹⁰ dosage levels below 25 to 30 mg/kg may be safe and effective, whereas higher doses increase risks of drug-induced adverse effects. Iron coadministration may be judicious in some cases when extended chloramphenicol is anticipated. Consideration of alternative antimicrobials may be warranted in the treatment of individuals diagnosed with depleted iron stores or iron deficiency anemia or otherwise at elevated risk for adverse effects on erythropoiesis and iron function.

Chloramphenicol, although used in some countries such as Mexico, is used extremely rarely in the U.S., and then only in the hands of infectious disease specialists when no alternatives exist. It is not generally available because of the risk of aplastic anemia associated with its use (a life-threatening complication quite different from simple bone marrow suppression).

Minimal to Mild Adverse Interaction—Vigilance Necessary

Consensus

Effect and Mechanism of Action

Tooth staining is an adverse effect associated with both chlorhexidine and ingestion of iron in liquid preparations. Concurrent intake may increase the probability and severity of dental staining.

Research

The mechanism and significant probability of this interaction are accepted as consensus within the pharmacological literature, even though the body of direct evidence from controlled clinical trials is relatively limited. In a controlled study using analytical electron microscopy, Warner et al. ¹¹¹ demonstrated that individuals administered iron immediately after using chlorhexidine developed severe dental staining within 2 weeks. They noted that enhanced levels of sulfur and transition metals, particularly iron, were found in stained regions, whereas unstained regions contained low sulfur and metal levels similar to those treated with water or nonstaining agents.

Clinical Implications and Adaptations

Physicians prescribing chlorhexidine, in liquid dosage forms, are advised to inform patients to prevent this adverse effect by separating intake of iron (as well as sulfur or other transition metals) by at least 1 hour before or 2 hours after using the drug.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Preliminary , treated as Consensus

Effect and Mechanism of Action

Clofibrate can bind to iron (and other nutrients) within the GI tract to form a chelation complex that is poorly absorbed and reduces bioavailability of both substances. ¹¹²

Research

Clinical research directly investigating this iron-clofibrate interaction is limited. However, the pharmacological literature accepts this pharmacokinetic interaction as representing a consensus position based on the principles involved and general knowledge of the agents involved.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing clofibrate are advised to inform patients of the probable pharmacokinetic interaction between iron and the medication and to recommend separating oral intake by at least 3 hours. Such measures should allow concurrent use of both agents without interfering with the intended therapeutic activity of either. In general, conservative principles of practice warrant advising patients against taking iron supplements without specific, well-founded therapeutic need and outside the context of medical supervision and monitoring.

	Prevention or Reduction of Nutrient Adverse Effect
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Consensus

Effect and Mechanism of Action

Desferoxamine mesylate (Desferal) is the chelator of choice for acute iron intoxication and of chronic iron overload caused by transfusion-dependent anemias. It is also used to decrease aluminum accumulation in patients with kidney failure. Desferoxamine can be administered intramuscularly, subcutaneously, or intravenously.

Because desferoxamine is administered to individuals with dangerously high levels of iron, it would be counterproductive to supplement or coadminister iron.

Research

It is self-evident that patients with acute or chronic iron excess being treated with desferoxamine to chelate and remove excess iron should avoid iron supplementation as well as iron-rich foods. Thus, no specific research studies have ever combined desferoxamine with iron coadministration because the interaction is obvious.

Clinical Implications and Adaptations

Chelation with desferoxamine or other agents requires appropriate training and proper monitoring. Assessment of nutrient status is appropriate, and clinical responses will vary accordingly. Iron supplementation would exacerbate the condition of patients prescribed desferoxamine. Thus, iron-containing products of any type are contraindicated in individuals receiving appropriate desferoxamine therapy and specifically need to be avoided during such treatment. Physicians who administer desferoxamine for chelation of heavy metals or other clinical applications routinely supplement their patients with minerals of nutritional importance. Patients undergoing iron removal therapy should be made aware that they should avoid over-the-counter (OTC) multivitamin-mineral preparations that contain iron.

Potentially Harmful or Serious Adverse Interaction—Avoid

Consensus

Effect and Mechanism of Action

Dimercaprol is an effective antidote in arsenic, cadmium, lead, and mercury poisoning and is most efficient if administered intramuscularly immediately after exposure to the metal. Dimercaprol's mechanism of action involves the formation of toxic complexes with iron, cadmium, selenium, and uranium. Nevertheless, dimercaprol cannot be used in poisoning from iron, cadmium, tellurium, selenium, vanadium, or uranium; it is also contraindicated in poisoning from elemental mercury vapor.

Research

Research into this interaction is implicitly contained within the clinical trials, case reports, and clinical experience of the therapeutic application of dimercaprol.

Clinical Implications and Adaptations

Physicians administering dimercaprol need to avoid iron administration out of sequence. Iron therapy is often administered 24 hours or more after the last dose of dimercaprol. However, the concomitant intake of iron and dimercaprol can result in serious renal injury. Warnings to patients to avoid iron supplements would seem reasonable but are usually unnecessary because this medication is typically administered in emergency or inpatient settings.

	Prevention or Reduction of Nutrient Adverse Effect
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Consensus

Effect and Mechanism of Action

EDTA binds to iron (and other minerals) and thereby increases iron excretion. EDTA may be used to treat iron overload, although it is much less efficient than desferoxamine. Conversely, chelation therapy with EDTA could induce or exacerbate depleted iron stores if compensatory nutrient augmentation is appropriate but not provided.

Research

The chelation function of EDTA is central to its primary pharmacological action in therapeutic application.

Conversely, iron chelates, such as ferric EDTA, sodium iron EDTA [NaFe(III)EDTA], and ferrous bisglycinate, have been proposed as promising alternatives to iron salts for food fortification based on recent studies involving healthy and at-risk infants and children. ^113,114 Continued research is warranted.

Clinical Implications and Adaptations

Chelation with EDTA or other agents requires appropriate training and proper monitoring. Assessment of iron status is appropriate, and clinical responses will vary accordingly. When properly administered, EDTA chelation is considered unlikely to result in adverse reactions caused by iron depletion. Physicians who administer EDTA for chelation of heavy metals or other clinical applications routinely coadminister minerals of nutritional importance as part of a strategic therapeutic protocol.

	Beneficial or Supportive Interaction, with Professional Management
	Bimodal or Variable Interaction, with Professional Management
	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid

Emerging , Mixed

Effect and Mechanism of Action

Erythropoietin is an endogenous peptide, produced primarily by the kidneys, which drives erythropoiesis in the bone marrow. It became available as a recombinant peptide hormone for therapeutic use in the 1980s.

Approximately 50% of oncology patients develop anemia, with that incidence rising dramatically in patients with more advanced cancer or in those receiving chemotherapy and/or radiation therapy. Within conventional oncology, recombinant human erythropoietin(rHuEpo) represents the standard of care in managing cancer therapy-related anemia and fatigue, increasing hemoglobin levels, reducing transfusion need, and improving patient quality of life. Likewise, rHuEpo may correct anemia in chronic renal failure (CRF) patients, in iron-deficient erythropoiesis associated with the anemia of chronic disease (ACD), and in primary bone marrow dysfunction states, such as myelodysplastic syndrome. By stimulating erythropoiesis, erythropoietin may increase synthesis of RBCs, thereby increasing metabolic need for iron. Iron coadministration, intravenous/parenteral or oral, could improve the response to erythropoietin or rHuEpo in cases of iron-deficient erythropoiesis by delivering adequate iron to the bone marrow.

Research

Since the late 1980s, rHuEpo has provided a safe and effective option for treating cancer-related anemia and fatigue. Recent research confirmed that epoetin beta, 30,000 IU once weekly, is equally effective as the conventional 10,000 IU three times weekly in alleviating cancer-related anemia. ¹¹⁵ Nevertheless, erythropoietin therapy exhibits variable response rates, and 30% to 50% of patients did not respond adequately to treatment in some trials. True iron deficiency is the most common cause of an inadequate response to rHuEpo in CRF patients. However, in oncology patients, this failure may be caused by factors related to the underlying disease, adverse effects of chemotherapy or radiotherapy, functional iron deficiency, or some combination. ^116,117 Thus, in cases of functional iron deficiency, patients may not respond to rHuEpo when iron availability is inadequate to the demands of erythropoietin-induced erythropoiesis, despite the presence of adequate bone marrow iron stores.

Since the emergence of rHuEpo as a standard treatment, concomitant iron has often been proposed as an important therapeutic option in optimizing the response of cancer-related anemia to rHuEpo. ¹¹⁸ Guidelines published by the American Society of Clinical Oncology and American Society of Hematology recommend iron repletion in patients receiving rHuEpo when functional iron deficiency is present, based on indirect evidence and biological inferences. ¹¹⁷ A growing body of literature regarding chronic renal failure patients has shown that iron coadministration can correct functional iron deficiency and may improve erythropoietin response, with IV iron doing so more effectively than oral iron.

Markowitz et al. ¹¹⁹ conducted a double-blind, placebo-controlled trial to evaluate the effectiveness of oral iron therapy in 49 hemodialysis patients receiving rHuEpo. They divided the subjects into two groups, based on adequate or deficient iron stores, and treated them for 3 months with 150 mg elemental iron (polysaccharide complex) or placebo, twice daily. Over 5 months they observed that iron-replete patients, in both oral iron and placebo subgroups, demonstrated decreasing iron stores; that is, oral iron failed to maintain their iron stores. Furthermore, compared to iron-replete patients, iron-deficient patients had a significantly greater dropout rate because of adverse effects, even though responses to the side effect questionnaire were equivalent, suggesting poor medication compliance. Beguin ¹¹⁶ found that oral iron is largely ineffective in the treatment of anemia in chronic diseases other than cancer, mainly because of the development of iron deficiency, which significantly limits the efficacy of rHuEpo therapy.

Oral iron products in patients with ESRD have been largely abandoned, and the safety of IV iron preparations has improved with the introduction of new-generation compounds that have significantly reduced incidence of allergenicity. Since its approval, sodium ferric gluconate complex (SFGC) has largely displaced iron dextran as the primary form of IV iron, which had been associated with significant adverse reactions, including anaphylaxis and death. Adverse reactions to SFGC are uncommon in hemodialysis patients, including both iron dextran–sensitive and dextran-tolerant patients. ¹²⁰ These findings indicate that dextran, rather than iron, is the cause of most reactions to iron dextran administration.

