Acne Differ Anhydrous Gel

Overview of Acne Differ Anhydrous Gel

Dosage Strength of Acne Differ Anhydrous Gel

Adapalene / Benzoyl Peroxide / Niacinamide 0.3/2.5/4% 30 mL Pump

General Information

Adapalene

Adapalene is a topical retinoid-like drug for the treatment of mild to moderate acne vulgaris. Unlike tretinoin, adapalene is a naphtholic acid derivative and causes less skin irritation. Adapalene is more effective than tretinoin gel (0.025%) in the treatment of acne vulgaris.1 Adapalene is commercially available as a cream, lotion, or gel and is reported to be cosmetically appealing to most patients, according to clinical trial data. The drug was approved by the FDA June 3, 1996.

Benzoyl Peroxide

Benzoyl peroxide is a topical acne product. Benzoyl peroxide exhibits antibacterial activity. It also has drying actions, sebostatic effects, and causes mild skin desquamation. Benzoyl peroxide improves both inflammatory and non-inflammatory acne lesions. Benzoyl peroxide is effective as monotherapy in mild cases of acne and is used as an adjuvant in moderate to severe cases of acne. A study 2 in the United Kingdom showed that an OTC 5% benzoyl peroxide topical formulation (Panoxyl Aquagel) was as effective as topical benzoyl peroxide/erythromycin combination and the oral tetracyclines minocycline and oxytetracycline for treatment of mild to moderate acne. Topical benzoyl peroxide and benzoyl peroxide/erythromycin combinations were not associated with propionibacterial antibiotic resistance which occurs with the tetracyclines. Benzoyl peroxide has also been used in the off-label treatment of decubitus ulcers. Benzoyl peroxide is available as prescription and non-prescription products and is available in combination with erythromycin, hydrocortisone, and sulfur (see separate monographs for each of the combination products). The FDA has revised labeling requirements for all non-prescription (over-the-counter) topical acne products, including benzoyl peroxide, to ensure consistency with the standardized 'Drug Facts' formatting. Benzoyl peroxide is a generally recognized as safe and effective (GRASE) active ingredient in over-the-counter topical acne drug products.

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.3 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.4 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.5 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.6 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.7 Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

 

Mechanism of Action

Adapalene

Adapalene binds to specific retinoic acid nuclear receptors but does not bind to the cytosolic receptor protein. Adapalene reportedly penetrates deeply into the hair follicle. As a result of its actions, adapalene modulates cell differentiation and keratinization. Adapalene also possesses potent antiinflammatory and comedolytic properties.

Benzoyl Peroxide

Benzoyl peroxide exhibits antimicrobial effects against Propionibacterium acnes, which is the predominant organism in sebaceous follicles and comedones. The antibacterial effects of benzoyl peroxide are due to the release of free-radical oxygen species, which are capable of oxidizing bacterial proteins. Resolution of acne usually occurs within 4—6 weeks of initiation of treatment. Resolution coincides with a reduction in levels of P. acnes, lipids, and free fatty acids in the skin follicle. Benzoyl peroxide also demonstrates keratolytic activity, which produces drying and desquamative actions that contribute to its efficacy in comedone treatment. In the treatment of decubitus ulcers, benzoyl peroxide stimulates epithelial cell proliferation and the production of granulation tissue.

Niacinamide

Dietary requirements for niacin can be met by the ingestion of either nicotinic acid or nicotinamide; as vitamins, both have identical biochemical functions. As pharmacologic agents, however, they differ markedly. Nicotinic acid is not directly converted into nicotinamide by the body; nicotinamide is only formed as a result of coenzyme metabolism. Nicotinic acid is incorporated into a coenzyme known as nicotinamide adenine dinucleotide (NAD) in erythrocytes and other tissues. A second coenzyme, nicotinamide adenine dinucleotide phosphate (NADP), is synthesized from NAD. These two coenzymes function in at least 200 different redox reactions in cellular metabolic pathways. Nicotinamide is released from NAD by hydrolysis in the liver and intestines and is transported to other tissues; these tissues use nicotinamide to produce more NAD as needed. Together with riboflavin and other micronutrients, the NAD and NADP coenzymes work to convert fats and proteins to glucose and assist in the oxidation of glucose.

