Anti-Aging Ultra Cream

Overview of Anti-Aging Ultra Cream

Dosage Strength of Anti-Aging Ultra Cream

Ascorbic Acid / Azelaic Acid / Alpha Lipoic Acid / Aloe Vera / Estriol / Progesterone 10/5/1/0.5/0.1/2% 30 mL Pump

General Information

As we grow older our skin will lose its ability to effectively repair the visible signs of age. As skin loses its youthful levels of firmness and elasticity, facial contours may become less defined even as wrinkles become increasingly pronounced.

Anti-Aging Ultra Cream is a mixture of scientifically backed, effective ingredients that may help to mitigate the effects of age on skin for a more youthful complexion.

Anti-Aging Ultra Cream accomplishes this with seven substances:

• Ascorbic Acid
• Azelaic Acid
• Alpha Lipoic Acid
• Aloe Vera
• Estriol
• Progesterone

This combination of ingredients may act to not only improve the surface appearance of facial skin but also may stimulate collagen production beneath the skin to minimize the appearance of fine lines and wrinkles and give the face a smoother, more refreshed appearance.

Azelaic Acid

Azelaic acid is a chemical not only commonly found in various grains, but is also naturally synthesized by the yeast that exists on healthy skin.1

Azelaic acid is a potent antioxidant with powerful anti-inflammatory and antibacterial properties that may show promising results including2

• Brigthen Skin Tone
• Visibly Improve Skin Texture
• Reduce The Visibility of Blemishes

Commonly used to treat acne, research has demonstrated that azelaic acid may be used to effectively treat rosacea, flaky skin, and hyper-pigmentation.3

Azelaic acid also functions as a keratolytic, which means it may help return abnormal growths on the skin back to normal.2

Ascorbic Acid

Although vitamin C is a critical nutrient for overall health, very little reaches the skin when taken orally.4

As levels of vitamin C in skin decline with age5 replenishing levels directly in the skin may help combat collagen degradation and oxidative stress. Results from clinical trials have shown that when applied topically, vitamin C may promote collagen formation and mitigate the effects of free radicals, helping to maintain firmer and more youthful skin.

Alpha Lipoic Acid

Alpha lipoic acid (ALA) is naturally found in the mitochondria of our cells as part of an enzyme system that assists in the production of energy.6

ALA is both water and fat-soluble so that it can be easily absorbed through the lipid (fat) layers of the skin and also works as a free-radical fighter in the cell’s plasma membrane to act as a strong antioxidant.7

Used topically, ALA may offer multiple benefits to skin. ALA may cause a significant decrease in the appearance of under-eye circles, loss of firmness, and puffiness.8

ALA’s anti-inflammatory effect may also help reduce visible blotchiness and redness, potentially resulting in a more even skin tone. ALA may also help minimize the appearance of pores and produce a healthier glow to skin.9

ALA may also be an effective solution to help minimize visible fine lines and wrinkles because of its capacity to regulate the production of nitric oxide, which influences blood flow to the skin.10

Aloe Vera

Aloe vera is a cactus plant belonging to the Liliaceae family. It is native to dry climates like those found in parts of Africa and India, and has been used for centuries in traditional medicine.

Aloe vera contains two hormones: Auxin and Gibberellins. These two hormones have wound healing and anti-inflammatory properties that may improve the appearance of skin. 11The Gibberellins in aloe vera may also stimulate the growth of new cells. Aloe vera may be used to encourage skin to heal with minimal scarring.11

Estriol

One of the many roles of estrogen in the body is to increase the synthesis of collagen,12 which is the skin’s underlying support structure. Collagen also promotes skin thickness and elasticity. The skin is an important estrogen-responsive endocrine tissue. Without the growth-promoting effects of estrogen, skin may wither away.

