Acne DNS Gel

Overview of Acne DNS Gel

Dosage Strength of Acne DNS Gel

Dapsone / Niacinamide / Spironolactone 6/2/5% 30 mL Pump

General Information

Dapsone

Dapsone is a versatile drug. It is a synthetic sulfone and is chemically similar to sulfonamides, but cross-sensitivity has not been substantiated. It is used as an antiinfective (for leprosy, Pneumocystis pneumonia (PCP), and prophylaxis of malaria) and as an immunosuppressive agent (for relapsing polychondritis and systemic lupus erythematosus). Dapsone also has been used to treat various dermatologic disorders such as actinomycotic mycetoma, dermatitis herpetiformis, pemphigoid, subcorneal pustular dermatosis, granuloma annulare, and pyoderma gangrenosum. In addition, dapsone is commonly used to treat Loxosceles reclusa (e.g., brown recluse spider) bites; however, both human and animal data to support its routine use are conflicting. A few case reports and small case series indicate efficacy in humans, but prospective human trials supporting its use are not available. Furthermore, in addition to the lack of evidence to support its use, dapsone can cause serious, life-threatening toxicities (e.g., hemolytic anemia, hepatitis, methemoglobinemia). A prospective epidemiologic study found that patients treated with dapsone for suspected loxoscelism experienced a nonsignificant increase in healing time and scarring.1 The benefits of administering dapsone for the treatment of loxoscelism should be carefully balanced against the risks; supportive therapy and wound care are the treatment modalities of choice in patients presenting with loxoscelism.23 Dapsone is currently the agent of choice in the treatment of all forms of leprosy, unless the organism exhibits dapsone resistance. Dapsone can be used for prophylaxis of PCP either as a single agent or in combination with pyrimethamine. In combination with trimethoprim, dapsone is effective for treatment of PCP.4 In combination with pyrimethamine, dapsone is effective for prevention of toxoplasmosis in patients with AIDS.5 Acedapsone is a long-acting repository form. In Canada, a commonly used brand name of oral dapsone is Avlosulfon. Dapsone was originally approved by the FDA in 1955. A topical dapsone gel (Aczone) was approved in a 5% strength for the treatment of acne vulgaris in July 2005, and in a 7.5% strength in February 2016.67 

Niacinamide

Niacin (nicotinic acid or 3-pyridinecarboxylic acid) is a B-complex vitamin. Good dietary sources of niacin are animal proteins, beans, green vegetables, liver, mushrooms, peanuts, whole wheat, and unpolished rice. Niacin is also present in cereal grains but is largely bound to plant proteins, and thus is poorly absorbed after ingestion. Niacin is one of the substances used in the enrichment of refined flour, and our dietary intake of pre-formed niacin comes primarily from enriched grains. However, the body's niacin requirement is also met by the biosynthesis of niacin from tryptophan, an amino acid. For example, milk and eggs do not contain niacin, but do contain large amounts of tryptophan from which niacin is derived. Each 60 mg of excess tryptophan (after protein synthesis) is converted to approximately 1 mg of niacin. Synthesis of the vitamin from tryptophan in proteins supplies roughly half the niacin requirement in man. Iron-deficiency or inadequate pyridoxine or riboflavin status will decrease the conversion of tryptophan to niacin and may contribute to deficiency, due to an interdependence of coenzymes in the niacin production pathway. A late and serious manifestation of niacin deficiency is pellagra, a clinical symptom complex principally affecting the GI tract, skin, and CNS, producing symptoms of diarrhea, dermatitis, and dementia, respectively. Pellagra may result from a niacin- and protein-deficient diet, isoniazid therapy, or certain diseases that result in poor utilization of tryptophan. Pellagra was the only vitamin-deficiency disease to ever reach epidemic proportions in the US; pellagra is rare today in industrialized countries due to the enrichment of refined flours.

Several synonyms for niacin and niacinamide exist. Synthetic niacin could be produced by the oxidation of nicotine, and the term 'nicotinic acid' evolved. Scientists also coined the terms 'nicotinamide' and 'niacinamide' for the amide form of nicotinic acid. The term 'niacin' has been used generically since the 1940's to label foods and to avoid association of the vitamins with the nicotine alkaloid from tobacco. Thus the name 'niacin' has been used to denote both chemical forms, which are equivalent as vitamins on a weight basis. Both nicotinic acid and nicotinamide are synthesized for inclusion in nutritional supplements. However, since nicotinic acid and nicotinamide have different pharmacologic properties outside of their use as vitamins, it is important to distinguish between the two forms in pharmaceutical products.

In clinical medicine, nicotinic acid is used as an antilipemic, but nicotinamide (niacinamide) is not effective for this purpose. Nicotinic acid was the first hypolipidemic agent shown to decrease the incidence of secondary myocardial infarction (MI) and reduce total mortality in MI patients. However, no incremental benefit of coadministration of extended-release niacin with lovastatin or simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for extended-release niacin, simvastatin, or lovastatin monotherapy has been established. In addition, the AIM-HIGH trial demonstrated that the concurrent use of extended-release niacin (1500—2000 mg/day PO) and simvastatin does not result in a greater reduction in the incidence of cardiovascular events than simvastatin alone.8 These results are consistent with those of the larger HPS2-THRIVE trial in which the addition of extended-release niacin to effective statin-based therapy did not result in a greater reduction in the incidence of cardiovascular events. Furthermore, there was an increased risk of serious adverse events including an increased incidence of disturbances in diabetes control and diabetes diagnoses, as well as serious gastrointestinal, musculoskeletal, dermatological, infectious, and bleeding adverse events. There was also a statistically insignificant 9% proportional increase in the incidence of death from any cause in the niacin group.9 The ARBITER 6-HALTS trial demonstrated that the addition of extended-release niacin 2000 mg/day to statins results in significant regression in atherosclerosis as measured by carotid intima-media thickness, and is superior to the combination of ezetimibe and a statin.10 In an MRI study, the addition of extended-release niacin 2000 mg/day to statin therapy resulted in a significant reduction in carotid wall area compared to placebo.11 However, the NIA Plaque study, which was presented at the American Heart Association (AHA) 2009 Scientific Sessions, did not find a significant reduction in the progression of atherosclerosis associated with the addition of niacin to statin therapy as compared to statin monotherapy. Additionally, nicotinic acid has been used as a therapy for tinnitus, but efficacy data are scant. Some sustained-release nicotinic acid formulations have a lower incidence of flushing but a higher incidence of hepatotoxicity when compared to immediate-release forms.12 Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

Spironolactone

Spironolactone is a potassium-sparing diuretic. In patients with severe heart failure (NYHA Class IV), spironolactone has been shown to improve overall survival and NYHA functional class, and to reduce hospitalizations when added to conventional therapy (e.g., ACE inhibitor, loop diuretic, digoxin).13 It is frequently used to treat ascites associated with cirrhosis and also has been used as a diagnostic aid for primary hyperaldosteronism. It is also used to treat hypokalemia. Compared to thiazide or loop diuretics, it is a relatively weak agent for treating hypertension or generalized edema, although its effects can be additive with thiazide diuretics. While not FDA-approved indications, acne vulgaris, polycystic ovary syndrome, and female hirsutism have been treated with spironolactone. Spironolactone was approved by the FDA in 1960. 