Iron deficiency is the most common cause of suboptimal response to rHuEpo in chronic hemodialysis patients. Intravenous iron can improve hemoglobin response, help maintain adequate iron stores, and decrease erythropoietin dosage requirements in hemodialysis patients and patients with anemia of kidney disease. In 1997, Kooistra et al. ¹²¹ investigated the effects of iron availability, inflammation, and aluminum on iron absorption in 19 chronic hemodialysis patients on maintenance erythropoietin (rHuEpo) therapy. They concluded that iron absorption is decreased in hemodialysis patients with elevated C-reactive protein (CRP) values and higher levels of aluminum ingestion. Iron absorption correlated significantly with transferrin saturation and CRP in the iron-deficient group, and with serum ferritin in the iron-replete group. Auerbach et al. ¹²² conducted a randomized trial involving 43 hemodialysis patients receiving rHuEpo (epoietin alpha) to investigate three iron dextran infusion methods for anemia. They reported no significant differences in efficacy and safety (as measured by time to the maximum hemoglobin and adverse reactions) when they compared subjects who received IV iron dextran as a total-dose infusion, 500-mg infusion to total dose, or 100-mg bolus to total dose, in each case during the dialysis procedure.

In a trial involving 24 patients of an outpatient dialysis center, Vankova et al. ¹²³ reported significant improvements obtained by tracking hematocrit, transferrin saturation, and ferritin levels and adjusting iron and rHuEpo dosage accordingly. In 23 patients (96%), transferrin saturation levels were within the recommended range after treatment. Hematocrit increased from 27.7% to 35.7%, with the recommended value of 33% being achieved in 18 patients. Overall, the weekly dose of rHuEPO fell from 3958 IU to 2042 IU, and the average dose of iron administered was 157 mg per week. Similarly, Chang et al. ¹²⁴ conducted a 12-month IV iron substitution trial in 149 iron-replete chronic hemodialysis patients receiving subcutaneous rHuEpo therapy. They maintained the available iron pool with 100 mg iron every 2 weeks or 1 month, depending on serum ferritin and transferrin saturation levels, with the rHuEpo dosage titrated depending on hematocrit levels. After 12 months these researchers reported increases in the hematocrit, serum ferritin, and transferrin saturation along with a 25% reduction in rHuEpo requirement. The authors concluded that maintaining high levels of serum ferritin and transferrin saturation could further reduce the requirement of erythropoietin in chronic hemodialysis patients, but cautioned that “the long-term effect of iron overloading…must be further evaluated in contrast to the economic saving.” ¹²⁴

However, oral heme iron may provide an effective option for iron therapy in hemodialysis patients because it is absorbed by patients with high ferritin levels, it has fewer adverse effects, and its absorption is stimulated by erythropoietin administration. In an open, 6-month, prospective evaluation of heme iron in 37 hemodialysis patients who had been on maintenance IV iron therapy, Nissenson et al. ¹²⁵ discontinued the IV iron and replaced it with oral heme iron. Among the 28 subjects who completed the study, the authors observed an initial slight reduction in average transferrin saturation, which subsequently reversed, and a significant reduction in average serum ferritin level was seen at months 4 through 6. No significant changes were seen in average transferrin saturation or hematocrit. The authors concluded that heme iron polypeptide successfully replaced IV iron therapy in a majority of hemodialysis patients during the 6-month study period, maintained target hematocrits with no concomitant use of IV iron, and thus was associated with a significant increase in rHuEpo efficiency.

Ongoing research is examining the role of concomitant IV iron during epoetin therapy with the aim of further improving the effectiveness of epoietins in anemia treatment. A study published in 2004 was the first controlled trial confirming that iron should be coadministered intravenously rather then orally in cancer patients with chemotherapy-related anemia. In a prospective, multicenter, open-label, randomized trial involving 157 patients, Auerbach et al. ¹²⁶ found that IV iron optimizes the response to rHuEpo in cancer patients with chemotherapy-related anemia. In addition to rHuEpo, 40,000 U subcutaneously once weekly, subjects received (1) no iron; (2) 325 mg iron orally twice daily; (3) iron dextran, repeated 100-mg IV bolus; or (4) iron dextran total-dose infusion (TDI). They reported that subjects in all four groups showed hemoglobin (Hb) increases from baseline with mean Hb increases for both IV iron groups were greater than for no-iron and oral iron groups. Patients in both groups receiving IV iron demonstrated higher hematopoietic responses (68%) than did those in the groups receiving no iron (25%) and oral iron (36%). Furthermore, subjects in the IV iron group showed increases in energy, activity, and overall quality of life from baseline, compared with a decrease in energy and activity for the no-iron group and no change in activity or overall quality of life for the oral iron group. The authors concluded that rHuEpo increases Hb levels and improves quality of life in patients with chemotherapy-related anemia, and that coadministration of IV iron significantly increased the magnitude of improvement for both outcomes. Patients were not followed long term to determine whether the therapy had any positive or negative impact on cancer specific survival. In a letter, Pedrazzoli et al. ¹²⁷ responded with a cautionary approach: “Because of absence of iron stores, in this subset of patients, it is clinically cautious to postpone treatment with erythropoietic agents until iron stores are replenished or to treat iron deficiency aggressively along with rHuEpo therapy.” In contrast, in a randomized, double-blind, placebo-controlled trial involving 351 head and neck cancer patients with anemia undergoing radiotherapy, Henke et al. ¹²⁸ found that epoetin beta corrected anemia but did not improve cancer control or survival, and in fact, locoregional progression-free survival was poorer with epoetin beta than with placebo. Moreover, whether concomitant iron can increase the proportion of patients without iron deficiency responding to erythropoietic agents remains the subject of ongoing controversy and an area in need of further elucidation within the field of rHuEpo therapy for anemia of cancer.

Anemia of chronic disease (ACD) is a frequent complication of chronic inflammation in rheumatoid arthritis and other conditions. The cytokine interleukin-6 (IL-6) mediates hypoferremia (anemia) of inflammation by inducing the synthesis of the iron-regulatory hormone hepcidin. ^129,130 Arndt et al. ¹³¹ investigated the concomitant use of rHuEpo and parenteral iron to correct iron-deficient erythropoiesis (IDE) in patients diagnosed with anemia of chronic disease. They treated 30 rheumatoid arthritis patients with ACD using subcutaneous rHuEpo, 150 IU/kg twice weekly. Intravenous iron (200 mg iron sucrose once weekly) was coadministered in cases of IDE, as defined by the presence of two of three criteria: saturation of transferrin 15% or less, hypochromic erythrocytes 10% or more, and serum ferritin concentration 50 µg/L or less. The authors reported that all 28 subjects who completed the trial met the treatment goal of successful correction of anemia, with an increase of the median Hb concentration from 10.3 to 13.3 g/dL, and concluded that such coadministration of erythropoietin and iron was safe, effective, and well tolerated in all patients.

Nutritional Therapeutics, Clinical Concerns and Adaptations

Physicians administering erythropoietin are advised to exercise caution in the coadministration of iron, especially IV iron within the context of oncological care. Combination therapy using erythropoietin and iron is controversial and awaits greater evolution of clinical research, particularly specificity to individuals, conditions, and stages of treatment. ¹¹⁶ The erythropoietic response is a tactical element within the broader therapeutic strategy and, although evoking apparent short-term benefits using narrow parameters of hematological response, may be irrelevant or deleterious, even counterproductive, to achieving the desired clinical outcome, such as the strategic goal of eliminating cancer. ¹³² Thus, this intervention could be beneficial or adverse, depending on the particulars of the case.

Most anemia is cancer patients is the “anemia of chronic inflammation,” which although sometimes similar in presentation to iron deficiency, is part of a protective response, similar to that in acute infection; the body “locks down” iron to keep it out of circulation to counter the proliferative process, because most malignant cells and pathogenic bacteria require iron for rapid proliferation. Erythropoietin (EPO) is most appropriate in anemic cancer patients, and then only after assessing the endogenous EPO level and determining that it is not already extremely elevated. Iron is coadministered most safely and effectively only when there has been no or only minor response to initial EPO therapy. It is essential to monitor iron status and to address either true or functional iron deficiency before and during rHuEpo therapy to optimize the effect of rHuEpo in cancer patients. It must also be kept in mind that oncology patients with limited iron stores may become iron deficient as a result of erythropoiesis stimulated by EPO therapy, which then limits further response unless iron is supplied. The IV route shows significantly greater efficacy than the oral route with inorganic iron preparations. Oral administration of heme iron should also be investigated in this population.

Coadministration of ascorbic acid may also be indicated in certain cases, especially involving resistance to EPO in hemodialysis patients with functional iron deficiency.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Consensus

Effect and Mechanism of Action

Iron and the 3-carbonyl and 4-oxo functional groups on quinolone antibiotics can bind within the GI tract to form a poorly absorbed, stable chelation complex, for example, a ferric ion–ciprofloxacin complex. A similar pharmacokinetic interaction can also occur with other divalent metal cations, such as aluminum, calcium, copper, magnesium, manganese, and zinc, as well as mineral-based antacids. ^49,133-141 This binding process can interfere to varying degrees with the absorption, bioavailability, and activity of both the antimicrobials in this class and the orally administered iron.

In contrast to most forms of iron, iron-ovotransferrin can combine directly with the transferrin receptors of intestinal cells, and thus may release only minimal amounts of elemental iron into the gut to bind with the quinolones. ^142,143

However, an experiment using a rat model to examine the pharmacokinetics and pharmacodynamics aspects of the interaction between oral ferrous sulfate and IV ciprofloxacin suggested that the observed effects may only partially be attributable to direct physical interaction in the GI tract. ¹⁴⁴

Research

In vitro experiments first demonstrated the pattern of interaction between quinolones and metals in an aqueous medium and the resultant effects on antimicrobial activity. Subsequently, changes in oral bioavailability and alterations in therapeutic efficacy have been the focus of many previous interaction studies involving metal cations and quinolones. Thus, through multiple lines of research, the ability of multivalent cations to reduce the absorption and serum levels of oral quinolone antibiotics is well established.

Iron salts, particularly ferrous fumarate, gluconate, and sulfate, can reduce the absorption of ciprofloxacin, gatifloxacin, levofloxacin, norfloxacin, ofloxacin, and sparfloxacin from the GI tract to a degree that can interfere with therapeutic activity. In contrast, iron only minimally affects lomefloxacin, and separation of intake renders insignificant any interaction between gemifloxacin and ferrous sulfate. Iron does not appear to interact significantly with fleroxacin. Notably, iron-ovotransferrin appears to exert no adverse effect on quinolone absorption because of its direct binding to intestinal transferrin receptors. Thus, in his review of the various interactions between iron and members of this drug class, Stockley ⁷⁷ summarizes the body of evidence as revealing a pattern of descending order in the degree to which the serum levels of the various quinolone antibiotics can become subtherapeutic and thus subject to clinically significant interaction, as follows:

Norfloxacin>levofloxacin>ciprofloxacin>gatifloxacin> ofloxacin>sparfloxacin>lomefloxacin.