Estriol is a “weak” estrogen, which can be synthesized from plant sources. Estriol doesn’t need to be counterbalanced by progesterone and may not have a widespread effect on the body. This makes estriol an ideal estrogen for topical use since research suggests its application remains primarily in the skin, rather than in the bloodstream.13

Progesterone

Progesterone is a hormone that occurs naturally in the body and is produced by the ovaries. It may reverse the acceleration of the skin's aging process due to menopause, helping to maintain a more youthful appearance.14

Mechanism of Action

Ascorbic Acid 

Ascorbic acid is necessary for collagen formation (e.g., connective tissue, cartilage, tooth dentin, skin, and bone matrix) and tissue repair. It is reversibly oxidized to dehydroascorbic acid. Both forms are involved in oxidation-reduction reactions. Vitamin C is involved in the metabolism of tyrosine, carbohydrates, norepinephrine, histamine, and phenylalanine. Other processes that require ascorbic acid include biosynthesis of corticosteroids and aldosterone, proteins, neuropeptides, and carnitine; hydroxylation of serotonin; conversion of cholesterol to bile acids; maintenance of blood vessel integrity; and cellular respiration. Vitamin C may promote resistance to infection by the activation of leukocytes, production of interferon, and regulation of the inflammatory process. It reduces iron from the ferric to the ferrous state in the intestine to allow absorption, is involved in the transfer of iron from plasma transferrin to liver ferritin and regulates iron distribution and storage by preventing the oxidation of tetrahydrofolate. Ascorbic acid enhances the chelating action of deferoxamine during treatment of chronic iron toxicity. Vitamin C may have a role in the regeneration of other biological antioxidants such as glutathione and a-tocopherol to their active state. 

Ascorbate deficiency lowers the activity of microsomal drug-metabolizing enzymes and cytochrome P-450 electron transport. In the absence of vitamin C, impaired collagen formation occurs due to a deficiency in the hydroxylation of procollagen and collagen. Non-hydroxylated collagen is unstable, and the normal processes of tissue repair cannot occur. This results in the various features of scurvy including capillary fragility manifested as hemorrhagic processes, delayed wound healing, and bony abnormalities. 

The use and dosage regimen of vitamin C in the prevention and treatment of diseases, other than scurvy, is unclear. Although further study is needed to recommend vitamin C therapy for the following ailments, data indicate a positive role for vitamin C for: overall decreased mortality, the prevention of coronary heart disease (especially in women), management of diabetes mellitus, reducing the risk of stroke, management of atherosclerosis in combination with other antioxidants, osteoporosis prevention, reducing the risk of Alzheimer disease in combination with vitamin E, and the prevention of cataracts. 

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.

Alpha Lipoic Acid 

Alpha Lipoic Acid, is a potent scavenger of hydroxyl radicals, superoxide radicals, peroxyl radicals, singlet oxygen and nitric oxide. LA also plays an important role in the mitochondrial dehydrogenase processes and as a modulator of the inflammatory response. Alpha Lipoic Acid is insoluble in water, but soluble in organic solvents. The small molecular weight of 206Æ3 in combination with the solubility characteristics suggests the possibility of Alpha Lipoic Acid being absorbed by the skin and, in the skin, exercising pharmacological activities.15 

Estriol 

Estriol exerts its activity by binding to estrogen receptors. Biologic response is initiated when ligand-binding domain of the estrogen receptor resulting in a conformational change that leads to gene transcription and activation or repression of target gene. The estrogen receptor mediates gene transcription using different response elements and other signal pathways. 16

Progesterone  

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is essential for the development of decidual tissue, and the effect of progesterone on the differentiation of glandular epithelia and stroma has been extensively studied. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy. Normal or near-normal endometrial responses to oral estradiol and intramuscular progesterone have been noted in functionally agonadal women through the sixth decade of life. Progesterone administration decreases the circulatory levels of gonadotropins. 

Progesterone can be used to achieve normalized progesterone levels in women with secondary amenorrhea. When a woman does not produce enough progesterone, menstrual irregularities may occur. Progesterone can thus help re-establish normal menstrual cycles in pre-menopausal women with such irregularities. 

The primary role of progesterone when used in the menopausal woman is for a protective effect that reduces the risk of endometrial hyperplasia when used with estrogen in the woman with an intact uterus. Micronized oral progesterone does not appear to have adverse effects on serum lipid profiles when used in regimens for hormone replacement therapy (HRT). 

Progesterone has also been used historically as a contraceptive, including in intrauterine contraceptive devices (IUDs). The primary contraceptive effect of exogenous progestins involves the suppression of the midcycle surge of luteinizing hormone (LH). The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Additional mechanisms may be involved in the contraceptive effect. Other actions of progestins include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus. 

