Description

Overview of Acne Ultra Gel

Dosage Strength of Acne Ultra Gel

Clindamycin / Niacinamide / Tretinoin 1/4/0.02% 30 mL Pump

General Information

Clindamycin Phosphate

Clindamycin is an antibiotic structurally just like lincomycin, from which it is derived. Clindamycin historically has been considered an effective anti-anaerobic antibiotic, however it lately has been shown to be effective in combination with pyrimethamine in treating toxoplasmic encephalitis in patients with AIDS. 1. Clindamycin become authorized with the aid of the FDA in 1970 and is advertised because the hydrochloride salt for oral management and because the phosphate salt for parenteral, topical or vaginal administration. The FDA authorized a single-dose vaginal cream (Clindesse™) for bacterial vaginosis in November 2004. The FDA accepted Evoclin™, an aerosol topical foam containing 1% clindamycin, for the treatment of acne vulgaris in December 2004.

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.2 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.3 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.4 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.5 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.6 Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

Tretinoin

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A. As vitamin A (retinol) derivatives, retinoids are important regulators of cell reproduction, and cell proliferation and differentiation; however, unlike vitamin A, retinoids are not converted into rhodopsin, which is needed for night vision. Topical tretinoin is indicated in the treatment of mild to moderate acne (e.g., grades I-III) and photodamaged skin. Topical tretinoin has also been used in the symptomatic management of keratinization disorders such as ichthyosis and keratosis follicularis. Tretinoin represents a new class of anticancer drugs, differentiating agents. Oral tretinoin is used in the treatment of acute promyelocytic leukemia (APL) and is undergoing phase III investigation in the treatment of Kaposi’s sarcoma. In the treatment of APL, tretinoin offers a less toxic means to induce complete remission than conventional chemotherapy; however, approximately 25% of patients who receive tretinoin for the treatment of APL have experienced acute promyelocytic leukemia differentiation syndrome.

Mechanisms of Action

Clindamycin Phosphate

Clindamycin binds to the 23S RNA of the 50S ribosomal subunit of the bacteria, which inhibits protein synthesis. As with lincomycin, antibacterial hobby outcomes from the inhibition of protein synthesis. Clindamycin is bacteriostatic. The mechanism of motion of clindamycin in treating pimples vulgaris is unknown.

The susceptibility interpretive criteria for clindamycin are delineated by means of the pathogen. The MICs are described for beta-hemolytic streptococci, S. Viridans group, and S. Pneumoniae as prone at 0.25 mcg/mL or much less, intermediate at 0.5 mcg/mL, and resistant at 1 mcg/mL or extra. The MICs are defined for Staphylococcus sp. As susceptible at zero.5 mcg/mL or much less, intermediate at 1 to 2 mcg/mL, and resistant at 4 mcg/mL or more. The MICs are defined for anaerobes as prone at 2 mcg/mL or much less, intermediate at 4 mcg/mL, and resistant at eight mcg/mL or greater.

Resistance to clindamycin is most usually as a result of modification of unique bases of the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is whole. Due to overlapping binding sites, pass-resistance is now and again located amongst lincosamides, macrolides, and streptogramin B. Clindamycin inducible resistance has been recognized in macrolide-resistant organisms; therefore, macrolide-resistant and clindamycin-inclined lines ought to be screened for inducible clindamycin resistance the use of the D-area take a look at.

Clindamycin is a well-known reason of pseudomembranous colitis, possibly because of overgrowth of Clostridia difficile, and 10% to 20% of lines of Clostridia perfringens may be proof against clindamycin.8 Increased resistance has also been seen in some strains of B. fragilis.13 One study reported marked antibiotic resistance after treatment of bacterial vaginosis with clindamycin; resistance persisted for up to 90 days after treatment.14

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.

Tretinoin

Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Tretinoin binds to all three RARs, but does not bind to RXRs except at very high concentrations. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone.

Skin Disorders: By binding to RARs, tretinoin modifies gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of RARs, other mechanisms such as irritation, or both. Tretinoin appears to prevent horny cell cohesion and to increase epidermal cell turnover and mitotic activity. Subsequently, in patients with acne, expulsion of existing comedones occurs, and formation of new comedones is prevented through sloughing and expulsion of horny cells from the follicle. Tretinoin reduces the cell layers of the stratum corneum. The bacterium involved in acne, Propionibacterium acnes, and sebum production are unaffected. An additional action of tretinoin may involve keratinization inhibition, which would explain its effectiveness in treating keratinization disorders.