Mechanism of Action

Dapsone

Similar to sulfonamides, dapsone inhibits dihyropteroate synthase in susceptible organisms. Other proposed mechanisms for dapsone include inhibition of the neutrophilic-cytotoxic system and interference with the alternate pathway of the complement system. Although the mechanism of dapsone in dermatologic disorders is unknown, it has been suggested that it may act as an immunomodulator. 

For many years, dapsone was the main therapy for leprosy (Mycobacterium leprae). Unfortunately, years of monotherapy has lead to significant resistance in this organism. Resistance to M. leprae develops in 2—10% of patients after prolonged administration. Nevertheless, dapsone remains a component of combination therapy for leprosy. 

Dapsone is administered orally or topically. It is widely distributed and is retained in the skin, muscles, kidneys, and liver. It also crosses the placenta and is distributed into breast milk. 

Dapsone and its primary acetylated metabolite, monoacetyldapsone (MADDS), undergo enterohepatic recirculation. Acetylation is accomplished via N-acetyltransferase. Unlike with other acetylated compounds, slow and fast acetylators have exhibited no differences in pharmacokinetics, side effects, or therapeutic response. Minor metabolites include diacetyl derivatives and hydroxylamine dapsone (NOH-DDS). The latter metabolite appears to be associated with methemoglobinemia and hemolysis, which have been reported during therapy. The hydroxylamine metabolite is primarily produced by N-hydroxylation via CYP3A and CYP2C9 enzymes. The average half-life of both dapsone and MADDS is 30 hours. About 20% of a dose is excreted unchanged in the urine, while 70—85% is excreted as metabolites. A small amount can be detected in the feces.

Niacinamide

Niacin (nicotinic acid or 3-pyridinecarboxylic acid) is a B-complex vitamin. Good dietary sources of niacin are animal proteins, beans, green vegetables, liver, mushrooms, peanuts, whole wheat, and unpolished rice. Niacin is also present in cereal grains but is largely bound to plant proteins, and thus is poorly absorbed after ingestion. Niacin is one of the substances used in the enrichment of refined flour, and our dietary intake of pre-formed niacin comes primarily from enriched grains. However, the body's niacin requirement is also met by the biosynthesis of niacin from tryptophan, an amino acid. For example, milk and eggs do not contain niacin, but do contain large amounts of tryptophan from which niacin is derived. Each 60 mg of excess tryptophan (after protein synthesis) is converted to approximately 1 mg of niacin. Synthesis of the vitamin from tryptophan in proteins supplies roughly half the niacin requirement in man. Iron-deficiency or inadequate pyridoxine or riboflavin status will decrease the conversion of tryptophan to niacin and may contribute to deficiency, due to an interdependence of coenzymes in the niacin production pathway. A late and serious manifestation of niacin deficiency is pellagra, a clinical symptom complex principally affecting the GI tract, skin, and CNS, producing symptoms of diarrhea, dermatitis, and dementia, respectively. Pellagra may result from a niacin- and protein-deficient diet, isoniazid therapy, or certain diseases that result in poor utilization of tryptophan. Pellagra was the only vitamin-deficiency disease to ever reach epidemic proportions in the US; pellagra is rare today in industrialized countries due to the enrichment of refined flours.

Several synonyms for niacin and niacinamide exist. Synthetic niacin could be produced by the oxidation of nicotine, and the term 'nicotinic acid' evolved. Scientists also coined the terms 'nicotinamide' and 'niacinamide' for the amide form of nicotinic acid. The term 'niacin' has been used generically since the 1940's to label foods and to avoid association of the vitamins with the nicotine alkaloid from tobacco. Thus the name 'niacin' has been used to denote both chemical forms, which are equivalent as vitamins on a weight basis. Both nicotinic acid and nicotinamide are synthesized for inclusion in nutritional supplements. However, since nicotinic acid and nicotinamide have different pharmacologic properties outside of their use as vitamins, it is important to distinguish between the two forms in pharmaceutical products.

In clinical medicine, nicotinic acid is used as an antilipemic, but nicotinamide (niacinamide) is not effective for this purpose. Nicotinic acid was the first hypolipidemic agent shown to decrease the incidence of secondary myocardial infarction (MI) and reduce total mortality in MI patients. However, no incremental benefit of coadministration of extended-release niacin with lovastatin or simvastatin on cardiovascular morbidity and mortality over and above that demonstrated for extended-release niacin, simvastatin, or lovastatin monotherapy has been established. In addition, the AIM-HIGH trial demonstrated that the concurrent use of extended-release niacin (1500—2000 mg/day PO) and simvastatin does not result in a greater reduction in the incidence of cardiovascular events than simvastatin alone.8 These results are consistent with those of the larger HPS2-THRIVE trial in which the addition of extended-release niacin to effective statin-based therapy did not result in a greater reduction in the incidence of cardiovascular events. Furthermore, there was an increased risk of serious adverse events including an increased incidence of disturbances in diabetes control and diabetes diagnoses, as well as serious gastrointestinal, musculoskeletal, dermatological, infectious, and bleeding adverse events. There was also a statistically insignificant 9% proportional increase in the incidence of death from any cause in the niacin group.9 The ARBITER 6-HALTS trial demonstrated that the addition of extended-release niacin 2000 mg/day to statins results in significant regression in atherosclerosis as measured by carotid intima-media thickness, and is superior to the combination of ezetimibe and a statin.10 In an MRI study, the addition of extended-release niacin 2000 mg/day to statin therapy resulted in a significant reduction in carotid wall area compared to placebo.11 However, the NIA Plaque study, which was presented at the American Heart Association (AHA) 2009 Scientific Sessions, did not find a significant reduction in the progression of atherosclerosis associated with the addition of niacin to statin therapy as compared to statin monotherapy. Additionally, nicotinic acid has been used as a therapy for tinnitus, but efficacy data are scant. Some sustained-release nicotinic acid formulations have a lower incidence of flushing but a higher incidence of hepatotoxicity when compared to immediate-release forms.12 Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

Spironolactone

Spironolactone inhibits the effects of aldosterone on the distal renal tubules. Unlike amiloride and triamterene, spironolactone exhibits its diuretic effect only in the presence of aldosterone, and these effects are enhanced in patients with hyperaldosteronism. Aldosterone antagonism enhances sodium, chloride, and water excretion, and reduces the excretion of potassium, ammonium, and phosphate. Spironolactone does not inhibit renal transport mechanisms or carbonic anhydrase activity. In addition, spironolactone acts as an androgen receptor blocker by competitively inhibiting dihydrotestosterone at its receptor sites, and at high doses, spironolactone interferes with steroid synthesis in the adrenal glands and gonads. Sebum excretion rates also are reduced in a dose-dependent manner with spironolactone. 

Spironolactone is a poor antihypertensive, but it does have modest hypotensive effects. The hypotensive mechanism of spironolactone is unknown. It is possibly due to the ability of the drug to inhibit aldosterone's effect on arteriole smooth muscle. Spironolactone also can alter the extracellular-intracellular sodium gradient across the membrane. In general, diuretics lower blood pressure by initially decreasing cardiac output and reducing plasma and extracellular fluid volume. Cardiac output and extracellular fluid volume eventually return to normal, but peripheral resistance is reduced, resulting in lower blood pressure. In general, diuretics worsen glucose tolerance and exert detrimental effects on the lipid profile.