Pharmacokinetics

Ascorbic Acid 

Vitamin C is administered orally, topically, by intramuscular, subcutaneous, and/or intravenous injection. The bioavailability of vitamin C from foods and supplements are similar; however, the bioavailability of vitamin C in foods is variable as it is easily degraded with cooking, processing, or the addition of preservatives (e.g., sodium bicarbonate). Approximately 70% to 90% of the usual dietary intake of ascorbic acid (30 to 180 mg/day) is absorbed, although absorption falls to 50% or less with doses above 1 g/day or in patients with GI disease (e.g., short bowel syndrome). Due to homeostatic regulation, the biological half-life of ascorbate varies widely from 8 to 40 days and is inversely related to body stores. Total body stores are approximately 1.5 g of ascorbic acid, with a daily turnover of 30 to 45 mg. Scurvy symptoms are associated with total body stores of less than 300 mg and 3 to 5 months of deficient vitamin C intake. High levels of ascorbate are maintained in the pituitary and adrenal glands, leukocytes, eye tissues and humors, and the brain. Vitamin C crosses the placenta and is distributed into breast milk. 

Most ascorbic acid is reversibly oxidized to dehydroascorbic acid. The remainder is metabolized to the inactive metabolites (ascorbic acid-2-sulfate and oxalic acid) which are excreted in the urine. Of note, tobacco smoking increases oxidative stress and metabolic turnover of vitamin C, thereby increasing the suggested daily intake of vitamin C in smokers. Unmetabolized ascorbate is not excreted with normal dietary intake (80 mg/day or less); however, renal excretion increases proportionately with higher intake. When body stores become saturated, excess ascorbic acid is excreted unchanged in the urine; this is the basis for the ascorbic acid saturation test for vitamin C nutritional status. With large oral doses, unabsorbed ascorbate is degraded in the intestine, which may be the cause of diarrhea and intestinal discomfort.

Azelaic Acid 

Azelaic acid is applied topically to the skin. Azelaic acid is mainly excreted unchanged in the urine but does undergo some beta-oxidation to shorter chain dicarboxylic acids. Plasma concentrations and daily urinary excretion of azelaic acid are highly dependent on dietary intake. 

Following a single application to human skin in vitro, the drug penetrates into the stratum corneum (approximately 3—5% of the applied dose) and other viable skin layers (up to 10% of the dose is found in the epidermis and dermis). Approximately 4% of the topically applied dose is absorbed systemically. Negligible cutaneous metabolism occurs after topical administration. The observed half-lives in healthy subjects are approximately 12 hours after topical dosing, indicating percutaneous absorption rate-limited kinetics. Following topical administration, plasma concentrations and urinary excretion of azelaic acid are not significantly different from baseline levels. 

Alpha Lipoic Acid 

Pharmacokinetics and bioavailability of both enantiomers of ALA have been studies in 12 subjects 

ALA appears to be readily absorbed orally and converted to its reduced from, DHLA, in many tissues of the body. Effects of ALA and DHLA are present both intra and extracellularly. R-ALA is bound to protein where it functions as an essential cofactor for many mitochondrial enzyme complexes. Human studies demonstrated plasma concentration of R-ALA to be higher than S-ALA. 17 

Estriol 

Intravaginal estriol (0.5-1mg) is well-absorbed and may have detectable effects on gonadotropins with an equivalent to 8-12mg oral doses of estriol. Estriol is readily absorbed through gastrointestinal tract, skin, and mucus membranes, and is associated with entero-hepatic recirculation. Estriol is eliminated in the urine and feces. The binding of estriol to sex hormone-binding globulin is less potent than estradiol and is therefore, more bioavailable.18 

Azelaic acid has not been well-studied in patients with dark complexions and should be used cautiously in these patients to avoid hypopigmentation.1920 

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.20 

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.19 

Estriol 

Contraindications: Breast cancer, ovarian cancer, endometrial cancers, coronary artery disease, thromboembolism, history of hypercoagualbe disease, history of ischemic stroke, migraine headaches, seizure disorder, history of dementia or neurocognitive disorders, hypertension, uterine leiomyomas, endometriosis, urinary incontinence, hyperlipidemia, gallbladder disease, liver disease, history of tobacco use.21 

Progesterone 

Progesterone is contraindicated in patients with pre-existing breast cancer or cancer of reproductive organs, such as cervical cancer, endometrial cancer, ovarian cancer, uterine cancer, or vaginal cancer. Likewise, progesterone formulations should not be used in patients with undiagnosed vaginal bleeding. Progesterone, like other hormones, can influence hormonally-dependent cancers. HORMONE REPLACEMENT THERAPY (HRT): Oral progesterone labeling contains a boxed warning regarding the potential risk for breast cancer (new primary malignancy) in post-menopausal women receiving estrogen and progestin hormonal replacement therapy (HRT). The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estrogen plus progestin. After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. Adding a progestin such as progesterone to estrogen HRT has been shown to reduce, but not completely eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen plus progestin HRT is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association. 

