Acne DNS Gel

A white container of Empower Pharmacy's Acne DNS Gel.

Overview of Acne DNS Gel

Dosage Strength of Acne DNS Gel

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.2 3 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 2016.6 7

Niacinamide

Niacin is a B-complex vitamin (nicotinic acid or 3-pyridine carboxylic acid). Animal proteins, beans, green vegetables, liver, mushrooms, peanuts, whole wheat, and unpolished rice are all good sources of niacin in the diet. Niacin is found in cereal grains as well, although it is primarily attached to plant proteins and so poorly absorbed after consumption. Niacin is one of the compounds used to enrich refined flour, and we get the majority of our pre-formed niacin from enriched grains. The body's niacin demand is supplied, however, by niacin biosynthesis from tryptophan, an amino acid. Milk and eggs, for example, do not contain niacin, but they do contain substantial levels of tryptophan, which is converted to niacin. After protein synthesis, 60 mg of extra tryptophan is converted to around 1 mg of niacin. Niacin is synthesized from tryptophan in proteins, which provides about half of the vitamin's requirement in humans. Due to the interdependence of coenzymes in the niacin manufacturing pathway, iron insufficiency or poor pyridoxine or riboflavin status will reduce the conversion of tryptophan to niacin and may contribute to deficiency. Pellagra is a late and significant indication of niacin insufficiency that affects the gastrointestinal tract, skin, and central nervous system, causing diarrhea, dermatitis, and dementia, respectively. Pellagra can be caused by a niacin- and protein-deficient diet, isoniazid medication, or conditions that cause inadequate tryptophan usage. Pellagra was the only vitamin deficient disease to ever reach epidemic proportions in the United States; because to the enrichment of refined flours, pellagra is now uncommon in industrialized countries.

Niacin and niacinamide have several aliases. Because the oxidation of nicotine might yield synthetic niacin, the term "nicotinic acid" was coined. For the amide form of nicotinic acid, scientists devised the words 'nicotinamide' and 'niacinamide.' Since the 1940s, the name 'niacin' has been used generally to label goods in order to avoid confusion with the nicotine alkaloid found in tobacco. As a result, the term 'niacin' has been used to refer to both chemical forms, which are weight-for-weight equivalents of vitamins. Nutritional supplements contain both nicotinic acid and nicotinamide, which are produced. Outside of their function as vitamins, nicotinic acid and nicotinamide have different pharmacologic qualities, therefore it's necessary to distinguish between the two in pharmaceuticals.8 These findings are in line with the findings of the larger HPS2-THRIVE study, which found that adding extended-release niacin to successful statin-based therapy did not result in a higher reduction in cardiovascular events. There was also a higher chance of major adverse events, such as disruptions in diabetes control and diabetes diagnoses, as well as serious gastrointestinal, musculoskeletal, dermatological, infectious, and bleeding complications. In the niacin group, there was also a statistically insignificant 9 percent proportionate increase in death from any cause.9 The ARBITER 6-HALTS trial found that combining statins with extended-release niacin 2000 mg/day results in considerable atherosclerotic regression as measured by carotid intima-media thickness, and is superior to ezetimibe and a statin. 10 The addition of extended-release niacin 2000 mg/day to statin medication resulted in a significant reduction in carotid wall area when compared to placebo in an MRI investigation. 11 However, the NIA Plaque study, which was presented at the American Heart Association (AHA) 2009 Scientific Sessions, found no significant reduction in atherosclerosis progression when niacin was added to statin therapy versus statin monotherapy. Additionally, nicotinic acid has been utilized as a tinnitus treatment, however there is limited evidence of efficacy. When compared to immediate-release versions, some sustained-release nicotinic acid formulations had a reduced incidence of flushing but a higher incidence of hepatotoxicity. 12 Without a prescription, some dosage forms are available. Niacin was approved by the FDA 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 have 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 is a B-complex vitamin (nicotinic acid or 3-pyridine carboxylic acid). Animal proteins, beans, green vegetables, liver, mushrooms, peanuts, whole wheat, and unpolished rice are all good sources of niacin in the diet. Niacin is found in cereal grains as well, although it is primarily attached to plant proteins and so poorly absorbed after consumption. Niacin is one of the compounds used to enrich refined flour, and we get the majority of our pre-formed niacin from enriched grains. The body's niacin demand is supplied, however, by niacin biosynthesis from tryptophan, an amino acid. Milk and eggs, for example, do not contain niacin, but they do contain substantial levels of tryptophan, which is converted to niacin. After protein synthesis, 60 mg of extra tryptophan is converted to around 1 mg of niacin. Niacin is synthesized from tryptophan in proteins, which provides about half of the vitamin's requirement in humans. Due to the interdependence of coenzymes in the niacin manufacturing pathway, iron insufficiency or poor pyridoxine or riboflavin status will reduce the conversion of tryptophan to niacin and may contribute to deficiency. Pellagra is a late and significant indication of niacin insufficiency that affects the gastrointestinal tract, skin, and central nervous system, causing diarrhea, dermatitis, and dementia, respectively. Pellagra can be caused by a niacin- and protein-deficient diet, isoniazid medication, or conditions that cause inadequate tryptophan usage. Pellagra was the first and only vitamin deficient disease to reach epidemic proportions. Pellagra was the only vitamin deficient disease to ever reach epidemic proportions in the United States; because to the enrichment of refined flours, pellagra is now uncommon in industrialized countries.

