Overview of Melasma HQ Cream
Dosage Strength of Melasma HQ Cream
Melasma HQ 4.1 Cream (Hydroquinone / Tretinoin / Kojic Acid / Hydrocortisone) 4/0.1/4/1% 30 mL Pump
Melasma HQ 6.1 Cream (Hydroquinone / Tretinoin / Kojic Acid / Hydrocortisone) 6/0.1/4/1% 30 mL Pump
Melasma HQ 8.1 Cream (Hydroquinone / Tretinoin / Kojic Acid / Hydrocortisone) 8/0.1/4/1% 30 mL Pump
Hydroquinone is a topical depigmenting agent. It is structurally related to monobenzone, a potent depigmenting agent. Unlike monobenzone, depigmentation caused by hydroquinone is reversible. Hydroquinone is used for temporary bleaching of hyperpigmented skin conditions such as chloasma (melasma), freckles, and lentigines. Sunscreens must be used concomitantly with topical hydroquinone; several commercial preparations do contain a sunscreen agent. Hydroquinone is also used as an antioxidant for ether and in photographic development. Hydroquinone has been available since before 1938.
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.1
Kojic acid is a chelation agent produced by several species of fungi, especially Aspergillus oryzae, which has the Japanese common name koji. Kojic acid is a by-product in the fermentation process of malting rice, for use in the manufacturing of sake, the Japanese rice wine. It is a mild inhibitor of the formation of pigment in plant and animal tissues and is used in food and cosmetics to preserve or change colors of substances.
Hydrocortisone is a naturally-occurring steroid hormone secreted by the adrenal cortex that has glucocorticoid and mineralocorticoid activity. Synthetic hydrocortisone is available pharmaceutically in a variety of rectal, parenteral, oral, and topical dosage forms. As a naturally occurring glucocorticoid that also has salt-retaining properties systemic hydrocortisone is used primarily as replacement therapy in adrenocortical deficiency states, and when emergency anti-inflammatory treatment is needed.2 Rectal hydrocortisone products are particularly useful in inflammatory gastrointestinal conditions limited to the rectum and anus. Systemic hydrocortisone may be used in many other allergic, immune, and inflammatory conditions in adult and pediatric patients; however, systemic corticosteroids that have more potent glucocorticoid activity and minimal mineralocorticoid activity, such as prednisone, are preferred for such uses, as they induce better response and reduce the risks of excess mineralocorticoid side effects.[3 Systemic corticosteroids may be added to other long-term maintenance medications in the management of uncontrolled severe persistent asthma and short courses may be used for asthma exacerbations; however, systemic hydrocortisone is rarely used for these purposes.[4 Topical hydrocortisone is considered low potency and is used in mild to moderate corticosteroid-responsive dermatoses, and many topical dosage forms are available without a prescription. Low potency topical corticosteroids are the safest for chronic use and may be used on the face or intertriginous areas, with occlusion, and in infants and young children.
Mechanism of Action
Hydroquinone inhibits melanin formation by blocking the enzymatic oxidation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) in melanocytes. Other melanocyte metabolic processes are also inhibited. Exposure to sunlight or ultraviolet light will cause repigmentation of bleached areas.
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.6
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 (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.7 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.
Kojic acid suppresses the formulation of pigment by the melanocyte due to its tyrosinase inhibitory activity. This produces a skin lightening effect.
Endogenous corticosteroids are secreted by the adrenal cortex, and their effects are believed to be due to enzyme modification rather than to a direct hormone-induced action. Corticosteroids are loosely classified into two categories, mineralocorticoids and glucocorticoids, depending on their primary pharmacological activity. Mineralocorticoids alter electrolyte and fluid balance by facilitating sodium resorption and hydrogen and potassium excretion at the level of the distal renal tubule, resulting in edema and hypertension. Glucocorticoids exert some mineralocorticoid effects but are also involved in a number of other metabolic pathways including gluconeogenesis, fat redistribution, protein metabolism, and calcium balance. Hydrocortisone possesses both mineralocorticoid actions and glucocorticoid actions.
Corticosteroids exhibit anti-inflammatory, antipruritic, and vasoconstrictive properties. At the cellular level, corticosteroids induce peptides called lipocortins. Lipocortins antagonize phospholipase A2, an enzyme which causes the breakdown of leukocyte lysosomal membranes to release arachidonic acid. This action decreases the subsequent formation and release of endogenous inflammatory mediators including prostaglandins, kinins, histamine, liposomal enzymes and the complement system.
Early anti-inflammatory effects of topical corticosteroids include the inhibition of macrophage and leukocyte movement and activity in the inflamed area by reversing vascular dilation and permeability. Later inflammatory processes such as capillary production, collagen deposition, keloid (scar) formation also are inhibited by corticosteroids. Clinically, these actions correspond to decreased edema, erythema, pruritus, plaque formation and scaling of the affected skin.