In addition to its role as a vitamin, niacin (nicotinic acid) has other dose-related pharmacologic properties. Nicotinic acid, when used for therapeutic purposes, acts on the peripheral circulation, producing dilation of cutaneous blood vessels and increasing blood flow, mainly in the face, neck, and chest. This action produces the characteristic "niacin-flush". Nicotinic acid-induced vasodilation may be related to release of histamine and/or prostacyclin. Histamine secretion can increase gastric motility and acid secretion. Flushing may result in concurrent pruritus, headaches, or pain. The flushing effects of nicotinic acid appear to be related to the 3-carboxyl radical on its pyridine ring. Nicotinamide (niacinamide), in contrast to nicotinic acid, does not contain a carboxyl radical in the 3 position on the pyridine ring and does not appear to produce flushing.

Nicotinic acid may be used as an antilipemic agent, but nicotinamide does not exhibit hypolipidemic activity. Niacin reduces total serum cholesterol, LDL, VLDL, and triglycerides, and increases HDL cholesterol. The mechanism of nicotinic acid's antilipemic effect is unknown but is unrelated to its biochemical role as a vitamin. One of nicotinic acid's primary actions is decreased hepatic synthesis of VLDL. Several mechanisms have been proposed, including inhibition of free fatty acid release from adipose tissue, increased lipoprotein lipase activity, decreased triglyceride synthesis, decreased VLDL-triglyceride transport, and an inhibition of lipolysis. This last mechanism may be due to niacin's inhibitory action on lipolytic hormones. Nicotinic acid possibly reduces LDL secondary to decreased VLDL production or enhanced hepatic clearance of LDL precursors. Nicotinic acid elevates total HDL by an unknown mechanism, but is associated with an increase in serum levels of Apo A-I and lipoprotein A-I, and a decrease in serum levels of Apo-B. Nicotinic acid is effective at elevating HDL even in patients whose only lipid abnormality is a low-HDL value. Niacin does not appear to affect the fecal excretion of fats, sterols, or bile acids. Clinical trial data suggest that women have a greater hypolipidemic response to niacin therapy than men at equivalent doses.

Pharmacokinetics

Adapalene

Adapalene is applied topically to the skin.  The distribution and metabolism of absorbed adapalene is unknown.  Excretion appears to be primarily by the biliary route.   

Route-Specific Pharmacokinetics 

Topical Route 

Following application, absorption through human skin is low. Trace amounts (< 0.25 ng/mL) of the parent compound have been found in the plasma of acne patients after chronic topical application in controlled clinical trials.

Benzoyl Peroxide

Benzoyl peroxide is applied topically. In the skin, benzoyl peroxide is metabolized to benzoic acid. Approximately 5% of the benzoic acid is systemically absorbed and excreted in the urine.

After topical application to the skin, benzoyl peroxide is absorbed through the epidermis. Approximately 5% of the benzoic acid is systemically absorbed.

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.

 

Contraindications/Precautions

Adapalene

According to the manufacturer, adapalene should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. There are no adequate and well controlled studies in pregnant women. Further, during clinical trials women of childbearing potential initiated treatment only after negative pregnancy tests were obtained. However, 2 women receiving the topical lotion and 6 women receiving the topical gel became pregnant during adapalene clinical trials. Pregnancy outcomes for these 8 women were: 3 healthy full term deliveries, 2 premature deliveries, 2 elective pregnancy terminations, and 1 lost to follow-up. In animal studies, teratogenic changes were observed in rats and rabbits receiving oral doses of more than 25 mg adapalene/kg/day representing 123- and 246-times the maximum recommended human dose. These teratogenic changes included cleft palate, microphthalmia, exophthalmos, encephalocele, skeletal abnormalities, umbilical hernia, and kidney abnormalities.89 

According to the manufacturer, it is not known whether adapalene distributes into breast milk. Because adapalene is poorly absorbed through human intact skin, the amount of drug excreted into the breast milk is expected to be low 10, and therefore risk to the nursing infant is also expected to be low.11 Do not apply near the nipple area, and be careful to avoid direct contact between the infant and the treated area. 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. 