Niacin and niacinamide have several aliases. Because the oxidation of nicotine might yield synthetic niacin, the term "nicotinic acid" was coined. For the amide form of nicotinic acid, scientists devised the words 'nicotinamide' and 'niacinamide.' Since the 1940s, the name 'niacin' has been used to label foods in order to avoid confusion with the nicotine alkaloid found in tobacco. As a result, the term 'niacin' has been applied to both chemical forms, which are weight-for-weight identical to vitamins. Nutritional supplements contain both nicotinic acid and nicotinamide, which are produced. Outside of their function as vitamins, nicotinic acid and nicotinamide have different pharmacologic qualities, so it's necessary to distinguish between the two in pharmaceutical goods. Nicotinic acid is utilized as an antilipemic in clinical medicine, although nicotinamide (niacinamide) is ineffective for this purpose. Nicotinic acid was the first hypolipidemic drug to be proven to reduce the risk of secondary myocardial infarction (MI) and total mortality in MI patients. However, no additional advantage of co-administration of extended-release niacin with lovastatin or simvastatin on cardiovascular morbidity and mortality has been reported over and above that seen with extended-release niacin, simvastatin, or lovastatin monotherapy. Furthermore, the AIM-HIGH study found that taking simvastatin and extended-release niacin (1500—2000 mg/day PO) together does not result in a lower risk of cardiovascular events than using simvastatin alone.8 These findings are in line with the findings of the larger HPS2-THRIVE study, which found that adding extended-release niacin to successful statin-based therapy did not result in a higher reduction in cardiovascular events. There was also a higher chance of major adverse events, such as disruptions in diabetes control and diabetes diagnoses, as well as serious gastrointestinal, musculoskeletal, dermatological, infectious, and bleeding complications. In the niacin group, there was also a statistically insignificant 9 percent proportionate increase in death from any cause.9 The ARBITER 6-HALTS trial found that combining statins with extended-release niacin 2000 mg/day results in considerable atherosclerotic regression as measured by carotid intima-media thickness, and is superior to ezetimibe and a statin.14 The addition of extended-release niacin 2000 mg/day to statin medication resulted in a significant reduction in carotid wall area when compared to placebo in an MRI investigation.11 However, the NIA Plaque study, which was presented at the American Heart Association (AHA) 2009 Scientific Sessions, found no significant reduction in atherosclerosis progression when niacin was added to statin therapy versus statin monotherapy. Additionally, nicotinic acid has been utilized as a tinnitus treatment, however there is limited evidence of efficacy. When compared to immediate-release versions, some sustained-release nicotinic acid formulations had a reduced incidence of flushing but a higher incidence of hepatotoxicity.12 Without a prescription, some dosage forms are available. Niacin was approved by the FDA 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.

