Rosacea AIMN Cream

Azelaic Acid

In addition to being commonly found in a variety of grains, azelaic acid is also produced spontaneously by the yeast that lives on healthy skin.^[1] It is a potent antioxidant with powerful anti-inflammatory and antibacterial properties that may show promising results including^[2] It brightens skin tone, visibly improves skin texture, reduces the visibility of blemishes.

Additionally, azelaic acid has keratolytic properties, which means it could aid in the normalization of abnormal skin growths.^[2] It is commonly used to treat acne, research has demonstrated that azelaic acid may be used to effectively treat rosacea, flaky skin, and hyper-pigmentation.^[3]

Ivermectin

Ivermectin belongs to the avermectin class of antiparasitic drugs, specifically dihydroavermectin B1. Despite not having any antibacterial properties, ivermectin shares structural similarities with macrolide antibiotics. Avermectins are produced naturally by the actinomycete Streptomycetes avermetilis. Ivermectin lotion is used topically to treat Pediculosis capitis (head lice). Ivermectin cream is used topically for the treatment of inflammatory lesions of rosacea. Oral ivermectin is used in treating infections due to Onchocerca volvulus (onchocerciasis) or Strongyloides stercoralis (strongyloidiasis). Ivermectin is only active against the tissue microfilariae of Onchocerca volvulus and the intestinal stage of Strongyloides stercoralis; ivermectin has no activity against adult Onchocerca volvulus. Although not FDA-approved for infections due to Sarcoptes scabiei (scabies), crusted (Norwegian) scabies, or superinfected scabies, ivermectin has been used successfully to treat these conditions.^[4][5] Ivermectin is effective against the circulating microfilariae of Wuchereria bancrofti (responsible for Bancroft’s filariasis) and other major filarial diseases (i.e., Loa loa).^[6] However, ivermectin is not effective against Mansonella perstans.^[7] Ivermectin has also demonstrated promise for the treatment of nematodes such as cutaneous larva currens and localized and disseminated cutaneous larva migrans. Ivermectin is recommend by The World Health Organization (WHO) for treating onchocerciasis (river blindness) and lymphatic filariasis (Bancroft’s filariasis). Resistance to ivermectin has not been reported. Ivermectin oral tablets were FDA-approved in November 1996. Ivermectin lotion was approved in February 2012. Ivermectin cream was approved in December 2014.

Metronidazole

Metronidazole is a member of the nitroimidazole class of synthetic antibacterial and antiprotozoal agents. It is a successful treatment for protozoa like giardiasis, amebiasis, and Trichomonas vaginalis. In addition, it is one of the most effective drugs available against anaerobic bacterial infections.^[8] Metronidazole is also used off-label to treat Crohn’s disease, antibiotic-associated diarrhea, and rosacea. Metronidazole can be used as a component of multiple regimens that have been shown effective to treat Helicobacter pylori (H. pylori) gastrointestinal infection. Combination therapy is necessary for successful eradication of H. pylori and to avoid the development of resistance, especially metronidazole resistance, which is prevalent in the US and many other countries.^[9][10] High eradication rates for H. pylori gastrointestinal infection have been documented with triple-drug regimens that include a proton pump inhibitor (PPI), clarithromycin, and metronidazole (or amoxicillin).^[11] Neurotoxicity, generally reversible, has been reported with metronidazole therapy.^[12]

Niacinamide

Vitamin B-complex, also known as nicotinic acid or 3-pyridinecarboxylic acid, is niacin. Animal proteins, beans, green vegetables, liver, mushrooms, peanuts, whole wheat, and unpolished rice are good dietary sources of niacin. 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.^[13] 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.^[14] 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.^[15] 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.^[16] 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.^[17] Some dosage forms are available without prescription. The FDA officially approved niacin in 1938.

Azelaic Acid

The efficacy of azelaic acid in acne vulgaris is due to an antimicrobial effect and an antikeratinizing effect on the follicular epidermis. The antimicrobial effects of azelaic acid involves inhibition of synthesis of microbial cellular proteins; the exact mechanism of action is unknown. Azelaic acid possesses bacteriostatic properties against a variety of aerobic microorganisms, especially Staphylococcus epidermidis and Propionibacterium acnes which are known to be elevated in acne-bearing skin; at high concentrations, azelaic acid is bactericidal against S. epidermidis and P. acnes. By reducing the concentration of bacteria present on the skin, azelaic acid decreases the inflammation associated with acne lesions. Azelaic acid may also possess a direct anti-inflammatory effect by scavenging oxygen radicals. The antikeratinizing effects of azelaic acid may be due to decreased synthesis of filaggrin (keratin filament aggregating protein). By inhibiting filaggrin, azelaic acid may normalize the keratinization of the follicle and produce a reduction in noninflamed acne lesions. Azelaic acid does not affect sebum excretion.

The mechanism of action that results in the efficacy of azelaic acid in acne rosacea is not clear; clinical studies suggest interference with the pathogenic effects in rosacea. Anti-inflammatory effects have been noted in vitro.

The antiproliferative and cytotoxic actions of azelaic acid may be due to reversible inhibition of a variety of oxidoreductive enzymes including DNA polymerase, tyrosinase, and mitochondrial enzymes of the respiratory chain. At the cellular level, azelaic acid causes mitochondrial swelling and accumulation of cytoplasmic lipid droplets. Azelaic acid has shown efficacy in treating such conditions as lentigo maligna, cutaneous malignant melanoma, and melasma (chloasma). When azelaic acid is applied topically in these conditions, there is a reduction in epidermal melanogenesis and replacement of abnormal melanocytes by normal cells; flattening of nodular areas may also occur. Hyperactive and malignant melanocytes are much more susceptible to the effects of azelaic acid than are normal melanocytes.

Ivermectin

Ivermectin is one of the broad-spectrum antiparasitic avermectins. They attach to glutamate-gated chloride ion channels found in invertebrate nerve and muscle cells with great selectivity and affinity. This binding leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. This class of compounds may also bind with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA). The avermectins’ selectivity is due to the fact that some mammals do not have glutamate-gated chloride channels and that the avermectins have a low affinity for mammalian ligand-gated chloride channels. Ivermectin does not cross the blood-brain barrier in humans.

Niacinamide

Nicotinamide or nicotinic acid, both of which are vitamins, can be consumed to fulfill dietary requirements for niacin. They both serve the same biological purposes. 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.

