Hair Restore Ultra Scalp Solution

Overview of Hair Restore Ultra Scalp Solution

Dosage Strength of Hair Restore Ultra Scalp Solution

Minoxidil / Azelaic Acid / Finasteride / Ketoconazole 5/12.5/0.1/2% 60 mL Dropper Bottle

General Information

Minoxidil

Oral minoxidil (Loniten) is an antihypertensive agent; topical minoxidil (Rogaine) is used for alopecia. Topical minoxidil is likely effective in producing moderate hair growth in approximately 30% of men and 60% of women with common hereditary hair loss.1 Lesser growth or a halt in the worsening of alopecia are also frequent outcomes.2Due to its potency and adverse reactions, oral minoxidil is used mainly for patients with severe, drug-resistant forms of hypertension. Tolerance to prolonged therapy with oral minoxidil does not appear to be a problem. Although the oral dosage form was originally approved in October 1979 for use in hypertension, minoxidil was first discovered in 1965. In August 1988 the topical formulation was approved for of alopecia. After declining Upjohn permission to market topical minoxidil as a non-prescription drug in July 1994, the 2% topical solution was subsequently approved for over-the-counter use in men with alopecia in February 1996. In September 1996, Pharmacia and Upjohn petitioned the FDA to increase the topical solution formulation from 2% to 5%; the higher-strength solution has been shown to elicit a more rapid hair growth response (8 weeks vs. 16 weeks) and to regrow an average of 45% more hair than Rogaine Regular Strength.2The 5% topical solution (Rogaine Extra Strength) for common hereditary hair loss was approved FDA in November 1997. Approval to market 2% topical solution to women was granted October 1996. Minoxidil foam (Men's Rogaine Foam) was approved for men in January 2006; potential advantages over the solution formulation include the absence of propylene glycol (potential irritant), ability to limit spread of medication, and less time to dry after application.3

Azelaic Acid

Azelaic acid is a topical anti-acne agent. Azelaic acid is a naturally occurring dietary constituent (whole grain and animal products) and can be formed endogenously from longer-chain dicarboxylic acids, metabolism of oleic acid, and omega-oxidation of monocarboxylic acids. Azelaic acid is used as a treatment for acne vulgaris and is one of the leading treatments for this condition in Europe where it has been marketed as a 20% cream since 1989 by Schering. The drug is also effective for reducing the number of inflammatory pustules and papules associated with rosacea. Reduction in erythema may occur; however, efficacy has not been established for erythema associated with rosacea without papules and pustules. Azelaic acid has been administered orally and intravenously; however, only a topical formulation is marketed in the United States. The drug was originally FDA approved as a 20% cream for the treatment of acne vulgaris in September 1995; several brand name creams are now available. A 15% topical gel and foam were FDA-approved for the treatment of rosacea in December 2002 and July 2015, respectively.456

Finasteride

Finasteride is a 5-alpha reductase inhibitor used to treat symptomatic benign prostatic hyperplasia (BPH), a condition found in the majority of men over the age of 50. Finasteride has been shown to increase and maintain maximum urine flow rate in men with BPH, although less than 50% of men show improvement despite a reduction in prostate size. In a typical patient undergoing treatment for BPH with finasteride (>= 6 months), a 50% decrease in serum PSA concentrations can be expected; however, individual patients may experience varying decreases in PSA values. During treatment, serum PSA concentrations may decrease even in the presence of prostate cancer. If clinicians use serum PSA concentrations as an aid in the detection of prostate cancer in men receiving finasteride, values should be doubled for comparison with normal ranges in untreated men. Any increase from baseline, even if the value is within the normal range for untreated men, may signal the presence of prostate cancer. If clinicians elect to use percent free PSA (free to total PSA ratio) as a marker, no adjustment in PSA values appear to be necessary as the value is not significantly decreased by finasteride.7 In June 2011, a review of two large, randomized controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial prompted the FDA to alert healthcare professionals of the potential risk of an increased incidence of high-grade prostate cancer in patients receiving finasteride or dutasteride treatment. Results from the PCPT trial showed that men receiving finasteride had a 26% decreased risk of being diagnosed with prostate cancer overall when compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of GS 8—10 prostate cancers with finasteride compared to placebo (1.8% vs. 1.1%, respectively).89Finasteride is also used for treating hair loss in men and has been shown to be effective for mild to moderate hair loss of the vertex and anterior mid-scalp area; efficacy in bitemporal recession has not been established. Finasteride (Proscar) was approved by the FDA in June 1992 for the treatment of BPH. Another finasteride oral dosage form, Propecia, was approved by the FDA in December 1997 for the treatment of male pattern baldness (i.e., androgenetic alopecia). Finasteride is also used investigationally as an alternative agent for treating hirsutism.