Ciprofloxacin

Many studies have confirmed that compounds containing elemental iron can greatly decrease absorption of ciprofloxacin, with demonstrated reductions in the AUC and C ^max of 30% to 90%. Several studies have documented this effect with ferrous sulfate. ^135,138,145 For example, in a four-way crossover trial with 12 healthy volunteers, Polk et al. ¹³³ (1989) observed a clinically significant reduction in the absorption of oral doses of ciprofloxacin (500 mg) when administered with ferrous sulfate (325 mg orally three times daily) or a multivitamin-mineral formulation containing zinc. Notably, peak concentrations of ciprofloxacin with ferrous sulfate regimen were below the minimum inhibitory concentration (MIC) for 90% of strains of many organisms normally considered susceptible to the antimicrobial activity of ciprofloxacin. Also in 1989, Lode et al. ¹⁴⁶ demonstrated a pharmacokinetic interaction between oral ciprofloxacin/ofloxacin and iron glycine sulfate. A year later, Brouwers et al. ¹⁴⁷ published research showing decreased ciprofloxacin absorption with concomitant administration of ferrous fumarate. Kara et al. ¹³⁵ investigated clinical and chemical interactions between ciprofloxacin and iron preparations and found impairment of absorption with ferrous gluconate and a multimineral preparation containing iron, magnesium, zinc, calcium, copper, and manganese (Centrum Forte). They reported that when ferrous ion was mixed with ciprofloxacin, rapid spectral changes occurred in a manner consistent with oxidation of the ferrous form of iron to its ferric form, followed by rapid formation of a Fe ³⁺ -ciprofloxacin complex. Ciprofloxacin seems to bind to ferric ion in a ratio of 3:1 by interacting with the 4-keto and 3-carboxyl groups on ciprofloxacin. These authors concluded that the formation of a ferric ion–ciprofloxacin complex was most likely responsible for the reduction in ciprofloxacin bioavailability in the presence of iron. In contrast, iron-ovotransferrin, a novel iron formulation in which iron ions are bound to ovotransferrin, has been found to have no significant effect on the absorption of ciprofloxacin from the GI tract and thus only minimally effects the drug's margin of efficacy. ^142,143

However, based on findings from an experiment using a rat model to examine the pharmacokinetics and pharmacodynamics of the interaction between oral ferrous sulfate and IV ciprofloxacin, Wong et al. ¹⁴⁴ suggested that the observed effects may only partially be attributable to direct physical interaction in the GI tract. Further research is warranted to investigate the concern that oral iron might interfere even with parenteral fluoroquinolones.

Fleroxacin

In a study involving 12 volunteers, Sorgel et al. ¹⁴⁸ observed that ferrous sulfate (equivalent to 100 mg elemental iron) exerted no significant effect on the pharmacokinetics of fleroxacin.

Gatifloxacin

Shiba et al. ¹⁴⁹ conducted a study of gatifloxacin pharmacokinetics involving six healthy volunteers that showed coadministration of ferrous sulfate (160 mg) and gatifloxacin (200 mg) produced a 49% decrease in the C ^max and 29% decrease in the AUC of gatifloxacin.

Gemifloxacin

Allen et al. ¹⁵⁰ observed no significant alterations in pharmacokinetics and bioavailability when they administered gemifloxacin (320 mg) to 27 healthy volunteers either 2 hours after or 3 hours before ferrous sulfate (325 mg).

Levofloxacin

Shiba et al. ¹⁵¹ reported that ferrous sulfate, when taken concurrently, inhibited levofloxacin absorption and reduced bioavailability by 79%.

Lomefloxacin

Lehto and Kivisto ¹⁵² demonstrated that coadministration of ferrous sulfate (equivalent to 100 mg elemental iron) with lomefloxacin (400 mg) reduced the lomefloxacin C ^max by approximately 28% and the AUC by approximately 14%.

Moxifloxacin

In their review of moxifloxacin, Balfour and Wiseman ¹⁴⁰ concluded that bioavailability of the medication is substantially reduced by coadministration with an iron preparation or antacid.

Norfloxacin

In a single-dose study assessing the pharmacokinetic interactions of norfloxacin with iron and metallic agents, Okhamafe et al. ¹³⁴ reported a 97% reduction in bioavailability with iron. Campbell et al. ¹⁵³ found that ferrous sulfate reduced the urinary recovery of norfloxacin by 55%; similar effects occurred with zinc sulfate. Subsequently, in eight normal subjects, Lehto et al. ¹³⁸ observed that ferrous sulfate reduced the AUC of a single 400-mg dose of norfloxacin by 73% and the C ^max by 75%. Similarly, Kanemitsu et al. ^154,155 noted a 51% reduction in the norfloxacin AUC with ferrous sulfate.

Ofloxacin

In a study involving 12 healthy subjects, Lode et al. ¹⁴⁶ found that an iron-glycine-sulfate complex (containing 200 mg elemental iron) reduced the bioavailability of ofloxacin (400 mg) by 36%. However, in an experiment with nine healthy volunteers, Martinez Cabarga et al. ¹⁵⁶ observed only an 11% decrease in GI absorption of ofloxacin (200 mg) with coadministration of ferrous sulfate (1050 mg). In a 1994 study with eight healthy subjects, Lehto et al. ¹³⁸ observed that coadministration of ferrous sulfate (100 mg elemental iron) reduced the AUC and C ^max after a single dose of ofloxacin (400 mg) by 25% and 36%, respectively.

Sparfloxacin

In a single-dose study assessing the effect of ferrous sulfate on the pharmacokinetics of sparfloxacin, Kanemitsu et al. ^154,155 reported that 525 mg ferrous sulfate (170 mg elemental iron) reduced the AUC of sparfloxacin (200 mg) by 27% in six subjects.

Iron Depletion

Iron depletion resulting from chelation by this class of medications has not been studied per se. Although plausible, such an adverse effect on iron status is highly improbable, given the normal physiological controls on iron levels, variable absorption rates, and the limited duration of standard fluoroquinolone antibiotic use. Long-term quinolone therapy and simultaneous oral iron intake in the face of iron deficiency could theoretically contribute to lack of tissue repletion. It is not clear whether or not long-term oral fluoroquinolone antibiotic therapy might cause iron deficiency in certain persons, such as menstruating women, by preventing dietary iron absorption.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The reduction of fluoroquinolone activity by concomitant iron is the primary established interaction between these two groups of agents; the potential depletion of iron through the same mechanisms is plausible, but it is generally improbable in standard clinical usage. Both directions of interaction and decreased bioavailability can be adequately avoided through proper patient education and dose timing.

Physicians treating patients for serious infections with quinolone antibiotics should advise that they refrain from ingesting iron supplements or using multivitamin-mineral formulations containing iron or other divalent mineral cations during the course of therapy, to avoid interfering with the absorption and thus the antimicrobial action of the medication.

Iron intake can usually be temporarily halted in most patients but can be continued with separation of intake timing in those for whom iron repletion has been confirmed as necessary to their therapeutic strategy. If this is not possible, administration of the medication 2 hours before or 6 hours after ingestion of an oral iron preparation is suggested and can effectively minimize risk of an adverse interaction (i.e., antibiotic malabsorption). This recommendation also applies to intake of iron-rich or iron-fortified foods. Monitor for decreased therapeutic effects of oral quinolones if inadvertently administered simultaneously with oral iron supplements. A special iron formulation, in which iron ions are bound to ovotransferrin, is less likely than the usual iron salts to reduce drug absorption.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Preliminary

Effect and Mechanism of Action

Hyoscyamine impairs absorption of ferrous citrate. The mechanism of this interaction has not been fully elucidated but may be caused by the drug's anticholinergic activity.

Research

Orrego-Matte et al. ¹⁵⁷ found that absorption of ferrous sulfate, which is usually well absorbed, was impaired in individuals administered hyoscyamine.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing hyoscyamine are advised to ask patients if they are taking supplements containing iron. Concomitant intake could limit the therapeutic activity and clinical efficacy of either agent. Long-term coadministration could potentially contribute to depletion of iron stores, particularly in individuals presenting with or susceptible to iron deficiency. If iron administration is clinically warranted, separation of intake is appropriate to avoid interference with absorption.

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Prevention or Reduction of Drug Adverse Effect
	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Adverse Interaction of Uncertain Severity

Consensus

Effect and Mechanism of Action

The activity of NSAIDs in inhibiting the effects of cyclooxygenase (COX) extends beyond those functions involved in inflammatory responses. In the stomach the enzyme's products build bicarbonate and mucus buffers against stomach acidity, without which the risk of ulceration can increase 20-fold. In general, NSAIDs can damage the epithelium of the stomach as well as the small and large intestines, causing ulceration, increased small intestine permeability, chronic bleeding, and eventually iron deficiency. ^158-160 Oral indomethacin is one of the most damaging NSAIDs in this regard. Iron coadministration may provide a means of countering the nutrient depletion effect of such medications.

Indomethacin's primary action is prostaglandin inhibition through the COX pathway. Indomethacin causes anemia by two possible mechanisms: (1) peptic ulceration or GI bleeding and (2) interference with normal iron metabolism and erythropoiesis. Curiously, edible black ink derived from black iron oxide is often used as a nonmedicinal ingredient in indomethacin capsules.

Both NSAIDs and iron can cause GI irritation; thus, concomitant use represents a potential additive adverse effect. Excessive iron intake can also contribute to inflammatory processes.

Research

Iron loss resulting from GI bleeding is well established as an adverse effect associated with indomethacin or other NSAIDs. Additionally, according to a nested case-control analysis of multiple linked health care databases conducted by Canadian researchers, patients taking warfarin at the same time as selective COX-2 inhibitors or nonselective NSAIDs have an increased risk of hospitalization for upper GI hemorrhage. ¹⁶¹

Animal research indicates that prostaglandins are necessary for normal iron metabolism and for erythropoiesis. ^162,163 Notably, indomethacin has also been associated with aplastic anemia. ^164-166

Although widely discussed as if evidence based, the specific use of iron coadministration to reverse this depletion pattern has not been the subject of significant human research, as indicated by a search of the scientific literature.

