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 retinoid-like topical medication used to treat mild to moderate acne vulgaris. Adapalene is a naphthoic acid derivative, unlike tretinoin, and causes less skin irritation. In the treatment of acne vulgaris, adapalene is more effective than tretinoin gel (0.025 percent). 1 According to clinical study data, adapalene is commercially accessible as a cream, lotion, or gel and is visually attractive to the majority of patients. On June 3, 1996, the FDA granted approval to the medication.

Benzoyl Peroxide

Topical benzoyl peroxide is used to treat acne. Benzoyl peroxide has antimicrobial properties. It also has drying, sebostatic, and mild skin desquamation properties. Both inflammatory and non-inflammatory acne lesions benefit from benzoyl peroxide. In mild cases of acne, benzoyl peroxide is useful as a monotherapy, while in moderate to severe cases of acne, it is used as an adjuvant. A research 2 An OTC 5 percent benzoyl peroxide topical formulation (Panoxyl Aquagel) was found to be as effective for treating mild to moderate acne as a topical benzoyl peroxide/erythromycin combination and the oral tetracyclines minocycline and oxytetracycline. Topical benzoyl peroxide and benzoyl peroxide/erythromycin combinations were not linked to tetracycline-induced propionibacteria antibiotic resistance. Off-label uses of benzoyl peroxide include the treatment of decubitus ulcers. Prescription and over-the-counter versions of benzoyl peroxide are available, as well as combinations with erythromycin, hydrocortisone, and sulfur (see separate monographs for each of the combination products). To guarantee uniformity with the standardized 'Drug Facts' layout, the FDA has amended labeling regulations for all non-prescription (over-the-counter) topical acne medications, including benzoyl peroxide. In over-the-counter topical acne medication treatments, benzoyl peroxide is a generally recognized as safe and effective (GRASE) active component.

Niacinamide

Niacin (nicotinic acid or 3-pyridine carboxylic 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 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 the 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 to 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 nuclear receptors for retinoic acid but not to the cytosolic receptor protein. Adapalene is said to reach deep into the hair follicle. Adapalene modulates cell differentiation and keratinization as a result of its effects. Adapalene has anti-inflammatory and comedolytic effects as well.

Benzoyl Peroxide

Antimicrobial activities of benzoyl peroxide against Propionibacterium acnes, the most common bacteria found in sebaceous follicles and comedones. The generation of free-radical oxygen species, which are capable of damaging bacterial proteins, is responsible for benzoyl peroxide's antibacterial properties. Acne normally clears up within four to six weeks of starting treatment. The reduction of P. acnes, lipids, and free fatty acids in the skin follicle correspond with resolution. Benzoyl peroxide also has keratolytic activity, which results in drying and desquamative effects that aid in the treatment of comedones. Benzoyl peroxide increases epithelial cell proliferation and granulation tissue development in the treatment of decubitus ulcers.

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 the 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 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 administered to the skin topically. The distribution and metabolism of adapalene that's been absorbed are unknown. The biliary pathway appears to be the primary route of excretion.

Route-Specific Pharmacokinetics

Topical Route

Absorption through human skin is low after application. In controlled clinical trials, trace quantities of the parent chemical ( 0.25 ng/mL) were identified in the plasma of acne patients following continuous topical administration.

Benzoyl Peroxide

Topically, benzoyl peroxide is used. Benzoyl peroxide is converted to benzoic acid in the skin. Approximately 5% of benzoic acid is absorbed systemically and eliminated in the urine.

Benzoyl peroxide is absorbed through the epidermis after topical application to the skin. Benzoic acid is absorbed systemically in around 5% of the time.

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

Adapalene should only be used during pregnancy if the possible benefit outweighs the risk to the fetus, according to the manufacturer. In pregnant women, there are no good and well-controlled trials. Furthermore, women of reproductive potential began treatment only after negative pregnancy tests were obtained during clinical studies. During the adapalene clinical trials, however, 2 women who received the topical lotion and 6 women who received the topical gel became pregnant. Three healthy full-term deliveries, two premature deliveries, two elective pregnancy terminations, and one lost to follow-up were the pregnancy outcomes for these eight women. Teratogenic alterations were detected in rats and rabbits given oral dosages of more than 25 mg adapalene/kg/day, which were 123- and 246-times the maximum recommended human dose, respectively, in animal investigations. Cleft palate, microphthalmia, exophthalmos, encephalocele, skeletal abnormalities, umbilical hernia, and kidney abnormalities were among the teratogenic alterations. 8 9

It is unknown whether adapalene is distributed into breastmilk, according to the manufacturer. Because adapalene is poorly absorbed via intact human skin, it is believed that the amount of medication discharged in breast milk will be little. 10 Avoid direct contact between the infant and the treated region by not applying near the nipple area. Consider the advantages of breastfeeding, the risk of baby drug exposure, and the risk of an illness that is ignored or inadequately treated. If a breastfeeding newborn has an adverse reaction to a medicine given to her by her mother, healthcare providers are advised to report the reaction to the FDA. 