Progesterone products are contraindicated in patients with hepatic disease or known hepatic dysfunction. 

Progesterone injections are formulated in oil and are for intramuscular use only. Never administer via intravenous administration. Oil microembolization, such as pulmonary oil microembolism, may occur if inadvertently administered intravenously, which may result in serious reactions. Some injection formulations are made from sesame oil and are not for use in patients with sesame oil hypersensitivity. Benzyl alcohol is also contained in some injection formulas, so use with caution in patients with benzyl alcohol hypersensitivity. 

Progesterone at high doses is an antifertility drug and high doses of progesterone injection would be expected to impair fertility until the cessation of treatment. Women of childbearing age may expect some degree of infertility during treatment with progesterone injection at high doses. 

The safety and effectiveness of progesterone formulations have not been established in children or infants. The safety and efficacy of progesterone have only been established in females of reproductive age. Use of progesterone in female children before menarche is not usually indicated. In neonates, inadvertent exposure to progesterone injections, which may contain benzyl alcohol, can result in a "gasping syndrome". 

Progesterone is contraindicated in patients with a history of thrombophlebitis, active or previous history of thromboembolism or thromboembolic disease (including stroke and myocardial infarction). Patients with risk factors for heart disease, thromboembolism, and stroke (e.g., known cerebrovascular disease, hypertension, diabetes mellitus, tobacco smoking, hypercholesterolemia, obesity, etc.) should be monitored closely and managed appropriately. During use of progesterone in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, heart attack, cerebrovascular disorder such as stroke or focal headache with symptoms consistent with cerebral ischemia, pulmonary embolism, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, progesterone therapy should be discontinued immediately.  

HORMONAL REPLACEMENT THERAPY (HRT): Progesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolic risks, which are highlighted in the oral progesterone boxed warnings. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with estrogen-progestin therapy, relative to placebo. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT vs. women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. Estrogens with or without a progestin such as progesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD. In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke. 

Progesterone should be used cautiously in patients with diabetes mellitus. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. There are possible risks which may be associated with the use of progestin treatment, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. Use with caution in patients with known hyperlipidemia.  

Progesterone should be prescribed cautiously in patients with asthma, congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions.  

Progesterone should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients. If a patient receiving progesterone develops changes in migraine patterns, or a focal migraine with symptoms consistent with cerebral ischemia, or a severe headache pattern that may indicate a cerebrovascular disorder, consider discontinuation of the drug. Some cases of seizures following administration of progestins have been reported. 

An intrauterine device containing progesterone should not be used if there is any infection or inflammation in the female reproductive tract. There is a risk of infection progressing to pelvic inflammatory disease. Exposure to sexually transmitted disease also increases this risk. 

Progesterone may cause transient dizziness in some patients. Use caution when driving or operating machinery. 

Estrogen/progestin combination therapy has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).

Pregnancy

Ascorbic Acid 

There are no data available on ascorbic acid injection in human pregnancy to inform a drug-associated risk of adverse developmental outcomes; however, use of oral ascorbic acid has been used in pregnancy and no adverse developmental outcomes have been reported. In a meta-analysis of randomized studies of pregnant women who took oral vitamin C at doses ranging from 500 to 1,000 mg/day (2.5 to 5 times the recommended daily intravenous dose, respectively) between the ninth and 16th week of pregnancy, no increased risk of adverse pregnancy outcomes, such as miscarriage, preterm premature rupture of membranes, preterm delivery, or pregnancy-induced hypertension, were observed when compared to placebo. Follow the US Recommended Dietary Allowances (RDA) for pregnant women during treatment with ascorbic acid. 