Azelaic Acid

Patients who have a known hypersensitivity to propylene glycol should not use azelaic acid products that contain it; similarly, patients who are hypersensitive to any other ingredients in the prescribed formulation should not use it.
^[18] It has not been well-studied in patients with dark complexions and should be used cautiously in these patients to avoid hypopigmentation.^[18][19]

An occlusive dressing should not be used with azelaic acid. Avoid ocular exposureand accidental exposure/contact with the mouth and other mucous membranes. If contact with the eye(s) occur, the eye(s) should be washed with large amounts of water; patients should contact their physician if ocular irritation persists. The safety and effectiveness of azelaic acid cream and gel formulations in neonates, infants, and children under 12 years of age have not been established. The foam formulation is not approved for use in pediatric patients less than 18 years of age.^[19]

Do not apply azelaic acid to areas affected by herpes labialis; exacerbations of herpes infection have been reported.

Worsening or deterioration of asthma has been observed in patients treated with azelaic acid. Instruct drug recipients to contact their physician if signs of an asthma exacerbation (i.e., dyspnea, wheezing) develop during therapy.^[18]

Ivermectin

FDA approval is not available for ivermectin to treat or prevent COVID-19 because it is not an antiviral medication. Any medication used off-label can have major side effects. Ivermectin intended for veterinary use in animals has not been evaluated for use in humans. Animal products are often highly concentrated and such high doses can be toxic in humans. Do not use veterinary ivermectin products as substitutes for FDA-approved human ivermectin products prescribed by a health care provider for appropriate indications.^[20][21]

Ivermectin is contraindicated in patients with hypersensitivity to any component of the product.^[22]

Patients with a history of severe asthma should receive ivermectin with caution. Occasionally, systemic ivermectin has been reported to worsen bronchial asthma.^[22]

Although not extensively studied, due to its extensive hepatic metabolism, ivermectin should be administered with caution in patients with significant hepatic disease.^[22]

In patients with immunosuppression (including those with human immunodeficiency virus (HIV) infection) treated for intestinal strongyloidiasis, repeated ivermectin courses may be necessary. Adequate and well-controlled clinical studies have not been conducted in such patients to determine the optimal dosing regimen. Several treatments (i.e., at 2 week intervals) may be required and a cure may not be achievable. Control of extra-intestinal strongyloidiasis in these patients is difficult, however, suppressive therapy (i.e., once per month) may be helpful.^[22]

Data with oral ivermectin use during pregnancy are insufficient to inform a drug-associated risk. Systemic exposure from topical use of ivermectin is much lower than from oral use. Four published epidemiology studies evaluated the outcomes of a total of 744 women exposed to oral ivermectin in various stages of pregnancy. In the largest study, 397 women in the second trimester of pregnancy were treated open-label with single doses of ivermectin or ivermectin plus albendazole; there was no observed difference in pregnancy outcomes between treated and untreated populations. However, these studies cannot definitely establish or exclude the absence of drug-associated risk during pregnancy, because either the timing of the administration during gestation was not accurately ascertained or the administration only occurred during the second trimester. In animal embyrofetal development studies of oral ivermectin given during organogenesis, adverse developmental outcomes, including cleft palate, exencephaly, wavy ribs, and clubbed forepaws, occurred at or near doses that were maternally toxic. Pre-implantation loss and abortion were also noted.^[22][23]

After oral administration, ivermectin is excreted in human breast milk in low concentrations. Excretion in human breast milk after topical administration has not been evaluated.^[22][23] According to the manufacturer, treatment with oral ivermectin in mothers who are breast-feeding should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn.^[22] Previous American Academy of Pediatrics (AAP) recommendations considered oral ivermectin to be usually compatible with breast-feeding.^[24] The amount of ivermectin present in human milk after topical application has not been studied; however, systemic exposure from topical ivermectin use is much lower than from oral use. According to the manufacturer, discontinue nursing or discontinue the topical cream, taking into account the importance of the drug to the mother.^[23] Women who are breast-feeding while using topical ivermectin should avoid accidental transfer of ivermectin to the breast area where it might be directly ingested while nursing.^[25]

The topical administration of ivermectin to infants and children should be under the direct supervision of an adult to prevent ingestion of the lotion.^[26]

Rarely, patients with onchocerciasis and Loa loa coinfection may develop a serious or even fatal encephalopathy either spontaneously or after treatment with an effective microfilaricide. This syndrome has been seen very rarely after the use of ivermectin. In individuals who warrant treatment with ivermectin for any reason and have had significant exposure to Loa loa-endemic areas of West and Central Africa, pretreatment assessment for loiasis and careful posttreatment follow-up is recommended.^[22]

Patients with hyperreactive onchodermatitis (i.e., sowda) may be more likely than others to experience severe edema and worsening of onchodermatitis after ivermectin use.^[22]

Metronidazole

Patients with a history of metronidazole or other nitroimidazole derivative hypersensitivity should not take metronidazole. Systemic metronidazole should be used with care in patients with evidence of or history of hematological disease; monitor complete blood count (CBC) in these patients. Agranulocytosis, leukopenia, and neutropenia have been associated with systemic metronidazole administration.^[27]

Systemic metronidazole and its metabolites may accumulate significantly in patients with severe renal impairment or end stage renal disease (renal failure), including in patients receiving peritoneal dialysis, due to reduced urinary excretion. Monitor for metronidazole-associated adverse events.^[12][27]

Use metronidazole injection with caution in patients with cardiac disease, heart failure, or who are otherwise predisposed to edema, because it contains 28 mEq of sodium per gram of metronidazole. This large amount of sodium can promote sodium retention and exacerbate peripheral edema or congestive heart failure. QT prolongation has been reported with metronidazole use. Use metronidazole with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.^{[28][29][27][30][31][32][33]}

Metronidazole, when given systemically, has been reported to be carcinogenic in mice and rats. Similar studies in the hamster gave negative results. Also, metronidazole has shown mutagenic activity in a number of in vitro assay systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage. Human data are not available to describe the risk of a new primary malignancy secondary to use. The boxed warning states that systemic metronidazole use should be reserved for conditions where the drug is clearly needed; avoid unnecessary use.^{[12][34][27][35]} Vaginal and topical forms of metronidazole do not carry the boxed warning regarding carcinogenicity.^[36][37][38]

Oral, injectable, and intravaginal dosage forms of metronidazole should be used with caution in patients with alcoholism or ethanol intoxication. Metronidazole may interfere with the metabolism of ethanol, resulting in disulfiram-like effects. Patients should try to avoid ethanol ingestion to avoid the risk of undesirable side effects. It is recommended that alcoholic beverages or medicines not be used concurrently with metronidazole or for at least 3 days following the discontinuation of the drug. Psychotic reactions have been reported in alcoholic patients on metronidazole and disulfiram therapy.^[12][27][39]