In the treatment of asthma, corticosteroids block the late phase allergic response to allergens. Mediators involved in the pathogenesis of asthma include histamine, leukotrienes (slow releasing substance of anaphylaxis, SRS-A), eosinophil chemotactic factor of anaphylaxis (ECF-A), neutrophil chemotactic factor (NCF), cytokines, hydroxyeicosatetraenoic acids, prostaglandin-generating factor of anaphylaxis (PGF-A), prostaglandins, major basic protein, bradykinin, adenosine, peroxides, and superoxide anions. Different cell types are responsible for release of these mediators including airway epithelium, eosinophils, basophils, lung parenchyma, lymphocytes, macrophages, mast cells, neutrophils, and platelets. Corticosteroids inhibit the release of these mediators as well as inhibit IgE synthesis, attenuate mucous secretion and eicosanoid generation, up-regulate beta-receptors, promote vasoconstriction, and suppress inflammatory cell influx and inflammatory processes. Clinical effects in asthma include a reduction in bronchial hyperresponsiveness to allergens, a decreased number of asthma exacerbations, and an improvement in FEV1, peak-flow rate, and respiratory symptoms. Since corticosteroid effects take several hours to days to become clinically noticeable, they are ineffective for primary treatment of severe acute bronchospastic attacks or for status asthmaticus. Inhaled corticosteroids have no bronchodilatory properties.
It is not known whether percutaneous absorption of hydroquinone occurs. Absorption of a topically applied drug may be affected by the conditions of the epidermis including overall pH, disease state, and genetically driven factors such as oiliness or dryness of the skin. The rate of absorption can affect the efficacy and tolerability of hydroquinone.
The sustained release formulation of hydroquinone (EpiQuin Micro) is a multi-phasic formulation containing 4 distinct phases including an oil phase, a water phase, and 2 microparticulate phases resulting from the incorporation of two different Microsponge delivery systems. The Microsponge delivery system extends the release of hydroquinone. The multi-phasic formulation allows for both immediate and gradual release of the hydroquinone.
Systemic tretinoin is greater than 95% bound to plasma proteins, primarily albumin. The distribution of tretinoin has not been determined. Tretinoin is metabolized by the cytochrome P450 hepatic enzyme system. The metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. Tretinoin appears to induce its own metabolism. An approximately 10-fold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide is observed after 2—6 weeks of continuous dosing when compared with baseline.
Topical Route: Following topical application, a minimal amount of drug is absorbed systemically. There is no expected difference in the systemic absorption of tretinoin from the microsphere formulation. Prolonged treatment or application to large body surface areas can enhance systemic absorption.
The topical absorption of kojic acid according to pharmacokinetic absorption studies in rats and human skin, is estimated to be 0.03–0.06 mg/kg/day. The genotoxic risk of kojic acid as a skin lightening agent for humans is less. The in vitro percutaneous absorption values of KA in human skin resulted in 17%, and the maximum potential human systemic exposure dose (SED) would be 1.7 mg or 0.028 mg/kg/day for a 60 kg adult human. This SED range is based on the application area of hands and face. 8
Hydrocortisone is administered via oral, parenteral, topical, and rectal routes. Circulating drug binds extensively to plasma proteins, and only the unbound portion of a dose is active. Systemic hydrocortisone is quickly distributed into the kidneys, intestines, skin, liver, and muscle. Corticosteroids distribute into breast milk and cross the placenta. Systemic hydrocortisone is metabolized by the liver to inactive metabolites. These inactive metabolites, as well as a small portion of unchanged drug, are excreted in the urine. The biological half-life of hydrocortisone is 8 to 12 hours.
Systemic absorption after topical application of hydrocortisone is dependent on the vehicle, the state of the skin at the application site, the use of occlusive dressings, and the age of the patient. Absorption is increased in areas that have skin damage, inflammation, or occlusion, or where the stratum corneum is thin such as the eyelids, genitalia, and face. Factors that can increase systemic absorption of topical hydrocortisone include occlusive dressings, large surface area, frequent application, longer duration of treatment, increased humidity or temperature, and younger age.9 Topical preparations distribute throughout the area of application but are only minimally absorbed into the circulation. Topical preparations of hydrocortisone are metabolized in the skin.
Some hydroquinone products contain parabens and/or sodium metabisulfite. Do not use hydroquinone in any patient that has a prior history of hydroquinone hypersensitivity, paraben hypersensitivity, sulfite hypersensitivity, or hypersensitivity to any of the ingredients contained in a product. Avoid ocular exposure as well as contact with the mouth and other mucous membranes. Do not use on skin which is irritated, denuded, or damaged or has a skin abrasion or sunburn. If hypersensitivity or contact dermatitis occur during hydroquinone therapy, immediately discontinue the drug and contact a physician. High concentrations or prolonged use of hydroquinone can produce skin hyperpigmentation, especially on areas exposed to sunlight. If sunlight (UV) exposure can not be avoided, use a product containing a sunscreen agent.