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 the 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.15 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).6 7

Dapsone is distributed into breast milk in large quantities after oral dosing and can cause hemolytic anemia in nursing infants with G6PD deficiency.15 However, the American Academy of Pediatrics (AAP) states that dapsone is usually compatible with breastfeeding.16 Absorption after topical administration is minimal relative to oral dapsone administration.6 Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

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.17 6 7

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 is 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.18 19 20 In general, patients with a history of hypersensitivity to any drug are predisposed for subsequent hypersensitivity reactions to other drugs.19 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.21

Niacinamide

Patients with a known hypersensitivity to niacin or any other component of the medicine should not be administered it.

While women's steady-state plasma niacin concentrations are normally greater than men's, niacin absorption, metabolism, and excretion appear to be similar in both genders. When compared to men, women exhibit a stronger reaction to the lipid-lowering effects of nicotinic acid (niacin).

There were no differences in overall safety and efficacy between elderly and younger niacin recipients. Other clinical experience hasn't found any differences in responses between aged and younger patients, although it's impossible to rule out the possibility of greater sensitivity in some older people.

In patients with substantial or unexplained hepatic illness, niacin is contraindicated. Patients who drink a lot of ethanol (alcoholism), have hepatic disease risk factors, or have a history of gallbladder disease, jaundice, or hepatic dysfunction may be given niacin under under therapeutic supervision. Increases in liver function tests (LFTs) seem to be dose-dependent. When compared to immediate-release dose forms, several sustained-release nicotinic acid (niacin) formulations have a higher risk of hepatotoxicity. Extended-release nicotinic acid preparations (e.g., Niaspan, Slo-Niacin) should not be used in place of immediate-release (crystalline) nicotinic acid dosages (e.g., Niacor and others). Regardless of previous therapy with other niacin formulations, follow the manufacturer's suggested initial dosage titration schedules for extended-release products. LFTs should be checked in all patients at 6-month intervals or whenever clinically recommended during treatment. Niacin should be stopped if transaminase levels (i.e., ALT or AST) rise to 3 times the upper limit of normal or if clinical indications of hepatic dysfunction are evident.

Nicotinic acid (niacin) can increase histamine production, which can increase stomach acid secretion. Niacin is not recommended for people who have active peptic ulcer disease (PUD) since it can worsen symptoms. In patients with a history of peptic ulcer disease or those on maintenance medication to avoid PUD recurrence, use niacin with caution.

Nicotinic acid (niacin) should be used with caution in patients with uncorrected hypotension (or a predisposition to orthostatic hypotension), acute myocardial infarction, or unstable angina, especially when vasodilator medications like nitrates, calcium channel blockers, or adrenergic blocking agents are coadministered (see Drug Interactions). Because the vasodilatory response to niacin may be more pronounced at the start of therapy, activities that require mental attention (such as driving or operating machinery) should be avoided until the response to niacin has been determined.

Hyperuricemia can be caused by niacin, especially in high dosages. Patients with gout should be given niacin with caution (or predisposed to gout). These people should be told not to buy niacin over-the-counter without first consulting a doctor.

Hypophosphatemia can be caused by niacin, especially at high doses. Although phosphorus deficiency is usually temporary, doctors should check serum phosphorus in people at risk for electrolyte imbalance on a regular basis.

Rare incidences of rhabdomyolysis have been documented in patients who are taking nicotinic acid (niacin) and statin-type drugs at the same time (see Drug Interactions). Muscle soreness, tenderness, or weakness in patients receiving combination therapy should be closely watched, especially in the early months of treatment or during periods of upward dose titration of either drug. While CPK and potassium levels should be checked on a regular basis, there is no evidence that these tests will prevent severe myopathy. The offending therapies should be stopped if rhabdomyolysis occurs.

Hyperglycemia can be caused by niacin, especially in high dosages. Patients with diabetes mellitus should be given niacin with caution. These people should be told not to buy niacin over-the-counter without first consulting a doctor. In urine glucose tests containing cupric sulfate solution (e.g., Benedict's reagent, Clinitest), niacin has been known to cause false-positive findings.