Pharmacokinetics

Niacinamide

Nicotinic acid may be administered by the oral or parenteral routes. Nicotinamide is administered orally. Niacin is widely distributed throughout the body and it concentrates in the liver, spleen, and adipose tissue. Niacin undergoes rapid and extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. Niacin is conjugated with glycine to form nicotinuric acid (NUA), which is then excreted in the urine. Some reversible metabolism from NUA back to niacin may occur in small amounts. The other pathway results in the formation of NAD. Nicotinamide is most likely released after the formation of NAD. Nicotinamide does not have hypolipidemic activity and is further metabolized in the liver to produce N-methylnicotinamide (MNA) and nicotinamide-N-oxide (NNO). MNA is metabolized to two other N-methylated compounds known as 2PY and 4PY, which are excreted in the urine. The formation of 2PY predominates over 4PY in humans. Roughly 12% of nicotinic acid is excreted unchanged in the urine with normal dosages. Greater proportions of niacin are renally excreted unchanged as dosages exceed 1000 mg/day and metabolic pathways become saturated.

Spironolactone

Spironolactone is administered orally. Spironolactone is extensively metabolized, via hepatic pathways, to active metabolites. The clinical effects of spironolactone are partially due to canrenone, a metabolite. The parent drug and canrenone are greater than 90% plasma protein-bound.14 The duration of action after multiple doses of spironolactone is 2 to 3 days. Both unchanged drug (less than 10%) and its metabolites are excreted primarily in the urine. The remainder of a dose is excreted in the feces via biliary elimination. The half-life of spironolactone after a single dose is 1 to 2 hours. The half-life of canrenone ranges from 10 to 35 hours.151617 

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4/5, CYP2C8 

Spironolactone is rapidly and extensively metabolized primarily by CYP3A4/5, and to a lesser extent by CYP2C8. In vitro studies also show that spironolactone is an irreversible inhibitor of CYP3A4/5 and CYP2C8.17 

Contraindications/Precautions

Dapsone

Dapsone should be used with caution in cases of severe anemia, G6PD deficiency (glucose 6-phosphate dehydrogenase deficiency) or methemoglobin reductase deficiency because hemolytic anemia can occur. The safety of dapsone topical gel (Aczone) was evaluated in a randomized, double-blind, cross-over study of 64 patients with G6PD deficiency and acne vulgaris. After 2 weeks, a mean decline of 0.32 g/dL in hemoglobin was noted in patients treated with Aczone gel; however, by week 12, hemoglobin levels generally returned to baseline levels. Decreases in hemoglobin of > 1g/dL were noted in a similar proportion of patients in the Aczone gel group and the vehicle group (Aczone: 8 out of 58, vehicle: 7 out of 56). The study found no evidence of clinically significant hemolytic anemia following application of dapsone topical gel. Laboratory changes suggestive of mild hemolysis were noted in some subjects.6 Glucose 6-phosphate dehydrogenase levels should be obtained in all patients before using systemically administered dapsone. Baseline complete blood counts, including a reticulocyte count, should be obtained in patients who are G6PD deficient or with a history of anemia. Routine follow-up for complete blood count and reticulocyte count should be implemented for patients at risk. 

Toxic hepatitis, cholestatic jaundice, and hyperbilirubinemia have been reported during the initial stages of systemic dapsone treatment. Periodic monitoring of liver-function tests is recommended. Dapsone should be used cautiously in patients with preexisting hepatic disease. 

Uncontrolled studies of systemic dapsone use in pregnant women have not demonstrated fetal risk during any trimester of pregnancy nor did use affect reproduction capacity. Although further study is needed, it has been recommended by some authorities that dapsone therapy be maintained during pregnancy in cases of leprosy or dermatitis herpetiformis.18 Information on the use of topical dapsone in pregnant patients is not available; however, systemic exposure of the topical gel is low compared to oral dapsone administration (approximately 100 times less).67 

Dapsone is distributed into breast milk in large quantities after oral dosing and can cause hemolytic anemia in nursing infants with G6PD deficiency.18 However, the American Academy of Pediatrics (AAP) states that dapsone is usually compatible with breast-feeding.19 Absorption after topical administration is minimal relative to oral dapsone administration.6 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA. 

Oral dapsone can be used safely in pediatric patients (i.e., infants, children, and adolescents); however, no dosing information is available for neonates. The 5% topical gel is indicated for use in children 12 years and older; while the 7.5% topical gel is approved for use in children as young as 9 years.2067 

Administer dapsone, a synthetic sulfone, with caution in patients with sulfonamide hypersensitivity. It may be prudent to monitor patients for allergic-type reactions when initiating dapsone. Although structurally it contains an aromatic amine known to trigger adverse reactions at position N4, dapsone does not contain the N1-moiety that is present in sulfonamide antibiotics and thought to be responsible for hypersensitivity-type adverse reactions. The risk of cross-sensitivity in patients taking a nonantibiotic sulfonamide that have a history of sulfonamide hypersensitivity is low and has been confirmed by observational studies.212223 In general, patients with a history of hypersensitivity to any drug are predisposed for subsequent hypersensitivity reactions to other drugs.22 Because of this, patients with a history of sulfonamide hypersensitivity should be monitored for hypersensitivity reactions to other drugs, including dapsone; however, treatment with a nonantibiotic sulfonamide may not need to be withheld in patients with a sulfonamide allergy as long as patients are monitored appropriately, especially if alternative therapies are not available.24

Niacinamide

Patients who have a known hypersensitivity to niacin or any product component should not be given the drug.

While steady state plasma concentrations of niacin are generally higher in women than in men, the absorption, metabolism, and excretion of niacin appears to be similar in both genders. Women have been reported to have greater response to the lipid-lowering effects of nicotinic acid (niacin) when compared to men.

No overall differences in safety and efficacy were observed between geriatric and younger individuals receiving niacin. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity for some older individuals cannot be ruled out.

Niacin is contraindicated in patients who have significant or unexplained hepatic disease. Patients who consume large quantities of ethanol (alcoholism), who have risk factors for hepatic disease, or who have a past-history of gallbladder disease, jaundice, or hepatic dysfunction may receive niacin with close clinical observation. Elevations in liver function tests (LFTs) appear to be dose-related. Some sustained-release nicotinic acid (niacin) formulations have a higher incidence of hepatotoxicity when compared to immediate-release dosage forms. Extended-release nicotinic acid preparations (e.g., Niaspan, Slo-Niacin) should not be substituted for equivalent dosages of immediate-release (crystalline) niacin (e.g., Niacor and others). Follow the manufacturer-recommended initial dosage titration schedules for extended-release products, regardless of previous therapy with other niacin formulations. Monitor LFTs in all patients during therapy at roughly 6-month intervals or when clinically indicated. If transaminase levels (i.e., ALT or AST) rise to 3 times the upper limit of normal, or clinical symptoms of hepatic dysfunction are present, niacin should be discontinued.

Nicotinic acid (niacin) can stimulate histamine release, which, in turn, can stimulate gastric acid output. Niacin is contraindicated in patients with active peptic ulcer disease (PUD) because it can exacerbate PUD symptoms. Use niacin with caution in patients with a past history of peptic ulcer disease or in those on maintenance therapy to prevent PUD recurrence.