Topical adapalene is for external use only. Avoid contact with the eyes, lips, angles of the nose and other mucous membranes. Apply only to affected areas; accidental exposure to unaffected skin may cause irritation. Do not apply to skin that is cut or is affected with seborrheic dermatitis, eczema, a skin abrasion, or sunburn. As with other retinoids, avoid the use of waxing as a depilatory method. Avoid the use of other potentially irritating topical products. If sun exposure cannot be avoided during topical adapalene therapy, sunscreen products and physical sun blocks (protective clothing, hats) are recommended for protection of treated areas.12 Sunlight (UV) exposure may potentiate the effects of adapalene. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using topical adapalene. Weather extremes, such as wind or cold, also may be irritating to patients receiving adapalene. 

No information is available on the relationship of age to the effects of adapalene in pediatric patients. Safety and efficacy in children less than 12 years of age have not been established. 

Clinical studies of adapalene were mainly conducted in patients aged 12 to 30 years, and did not include a sufficient number of geriatric patients (>= 65 years) to determine any differences in response as compared to younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.

Benzoyl Peroxide

Benzoyl peroxide is contraindicated in individuals having known sensitivity to benzoyl peroxide or any other listed ingredients.13

Use of benzoyl peroxide products in patients with skin disease such as dermatitis, seborrhea, and eczema or with skin abrasion or inflammation, denuded skin, including sunburn or windburn, may increase the risk of skin irritation. The benzoyl peroxide product should be discontinued until skin sensitivity resolves. Patients should limit their sunlight (UV) exposure and use sunscreen while using benzoyl peroxide products to decrease the risk for skin irritation.

Avoid accidental exposure of benzoyl peroxide products to the eyes, lips, mucus membranes and inflamed or raw skin due to severe irritation. If unintended mucus membrane or ocular exposure occurs, thoroughly rinse affected areas with water.

The safety and efficacy of benzoyl peroxide products have not been established in children.

Benzoyl peroxide products are considered FDA pregnancy risk category C agents. It is not known if benzoyl peroxide causes fetal harm or can affect reproductive capacity. However, topical application is generally considered safe during pregnancy.

It is not known if benzoyl peroxide is excreted in breast milk. However, very little benzoic acid is absorbed systemically with topical use of benzoyl peroxide; therefore, minimal risk to the infant would be expected.14 Only water-miscible cream products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins.15 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

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.16 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.17

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.3

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.3 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.18 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.19

 

Pregnancy

Adapalene

According to the manufacturer, adapalene should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. There are no adequate and well controlled studies in pregnant women. Further, during clinical trials women of childbearing potential initiated treatment only after negative pregnancy tests were obtained. However, 2 women receiving the topical lotion and 6 women receiving the topical gel became pregnant during adapalene clinical trials. Pregnancy outcomes for these 8 women were: 3 healthy full term deliveries, 2 premature deliveries, 2 elective pregnancy terminations, and 1 lost to follow-up. In animal studies, teratogenic changes were observed in rats and rabbits receiving oral doses of more than 25 mg adapalene/kg/day representing 123- and 246-times the maximum recommended human dose. These teratogenic changes included cleft palate, microphthalmia, exophthalmos, encephalocele, skeletal abnormalities, umbilical hernia, and kidney abnormalities.89

Benzoyl Peroxide

Benzoyl peroxide products are considered FDA pregnancy risk category C agents. It is not known if benzoyl peroxide causes fetal harm or can affect reproductive capacity. However, topical application is generally considered safe during pregnancy.