Safe and effective use of hydroquinone during pregnancy has not been established. Animal reproduction studies have not been conducted with topical hydroquinone. It is also not known whether it can cause fetal harm when used topically on a pregnant woman or affect reproductive capacity. The degree of systemic absorption, if any, is not known. Use during pregnancy only when clearly needed.10
According to the manufacturer, it is not known whether topical hydroquinone is absorbed or excreted in human milk and caution is advised when it is used in breast-feeding mothers.[10 The molecular weight is low enough for passage into breast-milk, but systemic absorption of the drug has not been studied. However, because it is a strong base, if it is absorbed, most of the compound would be in the ionized state and thus not available for excretion into milk.[11 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.
Safe and effective use of hydroquinone in neonates, infants, and children under 12 years has not been established.
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.12
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.13 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.12
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.12
Systemic corticosteroids can aggravate Cushing's syndrome and should be avoided in patients with Cushing's syndrome. Prolonged administration of pharmacological doses of systemic corticosteroids or topical preparations (resulting in systemic absorption) may result in hypothalamic-pituitary-adrenal (HPA) suppression and/or manifestations of Cushing's syndrome in some patients. Acute adrenal insufficiency and even death may occur following abrupt discontinuation of prolonged systemic therapy. In addition, a withdrawal syndrome unrelated to adrenocortical insufficiency may occur following sudden discontinuation of corticosteroid therapy. These effects are thought to be due to the sudden change in glucocorticoid concentration rather than to low corticosteroid levels. Withdrawal from prolonged systemic corticosteroid therapy should be gradual. HPA suppression can last for up to 12 months following cessation of systemic therapy. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the topical corticosteroid. HPA-suppressed patients may need supplemental corticosteroid treatment during periods of physiologic stress, such as surgical procedures, acute blood loss, or infection, even after the corticosteroid has been discontinued. Conditions that increase systemic absorption of topical corticosteroids include use over large surface areas, prolonged use, use in areas where the epidermal barrier is disrupted (i.e., skin abrasion), and the use of an occlusive dressing. Patients receiving large doses of hydrocortisone applied to a large surface area should be evaluated periodically for evidence of HPA axis suppression and/or manifestations of Cushing's syndrome. If these effects are noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid.
Chronic corticosteroid therapy in pediatric patients may interfere with growth and development. Chronic use of systemic or topical corticosteroids may cause growth inhibition (including linear growth retardation and delayed weight gain) in pediatric patients. Children and infants may absorb proportionally larger amounts of topical corticosteroids due to a larger skin surface area to body weight ratio, and therefore are more susceptible to developing systemic toxicity, especially with very-high-potency topical products. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and increased intracranial pressure have been reported in children receiving corticosteroids. Administration of corticosteroids to pediatric patients should be limited to the least amount compatible with an effective therapeutic regimen. If children are being treated topically in the diaper area, tight-fitting diapers or plastic pants should be avoided as these garments may act as an occlusive dressing and increase systemic absorption of the drug.1415
Reactivation of tuberculosis may occur in patients with latent tuberculosis or tuberculin reactivity; close observation for disease reactivation is needed if corticosteroids are indicated in such patients. Further, chemoprophylaxis is advised if prolonged corticosteroid therapy is needed. Patients receiving immunosuppressive doses of systemic corticosteroids should be advised to avoid exposure to viral infections (i.e., measles or varicella) because these diseases may be more serious or even fatal in immunosuppressed patients. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin may be indicated. Pediatric patients dependent on systemic corticosteroids should undergo anti-varicella-zoster virus antibody testing. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin may be indicated. Instruct patients to avoid exposure to chicken pox and measles and to get immediate medical advice if exposure occurs. Application of topical corticosteroids to areas of infection, including tuberculosis of the skin, dermatologic fungal infection, and cutaneous or systemic viral infection (e.g., herpes infection, measles, varicella), should be initiated or continued only if the appropriate antiinfective treatment is instituted. If the infection does not respond to the antimicrobial therapy, the concurrent use of the topical corticosteroid should be discontinued until the infection is controlled. Topical corticosteroids should not be used to treat acne vulgaris, acne rosacea, or perioral dermatitis as they may exacerbate these conditions. Topical corticosteroids may delay the healing of non-infected wounds, such as venous stasis ulcers. Use topical hydrocortisone preparations with caution in patients with markedly impaired circulation or peripheral vascular disease; skin ulceration has been reported in these patients following topical corticosteroid use.