Azelaic Acid  

Azelaic acid is classified FDA pregnancy risk category B. Animal data suggests embryotoxic effects when administered orally; no teratogenic effects were observed. 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.1922 

Progesterone 

Select progesterone products are specifically labeled for use to provide luteal support during early pregnancy. Animal studies involving oral, vaginal, or in utero administration of progesterone have not indicated evidence of fetal harm. Progesterone vaginal gel may be used to support early pregnancy as part of an Assisted Reproductive Technology (ART) program; if pregnancy occurs, the gel is typically continued for 10 to 12 weeks until placental production of progesterone is adequate to support the pregnancy. Similarly, progesterone vaginal inserts are used for up to 10 weeks in ART. Progesterone should only be used during early pregnancy under the observation of an ART specialist. Data suggest that vaginal progesterone is effective in preventing preterm delivery and associated neonatal complications, especially during high-risk singleton pregnancy; administration usually is initiated at 16 to 24 weeks gestation and continues through 34 weeks gestation. Progesterone should not be used if there is ectopic pregnancy, missed/ incomplete abortion, or during diagnostic tests for pregnancy. Progesterone capsules are only indicated in postmenopausal women, and thus this dosage form is specifically contraindicated for use during pregnancy.

Breast-feeding

Ascorbic Acid 

Ascorbic acid, vitamin C is distributed into breast milk. There are no data available on the effects of ascorbic acid on milk production or the breastfed infant. However, use of ascorbic acid within the recommended daily dietary intake for breast-feeding women is generally recognized as safe. In mothers not taking vitamin C supplements, vitamin C in human milk in the first 6 months of lactation varies from 34 to 83 mg/L. In mothers taking vitamin C supplements ranging from 45 to more than 1,000 mg/day, vitamin C content of human milk varies from 45 to 115 mg/L. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ascorbic acid and any potential adverse effects on the breast-fed infant from ascorbic acid or the underlying maternal condition. Follow the US Recommended Daily Allowances (RDA) for lactating women during treatment with ascorbic acid. 

Azelaic Acid 

According to the manufacturer, caution should be exercised when azelaic acid is administered to breast-feeding women. In vitro studies assessing human milk partitioning suggests that azelaic acid may be distributed into breast milk. 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.1923 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. 

Progesterone 

Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the breast-feeding infant has not been determined. In general, use of progestins has not had adverse effects on lactation. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for progesterone and the potential adverse effects on the breast-fed infant. 

Adverse Reactions/Side Effects

Ascorbic Acid 

Oxalate, urate, or cystine renal stones (nephrolithiasis) causing renal tubular obstruction, characterized by costovertebral pain or lower back pain, can occur following large doses of ascorbic acid. Hyperoxaluria develops in 5% of patients taking large doses. Patients at an increased risk are those with renal disease, on hemodialysis, those with a history of nephrolithiasis, and children younger than 2 years. 

Ascorbic acid is generally nontoxic. Diarrhea has resulted from oral dosages of more than 1 g daily; vomiting and abdominal cramps have also been reported. Rapid IV administration has resulted in temporary faintness or nausea, lethargy, flushing, dizziness, and headache. IV ascorbic acid should not be rapidly administered; follow administration rate guidelines. 

Hemolytic anemia due to hemolysis has been observed in some patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency after receiving large IV or oral doses of ascorbic acid. 

Excessive use of chewable ascorbic acid formulations can lead to dental caries or sensitivity from the breakdown of dental enamel. 

Injection site reaction, such as pain and swelling, has been reported with intravenous administration of ascorbic acid. 

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).241920 

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.19 

Alpha Lipoic Acid 

None well-documented.  

Alcohol (Ethyl): Alcohol (ethyl) may diminish the therapeutic effect of Alpha-Lipoic Acid. Avoid combination 

Antidiabetic agents: ALA may enhance the therapeutic effect of ALA. Avoid combination.  

Calcium Salts: Calcium salts may decrease the absorption of ALA. ALA may decrease the absorption of calcium salts. This interaction applies to oral administration. Consider therapy modification.  

Cisplatin: ALA may diminish the therapeutic effect of Cisplatin. Monitor therapy.  

Iron Salts: Iron salts may decrease the absorption of ALA. ALA may decrease the absorption of iron salts. This interaction applies to oral administration. Consider therapy modification. 

Magnesium Salts: Magnesium salts may decrease the absorption of ALA. ALA may decrease the absorption of magnesium salts. This interaction applies to oral administration. Consider therapy modification. 