Due to its vasodilatory action, nicotinic acid (niacin) should be used with caution in those patients with uncorrected hypotension (or predisposition to orthostatic hypotension), acute myocardial infarction, or unstable angina, particularly when vasodilator medications such as nitrates, calcium channel blockers, or adrenergic blocking agents are coadministered (see Drug Interactions). Because the vasodilatory response to niacin may be more dramatic at the initiation of treatment, activities requiring mental alertness (e.g., driving or operating machinery) should not be undertaken until the response to niacin is known.

Niacin, especially in high doses, can cause hyperuricemia. Niacin should be prescribed cautiously to patients with gout (or predisposed to gout). These individuals should be advised not to purchase OTC forms of niacin without the guidance of a physician.

Niacin, especially in high doses, can cause hypophosphatemia. Although the reductions in phosphorus levels are usually transient, clinicians should monitor serum phosphorus periodically in those at risk for this electrolyte imbalance.

Rare cases of rhabdomyolysis have been reported in patients taking lipid-altering dosages of nicotinic acid (niacin) and statin-type agents concurrently (see Drug Interactions). Patients undergoing combined therapy should be carefully monitored for muscle pain, tenderness, or weakness, particularly in the early months of treatment or during periods of upward dose titration of either drug. While periodic CPK and potassium determinations may be considered, there is no evidence that these tests will prevent the occurrence of severe myopathy. If rhabdomyolysis occurs, the offending therapies should be discontinued.

Niacin, especially in high doses, may cause hyperglycemia. Niacin should be prescribed cautiously to patients with diabetes mellitus. These individuals should be advised not to purchase OTC forms of niacin without the guidance of a physician. Niacin has also been reported to cause false-positive results in urine glucose tests that contain cupric sulfate solution (e.g., Benedict's reagent, Clinitest).

Niacin therapy has been used safely in children for the treatment of nutritional niacin deficiency. However, the safety and effectiveness of nicotinic acid for the treatment of dyslipidemias have not been established in neonates, infants and children <= 16 years of age. Nicotinic acid has been used for the treatment of dyslipidemia in pediatric patients under select circumstances. Children may have an increased risk of niacin-induced side effects versus adult populations. At least one pediatric study has concluded that niacin treatment should be reserved for treatment of severe hypercholesterolemia under the close-supervision of a lipid specialist.25 In general, the National Cholesterol Education Program (NCEP) does not recommend drug therapy for the treatment of children with dyslipidemias until the age of 10 years or older.26

Since niacin is an essential nutrient, one would expect it to be safe when administered during pregnancy at doses meeting the recommended daily allowance (RDA). Niacin is categorized as pregnancy category A under these conditions. However, when used in doses greater than the RDA for dyslipidemia, or when used parenterally for the treatment of pellagra, niacin is categorized as pregnancy category C. Most manufacturers recommend against the use of niacin in dosages greater than the RDA during pregnancy. The potential benefits of high-dose niacin therapy should be weighed against risks, since toxicological studies have not been performed.8

According to a manufacturer of niacin (Niaspan), although no studies have been conducted in nursing mothers, excretion into human milk is expected. The manufacturer recommends the discontinuation of nursing or the drug due to serious adverse reactions that may occur in nursing infants from lipid-altering doses of nicotinic acid.8 Niacin, in the form of niacinamide, is excreted in breast milk in proportion to maternal intake. Niacin supplementation is only needed in those lactating women who do not have adequate dietary intake. The Recommended Daily Allowance (RDA) of the National Academy of Science for niacin during lactation is 20 mg.27 There are no safety data regarding the use of nicotinic acid in doses above the RDA during breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Use niacin with caution in patients with renal disease (renal failure or severe renal impairment) since niacin metabolites are excreted through the kidneys. It appears that no special precautions are needed when administering niacin to meet the recommended nutritional daily allowance (RDA). Use caution when administering higher dosages.

Nicotinic acid (niacin) occasionally causes slight decreases in platelet counts or increased prothrombin times and should be used with caution in patients with thrombocytopenia, coagulopathy, or who are receiving anticoagulant therapy. Patients who will be undergoing surgery should have blood counts monitored. Nicotinic acid (niacin) is contraindicated in patients with arterial bleeding.

The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to OBRA, glucose and liver function tests should be evaluated regularly because niacin interferes with glucose control, can aggravate diabetes, and can exacerbate active gallbladder disease and gout. Flushing is a common side effect of niacin.28

Spironolactone

Spironolactone is contraindicated in patients with hyperkalemia, Addison's disease (chronic adrenal insufficiency), or other conditions associated with hyperkalemia and should not be administered to those who are receiving other potassium-sparing agents.1417 The Endocrine Society guidelines on the diagnosis and treatment of primary adrenal insufficiency state that use of aldosterone antagonists, such as spironolactone, are contraindicated in patients with adrenal insufficiency (Addison's disease). Hyperkalemia stimulates aldosterone production and aldosterone, in turn, enhances sodium and water reabsorption in exchange for potassium excretion in the distal tubule and collecting duct of the kidney. In Addison's disease, aldosterone deficiency results in hyponatremia, hypovolemia, hypotension and hyperkalemia. Thus, spironolactone therapy will exacerbate the hyponatremia, hypovolemia, hypotension and hyperkalemia seen in adrenal insufficiency and worsen the signs and symptoms of the disease.293031 Spironolactone-induced hyperkalemia can cause life-threatening cardiac arrhythmias, and it is more likely to occur in patients with impaired renal function or diabetes mellitus. Excessive diuresis may cause symptomatic dehydration, hypotension, and worsening renal function. Spironolactone tablets are contraindicated in patients with anuria or any renal disease associated with severe renal impairment (CrCl less than 10 mL/minute) or acute renal failure. Monitor serum potassium and renal function 3 days and 1 week after initiation or dosage increase, monthly for 3 months, quarterly for a year, and every 6 months thereafter. Monitor volume status periodically. Patients receiving spironolactone should not receive potassium supplementation or increase their dietary intake of potassium unless they have refractory hypokalemia. In adults, the risk of hyperkalemia increases progressively when serum creatinine exceeds 1.6 mg/dL; the threshold for pediatric patients is unknown. In adults, spironolactone should be discontinued if the serum creatinine is greater than 4 mg/dL or serum potassium is greater than 5 mEq/L. Spironolactone may cause a transient elevation of BUN, especially in patients with preexisting renal impairment. The precaution for spironolactone in patients with diabetes mellitus is primarily due to the risk of hyperkalemia and not the risk of inducing hyperglycemia, which may occur with thiazide or loop diuretics.143217 

Correct significant acid/base imbalance before spironolactone is initiated, as mild acidosis or hypochloremic metabolic alkalosis may occur with its use.14 Close monitoring of the acid-base status is required in debilitated patients or severely ill patients in whom respiratory acidosis or metabolic acidosis may occur (e.g., cardiopulmonary disease or uncontrolled diabetes). These patients are at a higher risk for developing sudden metabolic acidosis or respiratory acidosis, with resultant rapid increases in serum potassium concentrations that could be exacerbated by potassium-sparing diuretic therapy. 