Corticosteroid therapy, such as hydrocortisone, has been associated with left ventricular free-wall rupture in patients with recent myocardial infarction, and should therefore be used cautiously in these patients.
True corticosteroid hypersensitivity reactions are rare. While a hypersensitivity reaction could be to a specific salt of the corticosteroid (i.e., hydrocortisone sodium succinate), patients who have demonstrated a prior hypersensitivity reaction to hydrocortisone should receive any form of hydrocortisone with extreme caution. It is possible, though also rare, that such patients will display cross-hypersensitivity to other corticosteroids; there have been reports that a cross-sensitivity between hydrocortisone and methylprednisolone may exist.16 Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid.17 Some injectable formulations of hydrocortisone contain benzyl alcohol and should be used with caution in those patients with benzyl alcohol hypersensitivity.1518
Corticosteroids should be used cautiously in patients with glaucoma or any other visual disturbance. Corticosteroids are well known to cause cataracts and can exacerbate glaucoma during long-term administration. Patients receiving corticosteroids chronically should be periodically assessed for cataract formation. There is also an increase in the propensity for secondary ocular infection caused by fungal or viral infections. Care should be taken to avoid ocular exposure; ophthalmic administration of topical hydrocortisone preparations should be avoided. Visual impairment, ocular hypertension and worsened cataracts have been reported with ocular exposure to other high potency topical corticosteroids. Preexisting glaucoma may be aggravated if hydrocortisone is applied in the periorbital area.
Topical corticosteroids, such as hydrocortisone, should be used for brief periods, or under close medical supervision in patients with evidence of pre-existing skin atrophy. Use of lower potency topical corticosteroids may be necessary in some patients, such as the elderly adult. Prolonged use of a topical corticosteroid, and the application of the steroid to thin areas of skin appear to increase the risk for atrophy.19
Use hydrocortisone with caution in patients with diagnosed or suspected pheochromocytoma. Pheochromocytoma crisis, which can be fatal, has been reported after administration of systemic corticosteroids. Consider the risk of pheochromocytoma crisis prior to administering corticosteroids in any patients with suspected pheochromocytoma.20
Safe and effective use of hydroquinone during pregnancy has not been established. Animal reproduction studies have not been conducted with topical hydroquinone. It is also not known whether it can cause fetal harm when used topically on a pregnant woman or affect reproductive capacity. The degree of systemic absorption, if any, is not known. Use during pregnancy only when clearly needed.
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.212212
Safe and effective use of kojic acid during pregnancy has not been established. It is also not known whether it can cause fetal harm when used topically on a pregnant woman or affect reproductive capacity. Use during pregnancy may not be recommended.
Systemic and rectal preparations of hydrocortisone must be used with caution during human pregnancy. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Complications, including cleft palate, stillbirth, and premature abortion, have been reported during animal studies. If hydrocortisone must be used during pregnancy, the potential risks should be discussed with the patient. However, insufficient treatment of an underlying condition (e.g., Addison's disease) during pregnancy is also associated with fetal and maternal risks and the mother may require additional monitoring to ensure adequate replacement during pregnancy and in the post-partum period as requirements return to pre-pregnancy levels. Infants born to mothers who have taken substantial doses of corticosteroids during pregnancy should be monitored for signs of hypoadrenalism.152023 2425 Topical application of hydrocortisone warrants caution during pregnancy as there are no adequate and well-controlled studies. Topical corticosteroids should not be used in large amounts, on large areas, or for prolonged periods of time in pregnant women. Guidelines recommend mild to moderate potency agents, such as topical hydrocortisone, over potent topical corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birthweight has been reported with use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.262728 Systemic corticosteroids have been shown to impair fertility in male rats; the impact to human male fertility is not certain.1523
According to the manufacturer, it is not known whether topical hydroquinone is absorbed or excreted in human milk and caution is advised when it is used in breast-feeding mothers.10 The molecular weight is low enough for passage into breast-milk, but systemic absorption of the drug has not been studied. However, because it is a strong base, if it is absorbed, most of the compound would be in the ionized state and thus not available for excretion into milk.11 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.
According to the manufacturers, breast-feeding should be discontinued prior to receiving oral tretinoin and caution should be used with topical tretinoin.2122 It is unknown whether oral or topical tretinoin is distributed into breast milk. Systemic absorption of tretinoin after topical application is low 22, 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.
It is unknown whether topical kojic acid is absorbed or excreted in human milk and caution is advised when it is used in breast-feeding mothers.