Progesterone 

The most common adverse reactions occurring during therapy with progesterone include menstrual irregularity, menstrual flow changes, and dysmenorrhea or amenorrhea. These effects may be indistinguishable from pregnancy. Progesterone also causes spotting, breakthrough bleeding, weight gain, nausea, vomiting, breast tenderness or mastalgia, and mild headache. These adverse effects occur less frequently with progestin-only OCs compared to combination OCs. Other reported adverse reactions during therapy include melasma, chloasma, libido decrease, libido increase, breast discharge, cervicitis, galactorrhea, hirsutism, leukorrhea, unusual weakness, and vaginitis. Post-marketing experiences with oral progesterone include endometrial carcinoma, hypospadia, intra-uterine death, menorrhagia, menstrual disorder, metorrhagia, ovarian cyst, and spontaneous fetal abortion. Additional adverse reactions associated with the intravaginal gel include breast enlargement, dyspareunia, nocturia, perineal pain, dysmenorrhea, premenstrual tension, vaginal dryness, and vaginal discharge. Adverse reactions associated with vaginal inserts include vaginal irritation, vaginal itching, vaginal burning, and vaginal pain/discomfort. 

Fluid retention and/or edema may occur in patients receiving progesterone. Patients with heart failure and/or renal disease may experience an exacerbation of their condition. Post-marketing reports of adverse reactions with oral progesterone include facial edema, circulatory collapse, congenital heart disease, hypertension, hypotension, and sinus tachycardia. 

Patients receiving progesterone or other hormonal contraceptives can experience emotional lability. This adverse effect may be manifest as mental depression, anxiety, frustration, irritability, anger, or other emotional outbursts. Additional CNS and psychiatric adverse events reported include insomnia, aggression, forgetfulness, migraine, tremor, headache, dizziness, drowsiness, and fatigue. Post-marketing experience reports include convulsions, depersonalization, disorientation, dysarthria, loss of consciousness, paresthesias, sedation, stupor, difficulty walking, syncope, transient ischemic attack, suicidal ideation, and feeling drunk.  

During use of progesterone, the provider should be alert to the earliest manifestations of a thrombotic disorder (e.g., thrombophlebitis, deep vein thrombosis, migraine /headache or other neurologic event with focal symptoms that suggest cerebral ischemia, pulmonary embolism, heart attack, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, progesterone therapy should be discontinued immediately. 

HORMONAL REPLACEMENT THERAPY (HRT): Progesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolism risks in postmenopausal women, which are highlighted in the oral progesterone boxed warnings. The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with estrogen-progestin therapy, relative to placebo. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT vs. women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. Estrogens with or without a progestin such as progesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5. Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD. In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke. 

Gastrointestinal (GI) adverse reactions reported with progesterone use include abdominal pain, bloating, nausea, vomiting, dyspepsia, eructation, flatulence, diarrhea, constipation, anorexia, appetite stimulation, and weight loss. Gastritis and dysphagia have been reported with oral progesterone capsules and acute pancreatitis, hepatic failure, hepatic necrosis, hepatitis, and swollen tongue (glossitis) were reported postmarketing. Cholestasis, cholestatic hepatitis, elevated hepatic enzymes (including ALT increased, AST increased, GGT increased), and jaundice have also been rarely reported postmarketing with use of progesterone capsules or injections. 

Adverse reactions reported with progesterone use include abnormal gait, arthralgia, choking (with oral formulations), cleft lip, cleft palate, tinnitus, vertigo, cystitis, dysuria, increased urinary frequency, leg pain, musculoskeletal pain, flu-like symptoms, xerophthalmia, benign cyst, purpura, anemia, infection, pharyngitis, sinusitis, urinary tract infection, and conjunctivitis. 

Estrogen/progestin combination hormone replacement therapy (HRT) has been found to fail to prevent mild impaired cognition (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory). 

The issue of hormonal influences on the development of cancers (new primary malignancy) has been widely researched for many decades. The risks of various cancers for progestins used for infertility or for short term treatment of irregular uterine bleeding are expected to differ from the risks associated with postmenopausal hormone replacement therapy (HRT). Undiagnosed vaginal bleeding should be evaluated in any patient using progesterone as is clinically appropriate, since female genital cancers may be influenced by hormonal therapy. 