Spironolactone-induced fluctuations in serum electrolyte concentrations can occur rapidly and precipitate hepatic encephalopathy and hepatic coma in patients with hepatic disease with biliary cirrhosis and ascites. In these patients, initiate spironolactone in the hospital. Clearance of spironolactone and its metabolites is reduced in patients with cirrhosis; start with the lowest initial dose and titrate slowly in these patients.17 Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported in patients with decompensated hepatic cirrhosis, even with normal renal function.14 

Spironolactone can cause antiandrogenic and endocrine effects; use with caution in patients with menstrual irregularity or breast enlargement.14 

Spironolactone has been demonstrated to be tumorigenic in chronic toxicity studies in rats. Although human data are not available, the potential for tumorigenicity or development of a new primary malignancy are potential risks to consider during spironolactone therapy. FDA-approved labeling for the tablet product recommends that spironolactone only be used as indicated within the prescribing information; avoid unnecessary use.14 

Use spironolactone with caution in patients with prostate cancer. In addition to being an aldosterone antagonist, it has been shown to have some antiandrogenic activity. However, in vitro and in animal studies have confirmed that spironolactone is only a weak and partial androgen antagonist, and has intrinsic androgenic activity.33343536 One case report has been published regarding a patient with progression of heavily pretreated castration-refractory prostate cancer (CRPC) after the addition of spironolactone for heart failure to abiraterone therapy; this patient's PSA returned to its previous level 2 weeks after discontinuation of spironolactone.37 In another case, a patient with progressive metastatic CRPC on abiraterone and subsequent enzalutamide therapy twice had significant decreases in PSA and stabilization of visceral disease after discontinuation of spironolactone.38 

Somnolence and dizziness have been reported to occur in some patients. Therefore, caution is advised when driving or operating machinery until the response to treatment with spironolactone has been determined.14 

Periodic assessment of renal function, along with monitoring of serum electrolytes to detect possible electrolyte imbalances, especially hyperkalemia, should be done at appropriate intervals during spironolactone therapy, particularly in the geriatric patient.14 According to the Beers Criteria, diuretics are considered potentially inappropriate medications (PIMs) in geriatric patients; use with caution due to the potential for causing or exacerbating SIADH or hyponatremia. Sodium levels should be closely monitored when starting or changing dosages of diuretics in older adults. The Beers expert panel recommends avoiding spironolactone in geriatric patients with a creatinine clearance less than 30 mL/minute due to the potential for increased serum potassium.39 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. Diuretics may cause fluid and electrolyte imbalances and may precipitate or exacerbate urinary incontinence.28 

Avoid spironolactone in pregnancy or advise pregnant women of the potential risk to a male fetus. Because of its anti-androgenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. Animal studies report feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero. Animal offspring exposed to spironolactone during late pregnancy exhibited changes in the reproductive tract, including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction that persisted into adulthood. Limited data from published case reports and case series did not demonstrate an association between major malformations or other adverse pregnancy outcomes with spironolactone use.17 

Spironolactone is not present in breast-milk; however, canrenone, the major metabolite of spironolactone, does appear in breast-milk in low amounts that are not expected to be clinically relevant. Data from a breast-feeding woman at 17 days postpartum did not indicate any adverse effects on the breast-fed infant; long term effects on a breast-fed infant are unknown. There are no data on the effects of spironolactone on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for spironolactone and any potential adverse effects on the breast-fed child from spironolactone or from the underlying maternal condition.17 Previous American Academy of Pediatrics recommendations classified spironolactone as usually compatible with breast-feeding.19 

In animal studies involving female rats, spironolactone was associated with a reduction in circulating estrogen levels and retarded ovarian follicle development. Inhibition of ovulation and reduction in number of implanted embryos were observed with spironolactone administration to female mice. The potential for infertility in humans is unknown.14 

Pregnancy

Dapsone

Uncontrolled studies of systemic dapsone use in pregnant women have not demonstrated fetal risk during any trimester of pregnancy nor did use affect reproduction capacity. Although further study is needed, it has been recommended by some authorities that dapsone therapy be maintained during pregnancy in cases of leprosy or dermatitis herpetiformis.18 Information on the use of topical dapsone in pregnant patients is not available; however, systemic exposure of the topical gel is low compared to oral dapsone administration (approximately 100 times less).67

Niacinamide

Since niacin is an essential nutrient, one would expect it to be safe when administered during pregnancy at doses meeting the recommended daily allowance (RDA). Niacin is categorized as pregnancy category A under these conditions. However, when used in doses greater than the RDA for dyslipidemia, or when used parenterally for the treatment of pellagra, niacin is categorized as pregnancy category C. Most manufacturers recommend against the use of niacin in dosages greater than the RDA during pregnancy. The potential benefits of high-dose niacin therapy should be weighed against risks, since toxicological studies have not been performed.8

Spironolactone

Avoid spironolactone in pregnancy or advise pregnant women of the potential risk to a male fetus. Because of its anti-androgenic activity and the requirement of testosterone for male morphogenesis, spironolactone may have the potential for adversely affecting sex differentiation of the male during embryogenesis. Animal studies report feminization of male fetuses and endocrine dysfunction in females exposed to spironolactone in utero. Animal offspring exposed to spironolactone during late pregnancy exhibited changes in the reproductive tract, including dose-dependent decreases in weights of the ventral prostate and seminal vesicle in males, ovaries and uteri that were enlarged in females, and other indications of endocrine dysfunction that persisted into adulthood. Limited data from published case reports and case series did not demonstrate an association between major malformations or other adverse pregnancy outcomes with spironolactone use.17 

Breast-feeding

Dapsone

Dapsone is distributed into breast milk in large quantities after oral dosing and can cause hemolytic anemia in nursing infants with G6PD deficiency.18 However, the American Academy of Pediatrics (AAP) states that dapsone is usually compatible with breast-feeding.19 Absorption after topical administration is minimal relative to oral dapsone administration.6 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Niacinamide

According to a manufacturer of niacin (Niaspan), although no studies have been conducted in nursing mothers, excretion into human milk is expected. The manufacturer recommends the discontinuation of nursing or the drug due to serious adverse reactions that may occur in nursing infants from lipid-altering doses of nicotinic acid.8 Niacin, in the form of niacinamide, is excreted in breast milk in proportion to maternal intake. Niacin supplementation is only needed in those lactating women who do not have adequate dietary intake. The Recommended Daily Allowance (RDA) of the National Academy of Science for niacin during lactation is 20 mg.27 There are no safety data regarding the use of nicotinic acid in doses above the RDA during breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Spironolactone

Spironolactone is not present in breast-milk; however, canrenone, the major metabolite of spironolactone, does appear in breast-milk in low amounts that are not expected to be clinically relevant. Data from a breast-feeding woman at 17 days postpartum did not indicate any adverse effects on the breast-fed infant; long term effects on a breast-fed infant are unknown. There are no data on the effects of spironolactone on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for spironolactone and any potential adverse effects on the breast-fed child from spironolactone or from the underlying maternal condition.40 Previous American Academy of Pediatrics recommendations classified spironolactone as usually compatible with breast-feeding.19 