Photodamage: Topical tretinoin is effective in reducing fine wrinkling, mottled hyperpigmentation, roughness, and laxity associated with photodamaged skin. Ultraviolet irradiation induces three metalloproteinases in human skin: collagenase, 92-kd gelatinase, and stromelysin-1. The combined actions of these enzymes can fully degrade skin collagen. Pretreatment of skin with tretinoin inhibits the induction of these skin matrix metalloproteinase proteins and activity by 70—80% in both connective tissue and outer layers of irradiated skin.

Acute Promyelocytic Leukemia: Similar to other retinoids, tretinoin induces cellular differentiation in malignant cells. Acute promyelocytic leukemia (APL) is caused by a genetic lesion that disrupts the alpha retinoic acid receptor (RAR-alpha) gene found on the long arm of chromosome 17 and the PML gene found on chromosome 15. The fusion protein that is formed, PML-RAR-alpha, inhibits apoptotic pathways and blocks myeloid differentiation when present in levels greater than those of the normal RAR-alpha protein. The presence of this gene translocation [t(15;17)] is used for diagnosis of APL and as a marker of response following treatment with either cytotoxic agents or tretinoin. During tretinoin treatment, cells expressing PML/RAR-alpha undergo cellular differentiation at a rate higher than normal cells. At therapeutic doses of tretinoin, the activity of the fusion protein on differentiation converts from inhibitory to stimulatory. Terminal differentiation of APL cells as the mechanism of tretinoin therapy is supported by 1) the absence of bone marrow aplasia during treatment; 2) the appearance of cells during treatment with the morphologic characteristics of maturation stages intermediate between promyelocytes and neutrophils; 3) the presence, during treatment, of PML and RAR-alpha rearrangements in peripheral blood neutrophils that disappear after treatment.16 Treatment with tretinoin reverses the bleeding diathesis seen in APL, before any morphologic response is noted. A retinoic acid syndrome, similar to capillary leak syndrome, may be seen in some patients (see Adverse Reactions). The etiology of this syndrome is unknown, but may be due to decreases in leukocyte adhesion protein activity. Resistance to tretinoin may develop due to pharmacokinetic reasons (decreased bioavailability) and/or changes in proteins involved in the cellular activity of tretinoin.

Contraindications / Precautions

Clindamycin Phosphate

Clindamycin is contraindicated in patients with known clindamycin hypersensitivity. Because cross-sensitivity may additionally arise, lincomycin hypersensitive reaction is likewise a contraindication for clindamycin use. Use the drug with caution in patients with bronchial asthma or a great history of hypersensitivity (atopy). Some oral tablet arrangements comprise tartrazine dye and can precipitate bronchial asthma or other allergies in sufferers with tartrazine dye allergy. 17 Serious rash events, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), some with fatal outcomes, have been reported with systemic clindamycin therapy. Clindamycin should be permanently discontinued if severe skin or hypersensitivity reactions occur.

Clindamycin can reason the overgrowth of a nonsusceptible micro organism resulting in superinfection, in particular yeast and fungal contamination. Should superinfection arise, take appropriate measures.

Clindamycin has been associated with intense colitis, greater so than a few different antimicrobials. Topical (topical answer, gel, and lotion) and vaginal (cream, ovules) preparations of clindamycin are contraindicated in patients with a record of local enteritis or ulcerative colitis, or a history of pseudomembranous colitis; different product arrangements warn towards use in sufferers with pseudomembranous colitis.91718 Almost all antibacterial marketers were associated with pseudomembranous colitis (antibiotic-associated colitis), which can also range in severity from slight to existence-threatening. In the colon, overgrowth of Clostridia may arise when normal flora is altered next to antibacterial administration. The toxin produced by way of Clostridium difficile is a number one reason of pseudomembranous colitis. C. Difficile carriage charges common 37% for neonatal patients, 30% for infants 1 to 6 months of age, and 14% for toddlers 6 to one year of age; but, nursing drastically reduces carriage charges. 19 By 3 years of age, carriage charges are much like those of non-hospitalized adults (three% or much less). Consider pseudomembranous colitis as a ability analysis in sufferers presenting with diarrhea after antibacterial management. Systemic antibiotics have to be prescribed with caution to sufferers with inflammatory bowel disorder inclusive of ulcerative colitis or different GI disease. If diarrhea develops throughout therapy, stop the drug. After a diagnosis of pseudomembranous colitis, institute therapeutic measures. Practitioners should be conscious that antibiotic-related colitis can occur over 2 months or extra after discontinuation of systemic antibiotic therapy; a careful scientific history should be taken.