Ketoconazole

Ketoconazole is an imidazole antifungal agent and is available as an oral tablet and various topical formulations. Oral ketoconazole has been associated with fatal hepatotoxicity, adrenal gland suppression, and harmful drug interactions. Due to the potential for severe adverse events, oral ketoconazole should only be used to treat serious blastomycosis, histomycosis, coccidioidomycosis, paracoccidioidomycosis, and chromomycosis infections when no other antifungal therapies are available. The topical formulations are indicated for the treatment of tinea corporis, tinea cruris, tinea pedis, tinea versicolor, mucocutaneous candidiasis, seborrheic dermatitis, and dandruff. Ketoconazole was FDA-approved in 1981.1011121314

Mechanism of Action

Minoxidil

Minoxidil has a direct vasodilatory effect on arterial smooth muscle, causing a reduction in peripheral resistance and blood pressure. Minoxidil does not exhibit CNS or adrenergic neuronal blocking effects; minoxidil retains its activity despite adrenergic denervation. Cyclic adenosine monophosphate (cAMP) may contribute to relaxation of vascular smooth muscle. Minoxidil-induced delay in the hydrolysis of cAMP via inhibition of phosphodiesterase may contribute to the drug's vasodilatory action.

All direct vasodilators produce a sympathetic response including an increase in heart rate, stroke volume, and cardiac output, and a marked increase in plasma renin activity, which, in turn, leads to increased sodium and water retention. This increased renin release is believed to be partially mediated by the beta-adrenergic system. These compensatory responses tend to diminish the hypotensive effects of minoxidil. Additional therapeutic effects can be achieved by using a beta-blocker to offset the predictable sympathetic stimulation caused by minoxidil. Methyldopa may be used if beta-blocker therapy is contraindicated; however, because of its delay in onset, methyldopa must be initiated 24 hours prior to initiating minoxidil. Vasodilator-induced fluid retention is somewhat related to the potency of the vasodilator. Due to its potency, fluid retention occurs routinely with minoxidil. Often, this fluid retention requires concomitant use of loop diuretics (see Adverse Reactions). Triple-drug therapy consisting of a loop diuretic, beta-blocker, and minoxidil produces prompt, sustained reduction in blood pressure in patients with severe hypertension.1516

Minoxidil preferentially dilates arterioles; therefore, postural hypotension may occur during therapy. As an antihypertensive, minoxidil does not lead to improvements in LVH. Minoxidil may actually worsen LVH, potentially due to reflex tachycardia and sympathetic stimulation, which may counteract the benefits of afterload reduction.17 Minoxidil does not affect glucose tolerance or serum lipids.

The exact mechanism responsible for minoxidil-induced hair growth is not known, but appears to be independent of vasodilation.18 While systemic therapy will stimulate hair growth, topical therapy usually does not cause hypotension. Current evidence suggests the primary action of topical minoxidil is to decrease the latent period of the hair cycle. The latent period (the time between shedding of telogen hair and the onset of the next anagen) is typically prolonged in male pattern balding; however, this effect has not been demonstrated in balding females.19 Calcium may also be involved in the process of hair regrowth. In the presence of calcium, epidermal growth factor (EGF) inhibits hair growth. The entry of calcium into a hair cell is opposed by potassium channel openers, such as minoxidil; therefore, EGF-induced inhibition of hair will be opposed by the action of minoxidil, and hair will grow more proficiently. Biopsy specimens have not demonstrated evidence of new follicle formation with the use of minoxidil.1 Furthermore, minoxidil appears to affect only suboptimal follicles with no further stimulation of normal hair follicles.18 Minoxidil also may alter the metabolism of androgens in the scalp. Minoxidil increases 17 beta-hydroxylated dehydrogenase activity by almost 40% in dermal papilla cells of a balding scalp, whereas the effect is much less in a nonbalding scalp. Whether this modification in testosterone metabolism of cells of a balding scalp is related to the therapeutic effect of minoxidil is unknown.20

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 epidermidisand 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 antiinflammatory 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.

Finasteride

Finasteride is a synthetic 4-aza analog of testosterone that acts as a competitive, specific inhibitor of type II 5-alpha-reductase, an intracellular enzyme that converts testosterone to the potent androgen 5-alpha-dihydrotestosterone (DHT). The type II 5alpha-reductase isozyme is primarily found in prostate, seminal vesicles, epididymides, and hair follicles, as well as liver. The type II isozyme is responsible for two-thirds of circulating DHT. DHT is the primary androgen that stimulates the development of prostate tissue. When used for the treatment of benign prostatic hyperplasia, as the enzymatic conversion from testosterone to DHT is inhibited, a desirable reduction in prostate hypertrophy is achieved, and urine flow should be improved. In male pattern hair loss, the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared with hairy scalp. Finasteride decreases scalp and serum DHT concentrations, thus interrupting a key factor in the development of androgenetic alopecia in those patients genetically predisposed. Finasteride does not appear to affect circulating concentrations of cortisol, estradiol, prolactin, thyroid-stimulating hormone, thyroxine or cholesterol. Research to date also suggests that finasteride does not affect the hypothalamic-pituitary-testicular-axis.