Lactoferrinis a glycoprotein present in human breast milk and other body fluids and is available as a supplement derived from bovine whey protein, which has been shown to act as an antioxidant, anti-inflammatory, and bactericidal agent as well as having an immunomodulatory effect. In a study presented at the Digestive Disease Week meeting on May 20, 2001, Dr. Troost observed the concomitant administration of this form of iron with indomethacin to iron-deficient women resulted in an additional increase in intestinal permeability. Furthermore, he reported: “When iron is bound to lactoferrin, it is not able to catalyze free radical formation.” ¹⁶⁷ In related research, Troost et al. ¹⁶⁸ conducted a randomized crossover dietary intervention involving 15 healthy volunteers to determine whether administration of recombinant human lactoferrin (rhLF) inhibits NSAID-induced gastroenteropathy in vivo as a model for disorders associated with increased permeability of the stomach and small intestine. They demonstrated that intestinal permeability after the administration of indomethacin and lactoferrin was significantly reduced compared with the permeability observed after ingestion of indomethacin and placebo, underscoring rhLF's potential as a GI-protective agent; in contrast, gastroduodenal permeability did not differ between the two interventions. These researchers concluded that “oral recombinant human lactoferrin supplementation during a short-term indomethacin challenge reduced the NSAID-mediated increase in small intestinal permeability and hence may provide a nutritional tool in the treatment of hyperpermeability-associated disorders.” The authors noted that the protective mechanism of lactoferrin is still undetermined, but it may be related to its ability to bind strongly to iron, thus acting as an antioxidant. ¹⁶⁸

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing NSAIDs for extended use are advised to monitor for blood loss and iron depletion; frank questioning of patients regarding self-medication is also necessary. In cases where both iron and indomethacin (or another NSAID) are required, based on established iron deficiency or tissue depletion, the patient should be advised to take the substances with food to reduce stomach irritation and bleeding risk. In cases of existing GI irritation, the use of iron-rich foods and herbs may be more efficacious and better tolerated. Investigation to identify and therapeutic intervention to address the causes of inflammatory processes are fundamental in individuals with chronic inflammation.

Potentially Harmful or Serious Adverse Interaction—Avoid

Emerging

Effect and Mechanism of Action

Pathogenic microorganisms such as the hepatitis C virus require iron to replicate. Reduction of iron levels, particularly in the liver, appears to inhibit viral replication and increase efficacy of interferon therapy, especially within the context of complementary measures, such as adding cytokines and antivirals. Iron supplementation would counter this therapeutic approach: moreover, reducing iron intake is consistent with the therapeutic strategy.

Research

Hepatic iron concentration has consistently been observed as being directly correlated with the response to interferon therapy in patients with chronic hepatitis C infection. In 1981, Blumberg et al. ¹⁶⁹ first reported that patients with hepatitis B viral infection who had higher serum iron or ferritin levels were more likely to develop chronic infections than those with lower levels, who more often experienced spontaneous resolution of their infections. Patients with chronic hepatitis C have high frequencies of elevated levels of serum ferritin, iron, and transferrin saturation, and these higher levels are generally associated with decreased likelihood of response to interferon therapy. Notably, complete responders to interferon, on average, demonstrate lower hepatic iron concentrations than do noncomplete responders. ^170,171 Hayashi et al. ¹⁷² reported that bloodletting through repeated venesection reduced iron levels to a degree sufficient to cause significant improvement in serum alanine transaminase (ALT) levels in subjects with chronic active hepatitis C and excess hepatic iron. In two studies, research teams led by Fong ¹⁷³ (1998) and Fontana ¹⁷⁴ (2000) observed that iron reduction through phlebotomy, combined with interferon alpha, reduces liver inflammation, but not fibrosis. Although not statistically significant, their findings indicate that this combination appears to reduce the viral load and may improve sustained response. Notably, ribavirin, which tends to cause anemia (via direct bone marrow suppression), was not part of either treatment protocol being investigated.

In a multicenter, prospective, randomized, controlled trial involving 96 patients with chronic hepatitis C who have previously not responded to interferon, Di Bisceglie et al. ¹⁷⁵ compared iron reduction by phlebotomy with iron reduction followed by re-treatment with interferon. They concluded that, “although prior phlebotomy therapy does not improve the rate of sustained response to interferon retreatment, it does result in less liver injury manifested by a decrease in serum transaminase activity and a slight improvement in liver histopathology.” In the first randomized, controlled study on the effect of phlebotomy before long-term and high-dose interferon therapy in naive patients with hepatitis C virus–related chronic liver disease, Fargion et al. ¹⁷⁶ assessed the outcomes of 114 subjects who were randomized to receive interferon alone or interferon preceded by phlebotomy. In both groups, interferon was given at a dose of 6 mU three times a week for 4 months, followed by 3 mU three times a week for 8 months. The virological sustained response rate in the interferon-only group was 15.8% compared with 28.1% in the iron-depletion group. Patients who underwent phlebotomy tended to respond better to interferon therapy than patients without iron reduction. The difference in sustained response rates between the treatment groups was almost significant for subjects with hepatic iron concentrations no greater than 1100 µg/g dry weight. In contrast to earlier studies indicating that iron removal can improve the histological and virological response to short-term interferon therapy, this latest research demonstrates an improved sustained response when longer courses and higher doses of interferon therapy are administered.

Although the body of literature on use of iron reduction therapy together with interferon suggests the possibility of an effective cure rate of about 75% to 80%, which might be enhanced through the addition of cytokines and antivirals such as ribavirin, trials are evolving from being inconclusive toward consensus.

In India, phlebotomy is not socially acceptable as a means of reducing iron overload to improve the efficacy of interferon therapy. Tandon et al. ¹⁷⁷ investigated the efficacy of an indigenous, low-iron, vegetarian diet in reducing serum Fe levels in 19 patients with hepatitis B–related and hepatitis C–related chronic liver disease. One group of 10 subjects had normal (<25 µmol/l) baseline serum Fe levels, whereas another nine had high (>25 µmol/l) serum Fe levels. All the subjects were advised to eat a low-Fe rice-based diet, which decreased the daily Fe intake by approximately 50%. All patients complied with the dietary regimen, and at 4 months, significant reductions from baseline were seen in serum Fe and transferrin saturation index (TSI) in both groups, although earlier in those subjects with the higher initial serum Fe levels. Serum ferritin levels, however, were reduced only in the group with lower initial serum Fe levels and not in those with higher initial serum Fe levels. The ALT levels were reduced significantly in both groups. These authors concluded that a low-iron diet results in significant reductions in serum Fe and TSI levels, regardless of baseline Fe levels, and recommended that such a diet should be evaluated to improve the efficacy of interferon therapy in patients with hepatitis B/C–related chronic liver disease.

In a potentially related area, in a pilot study involving 11 patients with chronic hepatitis C virus (HCV) infection, Tanaka et al. ¹⁷⁸ found that bovine lactoferrin, 1.8 to 3.6 g daily for 8 weeks, suppressed ALT levels and viral load (as indicated by HCV RNA concentrations) in three of four patients with low pretreatment serum concentrations of HCV RNA. However, seven patients with high pretreatment concentrations showed no significant changes in these indices. The authors suggested that bovine lactoferrin, a subfraction of milk whey protein belonging to the iron transporter family, could be used with any combination of antiviral therapies, including interferon plus ribavirin, without adverse effects.

Clinical Implications and Adaptations

Iron supplementation is generally contraindicated during interferon therapy for viral hepatitis. Physicians treating individuals with hepatitis C virus are advised to consider a strategy of iron reduction, including dietary changes and modification of the nutritional support regimen to minimize iron intake, as well as more direct interventions, such as phlebotomy.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management

Consensus

Effect and Mechanism of Action

Limited but pharmacologically sound evidence indicates that thyroxine and iron (as ferrous sulfate) can bind to form a poorly soluble, stable complex when ingested simultaneously. Consequently, dietary and supplemental iron may reduce the GI absorption of oral levothyroxine, potentially adversely affecting therapeutic response in patients being treated for primary hypothyroidism. ^49,179 Simultaneous intake could also contribute to iron depletion in susceptible individuals by impairing iron absorption.

Iron deficiency may contribute to decreased thyroid hormone synthesis and impaired thermoregulation. ¹⁸⁰ Iron coadministration may enhance thyroid function, particularly in individuals with iron depletion or deficiency.

Research

Campbell et al. ^179,181 observed that the addition of ferrous sulfate to levothyroxine in vitro will produce a poorly soluble, purple, iron-levothyroxine complex.

Clinical observations suggest that a similar pharmacokinetic interaction occurs with in the human gut and is likely to impair absorption and bioavailability of both agents when ingested within the allotted time frame. Thus, in an experiment involving 14 patients with established primary hypothyroidism on stable thyroxine replacement, Campbell et al. ¹⁷⁹ observed a reduction in the efficacy of thyroid hormone, as indicated by an increase in thyroid-stimulating hormone (TSH) levels from 1.6 to 5.4 mU/L (although the free thyroxine index did not change significantly), when ferrous sulfate (300 mg) and the usual thyroxine dose were simultaneously ingested for a 12-week period. Thus, 9 of the 14 patients demonstrated an aggravation of their hypothyroid symptoms.

Iron deficiency anemia has been associated with lower plasma thyroid hormone. Beard et al. ¹⁸⁰ conducted several intriguing clinical trials looking at the synergistic relationship between iron administration and thyroid function. In an experiment, they exposed 10 women with iron deficiency anemia, eight with depleted iron stores (nonanemic), and 12 control women, all of similar percentage body fat, to a 28° C water bath to test the hypothesis that iron deficiency anemia impairs thermoregulatory performance. They observed that iron administration given to iron-deficient women was associated with improved thyroid function, as indicated by partially normalized plasma thyroid hormone concentrations, and decreased need for thyroid medication. Later, they found that 27 mg/day of iron supplementation helped maintain normal thyroid hormone levels in obese patients put on a very-low-calorie diet. ¹⁸² However, using a rodent model, these researchers also found that plasma thyroid hormone kinetics in iron deficiency anemia are corrected by simply providing more thyroxine. ¹⁸³

Reports

Schlienger ¹⁸⁴ reported the case of a woman with hypothyroidism, stable on levothyroxine, who demonstrated a significant elevation in TSH levels after administration of ferrous sulfate. Subsequently, the dosage of her levothyroxine was raised from 175 to 200 µg per day. In another case, Shakir et al. ^184a described a patient with primary hypothyroidism whose previously effective dose of levothyroxine sodium was impaired subsequent to her beginning treatment with ferrous sulfate. Initially, the patient was restabilized by increasing the dose of L-thyroxine. However, she later became hyperthyroid at that higher dosage level when she discontinued the iron supplementation. ¹⁸⁴

Clinical Implications and Adaptations

Physicians prescribing exogenous thyroid hormone preparations to individuals with primary hypothyroidism are advised to inform these patients to avoid unsupervised iron supplementation and, when concurrent iron administration is indicated by established iron deficiency or depleted iron stores, to separate intake by at least 2 hours to avoid pharmacokinetic interaction that could reduce absorption and bioavailability of both agents. Because hypothyroidism and iron deficiency anemia may coexist, more frequent thyroid function testing is recommended in patients treated concurrently with iron and L-thyroxine. Research suggests that individuals wanting to enhance thyroid function and increase thermogenic effects may benefit from concomitant iron, especially if they have been diagnosed with iron deficiency.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Emerging

Effect and Mechanism of Action

Limited but consistent research has found that iron binds strongly to methyldopa, producing ferric iron–methyldopa complexes, and thereby reduces the absorption and bioavailability of both the methyldopa and the iron salt. ^49,185 Thus, the pharmacokinetic interaction could reduce the antihypertensive effects of methyldopa and might contribute to compromised iron status, particularly in individuals with iron deficiency or susceptible to depleted iron stores.