Clindamycin topical solution contains an alcohol base that will cause burning and irritation of the eye; therefore, avoid ocular exposure. In the event of accidental contact with sensitive surfaces (eye, abraded skin, mucous membranes), bathe with water.

Clindamycin can be used to treat certain sexually transmitted sicknesses (STD). All patients with a diagnosed or suspected STD need to be tested for different STDs, which may also consist of HIV, syphilis, chlamydia, and gonorrhea, on the time of diagnosis. Initiate appropriate therapy and perform follow-up checking out as endorsed primarily based upon sexually transmitted disease prognosis.

Reported scientific enjoy shows that antibiotic-associated colitis and diarrhea (because of Clostridium difficile) visible in association with most systemic antibiotics, consisting of clindamycin, arise more frequently in the geriatric grownup (60 years or older) and can be more extreme. These patients have to be carefully monitored for the improvement of diarrhea. 817 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, use of antibiotics must be limited to showed or suspected bacterial infections. Antibiotics are non-selective and might bring about the eradication of beneficial microorganisms even as promoting the emergence of undesired ones, inflicting secondary infections along with oral thrush, colitis, or vaginitis. Any antibiotic can also motive diarrhea, nausea, vomiting, anorexia, and allergic reaction reactions.

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.22 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.

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.

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.2 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.24 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.

Tretinoin

Tretinoin is contraindicated in patients who experience retinoid hypersensitivity reactions to vitamin A or other retinoids because cross-sensitivity between agents is possible. True contact allergy to tretinoin is rare.

The Atralin brand of tretinoin gel and Altreno brand of tretinoin lotion contain soluble fish proteins and should be used with caution in patients with known fish hypersensitivity. Patients should be instructed to contact their health care provider if they develop pruritus or urticaria following application.

Approximately 25% of patients who receive tretinoin for the treatment of acute promyelocytic leukemia have experienced acute promyelocytic leukemia differentiation syndrome. When seen in association with the use of tretinoin, this syndrome is also known as retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions for more detailed description of RA-APL syndrome). Patients must be carefully monitored for any signs or symptoms of this syndrome.

In the treatment of acute promyelocytic leukemia, approximately 40% of patients will develop rapidly evolving leukocytosis, and these patients have a higher risk of life-threatening complications. High initial leukocyte counts or rapidly increasing leukocyte counts during treatment may be predictive of retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions). However, RA-APL syndrome has been observed with or without concomitant leukocytosis. The manufacturer recommends the immediate initiation of high-dose steroids if signs and symptoms of RA-APL are present together with leukocytosis. Some clinicians routinely add chemotherapy to oral tretinoin therapy when patients present with a WBC count > 5000/mm3 or in the case of a rapid increase in WBC count in leukopenic patients at the start of treatment. Consideration could be given to adding chemotherapy (usually cytarabine and an anthracycline, if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count > 5000/mm3 or immediately, for patients presenting with a WBC count of < 5000/mm3, if the WBC count reaches >= 6000/mm3 by day 5, >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. The majority of patients do not require discontinuation of tretinoin therapy during RA-APL syndrome.

Retinoids may cause photosensitivity.26 Treatment with topical tretinoin should be postponed until sunburn has resolved to avoid exacerbation of the irritation, inflammation, and dryness associated with sunburned skin. Patients with a skin photosensitivity disorder should be closely evaluated prior to receiving tretinoin therapy. If sun exposure cannot be avoided during topical tretinoin therapy, sunscreen products and physical sun blocks (protective clothing, hats) are recommended for protection of treated areas. Sunlight (UV) exposure potentiates the inflammatory effects of tretinoin. 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 tretinoin. Weather extremes, such as wind or cold, also may be irritating to patients receiving tretinoin.

Topical tretinoin should be avoided, if possible, in patients with eczema because severe irritation of eczematous skin is likely.