HORMONE REPLACEMENT THERAPY POSTMENOPAUSE: Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. The Women's Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Due to breast cancer and other cancer risks, combined HRT should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Among combined estrogen/progestin HRT users, roughly 10% will have some endometrial thickening. Postmarketing reports of endometrial hyperplasia have been reported in women receiving combined estrogen/progestin HRT; however, the incidence of endometrial hyperplasia is estimated to be 1% or less in these patients. Women who used HRT for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. The contraindications and precautions sections for progesterone HRT product labels more fully discuss the data and what is known about HRT use with respect to risks for various cancers.

Storage

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

• 1. 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. a. b. 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. Farris PK. Topical vitamin C: a useful agent for treating photoaging and other dermatologic conditions. Dermatol Surg. 2005 Jul;31(7 Pt 2):814-7.
• 5. Rhie G1, Shin MH, Seo JY, Choi WW, Cho KH, Kim KH, Park KC, Eun HC, Chung JH. Aging- and photoaging-dependent changes of enzymic and nonenzymic antioxidants in the epidermis and dermis of human skin in vivo. J Invest Dermatol. 2001 Nov;117(5):1212-7.
• 6. Liu J1. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008 Jan;33(1):194-203. Epub 2007 Jun 29.
• 7. University of Maryland Medical Center. http://www.umm.edu/health/medical/altmed/supplement/alphalipoic-acid.
• 8. Beitner, Harry. (2003). Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% α-lipoic acid related to photoageing of facial skin. The British journal of dermatology. 149. 841-9. 10.1046/j.1365-2133.2003.05597.x.
• 9. Beitner, Harry. (2003). Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% α-lipoic acid related to photoageing of facial skin. The British journal of dermatology. 149. 841-9. 10.1046/j.1365-2133.2003.05597.x.
• 10. Oregon State University. Linus Pauling Institute. http://lpi.oregonstate.edu/mic/dietary-factors/lipoic-acid.
• 11. a. b. Surjushe, Amar, Resham Vasani, and D G Saple. “ALOE VERA: A SHORT REVIEW.” Indian Journal of Dermatology 53.4 (2008): 163–166. PMC. Web. 19 Sept. 2017.
• 12. Stevenson, Susan, and Julie Thornton. “Effect of Estrogens on Skin Aging and the Potential Role of SERMs.” Clinical Interventions in Aging 2.3 (2007): 283–297. Print.
• 13. Schmidt JB1, Binder M, Demschik G, Bieglmayer C, Reiner A. Treatment of skin aging with topical estrogens. Int J Dermatol. 1996 Sep;35(9):669-74.
• 14. John R. Lee, M.D. Slowing the Aging Process With Natural Progesterone. https://www.bellissimomedical.com/pdf/case-studies/women/progesterone-benefits/slowing-aging-with-progesterone.pdf
• 15. Beitner H. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoaging of facial skin. Br J Dermatol. 2003;149(4):841-849.
• 16. National Center for Biotechnology Information (2020). PubChem Compound Summary for CID 5756, Estriol.
• 17. Lexi-drugs. Lexicomp. Wolters Kluwer Health, Inc Riverwoods, IL.
• 18. Ali ES, Mangold C, Peiris AN. Estriol: emerging clinical benefits. Menopause. 2017;24(9):1081-1085. 

  Progesterone 

  Progesterone is administered orally (Prometrium micronized soft gelatin capsules), topically, intramuscularly, intravaginally (Crinone gel, Prochieve gel), or as a component of an intrauterine device (IUD). Vaginal suppositories are also compounded for use, however, pharmacokinetic data is unavailable. Once in the systemic circulation, progesterone is extensively (96—99%) bound to cortisol binding globulin, sex hormone binding globulin, and albumin. The drug is metabolized hepatically to pregnanediol and conjugated with glucuronic acid. The plasma elimination half-life ranges 5—20 minutes. The metabolites are excreted primarily in the urine (50—60%). About 10% is eliminated via the bile and feces. 