Ferrous iron, such as ferrous sulfate, is formed from ferric iron when it is reduced under the influence of the acidic pH of the GI environment. However, ferrous iron undergoes auto-oxidation to the ferric form in the presence of methyldopa and levodopa. The formation of these complexes is rapid at high pH (i.e., 9), whereas the rate slows considerably as the pH is lowered (e.g., 4). A variety of iron-methyldopa complexes can be formed between pH 4 and 9. Complexation is absent below pH 2. Together, these processes can result in both catechol oxidation and production of the toxic hydroxyl radical. ⁹⁶

Research

Campbell et al. ¹⁸⁶ conducted a randomized crossover trial involving 12 normal subjects in which they administered a 500-mg tablet of methyldopa (2.37 mmol) with and without ferrous sulfate (325 mg) and measured absorption and excretion of methyldopa. When ferrous sulfate and methyldopa were coadministered, they observed a decrease in the proportion of methyldopa excreted as “free” methyldopa (49.5% vs. 21.1%), a significant increase in the proportion excreted as methyldopa sulfate (37.8% vs. 65.8%), and a decrease in the percentage of methyldopa absorbed (29.1% vs. 7.88%). Together these factors resulted in an 88% reduction in the quantity of “free” methyldopa excreted. Ferrous gluconate (600 mg) produced similar effects. These researchers also found that concurrent intake of ferrous sulfate and methyldopa for 2 weeks produced an increase in both systolic and diastolic blood pressure in four of five hypertensive subjects receiving chronic methyldopa therapy, with substantial increases in blood pressure seen in three of the patients. A decrease in blood pressure occurred in all patients after ferrous sulfate was discontinued. ¹⁸⁶

Subsequently, Campbell ¹⁸⁵ and another team used a rat model to investigate the mechanism(s) by which ferrous sulfate (and sodium sulfate) reduces methyldopa absorption. They observed that ferrous sulfate reduced methyldopa absorption by 52.9% when they injected solutions of 14C methyldopa alone and with ferrous sulfate or sodium sulfate in vivo into closed duodenal segments. In the presence of methyldopa, iron in its ferrous form rapidly oxidizes to the ferric form, in vitro. “The ferric form of iron binds strongly to methyldopa, presumably resulting in the decreased methyldopa absorption.” Methyldopa was stable in vivo and in vitro, in the presence of ferrous sulfate and sodium sulfate.

Clinical Implications and Adaptations

Physicians prescribing methyldopa are advised to inform patients to avoid unsupervised iron supplementation and, when concurrent iron administration is indicated by established iron deficiency or depleted iron stores, to separate intake by at least 2 hours to avoid pharmacokinetic interaction that could reduce absorption and bioavailability, and thus therapeutic activity, of methyldopa. Concomitant use, with simultaneous or proximate intake, could also potentially, over time, contribute to or aggravate iron deficiency or depletion of iron stores in susceptible individuals.

	Drug-Induced Nutrient Depletion, Supplementation Contraindicated, Professional Management Appropriate
	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Preliminary

Effect and Mechanism of Action

Neomycin may impair the absorption of iron and many other nutrients. ^77,187

Research

Jacobson et al. ¹⁸⁸ coadministered neomycin and ferrous citrate to six nonanemic subjects in an experimental malabsorption syndrome study. They observed marked reduction in iron absorption in four subjects but increased iron absorption in the other two subjects, both of whom initially demonstrated low serum iron levels. These findings suggest that an individual's initial iron status may play a pivotal role in their response to iron absorption under the influence of neomycin.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing neomycin for an extended period are advised to monitor iron status and consider the potential need for iron supplementation in individuals susceptible to iron depletion. Oral intake should be separated by at least 2 hours if iron supplementation is determined to be clinically appropriate for a given patient. However, it is generally inappropriate to administer iron during an infection because iron may enhance pathogenic activity and contribute to the inflammatory process. Short-term use, such as preparation for surgery using oral neomycin, is unlikely to result in clinically significant iron deficiencies.

	Beneficial or Supportive Interaction, with Professional Management
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Emerging

Effect and Mechanism of Action

Oral contraceptive (OC) use is associated with decreased menstrual blood loss and potentially a reduced need for supplemental iron if increased iron stores result.

Research

The volume of blood loss associated with menstrual flow is usually decreased among certain women using OCs, but evidence of associated benefits in iron stores is less definite. Several early studies and reviews reported that OCs have beneficial effects on iron status, even though clinical research investigating the effects of OCs on iron metabolism was largely scarce. ^189-191 For example, in 1984, Tyrer ¹⁹² presented the conventional position in summarizing that OCs have been “shown to decrease the physiologic levels of six nutrients—riboflavin, pyridoxine, folacin, vitamin B ¹² , ascorbic acid and zinc.” However, they followed with the optimistic conclusion: “Women who take OCs and have adequate diets need little or no supplemental vitamins.” After further noting that OCs are associated with increased levels of vitamin C, iron, copper, and vitamin A, the author suggested: “Vitamin and mineral increases caused by OCs do not require treatment.” Thus, iron supplementation would be considered less important to women using OCs and experiencing decreased menstrual blood loss than to those not having their menstrual processes altered with exogenous hormones.

Frassinelli-Gunderson et al. ¹⁹³ compared serum ferritin and other parameters of iron status in 46 women using OCs for 2 or more years continuously and 71 women who never took OCs. They found that the mean serum ferritin level for the OC users was significantly higher, 39.5 ng/mL, compared to a mean level of 25.4 ng/ml in the control group. Serum transferrin, serum iron, TIBC, mean corpuscular hemoglobin (MCH), and MCH concentration (MCHC) levels were also significantly greater among the OC users. However, significantly lower RBC and hematocrit levels were found for OC users, whereas other parameters, such as hemoglobin, mean corpuscular volume (MCV), and percent transferrin saturation, were not significantly different between the groups. OC users also reported decreased menstrual cycle blood losses and a higher heme iron content in their diet. Palomo et al. ¹⁹⁴ found that use of OCs was not associated with hemoglobin decrease, but they did observe a significant rise in saturation of transferrin. Masse and Roberge ¹⁹⁵ investigated the effect of low-dose OC use for at least 1 year on iron metabolism and body iron status in 64 active and healthy adult women. The serum iron concentration was significantly higher in OC users than an age-matched control group. However, they found that serum ferritin, a marker for body iron stores, was marginal in both OC users and control subjects, even though mean dietary iron intake was adequate in both groups. These researchers noted that this finding indicated an underlying “high prevalence of deficient-iron reserves among subjects” that was not correlated to dietary iron content. These researchers concluded that their findings “commanded a discussion on the pertinence of evaluating the total dietary iron intake and on the sensitivity of biochemical methods used to assess the iron status.” ¹⁹⁵

Steegers-Theunissen et al. ¹⁹⁶ conducted a study of the effects of long-term use of OCs containing less than 50 µg of estrogen (sub-50 OCs) on the kinetics of folic acid monoglutamate, vitamin B ¹² levels, and iron status in 29 OC users and in 13 non-OC-user controls. OC users showed significantly higher TIBC. The OC users also demonstrated significantly lower serum vitamin B ¹² concentrations and significantly lower median serum folate concentration at 210 minutes after oral folate loading compared with the control group, but the authors concluded that even with these “significant effects upon folate kinetics and vitamin B ¹² levels, the folate and vitamin B ¹² status does not seem to be at risk.” ¹⁹⁶

Mooij et al. ¹⁹⁷ compared the effects of multivitamin supplementation on serum ferritin and hematological parameters in 28 women using OCs (sub-50 OCs) and 31 non-OC users over three consecutive cycles. Comparison of the baseline values on days 3 and 23 of the first cycle of the two groups revealed that the parameters of serum iron status were all significantly increased for the OC users compared to the non-OC control group, even though there were no significant different hematological parameters from OC use. Multivitamin supplementation was started on day 1 of the second cycle and continued daily throughout three consecutive cycles until the end of the study. The multivitamin was associated with a significantly decreased MCHC in both groups, increased MCV, and significantly increased serum iron and TIBC, whereas serum ferritin decreased during multivitamin supplementation and hematocrit and MCH remained unaltered.

Recent reviews continue to state that enhancement of iron status is among the noncontraceptive benefits of OCs. ^198,199 However, human research has yet to emerge investigating the clinical implications of apparent pharmacogenomic variability in responses to synthetic, exogenous hormones such as OCs and their influence on menstrual flow, blood loss, and iron metabolism.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing OCs are advised to monitor the iron status of these female patients with periodic assessment of serum ferritin, ferritin saturation, and serum transferrin receptor levels. Increased iron levels in the blood are not necessarily a problem, but decreased monthly blood loss could potentially result in increased iron stores over time. Consequently, premenopausal women using OCs may have a decreased need for supplemental iron. Evaluation of iron status is essential before initiation of iron supplementation. Regular monitoring of folate and vitamins B ¹² and B ⁶ is also recommended in such women, and preventive supplementation is usually advisable.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Bimodal or Variable Interaction, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Consensus

Effect and Mechanism of Action

The chelation function of penicillamine is central to its primary pharmacological action in therapeutic application. Penicillamine and iron bind together, thereby increasing iron excretion and impairing bioavailability and reducing therapeutic activity of penicillamine. ²⁰⁰

Penicillamine may be used to treat iron overload. Conversely, chelation therapy with penicillamine aimed at removal of other metals could induce or exacerbate depleted iron stores if compensatory nutrient augmentation is appropriate but not provided.

Research

After administering single 500-mg oral doses of penicillamine to six healthy men, Osman et al. ²⁰¹ observed that penicillamine levels were reduced to 35% of those from a fasting dose. Stockley ⁷⁷ reported that the absorption of penicillamine can be reduced as much as two-thirds by the concurrent use of oral iron preparations.

Reports

Harkness and Blake ²⁰² described four cases of penicillamine-induced kidney damage that occurred when concomitant iron therapy was stopped, presumably as a result of increased penicillamine absorption and toxicity.