Adapalene topical is only for external usage. Contact with the eyes, lips, nose angles, and other mucous membranes should be avoided. Only apply to the affected regions; contact with unaffected skin may cause irritation. Do not use on skin that has been cut, or that has seborrheic dermatitis, eczema, abrasions, or sunburn. Avoid waxing as a depilatory procedure, as you would with other retinoids. Other possibly irritating topical treatments should be avoided. Sunscreen products and physical sunblocks (protective clothes, caps) are indicated for the protection of treated regions if sun exposure cannot be avoided during topical adapalene therapy. 11 

When using topical adapalene, patients who may be exposed to a lot of sun as a result of their job or who have a natural sensitivity to sunlight should use it with caution. Adapalene patients may also be irritated by weather extremes such as wind or cold.

There is no information on the effects of adapalene in pediatric patients based on their age. There is no evidence of safety or efficacy in children under the age of 12.

Clinical trials of adapalene were mostly undertaken in patients aged 12 to 30 years old, with a small number of geriatric patients (> 65 years old) included seeing if there were any changes in response between younger and older individuals. Other clinical experience hasn't revealed any distinctions in responsiveness between the elderly and the younger.

Benzoyl Peroxide

Individuals who have a known intolerance to benzoyl peroxide or any of the other specified chemicals should avoid using it. 12

The use of benzoyl peroxide products in individuals with skin diseases such dermatitis, seborrhea, and eczema, as well as skin abrasions or inflammation, including sunburn or windburn, may increase the risk of skin irritation. The use of benzoyl peroxide should be avoided until the skin irritation has subsided. To reduce the risk of skin irritation, patients should restrict their UV exposure and apply sunscreen while taking benzoyl peroxide treatments.

Due to significant irritation, avoid accidentally exposing benzoyl peroxide products to the eyes, lips, mucous membranes, and inflammatory or raw skin. If a mucus membrane or ocular exposure occurs unintentionally, thoroughly rinse the affected regions with water.

The safety and efficacy of benzoyl peroxide products in children have yet to be determined.

Products containing benzoyl peroxide are classified as pregnancy risk category C by the FDA. It's unclear whether benzoyl peroxide can harm a fetus or affect reproductive potential. Topical use, on the other hand, is typically regarded as safe during pregnancy.

If benzoyl peroxide is secreted in breast milk, it is unknown. However, because only a little amount of benzoic acid is absorbed systemically when benzoyl peroxide is applied topically, there is no risk to the infant. 13 Because ointments may expose the newborn to excessive quantities of mineral paraffins, only water-miscible cream products should be administered to the breast. 14 Consider the advantages of breastfeeding, the risk of baby drug exposure, and the risk of an illness that is ignored or inadequately treated. If a breastfeeding newborn has an adverse reaction to a medicine given to her by her mother, healthcare providers are advised to report the reaction 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 a 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 the 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.15 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.16

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.17 There are no safety data regarding the use of nicotinic acid in doses above the RDA during breast-feeding. 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 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.18

Pregnancy

Adapalene

Adapalene should only be used during pregnancy if the possible benefit outweighs the risk to the fetus, according to the manufacturer. In pregnant women, there are no good and well-controlled trials. Furthermore, women of reproductive potential began treatment only after negative pregnancy tests were obtained during clinical studies. During the adapalene clinical trials, however, 2 women who received the topical lotion and 6 women who received the topical gel became pregnant. Three healthy full-term deliveries, two premature deliveries, two elective pregnancy terminations, and one lost to follow-up were the pregnancy outcomes for these eight women. Teratogenic alterations were detected in rats and rabbits given oral dosages of more than 25 mg adapalene/kg/day, which were 123- and 246-times the maximum recommended human dose, respectively, in animal investigations. Cleft palate, microphthalmia, exophthalmos, encephalocele, skeletal abnormalities, umbilical hernia, and kidney abnormalities were among the teratogenic alterations. 8 9

Benzoyl Peroxide

Products containing benzoyl peroxide are classified as pregnancy risk category C by the FDA. It's unclear whether benzoyl peroxide can harm a fetus or affect reproductive potential. Topical use, on the other hand, is typically regarded as 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

Breastfeeding

Adapalene

It is unknown whether adapalene is distributed in breastmilk, according to the manufacturer. Because adapalene is poorly absorbed via intact human skin, it is believed that the amount of medication discharged in breastmilk will be little. 19 Avoid direct contact between the infant and the treated region by not applying near the nipple area. Consider the advantages of breastfeeding, the risk of baby drug exposure, and the risk of an illness that is ignored or inadequately treated. If a breastfeeding newborn has an adverse reaction to a medicine given to her by her mother, healthcare providers are advised to report the reaction to the FDA.