  Contraindications/Precautions

  Ascorbic Acid 

  There are no data available on ascorbic acid injection in human pregnancy to inform a drug-associated risk of adverse developmental outcomes; however, use of oral ascorbic acid has been used in pregnancy and no adverse developmental outcomes have been reported. In a meta-analysis of randomized studies of pregnant women who took oral vitamin C at doses ranging from 500 to 1,000 mg/day (2.5 to 5 times the recommended daily intravenous dose, respectively) between the ninth and 16th week of pregnancy, no increased risk of adverse pregnancy outcomes, such as miscarriage, preterm premature rupture of membranes, preterm delivery, or pregnancy-induced hypertension, were observed when compared to placebo. Follow the US Recommended Dietary Allowances (RDA) for pregnant women during treatment with ascorbic acid. 

  Ascorbic acid, vitamin C is distributed into breast milk. There are no data available on the effects of ascorbic acid on milk production or the breastfed infant. However, use of ascorbic acid within the recommended daily dietary intake for breast-feeding women is generally recognized as safe. In mothers not taking vitamin C supplements, vitamin C in human milk in the first 6 months of lactation varies from 34 to 83 mg/L. In mothers taking vitamin C supplements ranging from 45 to more than 1,000 mg/day, vitamin C content of human milk varies from 45 to 115 mg/L. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ascorbic acid and any potential adverse effects on the breast-fed infant from ascorbic acid or the underlying maternal condition. Follow the US Recommended Daily Allowances (RDA) for lactating women during treatment with ascorbic acid. 

  Acute and chronic oxalate nephropathy has been reported with prolonged administration of high doses of ascorbic acid. Acidification of the urine by ascorbic acid may lead to precipitation of cysteine, urate, or oxalate stones. Patients with renal disease, renal impairment, or renal failure, patients with a history of nephrolithiasis, and geriatric patients may be at increased risk. Infants and children less than 2 years may also be at increased risk due to immature kidney function. Monitor renal function during treatment with ascorbic acid in patients at increased risk. Discontinue ascorbic acid therapy in patients who develop oxalate nephropathy and treat as needed. 

  Large intravenous or oral doses of ascorbic acid have caused hemolysis and hemolytic anemia in some patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency). Monitor hemoglobin and blood counts and use a reduced dose of ascorbic acid in patients with G6PD deficiency. Discontinue ascorbic acid treatment if hemolysis is suspected, and treat as required. 

  The sodium ascorbate preparation contains sodium. This can be of significance when treating patients on a sodium restriction diet, particularly if high doses of the sodium ascorbate preparation are given. 

  Ascorbic acid may increase the risk of iron toxicity in patients with hemochromatosis; therefore, patients with hemochromatosis should limit their intake of ascorbic acid to no more than 500 mg/day. Rarely, ingestion of large quantities of ascorbic acid have been associated with fatal cardiac arrhythmias in patients with iron overload. 

  Because ascorbic acid is a strong reducing agent, it can lead to laboratory test interference with laboratory tests based on oxidation-reduction reactions. Chemical detecting methods based on colorimetric reactions are generally those tests affected. Ascorbic acid can lead to inaccurate results (false negatives) obtained for checking blood or urinary glucose levels, nitrite, bilirubin, and leukocytes if tested during or within 24 hours after ascorbic acid infusion. If possible, laboratory tests based on oxidation-reduction reactions should be delayed until 24 hours after ascorbic acid infusion. Patients with diabetes mellitus should be made aware of the possibility of falsely decreased glucose concentrations with these tests. Additionally, ascorbic acid should not be ingested 48 to 72 hours before amine-dependent stool occult blood tests are conducted because false negatives may occur. 

  Azelaic Acid 

  Azelaic acid products that contain propylene glycol should be avoided in patients with a known propylene glycol hypersensitivity; avoid use in patients hypersensitive to any other ingredients of the particular formulation prescribed.Finacea (azelaic acid) topical gel package insert. Whippany, NJ: Bayer Healthcare; 2016 Aug.

• 19. a. b. c. d. e. f. Finacea (azelaic acid) topical gel package insert. Whippany, NJ: Bayer Healthcare; 2016 Aug.
• 20. a. b. c. Finacea (azelaic acid) 15% topical foam package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2015 Jul.
• 21. Delgado BJ, Lopez-Ojedo W. Estrogen. StatPearls; 2020.
• 22. Azelex (azelaic acid) package insert. Irvine, CA: Allergan, Inc.; 2004 May.
• 23. Azelex (azelaic acid) package insert. Irvine, CA: Allergan, Inc.; 2004 May.
• 24. Azelex (azelaic acid cream) 20% [package insert]. Irvine, CA: Allergan; 2013.