Adverse Reactions/Side Effects

Dapsone

The most frequently reported adverse reactions during therapy with dapsone are dose-related hematologic effects. Hemolysis is reported in the majority of patients receiving at least 200 mg of dapsone daily. Symptomatic anemia has occurred occasionally. Almost all patients experience hemoglobin decreases of 1—2 g/dl, reticulocyte count increases of 2—12%, erythrocyte life span decreases, and methemoglobinemia. Patients with glucose 6-phosphate dehydrogenase deficiency or methemoglobin reductase deficiency can experience more pronounced adverse hematologic effects, such as hemolytic anemia and Heinz body formation, than do other patients. It does not appear that topical administration of dapsone is associated with adverse hematologic effects; however, laboratory changes suggestive of a mild hemolysis in G6PD deficient patients have been reported.186 In a double-blind, randomized, vehicle-controlled, crossover trial, dapsone gel 5% was applied topically twice daily for 12 weeks to patients 12 years and older with G6PD deficiency and acne vulgaris. No changes indicative of hemolytic anemia were noted in clinical or laboratory parameters. The proportion of subjects with a >= 1 g/dL decrease in hemoglobin was similar between dapsone treatment and vehicle. Additionally, subjects with severely deficient G6PD levels experienced no difference in risk of hemolysis after dapsone gel treatment, similar to patients with the lowest enzyme activity.41 AIDS patients who have preexisting hypoxemia or anemia and are being treated for Pneumocystis pneumonia can exhibit an exaggerated response to the hematologic effects of dapsone; however, the drug is well tolerated in most AIDS patients. In rare instances, acute methemoglobinemia occurs and can cause anemia, vascular collapse, or death. Potentially fatal agranulocytosis, pancytopenia, and aplastic anemia have been documented in isolated case reports. Leukopenia also has been observed during treatment with dapsone. 

Severe dermatologic reactions develop rarely during therapy with dapsone and are frequently the result of sensitization to the drug. Cutaneous effects that have been reported during oral therapy include bullous rash, exfoliative dermatitis, toxic erythema, erythema multiforme, morbilliform and scarlatiniform reactions, urticaria, toxic epidermal necrolysis, and erythema nodosum leprosum in patients being treated for leprosy. These reactions have not been observed during clinical trials with the topical formulation; however, rash (including erythematous rash) and swelling of the face (including lip and eye swelling) have been noted in postmarketing reports with the topical product. Photosensitivity has also been observed during oral dapsone therapy. Application site reactions have been reported with the use of topical dapsone and include unspecified reactions (18%), dryness or xerosis (up to 16%), erythema (13%), burning (1%), pruritus (1%), and oiliness or peeling (up to 13%).1867 

Adverse gastrointestinal effects that can occur during therapy with oral dapsone include nausea, vomiting, and abdominal pain.18 

In rare cases, peripheral neuropathy has occurred in patients receiving oral dapsone for non-leprosy purposes. This complication, which is characterized by motor loss and muscle weakness, usually resolves following discontinuance of the drug. In leprosy patients, this complication may be difficult to distinguish from a leprosy reactional state. No cases of peripheral neuropathy were reported during clinical trials with topical dapsone.186 

Toxic hepatitis and cholestatic jaundice have occurred, particularly during the initial stages of therapy with oral dapsone. These complications can manifest as elevated hepatic enzymes, specifically elevations in alkaline phosphatase, SGOT, bilirubin, and LDH. Hyperbilirubinemia may occur more often in G6PD deficient patients.18 

Adverse renal effects observed during therapy with oral dapsone include albuminuria, nephrotic syndrome, and renal papillary necrosis.18 

Abrupt changes in the patient's clinical status during effective treatment with dapsone for leprosy can cause leprosy reactional states. These reactional states can be divided into two categories: reversal reactions (type I) and lepromatous lepra reactions (type II). Type I reactions occur primarily in borderline or tuberculoid leprosy patients. Patients can exhibit an enhanced delayed hypersensitivity reaction to the infection, which can manifest as swelling of the skin and nerve lesions, ulceration of lesions, acute neuritis, and loss of nerve function. Type II reactions occur primarily in patients with lepromatous or borderline leprosy. Approximately 50% of patients experience this complication within the first year of treatment. These reactions are the result of increased immune complexes on sensitized tissues. Primary manifestations include fever and erythematous skin lesions, sometimes in conjunction with joint swelling, epistaxis, neuritis, orchitis, albuminuria, malaise, iritis, or depression. Histologically, there is a vasculitis with an intense polymorphonuclear infiltrate. Fever has also been associated with 1% of patients receiving the topical gel.186 

Headache has been reported with the use of oral and topical (4%) dapsone. Insomnia and psychosis have been noted in patients treated with oral dapsone.186 

Nasopharyngitis (5%), unspecified upper respiratory tract infection (3%), sinusitis (2%), influenza (1%), pharyngitis (2%), and cough (2%) have been reported with the use of topical dapsone in clinical trials.6 An infectious mononucleosis-like syndrome has been reported with the use of oral dapsone.18 

Vertigo, blurred vision, and tinnitus have been reported with the use of oral dapsone.18 

Pancreatitis has been reported with the use of oral dapsone.18 

Pulmonary eosinophilia (eosinophilic pneumonia) and hypoalbuminemia without proteinuria have been reported with the use of oral dapsone.18 

Sinus tachycardia has been reported with the use of oral dapsone.18 

Male infertility has been reported with the use of oral dapsone.18 

A drug-induced Lupus erythematosus (lupus-like symptoms) has been reported with the use of oral dapsone.18

Niacinamide

Niacin (nicotinic acid), when administered in doses equivalent to the RDA, is generally nontoxic. Niacinamide also rarely causes adverse reactions. Larger doses of nicotinic acid (i.e., >= 1 g/day PO), can cause adverse reactions more frequently. Differences in adverse reaction profiles can be explained by the fact that nicotinic acid has pharmacologic properties that are different from niacinamide.

Peripheral vasodilation is a well-known adverse reaction to niacin. It is characterized by flushing; warmth; and burning or tingling of the skin, especially in the face, neck, and chest. Hypotension can be caused by this vasodilation. Patients should avoid sudden changes in posture to prevent symptomatic or orthostatic hypotension. Dizziness and/or headache, including migraine, can occur. Cutaneous flushing is more likely to occur with immediate-release preparations as opposed to sustained-release ones and also increases in incidence with higher doses.12 Following 4-weeks of maintenance therapy of 1500 mg daily, patients receiving immediate release niacin averaged 8.6 flushing events compared to 1.9 events in the Niaspan group. In placebo-controlled studies of Niaspan, flushing occurred in 55—69% of patients compared to 19% of patients receiving placebo. Flushing was described as the reason for discontinuing therapy for 6% of patients receiving Niaspan in pivotal studies.8 These reactions usually improve after the initial 2 weeks of therapy. Some patients develop generalized pruritus as a result of peripheral flushing. In placebo controlled trials, pruritus was reported in 0—8% of patients receiving Niaspan compared to 2% of patients taking placebo. Rash (unspecified) was reported in 0—5% of patients in the Niaspan group compared to no patients in the placebo group.8 Patients should avoid ethanol or hot drinks that can precipitate flushing. Flushing can be minimized by taking niacin with meals, using low initial doses, and increasing doses gradually. If necessary, taking one aspirin (e.g., 325 mg) 30 minutes before each dose can help prevent or reduce flushing. Spontaneous reports with niacin suggest that flushing may also be accompanied by symptoms of dizziness or syncope, sinus tachycardia, palpitations, atrial fibrillation, dyspnea, diaphoresis, chills, edema, or exacerbations of angina. On rare occasions, cardiac arrhythmias or syncope has occurred. Hypersensitivity or anaphylactoid reactions have been reported rarely during niacin therapy; episodes have included one or more of the following features: anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, laryngeal edema, face edema, peripheral edema, laryngospasm, maculopapular rash, and vesiculobullous rash (vesicular rash, bullous rash).