Metronidazole use may result in candidal overgrowth. Known or previously unrecognized candida fungal infection may present more prominent symptoms during therapy with metronidazole and requires treatment with an appropriate antifungal agent.^[12]

Crohn’s disease patients are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established.^{[35][27][12][34][39][37][38]}

Topical metronidazole gels or creams contain ingredients that may cause burning and irritation of the eye. In the event of accidental ocular exposure, rinse the eye with copious amounts of cool tap water.^[37]

Metronidazole may be used to treat certain sexually transmitted diseases (STD). All patients with a diagnosed or suspected STD should be tested for other STDs, which may include HIV, syphilis, chlamydia, and gonorrhea, at the time of diagnosis. Initiate appropriate therapy and perform follow-up testing as recommended based upon sexually transmitted disease diagnosis.^[40]

Reduce metronidazole dose in patients with severe hepatic disease or impairment (Child-Pugh C) or hepatic encephalopathy due to slowed metabolism and accumulation in plasma, which may cause exacerbations of CNS adverse events in patients with hepatic encephalopathy. Monitor patients with mild to moderate hepatic impairment for metronidazole-associated adverse effects.^[12][27]

Use metronidazole in patients with Cockayne syndrome only if no alternative treatment is available. Cases of severe hepatotoxicity and acute hepatic failure, including a fatal outcome with very rapid onset after treatment initiation with systemic metronidazole, have been reported in these patients. Obtain liver function tests prior to the start of therapy, within the first 2 to 3 days after initiation of therapy, frequently during therapy, and after the end of treatment. Discontinue metronidazole if there is an elevation of liver function tests, and monitor until baseline values are reached. Advise patients with Cockayne syndrome to stop taking metronidazole immediately and contact their healthcare provider if they experience any symptoms of potential hepatic injury, such as abdominal pain, nausea, change in stool color, or jaundice.^[27]

Use intravenous formulations of metronidazole with caution in patients that require sodium restriction, those on corticosteroid therapy, and those predisposed to edema. Certain formulations of intravenous metronidazole may contain sodium.^[27]

Systemic metronidazole therapy may cause laboratory test interference with certain laboratory measurements, such as AST, ALT, LDH, triglycerides, and hexokinase glucose; values of zero may be noted. All of the assays in which interference has been observed use enzymatic coupling of the assay to oxidation reduction of nicotinamide adenine dinucleotide. Interference is due to the similarity in the absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at a pH of 7. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values.^[12][27] Antimicrobials are also known to suppress H. pylori; thus, ingestion of these agents within 4 weeks of performing diagnostic tests for H. pylori may lead to false negative results. At a minimum, instruct the patient to avoid the use of metronidazole in the 4 weeks prior to the test.^[41][11]

Use metronidazole with caution in geriatric patients as they may also be at increased risk for QT prolongation.^{[28][29][27][30][31][32][33]} Additionally, geriatric patients may be likely to have hepatic impairment or renal impairment and the hepatic metabolism and/or renal clearance of metronidazole may be reduced. Therefore, monitoring of clinical response may be necessary to adjust the metronidazole dosage accordingly. No overall differences have been reported in safety and effectiveness between younger and older adult patients, but greater sensitivity of some older patients cannot be ruled out.^[12][27][35] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.^[42]

Oral metronidazole is contraindicated during the first trimester of pregnancy in patients with trichomoniasis.^[12] However, guidelines suggest metronidazole use for trichomoniasis at any stage of pregnancy as studies have not demonstrated an association between metronidazole and teratogenic effects.^[40] For indications other than trichomoniasis, avoid metronidazole during pregnancy whenever possible, with use occurring only after careful assessment of the potential risk to benefit ratio.^[12] Available data on metronidazole use in pregnant women from published cohort studies, case-control studies, case series, meta-analyses, and case reports over several decades have not established a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproductive studies, no adverse developmental effects were demonstrated when oral metronidazole was administered at doses up to 6 times the recommended human dose.^[43] While not an animal teratogen, systemically absorbed metronidazole readily crosses the placenta and enters the fetal circulation. Reports in humans are conflicting, and the effects of metronidazole on human fetal organogenesis are not known.^[12] In a large population-based cohort study (n = 139,938 live births) assessing antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, metronidazole use was not associated with an increased risk of major congenital malformations or organ specific major congenital malformations.^[44] However, in a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, metronidazole use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 1.7; 95% CI: 1.27 to 2.26; 53 exposed cases); residual confounding by severity of infection may be a potential limitation of this study.^[45]

Metronidazole is excreted into breast milk. Breast-feeding is not recommended during treatment with systemic products.^{[12][34][27][35]} There are no data on the presence of metronidazole in human milk after intravaginal administration.^[43] Because of the possibility of some systemic absorption after intravaginal administration, interrupt breast-feeding for 48 hours after the last intravaginal dose and feed the infant with previously stored human breast milk or formula.^[43][46] The 0.75% vaginal gel achieves 2% of the mean maximum serum concentration of a 500 mg oral dose.^[43] Caution is advised with other topical products.^[37] Metronidazole is a mutagen in vitro and has been shown to be carcinogenic in animal studies.^{[24][12][34][27][35]} In general, increased oral and rectal Candida colonization and loose stools have been reported in infants exposed to metronidazole via breast milk.^[47] Guidelines recommend a single 2 g oral dose for the treatment of trichomoniasis during breast-feeding.^[40] Previous American Academy of Pediatrics (AAP) recommendations suggested that if a single 2 g oral dose is given for trichomoniasis, then breast-feeding may be resumed in 12 to 24 hours; otherwise, breast-feeding may be resumed within 24 to 48 hours after the last dose of treatment is completed if other dosage regimens are used.^[24] In a study of 3 patients that received a single 2 g oral dose, peak milk concentrations ranged between 50 and 60 mcg/mL at 2 to 4 hours after the dose. If breast-feeding were to continue, the estimated infant exposure during the next 48 hours would be 25.3 mg; if breast-feeding was interrupted for 12 hours, the estimated 48-hour exposure would be 9.8 mg, and if breast-feeding was interrupted for 24 hours, the estimated 48 hour exposure would be 3.5 mg.^[48] In studies of women receiving 600 mg/day, metronidazole milk concentrations ranged from 1.1 to 15.2 mcg/mL and in patients receiving 1,200 mg/day concentrations ranged from 9.02 to 15.52 mcg/mL. The mean milk:plasma ratio in both groups was approximately 1, and the mean plasma concentrations in the exposed infants were approximately 20% of the maternal plasma concentration.^[49][50][47] Depending on the indication, oral vancomycin, amoxicillin; clavulanate, ampicillin; sulbactam, or clindamycin (systemic or intravaginal) may be potential alternatives to consider during breast-feeding. Assess site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility before choosing an alternative agent. Vancomycin is excreted in breast milk; however, absorption from the GI tract of any ingested vancomycin would be minimal.^[51][52] Alternative antimicrobials that previous AAP recommendations considered as usually compatible with breast-feeding include clindamycin and penicillins.^[24]

Niacinamide

The medication should not be administered to patients who have a history of niacin or any other product component hypersensitivity.