The use of systemic and rectal hydrocortisone has not been studied during breast-feeding; however cortisol is a normal component of breast milk.201523 2425 Other corticosteroids (prednisone and prednisolone) are usually considered compatible with breast-feeding.29It is not known whether topical administration of desonide could result in sufficient systemic absorption to produce detectable quantities in breast milk.2627However, most dermatologists stress that topical corticosteroids can be safely used during lactation and breast-feeding.30 If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Adverse Reactions/Side Effects
The most common adverse reactions to topical hydroquinone therapy include skin irritation (burning, erythema, stinging), sensitization and contact dermatitis. Application of high concentrations or prolonged use can produce skin hyperpigmentation, especially on areas exposed to sunlight. Exogenous ochronosis (blue-black skin hyperpigmentation or skin discoloration) has been reported and is considered to be an adverse reaction to hydroquinone rather than an idiosyncratic reaction. Ochronosis may develop after 6 months of use and may be irreversible once established. Application to the paranasal and infraorbital areas increases the risk of skin irritation; xerosis and fissuring has occurred in these areas. If applied to the eye, corneal staining and corneal opacification may occur. If applied to the lips, a bitter taste and anesthetic effect may occur. Reversible brown nail discoloration of the hand may occur when applying hydroquinone. Systemic adverse reactions to topical hydroquinone have not been reported.10
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.3132 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.31
Melasma patients who had used 1% kojic acid cream were followed for 2 years and no significant side effect or adverse reaction was observed.33 Common adverse reactions and disadvantages hsve been associated with kojic acid in cosmetic application. Contact dermatitis (especially for sensitive skins) is the main side effect of kojic acid which is accompanied by irritation, rashes, inflamed skin, itchiness, and pain. These side effects can be observed with a higher concentration more than 1% of kojic acid. Another adverse reaction may appear in long-term use of kojic acid, such as sunburn in sensitive skin.
Pharmacologic doses of systemic corticosteroids administered for prolonged periods can result in physiological dependence due to hypothalamic-pituitary-adrenal (HPA) suppression. Systemic absorption of topical hydrocortisone is minimal in adults, but theoretically could cause systemic adverse reactions, especially if applied to a large surface area and/or if occlusive dressings are used. Exogenously administered corticosteroids exert a negative feedback effect on the pituitary, inhibiting the secretion of adrenocorticotropin (ACTH). This results in a decrease in ACTH-mediated synthesis of endogenous corticosteroids and androgens by the adrenal cortex. The severity of secondary adrenocortical insufficiency varies among individuals and is dependent on the dose, frequency, time of administration, and duration of therapy. Systemic administration drug on alternate days may help to alleviate this adverse effect. Patients with HPA suppression will require increased doses of corticosteroid therapy during periods of physiologic stress. Acute adrenal insufficiency and even death can occur with abrupt discontinuation of therapy. Discontinuation of prolonged oral corticosteroid therapy should be gradual, since HPA suppression can last for up to 12 months following cessation of therapy. Patients may continue to need supplemental corticosteroid treatment during periods of physiologic stress or infectious conditions, even after the drug has been discontinued. A withdrawal syndrome unrelated to adrenocortical insufficiency can occur following sudden discontinuance of corticosteroid therapy. This syndrome includes symptoms such as loss of appetite, lethargy, stomach upset, fever, muscle and joint pain, exfoliative dermatitis, loss of weight, and hypotension. These effects are believed to be due to the sudden change in corticosteroid concentration rather than to low corticosteroid levels. HPA axis suppression and increased intracranial pressure have been reported in children receiving topical corticosteroids. Increased intracranial pressure with papilledema (i.e., pseudotumor cerebri) has also been reported with withdrawal of glucocorticoid therapy.
Prolonged corticosteroid (e.g., hydrocortisone) therapy can adversely affect the endocrine system, resulting in hypercorticism (Cushing's syndrome including fat abnormalities such as buffalo hump and moon face), menstrual irregularity (amenorrhea, postmenopausal bleeding, or dysmenorrhea), a decrease or increase in motility and number of spermatozoa, hyperthyroidism, and hypothyroidism in susceptible patients. In some patients, systemic absorption of topical corticosteroids can produce manifestations of Cushing's syndrome. Percutaneous absorption of betamethasone is dependent on many factors including the vehicle, the integrity of the epidermal barrier, duration of use, and use of an occlusive dressing. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios.