Niacin can produce a variety of GI effects, such as nausea/vomiting, abdominal pain, diarrhea, bloating, dyspepsia, or flatulence, when taken in large doses. Eructation and peptic ulcer has been reported with post-marketing experience of Niaspan. Compared to placebo, diarrhea was reported in 7—14% (vs. 13%), nausea in 4—11% (vs. 7%), and vomiting in 0—9% (vs. 4%) of patients receiving Niaspan.8 These effects are attributed to increased GI motility and may disappear after the first 2 weeks of therapy. Administering niacin with meals can reduce these adverse reactions.

Jaundice can result from chronic liver damage caused by niacin. It has been shown that elevated hepatic enzymes occur more frequently with some sustained-release niacin than with immediate-release products.12 However, in a study of 245 patients receiving Niaspan (doses ranging from 500—3000 mg/day for a mean of 17 weeks) no patients with normal serum transaminases at baseline experienced elevations to > 3x the upper limit of normal. Sustained-release products have been associated with post-marketing reports of hepatitis and jaundice, including Niaspan. Regular liver-function tests should be performed periodically. The changes in liver function induced by niacin are typically reversible with drug discontinuation. However, rare cases of fulminant hepatic necrosis and hepatic failure have been reported. Some cases have occurred after the substitution of sustained-release dosage forms for immediate-release products at directly equivalent doses; these dosage forms are not bioequivalent. Dosage titration schedules must be observed for any patient switched to a sustained-release niacin product, even if the patient was previously taking immediate-release therapy.8

Niacin interferes with glucose metabolism and can result in hyperglycemia.8 This effect is dose-related. During clinical anti-lipemic trials, increases in fasting blood glucose above normal occurred frequently (e.g., 50%) during niacin therapy. Some patients have required drug discontinuation due to hyperglycemia or exacerbation of diabetes. In the AIM-HIGH trial of patients with stable cardiovascular disease, the incidence of hyperglycemia (6.4% vs. 4.5%) and diabetes mellitus (3.6% vs. 2.2%) was higher in niacin plus simvastatin-treated patients compared to the simvastatin plus placebo group. Close blood glucose monitoring is advised for diabetic or potentially diabetic patients during treatment with niacin; adjustment of diet and/or antidiabetic therapy may be necessary.8

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan.8 Therefore, patients predisposed to gout should be treated with caution.

Niacin, especially in high doses (>= 2 g/day PO), can cause hypophosphatemia (mean decrease 13%). Serum phosphorus concentrations should be monitored periodically in patients at risk for hypophosphatemia.8

Nicotinic acid (niacin) occasionally causes slight decreases in platelet counts (mean reduction 11%) or increased prothrombin times (mean increase 4%), especially in high doses (>= 2 g/day PO). Rarely do these reactions result in coagulopathy or thrombocytopenia, but clinically significant effects might occur in patients with other risk factors or who are predisposed to these conditions.8

Asthenia, nervousness, insomnia, and paresthesias have been reported during niacin therapy. Rare cases of rhabdomyolysis have been reported in patients taking niacin (nicotinic acid) in doses >=1 g/day PO and HMG-CoA reductase inhibitors (i.e., 'statins') concurrently. In the AIM-HIGH trial, 4 cases (0.2%) of rhabdomyolysis were reported in the niacin; simvastatin group compared with 1 case in the simvastatin plus placebo group. Rhabdomyolysis may present as myopathy (myalgia, myasthenia, muscle cramps, muscle weakness, muscle tenderness, fatigue), elevations in creatinine phosphokinase (CPK), or renal dysfunction (renal tubular obstruction). Toxicity to the skeletal muscle occurs infrequently but can be a serious adverse reaction. This toxicity appears to be reversible after discontinuation of therapy.8

Niacin also has been associated with a variety of ophthalmic adverse effects including blurred vision and macular edema.8

Although uncommon, niacin may be associated with skin hyperpigmentation or acanthosis nigricans. Dry skin (xerosis) also has been reported during post-marketing surveillance of Niaspan.842

During clinical trials, increased cough was reported in <2—8% (vs. 6%) of patients receiving Niaspan compared to placebo.8

Spironolactone

Spironolactone causes hyperkalemia and can cause life-threatening cardiac arrhythmias. Signs and symptoms of hyperkalemia include muscle weakness, paresthesias, fatigue, flaccid paralysis of the extremities, sinus bradycardia, shock, and electrocardiogram (ECG) changes. Patients who receive potassium supplements or patients with impaired renal function who are also receiving spironolactone therapy are particularly at risk for developing hyperkalemia. Monitor serum potassium and renal function 3 days and 1 week after initiation of therapy or dose increase, monthly for 3 months, quarterly for a year, and every 6 months thereafter. If hyperkalemia occurs, decrease the dose or discontinue spironolactone. In adults, spironolactone should be discontinued if serum creatinine is greater than 4 mg/dL or serum potassium is greater than 5 mEq/L; pediatric-specific recommendations are not available. In cases of severe hyperkalemia, urgent measures such as the administration of intravenous calcium, sodium bicarbonate, glucose, and a rapid-acting insulin may be necessary; persistent hyperkalemia may require dialysis.143217 

Spironolactone can cause hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic metabolic alkalosis, and hyperglycemia. Asymptomatic hyperuricemia can also occur; rarely, gout is precipitated. Monitor serum electrolytes, uric acid, and blood glucose periodically. Electrolyte abnormalities other than hyperkalemia may be more likely when spironolactone is used in combination with other diuretic therapy. Dilutional hyponatremia, which can present as dry mouth, thirst, lethargy, and drowsiness, may also occur in edematous patients during hot weather; appropriate therapy includes water restriction rather than sodium administration except in rare cases of life-threatening hyponatremia.1417 

A reversible hyperchloremic metabolic acidosis can occur in patients with decompensated hepatic cirrhosis who are receiving spironolactone. This effect is usually associated with hyperkalemia and can occur regardless of renal function.14 

Spironolactone is similar in structure to steroid compounds and can produce some of the same adverse effects. In males, spironolactone may cause gynecomastia; this effect is usually dose-related with an onset that varies widely from 1 to 2 months to over a year. Gynecomastia is usually reversible. Impotence (erectile dysfunction) has been reported in with spironolactone therapy. Females taking spironolactone may experience menstrual irregularity, including postmenopausal bleeding, breast tenderness or mastalgia, hirsutism, deepened voice, and amenorrhea. Such endocrine effects may produce a medication-induced infertility. These effects usually are reversible after discontinuance of therapy. Libido decrease has also been reported with spironolactone.1417 

While a cause-and-effect relationship has not been established for development of a new primary malignancy, breast cancer has been reported in adults receiving spironolactone. In addition, the tablet product label carries a boxed warning stating that spironolactone is a tumorigen in rats. However, human data are not available to describe the potential for tumorigenicity secondary to use.14 

Adverse GI effects reported during spironolactone therapy include nausea, vomiting, cramping, diarrhea, gastritis, abdominal pain, gastric bleeding, and ulceration.14 

Adverse nervous system effects that have been reported in patients receiving spironolactone therapy include headache, dizziness, drowsiness, lethargy, ataxia, and mental confusion. Muscular weakness may be a sign of drug-induced hyperkalemia.14 

Excessive diuresis may cause symptomatic dehydration, hypovolemia, hypotension, and worsening renal function including renal failure (unspecified). Transient increases in BUN may occur during spironolactone therapy, especially in patients with renal impairment. Monitor volume status and renal function periodically.1417 In addition, due to the diuretic action of spironolactone, polyuria can be troublesome for some patients during therapy. 