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.^[53] 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.^[54] 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.^[13] 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.^[13] 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.^[55] 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.^[42]

Azelaic Acid

Most side effects occurring with the use of azelaic acid are dermatologic in nature and mild in severity. These effects include burning sensation or stinging (1—6.2%), paresthesias or tingling (1—6.2%), pruritus (1—5%), xerosis (dry skin, < 5%), erythema (< 2%), skin irritation (< 2%), contact dermatitis (< 1%), rash (unspecified) (< 1%), peeling (< 1%), dermatitis (< 1%), and edema (< 1%). In patients with dark complexions, skin hypopigmentation may occur. The following additional adverse reactions have been reported rarely: vitiligo depigmentation, small depigmented spots, hypertrichosis, reddening (signs of keratosis pilaris), and exacerbation of recurrent herpes viral infection (i.e., herpes labialis).^[58][18][19] Post-marketing use of azelaic acid has been associated with the development of hypersensitivity reactions (including angioedema, ocular inflammation, facial swelling, and urticaria) and asthma exacerbation (i.e., dyspnea, wheezing). In addition, cases of iridocyclitis, or inflammation of the iris, have been noted following accidental exposure of the eye to the topical gel. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.^[18]

Ivermectin

Worsening of bronchial asthma has been reported with systemic ivermectin use in post-marketing experience.^[22]

Ivermectin is generally well tolerated, particularly with single-dose use. Compared to other antiparasitics used for similar indications, fewer adverse effects and better compliance are usually seen with ivermectin. Adverse events are typically not dose-related. The side effects reported in clinical experience have varied according to the underlying disease or indication for treatment. In patients being treated for onchocerciasis, the most common adverse reactions were related to allergic and inflammatory responses to the death of the microfilariae (the Mazzotti reaction). Especially in severe onchocerciasis disease, ivermectin may be administered with a corticosteroid, an antihistamine, or another antiinflammatory agent to minimize these reactions. Patients with hyperreactive onchodermatitis (sowda) may be more likely than others to experience severe adverse reactions, especially edema and aggravation of onchodermatitis. Mazzotti-type and ophthalmologic reactions associated with the treatment of onchocerciasis or the disease itself would not be expected in patients with strongyloidiasis being treated with ivermectin.^[22]

In patients being treated for onchocerciasis with ivermectin, adverse reactions related to allergic and inflammatory responses to the death of the microfilariae (the Mazzotti reaction) include arthralgia/synovitis (9.3%) as well as axillary, cervical, inguinal, and other lymph node enlargement (lymphadenopathy, 3—12.6%) and tenderness (1.2—13.9%).^[22]

In patients being treated for onchocerciasis with systemic ivermectin, adverse reactions related to allergic and inflammatory responses to the death of the microfilariae (the Mazzotti reaction) include pruritus (27.5%) and other skin involvement that may manifest as angioedema (1.2%), peripheral edema (3.2%), rashes including maculopapular rash, pustular rash, or urticaria (22.7%). Adverse reactions associated with strongyloidiasis treatment include pruritus (2.8%), rash (unspecified) (0.9%), and urticaria (0.9%). Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with ivermectin use in postmarketing experience.^[22] Adverse reactions reported in 1% or less of patients treated with ivermectin topical lotion and/or cream in trials include xerosis, and skin burning sensation/skin irritation.^[25][23][26] Contact dermatitis and allergic dermatitis were reported in postmarketing use of ivermectin topical cream.^[23]

In patients being treated for onchocerciasis with ivermectin, adverse reactions related to allergic and inflammatory responses to the death of the microfilariae (the Mazzotti reaction) include fever (22.6%).^[22]

Adverse reactions associated with ivermectin used for strongyloidiasis treatment include asthenia/fatigue (0.9%).^[22]

Adverse reactions associated with ivermectin used for strongyloidiasis treatment include abdominal pain (0.9%), anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), and nausea (1.8%), vomiting (0.9%).^[22]

Adverse reactions associated with ivermectin used for strongyloidiasis treatment include dizziness (2.8%), somnolence/drowsiness (0.9%), vertigo (0.9%), and tremor (0.9%). Seizures have been reported with ivermectin use in post-marketing experience.^[22]

Ophthalmological conditions (i.e., limbitis, punctate opacity) were examined in clinical trials involving adult onchocerciasis patients who received oral ivermectin. The ophthalmological changes observed were primarily deterioration from baseline 3 days post-treatment. Most changes returned to baseline or improved over baseline after 3 to 6 months. Significant adverse effects, such as visual impairment (e.g., loss of vision), do rarely occur and can occur with river blindness itself, but have also been reported with ivermectin therapy. These effects include abnormal sensation of the eyes, eyelid edema, anterior uveitis, conjunctivitis, limbitis, keratitis, and chorioretinitis or choroiditis. These effects generally resolve after treatment with corticosteroids. Conjunctival hemorrhage (ocular hemorrhage) has been reported with systemic ivermectin use for onchocerciasis in postmarketing experience.^[22] Adverse reactions reported in less than 1% of patients treated with ivermectin lotion include conjunctivitis, ocular hyperemia, and ocular irritation.^[25][26]

Orthostatic hypotension (1.1%) and sinus tachycardia (3.5%) have been reported with systemic ivermectin use.^[22]

Elevated hepatic enzymes have been reported in 2% of patients treated with systemic ivermectin. Hepatitis and hyperbilirubinemia have been reported post-marketing.^[22]

Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a serious or even fatal encephalopathy, either spontaneously or after treatment with an effective microfilaricide. This syndrome has been seen very rarely after the use of ivermectin. These patients may also experience back pain, neck pain, red eye, conjunctival hemorrhage, dyspnea, urinary incontinence, fecal incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, seizures, or coma.^[22]

Although studies are conflicted, patients treated with ivermectin may have prolonged bleeding time due to a potential antagonistic effect with vitamin K. One study reported hematomatous swellings in 2 of 28 onchocerciasis patients treated with ivermectin, with prothrombin times significantly above baseline from one week to one month after treatment.^[59] An additional study showed prolonged prothrombin ratios in 148 patients given ivermectin. There were no reported bleeding complications; however, Factor II and VII levels were reduced in most patients with increased prothrombin times.^[60] In contrast, another study of 20 patients reported no changes in prothrombin times compared with baseline for 13 days after treatment.^[61] Bleeding disorders were also not found in 15,000 patients treated with ivermectin.^[62] Although there is no direct interaction with warfarin noted in the literature, coadministration of ivermectin and warfarin should be used with caution as there may be potentiation of prolonged prothrombin time. Post-marketing reports of increased INR have been rarely reported with the co-administration of ivermectin and warfarin.^[22] Patients with potential increased prothrombin times, such as those on warfarin, should use ivermectin with caution.