The following adverse reactions (listed in decreasing order of occurrence) are reported with topical corticosteroids such as hydrocortisone and may occur more often when used with an occlusive dressing: skin irritation (including burning), pruritus, xerosis (dry skin), folliculitis, hypertrichosis, acneiform rash/eruptions, skin hypopigmentation, perioral dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, and miliaria. Erythema, telangiectasia, purpura, and maculopapular rash may also occur. Although skin atrophy usually occurs after prolonged use of topical corticosteroids, this effect may occur even with short-term use on intertriginous or flexor areas, or on the face. If irritation develops, discontinue topical corticosteroids and institute appropriate therapy. The anti-inflammatory activity of topical corticosteroids may also mask manifestations of infection. In the presence of dermatological infections, institute the use of an appropriate antifungal or antibacterial agent. If a favorable response does not promptly occur, discontinue the corticosteroid until the infection has been adequately controlled. Various adverse dermatologic effects reported during systemic corticosteroid therapy include skin atrophy, diaphoresis, acne vulgaris, striae, hirsutism, acneiform rash, alopecia, xerosis, lupus-like symptoms, perineal pain and irritation, purpura, rash (unspecified), telangiectasia, facial erythema, petechiae, ecchymosis, and easy bruising. Hypersensitivity reactions may manifest as allergic dermatitis, urticaria, anaphylactoid reactions, and/or angioedema. Parenteral corticosteroid therapy has also produced skin hypopigmentation, skin hyperpigmentation, scarring, and other types of injection site reaction (e.g., induration, delayed pain or soreness, subcutaneous and cutaneous atrophy, and sterile abscesses). Burning or tingling in the perineal area may occur following IV injection of corticosteroids.
In general, excessive use of systemic or topical corticosteroids can lead to impaired wound healing. Hydrocortisone should not be applied directly on or near healing wounds. Skin ulcer may develop in patients with markedly impaired circulation who use topical corticosteroids.
Corticosteroid therapy (systemic or topical) can mask the symptoms of infection and may result in secondary systemic or localized infections. Avoid systemic use of corticosteroids, such as hydrocortisone, in patients with an active infection unless adequately controlled by anti-infective agents. Leukocytosis is a common physiologic effect of systemic corticosteroid therapy and may need to be differentiated from the leukocytosis that occurs with inflammatory or infectious processes.343536 Immunosuppression is most likely to occur in patients receiving high-dose systemic corticosteroid therapy for any period of time, particularly in conjunction with corticosteroid-sparing drugs (e.g., troleandomycin) and/or concomitant immunosuppressant agents; however, patients receiving moderate dosages of systemic corticosteroids for short periods or low dosages for prolonged periods also may be at risk. Corticosteroids can reactivate tuberculosis and should not be used in patients with a history of active tuberculosis except when chemoprophylaxis is instituted concomitantly. Patients receiving immunosuppressive doses of corticosteroids should be advised to avoid exposure to measles or varicella (chickenpox) and, if exposed to these diseases, to seek medical advice immediately. Additionally, health care providers should monitor prednisone recipients for signs of an opportunistic fungal infection as cases of candidiasis have been reported with the use of corticosteroids. The development of Kaposi's sarcoma has been associated with prolonged administration of corticosteroids.23 19
Corticosteroids are divided into two classes: mineralocorticoids and glucocorticoids. Mineralocorticoids alter electrolyte and fluid balance by facilitating sodium retention and hydrogen and potassium excretion at the level of the distal renal tubule, resulting in edema and hypertension. Mineralocorticoids can cause fluid retention; electrolyte disturbances (hypokalemia, hypokalemic metabolic alkalosis, hypernatremia, hypocalcemia); edema; and hypertension. Prolonged administration of glucocorticoids, such as hydrocortisone, also can result in edema and hypertension. In a review of 93 studies of corticosteroid use, hypertension was found to develop 4 times as often in steroid recipients compared to control groups.37 Congestive heart failure can occur in susceptible patients. In a study, an increased risk of heart failure was observed for medium-dose glucocorticoid use as compared with nonuse. At the beginning of the study, patients were at least 40 years of age and had not been hospitalized for cardiovascular disease. Medium exposure was defined as less than 7.5 mg daily of prednisolone or the equivalent given orally, rectally, or parenterally.38
Adverse neurologic effects have been reported during prolonged corticosteroid therapy, such as hydrocortisone, including headache, insomnia, amnesia and memory impairment, increased motor activity, impaired cognition, neuritis, paresthesias, ischemic peripheral neuropathy, malaise, vertigo, restlessness, ischemic peripheral neuropathy, seizures, and EEG changes. Increased intracranial pressure with papilledema (pseudotumor cerebri) usually follows discontinuation of treatment. Mental status changes including depression, anxiety, euphoria, personality changes, emotional lability, delirium, dementia, hallucinations, irritability, mania, mood swings, schizophrenic reactions, withdrawn behavior, and psychosis also have been reported. Emotional lability and psychotic problems can be exacerbated by corticosteroid therapy.