Clinical Implications and Adaptations

Physicians prescribing penicillamine therapy are advised to question patients regarding use of supplements containing iron and other minerals and to caution against initiation of such substances or their abrupt, unsupervised discontinuation. Chelation with penicillamine or other agents requires appropriate training and proper monitoring. Assessment of iron status is appropriate, and clinical responses will vary accordingly.

During the course of penicillamine therapy, iron deficiency can often develop, especially in children and menstruating women. In Wilson's disease, this may be a result of adding the effects of the low-copper diet, which is probably also low in iron, and the penicillamine to the effects of blood loss or growth. In cystinuria, a low-methionine diet may contribute to iron deficiency because it is inherently low in protein.

In certain circumstances, physicians who administer penicillamine for chelation of copper or other metals or for other clinical applications should coadminister minerals of nutritional importance in accordance with the therapeutic strategy and individual patient needs. When properly administered, penicillamine chelation is considered unlikely to result in adverse reactions from iron depletion. Great caution needs to be exercised when changing the level of iron intake in individuals taking penicillamine. Adverse reactions have been reported in which the prescribing physician was unaware that a patient was using concomitant supplemental iron and responded to the lack of therapeutic response to penicillamine by increasing the drug dose, after which the patient discontinued the self-prescribed iron supplementation.

Orally administered iron has been shown to reduce the effects of penicillamine. If necessary, iron may be given in short courses, but at least 2 hours, or preferably 8 hours, should elapse between administration of penicillamine and oral intake of iron supplements or other iron-containing products.

Note: Tetrathiomolybdate is much less toxic than penicillamine (or trientine) and is emerging as the copper chelator of choice for Wilson's disease. However, it has not yet obtained final approval as a new drug. Tetrathiomolybdate probably has the same interaction with iron as the other copper chelators, but substantive evidence is lacking.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Consensus

Effect and Mechanism of Action

Despite long-standing clinical application, scientific understanding of sulfasalazine, its mechanisms, and actions is incomplete. Sulfasalazine is a prodrug that is broken down by gut bacteria into 5-aminosalicylic acid (5ASA) and sulfapyridine. Although the therapeutic activity of 5ASA has been established to some degree, controversy surrounds the role and significance of sulfapyridine. A systemic immunosuppressant effect appears to be involved, but much of the anti-inflammatory activity may result from local effects on the bowel. After oral administration, 33% of the sulfasalazine is absorbed, about 33% of the 5ASA is absorbed, and all the sulfapyridine is absorbed.

Iron and sulfasalazine tend to bind in the digestive tract to form a chelate that is poorly absorbed. Consequently, the concurrent ingestion of these substances can interfere with metabolism of the prodrug into its constituents and lead to their decreased absorption and bioavailability, as well as that of iron. ²⁰³

Research

Clinical research directly investigating the interaction between sulfasalazine and iron is limited. However, the pharmacological literature accepts the existence of this pharmacokinetic interaction as representing a consensus position, based on the principles involved and general knowledge of the agents.

Iron depletion resulting from chelation by concomitant sulfasalazine has not been studied per se. Such an adverse effect on iron status is not improbable, even with the normal physiological controls on iron levels and variable absorption rates, in light of the typically extended duration of standard sulfasalazine use. Clinical concern for iron deficiency is reasonable given the high incidence of blood loss and tissue iron depletion in individuals being treated with sulfasalazine for conditions such as ulcerative colitis or Crohn's disease. Thus, long-term sulfasalazine therapy and simultaneous oral iron intake in the face of iron deficiency could theoretically contribute to lack of tissue repletion, if care is not taken to separate intake of the two agents. Furthermore, evidence is lacking to determine whether or not long-term oral sulfasalazine therapy might cause or aggravate iron deficiency in certain persons, such as menstruating women, by preventing dietary iron absorption.

Evidence is lacking as to interactions between iron and other members of the sulfonamide class of drugs.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing sulfasalazine are advised to inform patients of the probable pharmacokinetic interaction between iron and the medication and to recommend separating oral intake by at least 3 hours. Such measures should allow concurrent us of both agents without interfering with the intended therapeutic activity of either. In general, conservative principles of practice warrant advising patients against taking iron supplements without specific, well-founded therapeutic need and outside the context of medical supervision and monitoring. Such cautions are particularly relevant in a patient population characterized by inflammation, even in the presence of blood loss and significant probability of anemia.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Consensus

Effect and Mechanism of Action

Tetracycline-class medications are primarily absorbed in the stomach and upper small intestine. When ingested concurrently, tetracyclines tend to form insoluble chelates with iron salts and other polyvalent metal cations, including calcium, magnesium, and zinc. This pharmacokinetic interaction can impair absorption and bioavailability of both agents, reduce the therapeutic activity of the antibiotic, and adversely affect iron balance. ^204,205

Research

Clinical research directly investigating this interaction is limited. However, the pharmacological literature accepts this pharmacokinetic interaction as representing a consensus position based on the principles involved and general knowledge of the agents involved.

Ingestion of iron supplements or iron-rich foods within a time frame allowing for binding in the gut can depress drug levels to such a degree that their therapeutic effectiveness is significantly reduced or neutralized. This adverse interaction can be avoided by maximally separating intake to minimize contact between the agents. ⁷⁷

Iron depletion resulting from chelation by antibiotics in the tetracycline class has not been the subject of substantial study. Although plausible, such an adverse effect on iron status is highly improbable with short-term tetracycline antibiotic use, given the normal physiological controls on iron levels and variable absorption rates. However, long-term tetracycline therapy and simultaneous oral iron intake in the face of iron deficiency could theoretically contribute to lack of tissue repletion. Evidence is lacking to determine whether or not long-term oral tetracycline antibiotic therapy might cause iron deficiency in certain persons, such as menstruating women, by preventing dietary iron absorption.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Iron in the form of preparations and iron-rich foods should generally be avoided while using drugs in the tetracycline class of antibiotics. Conservative principles of practice warrant advising patients against taking iron preparations without specific, well-founded therapeutic need and outside the context of medical supervision and monitoring. Such cautions regarding iron intake are particularly relevant during an infection because iron may enhance pathogenic activity and contribute to the inflammatory process.

In cases where iron administration is warranted, physicians prescribing tetracycline antibiotics are advised to inform patients of the probable pharmacokinetic interaction between iron and the medication and to recommend separating oral intake by at least 3 hours. Such measures should allow concurrent us of both agents without interfering with the intended therapeutic activity of either. Monitoring of iron status is warranted with extended administration.

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Bimodal or Variable Interaction, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Consensus

Effect and Mechanism of Action

Trientine is primarily used as a chelating agent in patients with Wilson's disease who are intolerant of penicillamine, to reduce the toxic load of excess copper on the liver, brain, and other organs. Iron from supplements or iron-rich foods can bind to trientine when ingested concurrently, thereby impairing trientine bioavailability and reducing its therapeutic activity (copper chelation) while increasing iron excretion.

Research

The chelation function of trientine is central to its primary pharmacological action in therapeutic application, and its interaction with iron is well established. Anemia is a common adverse effect associated with trientine and is more likely to occur in children, menstruating women, and pregnant women, who usually have greater needs for iron nutriture than other patients.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although clinical experience with trientine is limited, it is generally agreed that use of iron and mineral nutrients concurrently with trientine may impair absorption and decrease therapeutic activity of the medication. Physicians prescribing trientine always need to ask patients about supplement use and track dietary intake patterns of copper and other minerals; close supervision and regular monitoring are essential throughout the period of drug administration. Copper levels are typically monitored in patients undergoing trientine therapy, with determination of free serum copper being the most reliable index for monitoring treatment. Adequately treated patients will usually have less than 10 µg free copper/dL serum.

Close monitoring of iron status is also warranted in patients, especially children and menstruating or pregnant women, with a known history of or a high susceptibility to iron deficiency anemia or tissue iron depletion. Except for potential interference with iron absorption caused by the chelating activity of the medication, patients following the low-copper diet appropriate to Wilson's disease are at increased risk of insufficient dietary intake of iron and other key nutrients. In patients with an established need for concomitant iron or other mineral supplementation, iron is usually prescribed in short courses, and patients are advised to separate oral intake by at least 2 hours to minimize any incidence of mutual interference.

Note: Tetrathiomolybdate is much less toxic than trientine (or penicillamine) and is emerging as the copper chelator of choice for Wilson's disease. However, it has not yet obtained final approval as a new drug. Tetrathiomolybdate probably has the same interaction with iron as the other copper chelators, but substantive evidence is lacking.

Allopurinol (Oxypurinol; Aloprim, Apo-Allopurinol, Lopurin, Purinol, Zyloprim).

Allopurinol is a xanthine oxidase inhibitor used to prevent gout and to lower blood levels of uric acid in certain oncology patients undergoing chemotherapy. Allopurinol should always be used with caution during lactation and in patients with liver or renal disease.

Preliminary evidence from animal experiments indicates that concurrent intake of allopurinol and iron preparations could potentially result in an adverse interaction involving excess hepatic iron storage. ^206-209 For example, in a study involving hyperthermic rat liver perfusion, Powers et al. ²¹⁰ reported that allopurinol, as an inhibitor of the xanthine oxidase/reductase enzyme system, can both slow mobilization of iron from ferritin and reduce the oxidative stress associated with xanthine oxidase activity, which generates superoxide radicals. However, these effects have never been observed clinically in humans.

Based on a highly cautious approach to the limited data available, physicians might find it judicious to monitor ferritin levels in patients taking chronic allopurinol and iron supplements (in iron-deficient patients) because of a possible adverse interaction.

Amphetamine aspartate monohydrate, amphetamine sulfate, dextroamphetamine saccharate, dextroamphetamine sulfate; D-amphetamine, Dexedrine.

Methylphenidate (Metadate, Methylin, Ritalin, Ritalin-SR; Concerta).

Mixed amphetamines: Amphetamine and dextroamphetamine (Adderall; dexamphetamine).

Pemoline (Cylert).

Konofal et al. ²¹¹ found that iron deficiency is a clinically significant factor in many children diagnosed with attention deficit–hyperactivity disorder (ADHD), and that iron supplementation may improve therapeutic outcomes in certain cases. These findings suggest that further research is warranted into the role of iron nutriture and metabolism in the pathophysiology of ADHD and the potential for enhanced therapeutic efficacy from administration of supplemental iron along with conventional medications in cases where iron deficiency is diagnosed as a comorbid condition.

Dipyridamole (Permole, Persantine).

Dipyridamole is an older antiplatelet drug, often combined with aspirin before the availability of ticlopidine (Ticlid) and clopidogrel (Plavix) to prevent strokes, with warfarin (Coumadin) to prevent clotting after heart valve replacement, or used alone. Dipyridamole might reduce the oxidative damage caused by iron, particularly iron-induced platelet aggregation.