Hypersensitivity reactions such as fever, urticaria, erythema, maculopapular rash, erythematous cutaneous eruptions, vasculitis, and anaphylactoid reactions may occur during therapy with spironolactone. Stevens-Johnson syndrome, toxic epidermal necrolysis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), alopecia, chloasma, and pruritus have also been reported with spironolactone therapy.1417 

Leukopenia, including agranulocytosis, and thrombocytopenia have been reported during spironolactone therapy.14 

A few cases of mixed cholestatic/hepatocellular toxicity, including one report of hepatic failure resulting in death, have been reported with spironolactone administration.14 

Muscle cramps (leg cramps) have been reported in patients taking spironolactone.14 

Storage

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

  • 1. Mold JW, Thompson DM. Management of brown recluse spider bites in primary care. J Am Board Fam Pract 2004;17:347-52.
  • 2. Hogan CJ, Barbaro KC, Winkel K. Loxoscelism: old obstacles, new directions. Ann Emerg Med 2004;44(6):608-24.
  • 3. Swanson DL, Vetter RS. Bites of brown recluse spiders and suspected necrotic arachnidism. N Engl J Med 2005;352:700-7.
  • 4. Masur H. Prevention and treatment of pneumocystis pneumonia. N Engl J Med 1992;327:1853-60.
  • 5. Girard PM, Landman R, Gaudebout C, et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med 1993;328:1514-20.
  • 6. a. b. c. d. e. f. g. h. i. j. k. l. m. Aczone (dapsone gel 5%) package insert. Irvine CA: Allergan Inc.; 2018 May
  • 7. a. b. c. d. e. Aczone (dapsone gel 7.5%) package insert. Exton, PA: Almirall, LLC; 2019 Sept.
  • 8. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. Niaspan (niacin extended-release) tablet package insert. North Chicago, IL: Abbott Laboratories; 2015 Apr.
  • 9. a. b. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.
  • 10. a. b. Taylor AJ, Villines TC, Stanck EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009. Epub ahead of print, doi:10.1056/NEJMoa907569.
  • 11. a. b. Lee JMS, Robson MD, Yu LM, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: A randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54:1787—94.
  • 12. a. b. c. d. McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271:672-7.
  • 13. Pitt B, Zannad F, Remme WJ. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-717.
  • 14. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. Aldactone (spironolactone) package insert. New York, NY: G.D. Searle LLC Division of Pfizer Inc.; 2020 Jun.
  • 15. van der Vorst MMJ, Kist JE, van der Heijden AJ, et al. Diuretics in pediatrics: current knowledge and future prospects. Paediatr Drugs 2006: 8(4); 245-64.
  • 16. Karim A. Spironolactone: disposition, metabolism, pharmacodynamics, and bioavailability. Drug Metab Rev 1978;8:151-88.
  • 17. a. b. c. d. e. f. g. h. i. j. k. l. m. Carospir (spironolactone) oral suspension package insert. Farmville, NC: CMP Pharma, Inc.;2021 Jun.
  • 18. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. Dapsone tablet package insert. Pine Brook, NJ: Alvogen, Inc.; 2015 Jun.
  • 19. a. b. c. d. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.
  • 20. Panel on Opportunistic Infections in HIV-Exposed and HIV-infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-exposed and HIV-infected children: Department of Health and Human Services. Accessed Dec 18
  • 21. Verdel BM, Souverein PC, Egberts AC, et al. Difference in risks of allergic reaction to sulfonamide drugs based on chemical structure. Ann Pharmacother 2006;40:1040-6.
  • 22. a. b. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. New Engl J Med 2003;349:1628-35.
  • 23. Hemstreet BA, Page RL. Sulfonamide allergies and outcomes related to use of potentially cross-reactive drugs in hospitalized patients. Pharmacotherapy 2006;26:551-7.
  • 24. Johnson KK, Green DL, Rife JP, et al. Sulfonamide cross-reactivity: fact or fiction? Ann Pharmacother 2005;39:290-301.
  • 25. Colletti RB, Neufeld EJ, Roff NK, et al. Niacin treatment of hypercholesterolemia in children. Pediatrics 1993;92:78-82.
  • 26. Expert Panel: National Cholesterol Education Program. Report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992;89(suppl 2):525-84.
  • 27. a. b. Niacinamide. In: Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. Briggs GG, Freeman RK, Yaffe SJ, (eds.) 7th ed., Philadelphia PA: Lippincott Williams and Wilkins; 2005:1140-1
  • 28. a. b. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
  • 29. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:364-389.
  • 30. Esposito D, Pasquali D, Johannsson G. Primary adrenal insufficiency: managing mineralocorticoid replacement therapy. J Clin Endocrinol Metab. 2018;103:376-387.
  • 31. Inder WJ, Meyer C, Hunt PJ. Management of hypertension and heart failure in patients with Addison’s disease. Clin Endocrinol. 2015;82:789-792.
  • 32. a. b. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused Update Incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. Circulation 2009;119:e391-e479.
  • 33. Luthy IA, Begin DJ, Labrie F. Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture. J Steroid Biochem. 1988;31(5):845-852.
  • 34. Bedussi F, Galli D, Fragni M, et al. Amiloride is effective in the management of abiraterone-induced mineralocorticoid excess syndrome without interfering with its antineoplastic activity. Pharmacology. 2017;100:261-268.
  • 35. Richards J, Lim AC, Hay CW, et al. Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Research. 2012;72(9):2176-2182.
  • 36. Barthelemy P, Erdmann E, Duclos B, et al. Spironolactone: a selective androgen receptor modulator in castration-resistant prostate cancer. J Clin Oncol. 2014;32(4 suppl):abstract 212.
  • 37. Sundar S and Dickinson PD. Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate. BMJ Case Reports. 2012;doi:10.1136/bcr.11.2011.5238.
  • 38. Flynn T, Guancial EA, Kilari M, and Kilari D. Case report: spironolactone withdrawal associated with a dramatic response in a patient with metastatic castrate-resistant prostate cancer. Clinical Genitourinary Cancer. 2017;15(1):e95-e97.
  • 39. The American Geriatrics Society 2019 Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2019;00:1-21.
  • 40. Carospir (spironolactone) oral suspension package insert. Farmville, NC: CMP Pharma, Inc.;2021 Jun.
  • 41. Piette WW, Taylor S, Pariser D, et al. Hematologic safety of dapsone gel, 5%, for topical treatment of acne vulgaris. Arch Dermatol. 2008 ;144:1564-70.
  • 42. Niacor (Niacin tablets) package insert. Minneapolis, MN: Upsher-Smith Laboratories, Inc.; 2000 Feb.

Related Medications