With the exception of the 0.05% lotion (approved for use in children 9 years and older) and 0.05% gel (approved for use in children 10 years and older) formulations, safety and efficacy of topical tretinoin have not been established in neonates, infants and children under 12 years of age. Children are prone to developing severe headache and pseudotumor cerebri while receiving oral tretinoin. For relief, some patients may require treatment with analgesics or lumbar puncture. The safety and efficacy of oral tretinoin in infants have not been established.

Tretinoin cream, gel, lotion, and liquid are for external use only. Avoid ocular exposure, including eyelids, and contact with the mouth, angles of the nose, and mucous membranes. If eye contact occurs, rinse thoroughly with large amounts of water. Apply only to affected areas; accidental exposure to unaffected skin may cause irritation. Topical tretinoin is flammable; do not use near heat, open flame, or while smoking.

Pregnancy

Clindamycin Phosphate

In medical trials with pregnant girls, no congenital abnormalities had been related to systemic administration of clindamycin during the second or third trimester.17 However, in a large population-based cohort have a look at (n = 139,938 live births) assessing antibiotic exposure at some point of the first trimester of being pregnant (n = 15,469 exposures) and the threat of foremost beginning defects, clindamycin was related to an elevated threat of main congenital malformations (adjusted odds ratio (aOR) 1.34; 95% CI: 1.02 to at least one.Seventy seven; 60 uncovered instances). Clindamycin publicity extended the danger of musculoskeletal gadget malformations (aOR 1.Sixty seven; 95% CI: 1.12 to 2.48; 29 exposed cases) and ventricular/atrial septal defect (aOR 1.81; ninety five% CI: 1.04 to 3.16; thirteen uncovered cases). Use clindamycin during the first trimester of pregnancy only if clearly needed and the benefits outweigh the risks.17 Placental concentrations are roughly 50% of maternal serum concentrations.2829 Parenteral clindamycin also contains benzyl alcohol, which can cross the placenta; benzyl alcohol has been associated with a fatal ‘gasping syndrome’ in neonates. Clindamycin vaginal cream has been studied during pregnancy to reduce preterm birth and treat asymptomatic bacterial vaginosis. In 1 trial (n = 409), women who were treated with 2% clindamycin vaginal cream prior to 20 weeks gestation demonstrated a reduction in preterm birth compared to placebo (p less than 0.03).30 In 3 other trials, intravaginal clindamycin cream was administered at 16 to 32 weeks gestation, and an increase in adverse events, such as low birthweight, pre-term delivery, premature rupture of the membranes, and neonatal infections, was observed in newborns.313233 There are no adequate, well-controlled studies of topical clindamycin in pregnant women.

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.

Tretinoin

Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin or large doses (i.e., many times greater than the normal human dose) of topical tretinoin. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. Reproductive risk should be discussed. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception requirements must be followed even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until pregnancy testing results are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy.

Breastfeeding

Clindamycin Phosphate

Clindamycin is excreted into human breast milk after management by way of the oral or parenteral routes in concentrations of less than 0.5 to 3.8 mcg/mL. Because of the capability for serious gastrointestinal destructive reactions inside the breastfed baby, an alternative drug to clindamycin can be preferred during breastfeeding. Consider the developmental and health benefits of breastfeeding alongside the mom’s medical need for clindamycin and any potential adverse outcomes at the breastfed infant from clindamycin or the underlying maternal circumstance. If clindamycin is used for the duration of breastfeeding, monitor the little one for viable detrimental results on the gastrointestinal flora which includes diarrhea, candidiasis (thrush, diaper rash), or hardly ever, blood inside the stool indicating possible antibiotic-related colitis.817 Diarrhea and bloody stools were reported in a 5-day-old infant whose mother was receiving intravenous clindamycin and gentamicin for suspected endometriosis.37 Previous American Academy of Pediatrics recommendations considered clindamycin as usually compatible with breastfeeding.38 It is unknown if clindamycin is excreted into human breast milk after the use of vaginally or topically administered clindamycin.91734 If clindamycin is topically applied to the chest, care should be taken to avoid accidental ingestion by the infant.

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.2 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.24 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.