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.3

 

Breast-feeding

Adapalene

According to the manufacturer, it is not known whether adapalene distributes into breast milk. Because adapalene is poorly absorbed through human intact skin, the amount of drug excreted into the breast milk is expected to be low 10, and therefore risk to the nursing infant is also expected to be low.11 Do not apply near the nipple area, and be careful to avoid direct contact between the infant and the treated area. 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.

Benzoyl Peroxide

It is not known if benzoyl peroxide is excreted in breast milk. However, very little benzoic acid is absorbed systemically with topical use of benzoyl peroxide; therefore, minimal risk to the infant would be expected.14 Only water-miscible cream products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins.15 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.3 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.18 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.

Adverse Reactions/Side Effects

Adapalene

Local cutaneous adverse reactions may occur with adapalene therapy. Erythema, skin scaling, dryness of skin (xerosis), burning, and pruritus occur in 10—40% of patients using adapalene gel. Pruritus or burning immediately after application occurs in 20% of patients using adapalene gel. The frequency and severity (mild, moderate, or severe) of local cutaneous irritations were reported for patients using adapalene cream in clinical trials. Mild and moderate xerosis were reported in 42% and 9% of patients, respectively. Erythema was reported as mild in 38% of patients and moderate in 10% of patients. Mild scaling was reported in 35% of patients; moderate scaling was reported in 6% of patients. Persistent pruritus was reported as mild in 21% of patients and moderate in 4% of patients. Persistent burning and/or stinging was reported as mild in 24% of patients and moderate in 4% of patients. Erythema, scaling, dryness, persistent pruritus, and persistent burning/stinging were all reported as severe in < 1% of patients. Photosensitivity (sunburn) occurred in 2% of patients using adapalene cream and <= 1% of patients using the gel. Skin irritation and discomfort were reported rarely (<= 1%) among patients using the gel or cream. Acne vulgaris flares occur in patients receiving adapalene gel (<= 1%) and cream (< 1%). Additional adverse events reported in < 1% of patients using adapalene cream include dermatitis and contact dermatitis, blepharedema (eyelid edema), conjunctivitis, skin discoloration, rash (unspecified), and atopic dermatitis (as eczema).2021 Among patients receiving adapalene lotion in clinical trials, 7.7% reported dry skin, 1.5% reported skin irritation, 0.9% reported skin burning and discomfort, and 0.6% reported sunburn. For patients whose irritation scores were higher while on therapy compared to baseline, mild, moderate, and severe erythema occurred in 21.8%, 8%, and 0.2% of patients, respectively. Mild scaling occurred in 25.3% of patients; moderate and severe scaling were reported in 6.5% and 0.1% of patients, respectively. Dry skin was reported as mild in 36.1% of patients, moderate in 7.3% of patients, and severe in 0.3% of patients. Stinging and/or burning of the skin was reported as mild, moderate, and severe in 22.1%, 7%, and 0.9% of patients, respectively. In an open-label post-marketing study of 13 adolescent subjects, 8 out of 13 reported incidents of pruritus.8 The local cutaneous adverse reactions seen with use of adapalene are most common during the first 2—4 weeks of treatment, decrease in frequency and severity over time, and are reversible with discontinuation of therapy.20218 Depending upon the severity of cutaneous adverse reactions, patients should be instructed to use moisturizer,8 reduce the frequency of application of adapalene, or discontinue use.20218

Benzoyl Peroxide

The most common adverse reactions to benzoyl peroxide products are xerosis (drying of skin). Xerosis may include marked peeling, erythema, and skin irritation. Peeling of the skin usually occurs after a few days. Patients with skin irritation may experience mild stinging, feelings of warmth, or erythema upon application of benzoyl peroxide products. Occasionally, some patients may develop contact dermatitis including a rash (unspecified), pruritus, blistering, crusting or swelling of the skin.13 In patients who develop severe symptoms, discontinue benzoyl peroxide and consider using emollients, cool compresses, or topical corticosteroids (if indicated), to reduce symptoms and increase healing.