Decreased leukocyte count (3%), eosinophilia (3%), and increased hemoglobin (1%) have been reported with the use of systemic ivermectin. Leukopenia and and anemia were reported in one patients treated for strongyloidiasis.^[22]

Metronidazole

Gastrointestinal adverse reactions to metronidazole therapy include nausea (10% systemic; 1.6% to 4% vaginal product), vomiting (less than 1% to 4% vaginal product), xerostomia (dry mouth) (2% systemic and vaginal products), dysgeusia (usually manifested as a metallic taste) (9% systemic; 2% vaginal product), anorexia (less than 1% vaginal product), epigastric distress, abdominal cramping, constipation (less than 1% vaginal product), diarrhea (4% systemic; 1% to 2% vaginal product), abdominal pain or discomfort (4% systemic; 5% vaginal product), gastrointestinal discomfort (7% vaginal product), decreased appetite (1% vaginal product), abdominal bloating/gas, thirst, asthenia, flatulence (less than 1% vaginal product), gingivitis (less than 1% vaginal product), and dyspepsia (less than 1% vaginal product). Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39][46]}

Central and peripheral neurotoxicity has occurred from metronidazole. Severe neurological disturbances that have been reported include encephalopathy, cerebellar symptoms, convulsive seizures, peripheral neuropathy, optic neuropathy, and aseptic meningitis. Encephalopathy may manifest as confusion or decreased level of consciousness, and is associated with widespread lesions on MRI of the brain. Cerebellar toxicity may manifest as ataxia, dizziness (4% ER tab; less than 1% to 2% vaginal product), dysarthria, nystagmus, and saccadic pursuit (saccadic eye movement). It is accompanied by T2 flair lesions within the dentate nuclei seen on MRI. Cerebellar toxicity may concurrently occur with encephalopathy, peripheral neuropathy, or seizures. CNS symptoms and CNS lesions are generally reversible, with symptoms resolving within days to weeks after discontinuation of metronidazole therapy. Peripheral neuropathy, usually symmetric and mainly of sensory type, is characterized by numbness and paresthesias of the extremities. Symptoms may be prolonged after drug discontinuation. Aseptic meningitis may occur within hours of dose administration and generally resolves after discontinuation of therapy. Advise patients to report neurologic symptoms; discontinue treatment if any abnormal neurologic symptoms occur. Other adverse reactions during metronidazole therapy include confusion, depression (less than 1% vaginal product), insomnia (less than 1% vaginal product), hypoesthesia, headache (18% ER tab; 2.2% topical product; 2.2 to 7% vaginal product), somnolence (drowsiness), syncope, vertigo, incoordination, irritability, weakness, and psychosis. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39][46][66]}

Blood and lymphatic system disorders that have been reported with the use of metronidazole include agranulocytosis, leukopenia, neutropenia, thrombocytopenia, and eosinophilia. Increased/decreased white blood cell counts have been reported in 1.7% of patients receiving the vaginal products. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39]}

Hypersensitivity and anaphylactoid reactions have been reported in patients receiving metronidazole. Hypersensitivity or skin adverse events include toxic epidermal necrolysis, swelling of the face (angioedema), pruritus (1.6% to 6% vaginal product; less 3% than topical product), urticaria (less than 1% vaginal product), hyperhidrosis, erythema, rash (1% vaginal product), Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), flushing, nasal congestion (1.1% topical product), fever, acne vulgaris (less than 1% vaginal product; 0.5% topical product), sweating/diaphoresis (less than 1% vaginal product), and dryness of the vagina or vulva. Localized effects that have been reported in association with the use of topical (dermal) formulations include contact dermatitis (1.3% to 3%), application site reaction (0.5%), aggravated condition (0.5% to less than 3%), ocular irritation, skin irritation (burning/stinging) (less than 3%), transient skin erythema (less than 3% to 6%), dry skin/xerosis (1.1%), and redness. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal metronidazole products.^{[12][34][27][35][37][63][64][38][65][43][39]}

Phlebitis can occur from IV infusion of metronidazole and can be prevented by avoiding prolonged use of indwelling IV catheters. Patients receiving parenteral metronidazole should be monitored for an injection site reaction.^[27][66]

Urinary side effects of metronidazole include chromaturia (urine discoloration), dysuria (less than 1% vaginal product), cystitis, polyuria, urinary incontinence, increased urinary frequency (less than 1% vaginal product), and a sense of pelvic pressure. Although the pigment that is responsible darkened urine has not been positively identified, it is likely a metabolite of metronidazole and seems to have no clinical significance. Abnormal urine was noted in 3% of patients receiving the ER tablet. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39]}

Pancreatitis has been reported with the use of metronidazole. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][37][43][39][63][64][38][65][35]}

As with any antibiotic, the use of metronidazole alters the normal flora and may result in superinfection. Metronidazole therapy may cause Candida overgrowth and candidiasis (3% ER tabs; 12% vaginal product) including oral candidiasis or vaginal candidiasis (0.2% topical product; 5.6% to 10% vaginal product). Other adverse effects include furry tongue, glossitis, and stomatitis which may be related to Candida overgrowth. Other types of infection have been reported in studies including unspecified bacterial infection (7% ER tab), influenza-like symptoms (6% ER tab; 1.4% topical product; less than 1% vaginal product), upper respiratory tract infection (4% ER tab; 2.5% topical product), urinary tract infection (2% ER tab; 1.1% topical product; less than 1% vaginal product), unspecified infection (1% vaginal product), pyelonephritis (less than 1% vaginal product), and salpingitis (less than 1% vaginal product). Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39][46]}