Tretinoin

According to the manufacturers, breast-feeding should be discontinued prior to receiving oral tretinoin and caution should be used with topical tretinoin.3536 It is unknown whether oral or topical tretinoin is distributed into breast milk. Systemic absorption of tretinoin after topical application is low 36, and therefore it is unlikely that a significant amount of the drug is excreted into breast-milk. However, consideration for the use of an alternative topical agent (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin) may be appropriate for some patients. 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.

Adverse Reactions / Side Effects

Clindamycin Phosphate

Gastrointestinal (GI) negative events are more usually associated with systemic clindamycin therapy; however, GI disturbances have additionally been mentioned in association with using topical and vaginal preparations. Diarrhea has been stated in up to 20% of sufferers receiving systemic therapy and is extra commonplace with the oral components; it has also been reported in less than 1% of patients the use of vaginal merchandise and has befell with the use of topical products. Other destructive activities pronounced in much less than 1% of patients using vaginal merchandise and additionally with different formulations include belly ache/cramps, halitosis, nausea, vomiting, dyspepsia, flatulence, and gastrointestinal disease. Constipation has been reported in 2% or less of patients using the vaginal product. Administration of oral formulations with food can lessen minor gastric distress. Esophagitis may also arise with the oral formulations of clindamycin. Esophagitis may be associated with odynophagia, dysphagia, and retrosternal pain. Most signs and symptoms resolve within a few days to weeks after discontinuing the drug. Pseudomembranous colitis (Clostridium difficile-related diarrhea, CDAD) has been pronounced with the usage of clindamycin. Early reporting confirmed a charge of 0.01% to 10%; but, CDAD has end up greater common and excessive. CDAD may additionally occur throughout remedy or after therapy has been discontinued and might bring about minor diarrhea or fatal colitis. CDAD is more commonly related to systemic therapy; but, the topical and vaginal merchandise do have some systemic absorption, and CDAD may additionally arise. A metallic taste (dysgeusia) has been reported with the administration of the intravenous and oral clindamycin products and taste perversion has been reported in less than 1% of patients receiving the vaginal cream. Hematochezia was noted in postmarketing reports with the vaginal cream.

Transient neutropenia (leukopenia) and eosinophilia have been reported throughout clindamycin remedy. Reports of agranulocytosis and thrombocytopenia have been made. No direct relationship to concurrent clindamycin remedy has been made.

Rashes along with rash (unspecified), maculopapular rash, vesicular rash, or bullous rash in addition to urticaria have been determined for the duration of systemic clindamycin remedy and may be related to hypersensitivity. Severe pores and skin reactions, along with poisonous epidermal necrolysis and Stevens-Johnson syndrome, were said and a few cases were deadly. Clindamycin ought to be permanently discontinued if extreme skin or allergic reaction reactions occur. Acute generalized exanthematous pustulosis (AGEP), angioedema, drug response with eosinophilia and systemic symptoms (DRESS), erythema multiforme, and exfoliative dermatitis have additionally been reported with systemic clindamycin. 17 Pruritus/itching has also been noted with topical (1% to 11%), vaginal (less than 1% to 1.1%), and systemic therapy. Topical application has been associated with burning (6% to 11%), xerosis (dry skin) (1% to 23%), erythema (7% to 16%), oiliness/oily skin (1% to 18%), peeling (7% to 11%), seborrhea, application site rash, folliculitis, and application site pain. Xerosis may be attributed to the solvent used in the topical preparation. Alcohol in some topical formulations may cause ocular irritation or ocular pain or irritate the mucous membranes or abraded skin resulting in contact dermatitis.

Intramuscular injection of clindamycin can cause an injection site reaction consisting of pain, induration, and sterile abscess. Thrombo-phlebitis has been reported after intravenous infusion.

Although no direct relationship has been hooked up, renal disorder evidenced through azotemia, oliguria, and/or proteinuria has been determined in uncommon instances with clindamycin remedy. Dysuria turned into pronounced in less than 1% of patients using vaginal clindamycin.

Anaphylactoid reactions and anaphylactic shock have been reported with clindamycin. Clindamycin should be permanently discontinued if anaphylactic or serious hypersensitivity reactions occur. Treat patients with an allergy to tartrazine dye cautiously since some oral capsule preparations contain the dye.