In vitro research indicates that dipyridamole inhibits platelet aggregation induced by iron and oxygen-derived free radicals. De la Cruz et al. ²¹² observed that “ferrous salts (Fe2+) induced 34% platelet aggregation which was inhibited (79.6%) by a concentration of dipyridamole of 10 microM. Dipyridamole inhibited ferrous-induced lipid peroxidation with IC-50 values of 17.5 microM.”

An emerging body of evidence indicates that excess iron intake by individuals who are not iron deficient might cause tissue damage that could then contribute to heart disease. ³³

Well-designed human trials might be appropriate to investigate this potential therapeutic application of dipyridamole in reducing the effects of iron-induced oxidative damage on by platelet aggregation. Administration of dipyridamole with the specific aim of countering the effects of iron is unsupported at this time and requires supportive evidence from substantive research.

Haloperidol (Haldol).

Use of haloperidol is associated with decreased blood levels of iron. ²¹³ Ben-Shachar and Youdim ²¹⁴ observed that dopamine D ² receptor subsensitivity, a feature of iron deficiency, is absent in iron-deficient rats administered haloperidol, and that biochemical and behavioral D ² receptor supersensitivity is relatively greater than in control, haloperidol-treated animals. These researchers found that haloperidol (5 mg/kg daily for 21 days), as well as chlorpromazine (10 mg/kg daily for 21 days), caused a significant reduction (20%-25%) in liver nonheme iron stores compared with values in control rats. However, haloperidol had no effect in iron-deficient rats whose liver iron stores had been almost totally depleted. The authors interpreted these findings to suggest that lower iron levels may result in an increase in free haloperidol available to the dopamine D ² receptor.

No definitive research has emerged to confirm the occurrence or clarify the clinical significance of this interaction between haloperidol and iron in humans. Pending more conclusive findings from well-designed clinical trials or consistent, substantive, and well-documented case reports, physicians prescribing haloperidol are advised to ask patients about their supplement use and recommend that they avoid supplements containing iron unless iron deficiency has been diagnosed. Monitoring of haloperidol levels may be warranted if iron status is altered or dietary intake significantly changes.

Methotrexate (Folex, Maxtrex, Rheumatrex).

Concern has been raised that concomitant oral iron intake might alter absorption and therapeutic activity of methotrexate. In a randomized, double-blind, placebo-controlled crossover study, Hamilton et al. ²¹⁵ compared the urinary excretion of unmetabolized methotrexate in 10 patients with rheumatoid arthritis who were administered methotrexate, 7.5 mg weekly, and either ferrous sulfate, 300 mg twice daily, or placebo for 1 week. No significant difference was observed in average 24-hour urine excretion of methotrexate between the two groups.

Pending further research, the probability of a clinically significant interaction between methotrexate and supplemental iron can be considered as improbable. Nevertheless, it might be judicious to advise patients for whom both agents are medically appropriate to separate intake by at least 3 hours to avoid any as-yet undocumented pharmacokinetic interference with absorption of either agent.

Pyrimethamine (Daraprim); combination drug: sulfadoxine and pyrimethamine (Fansidar).

Deficiencies in vitamin A, zinc, iron, folate, and other micronutrients are responsible for a substantial proportion of malaria morbidity and mortality. Iron deficiency and Plasmodium falciparummalaria are the two main causes of anemia in young children in regions endemic for this disease, even though malaria infection itself does not contribute to iron deficiency. However, Stockley ⁷⁷ reports that iron may delay the therapeutic activity of pyrimethamine/sulfadoxine in eradicating P. falciparumor Plasmodium vivax, the malaria parasite. Thus, the determination of nutritional status and the appropriate timing of nutritional support can be of critical importance in promoting positive clinical outcomes.

In a trial of two-by-two factorial design, Verhoef et al. ²¹⁶ randomly assigned 328 anemic but symptom-free Kenyan children into four groups of equal size to receive either iron or placebo and sulfadoxine-pyrimethamine (SP) or placebo. Hematological indicators of iron status and inflammation at the end of the follow-up and occurrence of malaria attacks served as primary outcomes. Analyses were by intention to treat. These researchers observed that after 12 weeks, the groups administered iron plus SP, iron alone, or SP alone had higher hemoglobin concentrations than the group given placebo. Coadministration of iron and SP also lowered the proportion with anemia from 100% at baseline to 36% at 12 weeks, and with iron deficiency from 66% at baseline to 8% at 12 weeks. Survival analysis revealed no evidence of substantially increased risk of malaria after iron administration.

Desai et al. ²¹⁷ conducted a randomized, placebo-controlled trial involving 546 anemic children age 2 to 36 months in a malaria-endemic area of western Kenya. All children used bednets and received a single dose of SP on enrollment, followed by either intermittent preventive treatment (IPT) with SP at 4 and 8 weeks and daily iron for 12 weeks, daily iron and IPT with SP placebo, IPT and daily iron placebo, or daily iron placebo and IPT with SP placebo (double placebo). After assessing the mean hemoglobin concentration at 12 weeks, compared with that for the double-placebo group, these researchers determined that IPT reduced the incidence of malaria parasitemia and clinic visits, but iron provided no additional preventive benefit. Furthermore, although the combination of IPT and iron was most effective in treating mild anemia and IPT prevented malaria, with IPT “the hematological benefit…added to that of a single dose of SP and bednet use was modest.” ²¹⁷ However, in a subsequent cluster-randomized clinical trial investigating iron dosing in the treatment of anemia in preschool children, this research team found that, after initial antimalarial treatment with a single SP dose, 6 weeks of daily iron supplementation results in superior hematological responses, particularly hemoglobin concentrations, than does twice-weekly iron administration, regardless of whether adherence can be ensured. ²¹⁸

Iron supplementation can play an important role in the recovery of patients, especially malnourished children, after treatment for malaria. However, iron coadministration in cases of anemia associated with malaria is controversial. Introduction of weekly iron may be appropriate starting 2 weeks after the malaria is controlled. However, in children who have been severely malnourished or ill, especially edematous, it is advisable to withhold iron until the child is recovering (e.g., loss of edema, weight gain, no hepatomegaly), even if iron deficiency anemia has been diagnosed. Iron should not be administered until they regain their appetite, regardless of the hemoglobin level. These children generally have very low levels of transferrin, a high iron saturation, stainable iron in their marrow and liver, and high levels of iron excretion after desferrioxamine. Thus, iron should be initiated when the children start to grow rapidly, have resynthesized their transferrin, and have reversed the oxidized intracellular environment. Measuring GSH and NADPH longitudinally can guide the timing of iron introduction. Monitoring for iron overload is warranted, but the probability of this occurring in the affected patient populations is low. Life-threatening anemia (in the range of 3 g/dL) will usually require transfusion, but great caution and careful supervision are required so as not to precipitate cardiac failure.

Folic acid administration is warranted in many individuals because anemia is endemic in susceptible populations, particularly children, and the causes of anemia are multifactorial.

Stanozolol (Winstrol).

In a letter, Taberner ²¹⁹ reported that stanozolol therapy was associated with iron deficiency. Sixteen patients taking 10 mg stanozolol daily in a trial of fibrinolytic enhancement therapy in intermittent claudication experienced a significant fall in mean cell hemoglobin (MCH) after 3 months of treatment. The red blood cell (RBC) count did not change significantly, but hemoglobin (Hb) and mean cell volume (MCV) also declined, contrary to an expected rise in Hb and RBC count. After exclusion of one patient who was iron deficient at baseline, six patients remained on therapy for a year or more. Four of these had dietary histories indicating insufficient iron nutriture and demonstrated RBC indices suggestive of iron deficiency, later confirmed by biochemical measurement and ferritin assay. In one of these four patients, stanozolol was discontinued without iron supplementation; the RBC indices and iron status returned to normal. No GI bleeding or evidence of fecal blood loss was observed to account for the iron deficiency. The increase in muscle bulk induced by the anabolic steroids was hypothesized to cause utilization of iron at the expense of Hb, subsequently reflected in a change in RBC Hb. The author concluded by recommending that “patients taking stanozolol for long periods should have RBC indices and liver function monitored regularly”. ²¹⁹

Warfarin (Coumadin, Marevan, Warfilone).

Iron (as well as magnesium and zinc) can bind with warfarin, potentially decreasing absorption and activity of both agents. ²²⁰ However, these potential effects have never been confirmed by conclusive findings from well-designed clinical trials or consistent, substantive, and well-documented case reports.

According to a nested case-control analysis of multiple linked health care databases conducted by Canadian researchers, patients taking warfarin at the same time as selective COX-2 inhibitors or nonselective NSAIDs have an increased risk of hospitalization for upper GI hemorrhage. ¹⁶¹ Patients in such situations would be at increased risk of iron deficiency anemia or tissue iron depletion because of chronic blood loss.

Although the pharmacological principles of an interaction involving binding of warfarin by concurrent ingestion of common mineral nutrients are well founded, the frequency of occurrence and clinical significance of this potential interaction are uncertain. Physicians prescribing warfarin should be aware of the possible risk of reduced effectiveness of treatment in patients taking nutrient formulations containing iron, magnesium, and zinc. Separating oral intake of warfarin and such minerals by at least 2 hours will usually provide adequate protection from unwanted interference.

Calcium in foods or supplements may reduce absorption of iron, especially heme iron. When ingested concurrently, substantial doses of calcium (as carbonate, phosphate, or citrate) can significantly decrease iron absorption, by as much as 62%. ^221-226 The available findings suggest that the effects of this pharmacokinetic interaction may be clinically insignificant at calcium intake levels of 1000 to 1500 mg/day, as indicated by serum ferritin levels, in individuals who are neither iron deficient nor demonstrating malabsorption. ^227-229

Available evidence indicates that the absorption of iron in multimineral formulations containing iron and calcium is probably not significantly altered. Nevertheless, separating oral intake of calcium and iron supplements by 2 hours or more may reduce the adverse effects of potential pharmacokinetic interference with absorption of either or both nutrients.

Iron and copper exhibit a multifaceted synergistic relationship within human physiology. Adequate copper nutriture appears necessary for normal iron absorption and metabolism, iron transport to the bone marrow, and RBC formation. Animals deficient in copper tend to accumulate hepatic iron. Anemia is a clinical sign of copper deficiency. However, simultaneous oral administration of copper and iron in large doses may impair the absorption of either or both nutrients.

When consumed concurrently, fiber (particularly phytic acid–containing fiber, as from cereal brans) can reduce iron absorption. Other fibers, such as that from psyllium seed, have minimal if any effect on iron or other mineral absorption.