Metronidazole is mutagenic in vitro and carcinogenic in rodents. However, human data are not available to describe the potential for a new primary malignancy secondary to use. Crohn’s disease patients are known to have an increased incidence of new primary malignancy, including GI and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole systemically at high doses for extended periods of time. A cause and effect relationship has not been established.^[12] Basal cell carcinoma was reported in 0.2% of patients using the topical gel product.^[37]

Genital and reproductive adverse events have been reported with the use of metronidazole and include dyspareunia, proctitis, and libido decrease. Vaginitis was reported in 15% of patients receiving the ER tablet and in less than 1% of patients using the vaginal gel. Dysmenorrhea occurred in 3% of patients using the ER tablet and 1.2% to 3% of patients using the vaginal gel. Genital pruritus/pruritus ani was reported in 5% of patients receiving the ER tablet. Other side effects reported with the vaginal gel include vaginal discharge (12%), vulva or vaginal irritation or dryness (9%), pelvic discomfort (3%), breast pain (1%), and metrorrhagia (1%). Adverse events occurring in less than 1% of patients using the vaginal gel include breast enlargement, female lactation, labial edema, leukorrhea, menorrhagia, and vulvovaginal disorder. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39][46]}

Dyspnea, rhinitis (4% ER tabs; less than 1% vaginal product), sinusitis (3% ER tabs; 1.4% topical product), pharyngitis (3% ER tabs; 3.1% topical product; 2% vaginal product), bronchitis (1.1% topical product), and asthma (less than 1% vaginal product) have been noted in metronidazole clinical studies. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39]}

Palpitations and sinus tachycardia have occurred with the use of metronidazole.^[27] Hypertension was reported in 1.1% of patients using the topical gel.^[37] Also, ST-T wave changes (flattening of the T-wave) have been reported with metronidazole use.^[12] QT prolongation has been reported in a limited number of case reports with metronidazole use. One patient had a history of drug-induced QT prolongation associated with moxifloxacin, and therefore, may have been a carrier of a silent mutation in 1 of the congenital long QT syndrome-associated genes.^[31][32]

Arthralgia, muscle spasms (muscle cramps), myalgia, and fleeting joint pain sometimes resembling serum sickness has been reported with metronidazole use. Back pain was reported in less than 1% of patients receiving the vaginal gel. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39]}

General adverse events reported with metronidazole include malaise, face edema, peripheral edema, chest pain (unspecified), chills, and hiccups. Fatigue, unspecified cramping (1%), mucous membrane disorder (less than 1%), and unspecified pain (less than 1%) were reported with the use of metronidazole vaginal gel. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][34][27][35][37][63][64][38][65][43][39][66]}

Hepatotoxicity and hepatic failure have been reported in patients with Cockayne syndrome that have been exposed to metronidazole for systemic use. Elevated hepatic enzymes have also been reported with metronidazole. Although most adverse events have been reported with systemic metronidazole, systemic side effects have been reported with topical and vaginal products.^{[12][27][35][37][38][63][65][43][39][66]}

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.^[17] 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.^[13] 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.^[13] 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.^[13] 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.^[17] 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.^[13]

Niacin interferes with glucose metabolism and can result in hyperglycemia.^[13] 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.^[13]

Niacin, especially in high doses, can cause hyperuricemia. Gout has been reported in post-marketing surveillance of Niaspan.^[13] 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.^[13]

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.^[13]

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.^[13]

Niacin also has been associated with a variety of ophthalmic adverse effects including blurred vision and macular edema.^[13]

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.^[13][67]

During clinical trials, increased cough was reported in <2—8% (vs. 6%) of patients receiving Niaspan compared to placebo.^[13]

Azelaic Acid

Pregnancy risk category B is assigned by the FDA to azelaic acid. When taken orally, animal research indicates embryotoxic effects; teratogenic effects were not seen. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azelaic acid should be used during pregnancy only if clearly needed.^[18][56]

Ivermectin

Data with oral ivermectin use during pregnancy are insufficient to inform a drug-associated risk. Systemic exposure from topical use of ivermectin is much lower than from oral use. Four published epidemiology studies evaluated the outcomes of a total of 744 women exposed to oral ivermectin in various stages of pregnancy. In the largest study, 397 women in the second trimester of pregnancy were treated open-label with single doses of ivermectin or ivermectin plus albendazole; there was no observed difference in pregnancy outcomes between treated and untreated populations. However, these studies cannot definitely establish or exclude the absence of drug-associated risk during pregnancy, because either the timing of the administration during gestation was not accurately ascertained or the administration only occurred during the second trimester. In animal embyrofetal development studies of oral ivermectin given during organogenesis, adverse developmental outcomes, including cleft palate, exencephaly, wavy ribs, and clubbed forepaws, occurred at or near doses that were maternally toxic. Pre-implantation loss and abortion were also noted.^[22][23]

Metronidazole

Oral metronidazole is contraindicated during the first trimester of pregnancy in patients with trichomoniasis.^[12] However, guidelines suggest metronidazole use for trichomoniasis at any stage of pregnancy as studies have not demonstrated an association between metronidazole and teratogenic effects.^[40] For indications other than trichomoniasis, avoid metronidazole during pregnancy whenever possible, with use occurring only after careful assessment of the potential risk to benefit ratio.^[12] Available data on metronidazole use in pregnant women from published cohort studies, case-control studies, case series, meta-analyses, and case reports over several decades have not established a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproductive studies, no adverse developmental effects were demonstrated when oral metronidazole was administered at doses up to 6 times the recommended human dose.^[43] While not an animal teratogen, systemically absorbed metronidazole readily crosses the placenta and enters the fetal circulation. Reports in humans are conflicting, and the effects of metronidazole on human fetal organogenesis are not known.^[12] In a large population-based cohort study (n = 139,938 live births) assessing antibiotic exposure during the first trimester of pregnancy (n = 15,469 exposures) and the risk of major birth defects, metronidazole use was not associated with an increased risk of major congenital malformations or organ specific major congenital malformations.^[44] However, in a nested, case-control study (n = 87,020 controls; 8,702 cases) within the Quebec Pregnancy Cohort, metronidazole use during early pregnancy was associated with an increased risk of spontaneous abortion (adjusted odds ratio (aOR) 1.7; 95% CI: 1.27 to 2.26; 53 exposed cases); residual confounding by severity of infection may be a potential limitation of this study.^[45]

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.^[13]

Azelaic Acid

According to the manufacturer, caution should be exercised when azelaic acid is administered to breastfeeding women. In vitro studies assessing human milk partitioning suggests that azelaic acid may be distributed into breastmilk. However, since less than 4% of a topically applied dose is systemically absorbed, the uptake of azelaic acid into maternal milk is not expected to cause a significant change from baseline azelaic acid concentrations in the milk.^[18][57] 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.