Topical over-the-counter (OTC) acne products, including benzoyl peroxide, have been associated with rare but serious and potentially life-threatening hypersensitivity reactions. These reactions may occur within minutes to a day or longer after use of the product. Instruct patients to stop using topical acne products if they experience signs of anaphylactoid reactions such as throat tightness; difficulty breathing; feeling faint; or swelling of the eyes, face, lips, or tongue. The product should also be discontinued in patients who develop urticaria or pruritus. Based on the information reported to the FDA, it is uncertain whether the reactions are caused by the active ingredients benzoyl peroxide or salicylic acid, the inactive ingredients, or a combination of both. When initiating therapy with an OTC topical acne product, advise patients to apply a small amount to one or two small affected areas for 3 days and monitor for signs of a hypersensitivity reaction. If no discomfort occurs, the instructions on the Drug Facts label may be followed.22

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.7 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.3 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.3 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.3 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.7 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.3

Niacin interferes with glucose metabolism and can result in hyperglycemia.3 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.3

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan.3 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.3

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.3

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.3

Niacin also has been associated with a variety of ophthalmic adverse effects including blurred vision and macular edema.3

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.323

During clinical trials, increased cough was reported in <2—8% (vs. 6%) of patients receiving Niaspan compared to placebo.3

 

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. Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris. J Am Acad Derm 1996;34:482-5.
  • 2. Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet 2004;364:2188-95.
  • 3. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. Niaspan (niacin extended-release) tablet package insert. North Chicago, IL: Abbott Laboratories; 2015 Apr.
  • 4. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.
  • 5. 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.
  • 6. 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.
  • 7. a. b. c. 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.
  • 8. a. b. c. d. e. f. Differin lotion (adapalene) package insert. Fort Worth, TX: Galderma Laboratories, L.P.; 2013 Dec.
  • 9. a. b. Differin (adapalene 0.3% gel) package insert. Fort Worth, TX: Galderma Laboratories, L.P.; 2012 Feb.
  • 10. a. b. Adapalene cream 0.1% package insert. Melville, NY: E. Fougera and Co.; 2008 Aug.
  • 11. a. b. Adapalene. In: Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. Briggs GG, Freeman RK, Yaffe SJ, (eds.) 9th ed., Philadelphia PA: Lippincott Williams and Wilkins; 2011:26.
  • 12. Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf 2002;25:345-72.
  • 13. a. b. BP Wash (benzoyl peroxide) package insert. Dallas, TX: Cintex Services, LLC; 2011 Dec.
  • 14. a. b. Leachman SA, Reed BR. The use of dermatologic drugs in pregnancy and lactation. Dermatol Clin. 2006;24:167-97.
  • 15. a. b. Noti A, Grob K, Biedermann M et al. Exposure of babies to C(15)-C(45) mineral paraffins from human milk and breast salves. Regul Toxicol Pharmacol. 2003;38:317-25.
  • 16. Colletti RB, Neufeld EJ, Roff NK, et al. Niacin treatment of hypercholesterolemia in children. Pediatrics 1993;92:78-82.
  • 17. 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.
  • 18. 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
  • 19. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
  • 20. a. b. c. Adapalene gel package insert. Hawthorne, NY: Taro Pharmaceuticals U.S.A., Inc.; 2010 Jul.
  • 21. a. b. c. Adapalene cream package insert. Melville, NY: Fougera Pharmaceuticals, Inc.; 2013 Dec.
  • 22. Food and Drug Administration MedWatch. Over-The-Counter Topical Acne Products: Drug Safety Communication - Rare But Serious Hypersensitivity Reactions. Retrieved June 25, 2014. Available on the World Wide Web http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHum
  • 23. Niacor (Niacin tablets) package insert. Minneapolis, MN: Upsher-Smith Laboratories, Inc.; 2000 Feb.

Related Medications