For the treatment of dietary niacin deficit in children, niacin therapy has been used safely. However, the safety and efficacy of nicotinic acid for the treatment of dyslipidemias in neonates, infants, and children under the age of 16 have not been established. In certain cases, nicotinic acid has been utilized to treat dyslipidemia in pediatric patients. In comparison to adult populations, children may be at a higher risk of niacin-induced adverse effects. According to at least one pediatric study, niacin medication should be reserved for the treatment of severe hypercholesterolemia under the supervision of a lipid specialist.22 Drug therapy for children with dyslipidemias is generally not recommended until they are 10 years old or older, according to the National Cholesterol Education Program (NCEP).23

Because niacin is an essential nutrient, it should be safe to take during pregnancy in quantities that satisfy the recommended daily allowance (RDA). Under these circumstances, niacin is classified as pregnancy category A. Niacin, on the other hand, is classified as pregnancy category C when administered in levels more than the RDA for dyslipidemia or parenterally for the treatment of pellagra. During pregnancy, most manufacturers advise against taking niacin in doses higher than the RDA. Because toxicological studies have not been conducted, the possible benefits of high-dose niacin therapy should be balanced against the hazards.8

Although no studies have been undertaken in nursing women, excretion into human milk is expected, according to a niacin producer (Niaspan). Due to serious adverse effects that may develop in nursing infants from lipid-altering dosages of nicotinic acid, the company suggests discontinuing breastfeeding or taking the medicine.8 Niacin is excreted in breast milk in the form of niacinamide in proportion to maternal consumption. Niacin supplementation is only required in nursing women who do not get enough niacin from their diet. The National Academy of Science's Recommended Daily Allowance (RDA) for niacin during lactation is 20 mg.24 There are no studies on the safety of using nicotinic acid in doses higher than the RDA while breastfeeding. Consider the advantages of breastfeeding, the risk of drug exposure to a newborn, and the possibility of an untreated or inadequately treated ailment. If a breastfeeding newborn has an adverse reaction to a medicine that was taken by the mother, healthcare providers are encouraged to report the reaction to the FDA.

Because niacin metabolites are eliminated through the kidneys, it should be used with caution in people with renal disease (renal failure or severe renal impairment). When providing niacin to satisfy the recommended nutritional daily requirement, it appears that no particular precautions are required (RDA). When delivering greater doses, use caution.

In patients with thrombocytopenia, coagulopathy, or who are on anticoagulant therapy, nicotinic acid (niacin) might cause small declines in platelet counts or increased prothrombin times. It should be taken with caution in these patients. Blood counts should be checked in patients who are planning to have surgery. In patients with arterial hemorrhage, nicotinic acid (niacin) is contraindicated.

The federal Omnibus Budget Reconciliation Act (OBRA) governs medicine use in long-term care facility residents (e.g., elderly individuals) (LTCFs). Because niacin interferes with glucose regulation, can aggravate diabetes, and can exacerbate active gallbladder disease and gout, OBRA recommends that glucose and liver function tests be performed on a regular basis. Niacin causes flushing, which is a typical adverse effect.25

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.26 27 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.28 29 30 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.26 31 27

Correct significant acid/base imbalance before spironolactone is initiated, as mild acidosis or hypochloremic metabolic alkalosis may occur with its use.26 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.27 Reversible hyperchloremic metabolic acidosis, usually in association with hyperkalemia, has been reported in patients with decompensated hepatic cirrhosis, even with normal renal function.26

Spironolactone can cause antiandrogenic and endocrine effects; use with caution in patients with menstrual irregularity or breast enlargement.26

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.26

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.32 33 34 35 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.36 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.37

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.26

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.26 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.38 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.25

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.27

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.27 Previous American Academy of Pediatrics recommendations classified spironolactone as usually compatible with breast-feeding.16

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.26

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.15 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).6 7

Niacinamide

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.27

Breastfeeding

Dapsone

Dapsone is distributed into breast milk in large quantities after oral dosing and can cause hemolytic anemia in nursing infants with G6PD deficiency.15 However, the American Academy of Pediatrics (AAP) states that dapsone is usually compatible with breastfeeding.16 Absorption after topical administration is minimal relative to oral dapsone administration.6 Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Niacinamide