Although corticosteroids are used to treat Graves' ophthalmopathy, ocular effects, such as corneal perforation, exophthalmos, posterior subcapsular cataracts, retinopathy, central serous chorioretinopathy (CSCR), or ocular hypertension, can result from prolonged use of glucocorticoids and could result in glaucoma, or ocular nerve damage including optic neuritis.20 Temporary or permanent visual impairment, including blurred vision and blindness, has been reported with corticosteroid administration by several routes of administration including intranasal. If injectable systemic steroid therapy is continued for more than 6 weeks, monitor intraocular pressure. Also, evaluate any patient who develops changes in vision during corticosteroid therapy for ocular hypertension. Hydrocortisone can reduce host resistance to infection. Secondary fungal and viral infections of the eye (ocular infection) can be masked or exacerbated by corticosteroid therapy. Investigate the possibility of fungal infection if patients have persistent corneal ulceration. Ocular hypertension and cataracts leading to visual impairment have also occurred following prolonged application of corticosteroids to the skin around the eye. Case reports describe visual impairment patients using topical corticosteroids for eczema of the face; although, use of hydrocortisone has been reported to be safer for short-term use around eye area. The visual impairment was secondary to the onset of ocular hypertension. Such adverse effects, if they occur, could lead to blindness. Cataracts have also been reported with topical corticosteroids, usually with large doses or therapy > 6 months. The mechanism of corticosteroid-induced cataract formation is uncertain but may involve disruption of sodium-potassium pumps in the lens epithelium leading to accumulation of water in lens fibers and agglutination of lens proteins.39
Prolonged corticosteroid therapy such as hydrocortisone can result in hyperglycemia, glucosuria (glycosuria), and aggravation of diabetes mellitus in susceptible patients. In a review of 93 studies of corticosteroid use, the development of diabetes mellitus was determined to occur 4 times more frequently in steroid recipients compared to control groups.37 Systemic absorption of topical corticosteroids has produced hyperglycemia and glucosuria in some patients. Percutaneous absorption of hydrocortisone is dependent on many factors including the vehicle, the integrity of the epidermal barrier, duration of use, and use of an occlusive dressing. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. Insulin or oral hypoglycemic dosages may require adjustment.
Hypercholesterolemia, atherosclerosis, fat embolism, sinus tachycardia, palpitations, bradycardia, syncope, vasculitis, necrotizing angiitis, thrombosis, thromboembolism, and phlebitis have been associated with systemic corticosteroid therapy, such as hydrocortisone. Glucocorticoid use appears to increase the risk of cardiovascular events such as myocardial infarction, left ventricular rupture (in persons who recently experienced a myocardial infarction), angina, angioplasty, coronary revascularization, stroke, transient ischemic attack, cardiomegaly, arrhythmia exacerbation and ECG changes, hypertrophic cardiomyopathy (in premature infants), congestive heart failure and pulmonary edema, cardiac arrest or cardiovascular death. As determined from observational data, the rate of cardiovascular events was 17 per 1000 person-years among 82,202 non-users of glucocorticoids. In contrast, the rate was 23.9 per 1000 person-years among 68,781 glucocorticoid users. Furthermore, the rate of cardiovascular events was 76.5 per 1000 person-years for high exposure patients. After adjustment for known covariates by multivariate analysis, high-dose glucocorticoid use was associated with a 2.56-fold increased risk of cardiovascular events as compared with nonuse. At the beginning of the study, patients were at least 40 years of age and had not been hospitalized for cardiovascular disease. High glucocorticoid exposure was defined as at least 7.5 mg daily of prednisolone or the equivalent given orally, rectally, or parenterally whereas medium exposure was defined as less than the above dosage by any of the 3 routes. Low-dose exposure was defined as inhaled, topical, or nasal usage only.38
Tolerance may occur with the prolonged use of topical corticosteroids. Tolerance is usually described as a decreased acute vasoconstrictive response to the agent after a period of days to weeks. This may explain the dramatic responses noted initially by patients early in topical corticosteroid treatment and an apparent diminished response with time. Tolerance is reversible and may be attenuated by interrupted or cyclic schedules of application (e.g., hydrocortisone is given for 2—3 weeks, followed by a 1-week intermission).
Allergic contact dermatitis with topical corticosteroids such as hydrocortisone is usually diagnosed by observing a failure to heal. Appropriate diagnostic patch testing may help with the diagnosis.
Dizziness and anemia have been reported with corticosteroid use such as hydrocortisone. Corticosteroids may decrease serum concentrations of vitamin C (ascorbic acid) and vitamin A, which may rarely produce symptoms of vitamin A deficiency or vitamin C deficiency. Some loss of folic acid may also be caused by corticosteroid use; glossitis may be noted.
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. Vesanoid (tretinoin) capsules package insert. Nutley, NJ: Roche Laboratories Inc.; 2004 Oct.
- 2. Auron M, Raissouni N. Adrenal insufficiency. Pediatr Rev 2015;36:92-102.
- 3. Burns CM. The History of Cortisone Discovery and Development. Rheum Dis Clin North Am. 2016;42:1-14. Review.
- 4. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) 2020. Available from: http://www.ginasthma.org. Accessed May 20th, 2020.
- 5. Das A and Panda S. Use of topical corticosteroids in dermatology: an evidence-based approach. Indian J Dermatol. 2017;62(3):237-50.