Benzoyl Peroxide

If benzoyl peroxide is secreted in breast milk, it is unknown. However, because only a little amount of benzoic acid is absorbed systemically when benzoyl peroxide is applied topically, there is no risk to the infant. 20 Because ointments may expose the newborn to excessive quantities of mineral paraffins, only water-miscible cream products should be administered to the breast. 14 Consider the advantages of breastfeeding, the risk of baby drug exposure, and the risk of an illness that is ignored or inadequately treated. If a breastfeeding newborn has an adverse reaction to a medicine given to her by her mother, healthcare providers are encouraged to report the reaction 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.17 There are no safety data regarding the use of nicotinic acid in doses above the RDA during breast-feeding. 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 ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Adverse Reactions/Side Effects

Adapalene

Adapalene treatment may cause local cutaneous side effects. In 10—40 percent of individuals who use adapalene gel, erythema, skin scaling, dryness of the skin (xerosis), burning, and itching occur. Pruritus or burning occurs in 20% of individuals who use adapalene gel right after administration. Patients using adapalene cream in clinical studies reported the frequency and intensity (mild, moderate, or severe) of local cutaneous irritations. Mild and moderate xerosis were reported in 42% and 9% of the patients, respectively. Mild erythema was reported by 38% of patients, whereas significant erythema was recorded by 10%. Mild scaling was noted by 35% of patients, whereas significant scaling was recorded by 6% of those surveyed. Mild persistent pruritus was reported by 21% of patients, whereas strong pruritus was recorded by 4% of patients. 

Mild burning and/or stinging was experienced by 24% of patients, whereas significant burning and/or stinging was recorded by 4% of patients. In less than 1% of patients, erythema, scaling, dryness, persistent pruritus, and persistent burning/stinging were all rated as severe. Photosensitivity (sunburn) occurred in 2% of patients who used adapalene cream and 1% of those who used the gel. Patients who used the gel or cream experienced skin irritation and discomfort infrequently (less than 1%). Patients who receive adapalene gel (= 1%) or cream (1%), experience acne vulgaris flare-ups. Dermatitis and contact dermatitis, blepharedema (eyelid edema), conjunctivitis, skin pigmentation, rash (unspecified), and atopic dermatitis have all been documented in less than 1% of patients taking adapalene cream (as eczema). 21 22 7.7% of patients in clinical studies who received adapalene lotion had dry skin, 1.5 percent had skin irritation, 0.9 percent had skin burning and discomfort, and 0.6 percent had sunburn. Mild, moderate, and severe erythema occurred in 21.8 percent, 8%, and 0.2 percent of patients, respectively, whose irritation levels were higher while on medication than at baseline. Mild scaling was recorded in 25.3 percent of patients, with moderate and severe scaling occurring in 6.5 percent and 0.1 percent, respectively. 36.1 percent of patients had mild dry skin, 7.3 percent had moderate dry skin, and 0.3 percent of patients had severe dry skin. Mild, moderate, and severe stinging and/or burning of the skin were experienced by 22.1 percent, 7%, and 0.9 percent of patients, respectively. Eight of thirteen adolescent subjects participated in an open-label post-marketing study.  Eight out of thirteen adolescent subjects in an open-label post-marketing research reported occurrences of pruritus. 23 Adapalene-induced local cutaneous adverse effects are most common during the first 2–4 weeks of treatment, decrease in frequency and severity over time, and are reversible when therapy is stopped. 24 25 26 Patients should be instructed to apply moisturizer depending on the severity of cutaneous adverse effects. 23reduce the amount of adapalene you use or stop using it altogether. 27 28 23

Benzoyl Peroxide

Xerosis is the most common side effect of benzoyl peroxide products (drying of skin). Marked peeling, erythema, and skin irritation are all symptoms of xerosis. After a few days, the skin will begin to peel. When using benzoyl peroxide products, patients with skin irritation may suffer moderate stinging, warmth, or erythema. Some patients may develop contact dermatitis, which manifests itself as a rash, pruritus, blistering, crusting, or swelling of the skin. 12 Discontinue benzoyl peroxide in individuals who have severe symptoms and consider using emollients, cool compresses, or topical corticosteroids (if appropriate) to relieve symptoms and speed healing.

Topical over-the-counter (OTC) acne medications, such as benzoyl peroxide, have been linked to uncommon but acute hypersensitivity responses, which can be fatal. These reactions might happen anywhere from minutes to a day or more after using the product. Instruct patients to discontinue using topical acne products if they develop throat tightness, difficulty breathing, faintness, or swelling of the eyes, face, lips, or tongue, which are all signs of anaphylactoid reactions. Patients who experience urticaria or pruritus should stop using the medication. It's unclear if the responses are caused by the active chemicals benzoyl peroxide or salicylic acid, the inert substances, or a mix of both, according to the information provided to the FDA. When starting treatment with an over-the-counter topical acne remedy, tell patients to apply a modest amount to one or two minor afflicted areas for three days and watch for signs of hypersensitivity. If no discomfort occurs, follow the directions on the Drug Facts label. 29

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 a 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 have 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.330

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.

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