In females treated with vaginal clindamycin preparations, vaginal inflammation (3.Four%), vulvovaginitis (6% or less), vaginal pain (1.Nine%), vulvovaginal disorder (3.2% to 6.7%), trichomonal vaginitis (0.2%), vaginal erythema, vulvovaginal pruritus, vaginal discharge, vaginal swelling, and vaginal bleeding passed off. Other adverse occasions noted in less than 1% of sufferers include menstrual disorder, vaginal discharge, vaginal contamination, dysfunctional uterine bleeding, dysmenorrhea, intermenstrual bleeding, pelvic pain, vaginal burning, vaginal infection, vulvar erythema, vulvitis, vulvovaginal soreness, vulvovaginal dryness, vaginal pain, metrorrhagia, endometriosis, and menstrual ailment. Abnormal labor was mentioned in 1.1% of pregnant patients. Vaginitis has also been pronounced with vaginal products (3.6% or less) and with systemic use of clindamycin.

Jaundice and abnormal/elevated hepatic enzymes have been observed during clindamycin therapy.

Headache (7% or less) and dizziness (less than 1%) have been cited with the usage of the topical clindamycin foam as well as the vaginal merchandise. Vertigo (less than 1%) was also mentioned with the vaginal products.

Back pain (5%) has been reported with the use of vaginal clindamycin. Cases of polyarthritis have been reported with systemic therapy.

Use of clindamycin may additionally cause capacity infection with overgrowth of nonsusceptible organisms or superinfection. Systemic or local fungal infections, which include candidiasis, might also arise. Vaginal candidiasis has been stated to occur in 1.Five% to fourteen% of patients, and systemic candidiasis has been suggested in 1.7% or less of patients receiving vaginal clindamycin. Urinary tract infection changed into stated in 2% or less of sufferers using vaginal clindamycin, with pyelonephritis mentioned in much less than 1% of sufferers. Upper respiration tract infection and unspecified bacterial infection had been additionally stated in less than 1% of sufferers using the vaginal product.

General adverse events reported in less than 1% of patients with the use of clindamycin vaginal products include inflammatory swelling, hyperthyroidism, epistaxis, fever, generalized pain, localized edema, and fatigue.

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.6 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.2 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.2 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.2 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.6 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.

Niacin interferes with glucose metabolism and can result in hyperglycemia.2 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.

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan.2 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.

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.

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.

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

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.

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

Tretinoin

Skin changes can occur with both topical and oral tretinoin, but are more common with topical therapy. Almost all patients report a local inflammatory response, which is reversible following discontinuance of topical treatment. Almost all patients using topical tretinoin reported skin irritation such as peeling, xerosis (dry skin), burning, stinging, erythema, and pruritus. In 32% of all study patients, severe skin irritation led to temporary discontinuation of topical tretinoin 0.02% (about 7%), or led to use of a mild topical corticosteroid. About 7% of patients using tretinoin 0.02%, compared to less than 1% of the control patients, had sufficiently severe local irritation to warrant short-term use of mild topical corticosteroids to alleviate local irritation. About 4% of patients had to discontinue use of topical tretinoin because of adverse reactions. If severe erythema, edema, vesicle formation (e.g., vesicular rash), or crusting develops, topical tretinoin should be discontinued until skin integrity is restored. Therapy may be reinitiated with less frequent application or a lower concentration. Skin hyperpigmentation and skin hypopigmentation have been reported in about 2% of patients with topical tretinoin therapy, with resolution following discontinuation of tretinoin. Some patients experience increased photosensitivity during topical or oral tretinoin therapy; patients should use sunscreen (minimum SPF 15) and protective clothing. Patients with sunburn should not use topical tretinoin until fully recovered.4445 Dry skin/mucous membranes were reported in the majority of patients (77%) receiving oral tretinoin. Other dermatologic adverse reactions reported with oral tretinoin include rash (unspecified) (54%), pruritus (20%), alopecia (14%), unspecified skin changes (14%), cellulitis (8%), facial edema (6%), and pallor (6%). Isolated cases of erythema nodosum and Sweet’s syndrome have also been reported with oral tretinoin.

Storage

Store this medication 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.

Refrences

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4.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.
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25.Altreno (tretinoin lotion) package insert; Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2018 Aug.
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35.Tretinoin capsules package insert. Sellersville, PA: Teva Pharmaceuticals; 2009 Jun.
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40.Clindesse (clindamycin vaginal cream 2%) package insert. St. Louis, MO: Ther-Rx Corporation; 2011 May.
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