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.39 Previous American Academy of Pediatrics recommendations classified spironolactone as usually compatible with breast-feeding.16

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 mild hemolysis in G6PD deficient patients have been reported.15 6 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.40 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%).15 6 7

Adverse gastrointestinal effects that can occur during therapy with oral dapsone include nausea, vomiting, and abdominal pain.15

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.15 6

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.15

Adverse renal effects observed during therapy with oral dapsone include albuminuria, nephrotic syndrome, and renal papillary necrosis.15

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.15 6

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.15 6

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.15

Vertigo, blurred vision, and tinnitus have been reported with the use of oral dapsone.15

Pancreatitis has been reported with the use of oral dapsone.15

Pulmonary eosinophilia (eosinophilic pneumonia) and hypoalbuminemia without proteinuria have been reported with the use of oral dapsone.15

Sinus tachycardia has been reported with the use of oral dapsone.15

Male infertility has been reported with the use of oral dapsone.15

A drug-induced Lupus erythematosus (lupus-like symptoms) has been reported with the use of oral dapsone.15

Niacinamide

When taken in levels corresponding to the RDA, niacin (nicotinic acid) is typically safe. Niacinamide also has a low risk of side effects. Larger doses of nicotinic acid (>= 1 g/day PO) are more likely to cause side effects. Because nicotinic acid has distinct pharmacologic characteristics than niacinamide, differences in adverse reaction profiles can be explained.

Niacin causes peripheral vasodilation, which is a well-known side effect. It is characterized by flushing; warmth; and burning or tingling of the skin, especially in the face, neck, and chest. This vasodilation can result in hypotension. To avoid symptomatic or orthostatic hypotension, patients should avoid abrupt changes in position. It is possible to experience dizziness and/or headaches, including migraines. Cutaneous flushing is more common with immediate-release preparations than with sustained-release treatments, and it also rises with greater doses. 12 Patients receiving immediate release niacin experienced 8.6 flushing incidents on average after four weeks of 1500 mg daily maintenance medication, compared to 1.9 occurrences in the Niaspan group. Niaspan caused flushing in 55–69% of participants in placebo-controlled studies, compared to 19% of individuals who received placebo. In crucial studies, flushing was cited as the cause for 6 percent of Niaspan patients terminating treatment. 8 After the first two weeks of therapy, these reactions normally improve. As a result of peripheral flushing, some patients suffer generalized pruritus. Pruritus was recorded in 0—8% of patients receiving Niaspan in placebo-controlled trials, compared to 2% of those taking placebo. Rash (unspecified) was reported in 0—5% of Niaspan patients compared to none in the placebo group. 8 Patients should avoid ethanol and hot beverages, which can cause flushing. Flushing can be reduced by taking niacin with meals, starting with low dosages and progressively increasing them. If necessary, 30 minutes before each dose, take one aspirin (e.g., 325 mg). Flushing may be followed with vertigo or syncope, sinus tachycardia, palpitations, atrial fibrillation, dyspnea, diaphoresis, chills, edema, or angina exacerbations, according to spontaneous accounts with niacin. Cardiac arrhythmias or syncope have happened on rare occasions. Rarely, anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, laryngeal edema, face edema, peripheral edema, laryngospasm, maculopapular rash, and vesiculobullous rash have been observed after niacin therapy; episodes have included one or more of the following features: anaphylaxis (vesicular rash, bullous rash).

When used in large dosages, niacin can cause nausea/vomiting, gastrointestinal pain, diarrhea, bloating, dyspepsia, or flatulence, among other things. With Niaspan's post-marketing experience, eructation and peptic ulcer have been documented. In comparison to placebo, patients receiving Niaspan reported diarrhea in 7—14 percent (vs. 13 percent), nausea in 4—11 percent (vs. 7 percent), and vomiting in 0—9 percent (vs. 4 percent). 8 Increased GI motility is to blame for these side effects, which may fade during the first two weeks of treatment. These side effects can be reduced by taking niacin with meals.