Iron and folate work together in many aspects of human physiology, particularly RBC formation and function. Coadministration of iron and folate is common in the prevention and treatment of anemia, but proper diagnostic assessment is essential to determine causal factors.

Thompson et al. ²³⁰ at the Cancer Foundation of Western Australia found a protective association between maternal iron or folate supplementation in pregnancy and the risk of common acute lymphoblastic leukemia (ALL) in a population-based case-control study of children from birth to age 14 years and living in Western Australia from 1984 to 1992. For iron alone, the odds ratio was 0.75; only one mother took folate without iron. Further analyses of folate use with or without iron showed that the protective effect varies little by time of first use of supplements or for how long they were taken.

When iron and manganese are ingested together, the absorption of manganese may be impaired. In a study involving 47 women, Davis et al. ²³¹ observed that increased dietary intake of nonheme iron, typical of supplemental formulations, was associated with decreased manganese status. Notably, foods that contain significant amounts of manganese (green vegetables, breads, and cereals) often have significant amounts of nonheme iron and therefore greater probability of impaired manganese absorption. In contrast, heme iron intake was positively correlated with hematological status and had no consistent effect on nutritional status in regard to manganese. Similarly, Finley ²³² reported that young women with high iron status, as indicated by serum ferritin concentration, had relatively poor absorption and retention of manganese.

In a review of manganese research, Freeland-Graves ²³³ recommended that oral intake of iron and manganese be separated by 4 hours, or taken at a different time of day, to avoid absorption problems. However, these findings might also suggest that multimineral formulations containing both iron and manganese could be more effective in preventing manganese deficiency than iron-only preparations.

Iron absorption may potentially be reduced by concomitant use of pancreatic extracts.

Calcium phosphate (Tribasic); potassium phosphate; sodium phosphates.

After oral administration, divalent cations, such as iron salts, can bind to orally administered phosphate in the GI tract, potentially reducing the absorption and bioavailability of phosphate supplements. Administering oral phosphate preparations at least 1 hour before, or 2 hours after, oral iron salt intake can reduce the probability and significance of this interaction and maximize the therapeutic effect of the phosphate.

In a double-blind, randomized trial involving 51 female university students with iron deficiency anemia (IDA), Sirdah et al. ²³⁴ reported a possible beneficial additive effect associated with coadministration of oral taurine (1000 mg/day) and slow-release iron sulfate (325 mg/day), as indicated by changes in hemoglobin concentrations and normalization of iron deficiency markers. No significant adverse effects were reported. They noted that, at baseline, mean serum taurine was significantly lower in the IDA subjects than in the controls.

Vitamin A improves the absorption and utilization of iron, and vitamin A deficiency may exacerbate iron deficiency anemia. Vitamin A also prevents the inhibition of iron absorption by coffee and tea. ²²⁸ Two studies, one focusing on iron metabolism and protein status in children and the other involving pregnant women in West Java with nutritional anemia, found that coadministration of vitamin A enhanced treatment of iron deficiency anemia and improved iron status. The concomitant administration of vitamin A and iron ameliorated anemia more effectively than either iron or vitamin A alone. ^235,236 Likewise, in a study of Mexican preschoolers at high risk for deficiency of vitamin A, iron, and zinc, Muñoz et al. ²³⁷ demonstrated that supplementation with iron, or iron and zinc, improved indicators of vitamin A status. More recently, Zadik et al. ^237a reported that combined vitamin A and iron supplementation is as efficient as hormonal therapy in constitutionally delayed children.

Vitamin C, in supplemental formulations or vitamin C–rich foods, can strongly enhance the absorption of nonheme iron in the GI tract by reducing dietary ferric iron (Fe ³⁺ ) to ferrous iron (Fe ²⁺ ), forming a highly absorbable iron–ascorbic acid complex, and increasing bioavailability of the iron twofold to threefold. ^{62,77,238-241} This effect, however, appears to be influenced by gastric pH, bile function, and other dietary constituents, very dose dependent, and relatively minor at ascorbic acid doses under 200 mg, even in individuals with low iron stores. ^62,242,243 However, ascorbic acid can prevent the dose-dependent inhibitory effects of polyphenols and phytates on nonheme-iron absorption. ²⁴⁴ Furthermore, ascorbate stabilizes the iron cores of ferritin in cells and impairs ferritin degradation and autophagic uptake of ferritin clusters into lysosomes. ²⁴⁵

Iron deficiency anemia affects one third to half of children in the developing world. Zlotkin et al. ⁶ found that adding “sprinkles,” ferrous fumarate and ascorbic acid microencapsulated in a thin, soy-based coat, to weaning foods can be an effective tool in reducing rates of anemia in susceptible children.

Evidence: Ferrous sulfate, iron dextran complex.

Extrapolation: Ferric gluconate, ferrous fumarate, ferrous gluconate, iron sucrose, polysaccharide-iron complex.

Concomitant administration of vitamin E may diminish the therapeutic effects and mitigate the adverse effects of iron salts.

In an early study, Melhorn and Gross ²⁴⁶ observed a decrease in the hematological response to iron administration (iron dextran, 5 mg/kg/day for 3 days, followed by oral ferrous sulfate beginning on the seventh day) in children with iron deficiency anemia when oral vitamin E (200 IU) was coadministered on iron days 1 through 3. They reported that the reticulocyte response in patients receiving vitamin E was 4.4%, versus 14.4% in those not receiving vitamin E.

Large doses of iron may increase requirements for vitamin E. Roob et al. ²⁰ found that the antioxidant activity provided by concomitant vitamin E can attenuate oxidative stress induced by IV iron in patients on hemodialysis.

When administered orally, at the same time, iron and zinc can mutually reduce absorption. In particular, the ingestion of iron in high doses on an empty stomach can inhibit the absorption of zinc from simultaneous oral intake. However, supplemental iron does not appear to significantly inhibit zinc absorption in the presence of food. Similarly, iron-fortified foods do not appear to significantly alter zinc absorption. ^228,229

Zago and Oteiza ²⁴⁷ reported that the antioxidant activity of zinc may ameliorate oxidative stress induced by iron. Furthermore, the inhibition of Fe ²⁺ -induced lipid oxidation by either alpha-tocopherol or epicatechin was increased by the simultaneous addition of zinc.

Black tea, green tea (Camellia sinensis).

Coffee (Caffea arabica, Caffea canephora, Caffea robusta).

Coffee, black or green tea, chamomile, and many other plants, some commonly consumed as beverages, contain significant levels of polyphenols and tannins that can significantly impair absorption of iron by binding with iron to form insoluble complexes. In particular, phenolic compounds from plants consumed as foods and beverages are released during digestion and can complex with nonheme iron in the intestinal lumen, rendering it unavailable for absorption.

Black tea polyphenols are more inhibitory than the polyphenols from herb teas, cocoa, or wine, possibly because of their higher content of galloyl esters. Hurrell et al. ²⁴⁸ studied the effects of different polyphenol-containing beverages on nonheme iron absorption from a bread meal, containing a mere 2.1 mg iron, in adult human subjects from the erythrocyte incorporation of radiolabeled Fe. They tested beverages that contained different polyphenol structures and were rich in either phenolic acids (e.g., chlorogenic acid in coffee), monomeric flavonoids (as found in chamomile [ Matricaria recutitaL.], vervain [ Verbena officinalisL.], lime flower [ Tilia cordataMill.], peppermint [ Mentha piperitaL.], and other common herb teas, as well as pennyroyal [ Mentha pulegiumL.]; or complex polyphenol polymerization products (such as black tea and cocoa). All beverages were potent inhibitors of iron absorption and reduced absorption in a dose-dependent fashion depending on the content of total polyphenols. Compared with a water control meal, beverages containing 20 to 50 mg total polyphenols per serving reduced iron absorption from the bread meal by 50% to 70%. Herbal beverages containing 100 to 400 mg total polyphenols per serving reduced iron absorption by 60% to 90%. Black tea inhibited iron absorption by 79% to 94%, peppermint tea by 84%, pennyroyal by 73%, cocoa 71%, vervain 59%, lime flower 52%, and chamomile by 47%. Black tea was more inhibitory than cocoa, chamomile, vervain, lime flower, and pennyroyal at an identical concentration of total polyphenols. The addition of milk to coffee or tea did not significantly influence their inhibitory nature. Despite the relatively low dose of iron tested, the researchers concluded that these findings demonstrate that black tea, coffee, cocoa, and a variety of herbal teas can be potent inhibitors of iron absorption. ²⁴⁸

The effect of coffee's inhibition of iron absorption from supplemental or dietary sources may contribute to iron deficiency anemia, particularly in pregnant women; such effects might potentially reduce the levels of iron in breast milk to a clinically significant degree. Morck et al. ²⁴⁹ demonstrated that coffee inhibits iron absorption in a concentration-dependent fashion with simultaneous ingestion and when coffee was taken 1 hour later in iron-replete human subjects. In a controlled study involving pregnant low-income women in Costa Rica who consumed more than 450 mL coffee daily, Muñoz et al. ²⁵⁰ observed an association between coffee consumption and reductions in maternal hemoglobin levels and hematocrits, as well as similar effects in their infants, despite daily supplementation with ferric sulfate 200 mg (i.e., 60 mg elemental iron) and folate (500 µg). Iron deficiency anemia (hemoglobin <11 g/dL) was demonstrated in almost one quarter of the coffee-drinking mothers compared with none of the non-coffee-drinking mothers in the control group. Iron levels in breast milk were one-third lower in mothers who consumed coffee.

Merhav et al. ²⁵¹ report a much higher incidence of microcytic anemia among infants in Israel who consumed 50 to 750 mL tea per day (median, 250 mL). On studying 122 healthy infants, they found that the percentage of tea-drinking infants with microcytic anemia was significantly higher than that of the non–tea-drinking infants (32.6% vs. 3.5%). The tea drinkers had significantly lower mean Hb and MCV levels than the non–tea drinkers. However, in a study involving 10 iron-deficient children who consumed 150 mL of tea per day, Koren et al. ²⁵² reported no significant alterations in absorption of iron at daily doses of 2 to 15.8 mg/kg.

These preliminary findings suggest a pattern of impaired iron absorption and bioavailability of potentially meaningful dimensions, even in the presence of iron supplementation. Further research is warranted to determine the incidence and clinical import of these observations. In the meantime, healthcare providers are advised to recommend limited consumption of coffee, tea and other tannin-containing beverages by pregnant or lactating women as well as nursing infants or children drinking herbal beverages.

Samman et al. ²⁵³ reported that green tea or rosemary extract, added to foods, reduces nonheme iron absorption by as much as 26%. This apparently significant interaction may be clinically efficacious in the treatment of individuals with iron overload diseases, such as hemochromatosis.