Ivermectin

After oral administration, ivermectin is excreted in human breastmilk in low concentrations. Excretion in human breastmilk after topical administration has not been evaluated.^[22][23] According to the manufacturer, treatment with oral ivermectin in mothers who are breast-feeding should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn.^[22] Previous American Academy of Pediatrics (AAP) recommendations considered oral ivermectin to be usually compatible with breast-feeding.^[24] The amount of ivermectin present in human milk after topical application has not been studied; however, systemic exposure from topical ivermectin use is much lower than from oral use. According to the manufacturer, discontinue nursing or discontinue the topical cream, taking into account the importance of the drug to the mother.^[23] Women who are breast-feeding while using topical ivermectin should avoid accidental transfer of ivermectin to the breast area where it might be directly ingested while nursing.^[25]

Metronidazole

Metronidazole is excreted into breastmilk. Breast-feeding is not recommended during treatment with systemic products.^{[12][34][27][35]} There are no data on the presence of metronidazole in human milk after intravaginal administration.^[43] Because of the possibility of some systemic absorption after intravaginal administration, interrupt breastfeeding for 48 hours after the last intravaginal dose and feed the infant with previously stored human breast milk or formula.^[43][46] The 0.75% vaginal gel achieves 2% of the mean maximum serum concentration of a 500 mg oral dose.^[43] Caution is advised with other topical products.^[37] Metronidazole is a mutagen in vitro and has been shown to be carcinogenic in animal studies.^{[24][12][34][27][35]} In general, increased oral and rectal Candida colonization and loose stools have been reported in infants exposed to metronidazole via breast milk.^[47] Guidelines recommend a single 2 g oral dose for the treatment of trichomoniasis during breastfeeding.^[40] Previous American Academy of Pediatrics (AAP) recommendations suggested that if a single 2 g oral dose is given for trichomoniasis, then breast-feeding may be resumed in 12 to 24 hours; otherwise, breast-feeding may be resumed within 24 to 48 hours after the last dose of treatment is completed if other dosage regimens are used.^[24] In a study of 3 patients that received a single 2 g oral dose, peak milk concentrations ranged between 50 and 60 mcg/mL at 2 to 4 hours after the dose. If breastfeeding were to continue, the estimated infant exposure during the next 48 hours would be 25.3 mg; if breast-feeding was interrupted for 12 hours, the estimated 48-hour exposure would be 9.8 mg, and if breast-feeding was interrupted for 24 hours, the estimated 48 hour exposure would be 3.5 mg.^[48] In studies of women receiving 600 mg/day, metronidazole milk concentrations ranged from 1.1 to 15.2 mcg/mL and in patients receiving 1,200 mg/day concentrations ranged from 9.02 to 15.52 mcg/mL. The mean milk:plasma ratio in both groups was approximately 1, and the mean plasma concentrations in the exposed infants were approximately 20% of the maternal plasma concentration.^[49][50][47] Depending on the indication, oral vancomycin, amoxicillin; clavulanate, ampicillin; sulbactam, or clindamycin (systemic or intravaginal) may be potential alternatives to consider during breast-feeding. Assess site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility before choosing an alternative agent. Vancomycin is excreted in breast milk; however, absorption from the GI tract of any ingested vancomycin would be minimal.^[51][52] Alternative antimicrobials that previous AAP recommendations considered as usually compatible with breast-feeding include clindamycin and penicillins.^[24]

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.^[13] 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.^[55] There are no safety data regarding the use of nicotinic acid in doses above the RDA during breastfeeding. Consider the benefits of breastfeeding, 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.