Chronic liver damage caused by niacin can produce jaundice. Elevated liver enzymes have been found to occur more frequently with some sustained-release niacin formulations than with immediate-release solutions.12 However, no individuals with normal serum transaminases at baseline exhibited rises to > 3x the upper limit of normal in a study of 245 patients using Niaspan (doses ranging from 500—3000 mg/day for a mean of 17 weeks). Niaspan and other sustained-release medications have been linked to post-marketing allegations of hepatitis and jaundice. Liver function tests should be done on a regular basis. Niacin-induced alterations in liver function are usually reversible when the drug is stopped. However, there have been a few reports of fulminant liver necrosis and hepatic failure. Some occurrences have occurred after direct comparable doses of sustained-release dosage forms were substituted for immediate-release dosage forms; these dosage forms are not bioequivalent. Even if the patient was previously receiving immediate-release niacin, dosage titration protocols must be followed when switching to a sustained-release niacin product.8

Niacin can cause hyperglycemia by interfering with glucose metabolism.8 This is a dose-dependent effect. Increases in fasting blood glucose over normal occurred often (e.g., 50%) with niacin therapy in clinical anti-lipemic trials. Because of hyperglycemia or diabetic aggravation, some patients have had to stop taking their medications. Hyperglycemia (6.4 percent vs. 4.5 percent) and diabetes mellitus (3.6 percent vs. 2.2 percent) were more common in the niacin plus simvastatin group than in the simvastatin plus placebo group in the AIM-HIGH study of patients with stable cardiovascular disease. During treatment with niacin, diabetic or potentially diabetic patients should keep a close eye on their blood glucose levels; diet and/or anti-diabetic medication may need to be adjusted.8

Hyperuricemia can be caused by niacin, especially in high dosages. In Niaspan's post-marketing surveillance, gout has been recorded.8Patients who are prone to gout should be treated with prudence.

Hypophosphatemia can be caused by niacin, especially at high doses (>= 2 g/day PO) (mean decrease 13 percent ). Patients at risk of hypophosphatemia should have their serum phosphorus levels checked on a regular basis.8

Particularly in high doses (>= 2 g/day PO), nicotinic acid (niacin) can induce minor declines in platelet counts (mean reduction 11%) or increased prothrombin times (mean increase 4%). These responses seldom cause coagulopathy or thrombocytopenia, but they can have clinically important consequences in patients who have other risk factors or are susceptible to these disorders.8

During niacin therapy, asthenia, anxiety, sleeplessness, and paresthesias have been documented. Patients using niacin (nicotinic acid) in doses >=1 g/day PO and HMG-CoA reductase inhibitors (i.e.,'statins') concurrently have seen rare occurrences of rhabdomyolysis. Four occurrences of rhabdomyolysis were recorded in the AIM-HIGH study in the niacin; simvastatin group (0.2 percent), compared to one case in the simvastatin plus placebo group. Myopathy (myalgia, myasthenia, muscular cramps, muscle weakness, muscle discomfort, weariness), increases in creatinine phosphokinase (CPK), and renal failure are all symptoms of rhabdomyolysis (renal tubular obstruction). Although skeletal muscle toxicity is uncommon, it can be a significant side effect. This toxicity appears to be reversible once treatment is stopped.8

Niacin has also been linked to a number of ocular side effects, such as blurred vision and retinal edema.8

Niacin has been linked to skin darkening and acanthosis nigricans, albeit this is a rare occurrence. During Niaspan's post-marketing surveillance, dry skin (xerosis) was also reported.8 41

Increased cough was recorded in 2—8% of Niaspan-treated individuals (vs. 6% of placebo-treated patients) throughout clinical trials.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.26 31 27

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.26 27

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.26

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.26 27

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.26

Adverse GI effects reported during spironolactone therapy include nausea, vomiting, cramping, diarrhea, gastritis, abdominal pain, gastric bleeding, and ulceration.26

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.26

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.26 27 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.26 27

Leukopenia, including agranulocytosis, and thrombocytopenia have been reported during spironolactone therapy.26

A few cases of mixed cholestatic/hepatocellular toxicity, including one report of hepatic failure resulting in death, have been reported with spironolactone administration.26

Muscle cramps (leg cramps) have been reported in patients taking spironolactone.26

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.

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