- 6. Fisher GJ, Wang Z, Datta SC, et al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med 1997;337:1419-28.
- 7. Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from genetics to treatment. Blood 1994;83:10-25.
- 8. Final report of the safety assessment of kojic acid as used in cosmetics Int. J. Toxicol., 29 (6_suppl) (2010), pp. 244S-273S
- 9. Morley KW, Dinulos JG. Update on topical glucocorticoid use in children. Curr Opin Pediatr 2012;24(1):121-128
- 10. a. b. c. d. e. Nu-derm (hydroquinone) cream package insert. Long Beach, CA: OMP, Inc.; 2012 Sep.
- 11. a. b. Briggs GG, Freeman RK, Yaffee SJ. Hydroquinone. In: Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 9th ed. Philadelphia: Lippincott Williams & Wilkins: 2011;700-1.
- 12. a. b. c. d. Altreno (tretinoin lotion) package insert; Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2018 Aug.
- 13. Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Saf 2002;25:345-72.
- 14. Locoid (hydrocortisone butyrate lotion) package insert. Crawford, NJ: Triax Pharmaceuticals; 2008 Jan.
- 15. a. b. c. d. e. Solu-Cortef (hydrocortisone sodium succinate) injection package insert. New York, NY: Pharmacia and Upjohn Co.; 2019 Nov.
- 16. Kamm GL, Hagmeyer KO. Allergic-type reactions to corticosteroids. Ann Pharmacother 1999;33(4):451-460.
- 17. Butani L. Corticosteroid-induced hypersensitivity reactions. Ann Allergy Asthma Immunol 2002;89(5):439-445.
- 18. Hydrocortone (hydrocortisone sodium phosphate) injection package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2001 Nov.
- 19. a. b. Hydrocortisone 2.5% cream and ointment package insert. Bronx, NY: Perrigo; 2012 Dec.
- 20. a. b. c. d. Cortef (hydrocortisone tablets, USP) package insert. New York, NY: Pharmacia & Upjohn Co., Inc.; 2019 Nov.
- 21. a. b. Tretinoin capsules package insert. Sellersville, PA: Teva Pharmaceuticals; 2009 Jun.
- 22. a. b. c. Retin-A Micro (tretinoin gel) package insert. Quebec, Canada: Valeant Pharmaceuticals North America, LLC; 2017 Oct.
- 23. a. b. c. d. Solu-cortef (hydrocortisone sodium succinate) injection package insert. New York, NY: Pharmacia & Upjohn Co.; 2019 Nov.
- 24. a. b. Anusol HC (hydrocortisone acetate) suppository package insert. Morrisville, NC: Salix Pharmaceuticals, Inc.; 2005 Mar.
- 25. a. b. Cortenema (hydrocortisone retention enema) package insert. Baltimore, MD. ANI Pharmaceuticals, Inc.; 2007 Sept.
- 26. a. b. Hydrocortisone 1% cream package insert. Melville, NY: E. Fougera & Co.; 2006 Jun.
- 27. a. b. Hydrocortisone valerate 0.2% cream and ointment package insert. Haethorne, NY: Taro Pharmaceuticals USA, Inc; 2015 Oct.
- 28. Murase JE, Heller MM, Butler DC. Safety of dermatologic medications in pregnancy and lactation: Part I. Pregnancy. J Am Acad Dermatol. 2014;70:401.e1-14. Review.
- 29. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.
- 30. Butler DC, Heller MM, Murase JE. Safety of dermatologic medications in pregnancy and lactation: Part II. Lactation. J Am Acad Dermatol. 2014;70:417.e1-10. Review.
- 31. a. b. Tretinoin capsules package insert. Chestnut Ridge, NY: Par Pharmaceutical; 2017 Jan
- 32. Renova 0.02% (tretinoin cream) package insert; Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2013 Jun.
- 33. M. Nakagawa, K. Kawai, K. Kawa Contact allergy to kojic acid in skin care products Contact Derm., 32 (1) (1995), pp. 9-13
- 34. Schimmer B, Parker K. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Hardman JG, Limbird LE, Molinoff PB, et al., eds. Goodman and Gilman's the Pharmacological Basis of Therapeutics, 10th edition. New York: McGraw Hill, 2001;1649-1674.
- 35. Abramson N, Melton B. Leukocytosis: basic of clinical assessment. Am Fam Physician 2000;62:2053-60.
- 36. Shoenfeld Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis. Influenced of dosage, method and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-8.
- 37. a. b. Conn HO, Poynard T. Corticosteroids and peptic ulcer: meta-analysis of adverse events during steroid therapy. J Intern Med 1994;236:619-32.
- 38. a. b. Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004;141:764-70.
- 39. Cumming RG, Mitchell P, Leeder SR, et al. Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med 1997;337:8-14.