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

1. Del Rosso, James Q. “Azelaic Acid Topical Formulations: Differentiation of 15% Gel and 15% Foam.” The Journal of Clinical and Aesthetic Dermatology 10.3 (2017): 37–40. Print.
2. Fariba Iraji, Ali Sadeghinia, Zabiholah Shahmoradi, Amir Hossein Siadat, Abolfazl Jooya. Efficacy of topical azelaic acid gel in the treatment of mild-moderate acne vulgaris. Department of Dermatology, Al-Zahra Hospital.
3. Cutis [01 Jan 1996, 57(1 Suppl):36-45]. Melanin hyperpigmentation of skin: melasma, topical treatment with azelaic acid, and other therapies.
4. Chouela E, Abeldano A, et el. Arch Dematol 1999;135:651-5.
5. del Giudice P, Chosidow O, Caumes E. Ivermectin in dermatology. J Drugs Dermatol 2003;2:13-21.
6. Richard-Lenoble D, Chandenier J, and Gaxotte P. Ivermectin and filariasis. Fundam Clin Pharmacology 2003;17:199-203.
7. Ottesen EA, Campbell WC. Ivermectin in human medicine. J Antimicrobial Chemotherapy 1994;34:195-203.
8. Lamp KC, Freeman CD, Klutman NE, et al. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet 1999;36:353-373.
9. Duck WM, Sobel J, Pruckler JM, et al. Antimicrobial resistance incidence and risk factors among Helicobacter pylori-infected persons, United States. Emerg Infect Dis 2004;10:1088-1094.
10. Meyer JM, Silliman NP, Wang W, et al. Risk factors for Helicobacter pylori resistance in the United States: The surveillance of H. pylori antimicrobial resistance partnership (SHARP) study, 1993-1999. Ann Intern Med 2002;136:13-24.
11. Chey WD, Leontiadis GI, Howden CW, et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol 2017;112:212-238.
12. Flagyl (metronidazole tablets) package insert. New York, NY: Pfizer, Inc.; 2021 Mar.
13. Niaspan (niacin extended-release) tablet package insert. North Chicago, IL: Abbott Laboratories; 2015 Apr.
14. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.
15. 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.
16. Lee JMS, Robson MD, Yu LM, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: A randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54:1787—94.
17. McKenney JM, et al. A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients. JAMA 1994;271:672-7.
18. Finacea (azelaic acid) topical gel package insert. Whippany, NJ: Bayer Healthcare; 2016 Aug.
19. Finacea (azelaic acid) 15% topical foam package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2015 Jul.
20. US Food and Drug Administration (FDA). FDA Medwatch: ivermectin intended for animals: letter to stakeholders – do not use in humans as a treatment for COVID-19. Retrieved April 14, 2020. Available on the World Wide Web at:https://www.fda.gov/safety/medical-product-safety-information/ivermectin-intended-animals-letter-stakeholders-do-not-use-humans-treatment-covid-19.
21. US Food and Drug Administration (FDA). FDA Medwatch consumer updates: why you should not use ivermectin to treat or prevent COVID-19. Retrieved March 8, 2021. Available on the World Wide Web at: https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-covid-19.
22. Stromectol (ivermectin) package insert. Whitehouse Station, NJ: Merck and Co., Inc.; 2018 Feb.
23. Soolantra (ivermectin) package insert. Fort Worth, TX: Galderma Laboratories; 2018 Apr.
24. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.
25. Sklice (ivermectin lotion) package insert. Atlanta, GA: Arbor Pharmaceuticals; 2017 Jun.
26. Sklice OTC (ivermectin lotion) package insert. Atlanta, GA: Arbor Pharmaceuticals; 2020 Oct.
27. Metronidazole injection package insert. Deerfield, IL: Baxter Healthcare Corporation; 2021 Mar.
28. Roden, DM. Drug-induced prolongation of the QT interval. New Engl J Med 2004;350:1013-22.
29. Crouch MA, Limon L, Cassano AT. Clinical relevance and management of drug-related QT interval prolongation. Pharmacotherapy 2003;23:881-908.
30. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol 2010;70(1):16-23.
31. Altin C, Kanyilmaz S, Baysal S, et al. QT interval prolongation due to metronidazole administration. Anadolu Kardiyol Derg 2011;11:46-9.
32. Cohen O, Saar N, Swartzon M, et al. First report of metronidazole-induced QT interval prolongation. Int J Antimicrob Agents 2008;31:180-81.
33. Woosley RL, Heise CW, Gallo T, et al. QTFactors List. Oro Valley, AZ: AZCERT, Inc.; Accessed March 31, 2020. Available on the World Wide Web at: https://crediblemeds.org/ndfa-list/
34. Flagyl ER (metronidazole extended release tablets) package insert. New York, NY: Pfizer, Inc.; 2021 Mar.
35. Flagyl (metronidazole capsules) package insert. New York, NY: Pfizer, Inc.; 2021 Mar.
36. Metrogel (metronidazole gel), 1% package insert. Fort Worth, TX: Galderma Laboratories, L.P.; 2011 Oct.
37. Metrogel (metronidazole gel 1%) package insert. Forth Worth, TX: G.D. Galderma Laboratories; 2011 Oct.
38. MetroCream (metronidazole 0.75% topical cream). Forth Worth, TX: Galderma Laboratories, L.P.; 2002 Dec.
39. Metrogel-Vaginal (metronidazole gel) package insert. Bristol, TN: Graceway Pharmaceuticals, LLC; 2007 Apr.
40. Centers for Disease Control and Prevention (CDC). Sexually Transmitted Diseases Treatment Guidelines 2015. MMWR. 2015;64(3):1-137
41. Jones NL, Koletzko S, Goodman K, et al. Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016). J Pediatr Gastroenterol Nutr 2017;64:991-1003.
42. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
43. Vandazole (metronidazole vaginal gel 0.75%) package insert. Maple Grove, MN: Upsher-Smith Laboratories, Inc.; 2021 Feb.
44. Muanda FT, Sheehy O, Berard A. Use of antibiotics during pregnancy and the risk of major congenital malformations: A population based cohort study. Br J Clin Pharmacol 2017; July 19 [Epub ahead of print].
45. Muanda FT, Sheehy O, Berard A. Use of antibiotics during pregnancy and risk of spontaneous abortion. CMAJ 2017;189:e625-e633.
46. Nuvessa (metronidazole vaginal gel 1.3%) package insert. Florham Park, NJ: Exeltis USA, Inc.; 2018 Aug.
47. Passmore CM, McElnay JC, Rainey EA et al. Metronidazole excretion in human milk and its effect on the suckling neonate. Br J Clin Pharmacol. 1988;26:45-51.
48. Erickson SH, Oppenheim GL, Smith GH. Metronidazole in breast milk. Obstet Gynecol 1981;57:48-50.
49. Heisterberg L, Branebjerg PE. Blood and milk concentrations of metronidazole in mother and infants. J Perinat Med 1983;11:114-20.
50. [No authors listed]. An evaluation of metronidazole in the prophylaxis of anaerobic infections in obstetrical patients. J Antimicrob Chemother 1978;4 Suppl C:55-62.
51. Vancocin HCl capsules (vancomycin hydrochloride) package insert. Baudette, MN: Ani Pharmaceuticals, Inc.; 2021 Jan.
52. Vancomycin 10 g bulk intravenous vials package insert. Lake Forest, IL: Hospira, Inc.; 2021 Mar.
53. Colletti RB, Neufeld EJ, Roff NK, et al. Niacin treatment of hypercholesterolemia in children. Pediatrics 1993;92:78-82.
54. Expert Panel: National Cholesterol Education Program. Report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics 1992;89(suppl 2):525-84.
55. Niacinamide. In: Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. Briggs GG, Freeman RK, Yaffe SJ, (eds.) 7th ed., Philadelphia PA: Lippincott Williams and Wilkins; 2005:1140-1
56. Azelex (azelaic acid) package insert. Irvine, CA: Allergan, Inc.; 2004 May.
57. Azelex (azelaic acid) package insert. Irvine, CA: Allergan, Inc.; 2004 May.
58. Azelex (azelaic acid cream) 20% [package insert]. Irvine, CA: Allergan; 2013.
59. Homeida MM, Bagi IA, Ghalib HW, et al. Prolongation of prothrombin time with ivermectin. Lancet 1988;1:1346-7.
60. Whitworth JA, Hay CR, McNicholas AM, et al. Coagulation abnormalities and ivermectin. Ann Trop Med Parasitol 1992;86:301-5.
61. Richards FO, McNeely MB, Bryan RT, et al. Ivermectin and prothrombin time. Lancet 1989;1:1139.
62. Pacque MC, Munoz B, White AT, et al. Ivermectin and prothrombin time. Lancet 1989;1:1140.
63. MetroLotion (metronidazole 0.75% topical lotion) package insert. Fort Worth, TX: Galderma Laboratories, L.P.; 2015 Oct.
64. Vitazol (metronidazole 0.75% topical cream) package insert. Rochester, NY: Rochester Pharmaceuticals; 2009 Dec.
65. Noritate (metronidazole 1% topical cream) package insert. Bridgewater, NJ: Dermik Laboratories; 2006 Dec.
66. Metronidazole (Metro IV) injection package insert. Bethlehem, PA: B.Braun Medical Inc.; 2021 Apr.
67. Niacor (Niacin tablets) package insert. Minneapolis, MN: Upsher-Smith Laboratories, Inc.; 2000 Feb.