Ketoconazole

Like other azole antifungals, ketoconazole exerts its effect by altering the fungal cell membrane. Ketoconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme that is necessary for the conversion of lanosterol to ergosterol, an essential component of the membrane. In contrast, amphotericin B binds to ergosterol after it is synthesized. Inhibition of ergosterol synthesis results in increased cellular permeability, which causes leakage of cellular contents. Ketoconazole does not appear to have the same effects on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed21 and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of yeast transformation to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis.22 At higher concentrations, ketoconazole may have a direct physiochemical effect on the fungal cell membrane, which leads to a fungicidal action.

Ketoconazole possesses actions that may make it useful in conditions other than fungal infections. Ketoconazole can inhibit sterol synthesis in humans including the synthesis of aldosterone, cortisol, and testosterone. Ketoconazole's effects on testosterone synthesis occur at lower doses than do the effects on cortisol synthesis; doses of of 200—400 mg/day can inhibit testosterone secretion and doses of 400—600 mg/day have been shown to inhibit cortisol synthesis.2324 Ketoconazole acts at many of same steps as metyrapone and, in some sites, has been shown to be a more potent inhibitor.23Both ketoconazole and metyrapone affect multiple steps in the steroid-synthesis pathway, while finasteride appears to work at a single site. Ketoconazole has been used successfully for treating advanced prostate cancer.25 Finally, ketoconazole is a known potent inhibitor of thromboxane synthesis and has been used clinically to prevent ARDS in patients at high risk of this syndrome.26

Pharmacokinetics

Minoxidil

Minoxidil is administered orally and topically. Minoxidil distributes widely throughout the body tissues and is extensively metabolized in the liver. Both the unchanged drug and its metabolites (primarily the glucuronide conjugate) are excreted in the urine.

Minoxidil is not significantly bound to plasma proteins; it is freely filtered and undergoes no tubular secretion. Thus, renal clearance corresponds to glomerular filtration and accounts for approximately 10% of total clearance. In addition, little drug accumulation occurs in patients with renal insufficiency, perhaps due to a combination of minimal renal clearance and rapid hepatic metabolism.

Topical minoxidil is poorly absorbed through the skin; the systemic absorption averages 2% (range 0.3—4.5%). Roughly 95% of a topical dose will be eliminated after 4 days.

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.

Finasteride

Finasteride is administered orally in the treatment of either BPH or male pattern baldness. Approximately 90% is bound to plasma proteins; yet the drug has been found to cross the blood-brain barrier. This is not problematic, since finasteride generally does not affect other hormones. Daily dosing causes accumulation to occur, with plasma concentrations increasing by 50% over those observed from a single dose. The mean plasma elimination half-life of finasteride is 4.8 to 6 hours (range, 3 to 16 hours); however, the turnover rate for the type II 5-alpha-reductase enzyme complex is slow, with a turnover half-life of approximately 30 days. After oral dosing, about half of the unchanged drug is excreted in the feces, and one-third is metabolized in the liver to the 17-carboxylic acid, which is then excreted in the urine (39%) and the feces (57%).

A single 5 mg oral dose rapidly reduces serum DHT concentrations by as much as 70%, with the maximum reduction occurring at about 8 hours. The effect lasts for at least 24 hours, so once daily dosing is appropriate. Actual clinical effects, however, are not realized for 3 to 6 months after beginning therapy.

Affected cytochrome P450(CYP450) isoenzymes and drug transporters: CYP3A4, UGT1A4

While finasteride is metabolized by hepatic CYP3A4 isoenzymes, no drug interactions of clinical importance have been identified, likely due to the hormonal mechanisms of action and relatively large therapeutic window of effect. Finasteride does not appear to affect the CYP450-linked drug metabolizing enzyme system. Compounds that have been tested in man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful interactions were found. Finasteride has not been associated with clinically important drug interactions during clinical trials, including a 4-year safety trial of 3,040 males aged 45 to 78 years.2728729 while finasteride markedly inhibited UGT1A4 activity in vitro in a drug transporter study; the data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo.

Ketoconazole

Ketoconazole is administered orally and via topical administration. It is widely distributed into most body fluids, although CNS penetration is unpredictable and usually minimal. In animal studies, it crosses the placenta and is distributed into milk. Protein binding is 84—99%, mainly to albumin.

Ketoconazole plasma concentrations decline in a biphasic manner. Initial phase half-life is approximately 2 hours, and the terminal phase half-life is approximately 8 hours. It is partially metabolized through oxidation, dealkylation, and aromatic hydroxylation. Most of the ketoconazole and its metabolites are excreted into the bile and then the feces. The rest is excreted in the urine. In a study involving fasting adults with normal renal function, about 57% of a 200 mg oral dose was excreted in the feces within 4 days. Between 20—65% of the ketoconazole excreted in the feces was unchanged drug. Within 4 days, approximately 13% of the dose was excreted in the urine; approximately 2—4% of this portion was as unchanged ketoconazole.10

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9, CYP2C19, P-gp, UGT1A1, UGT2B7

Ketoconazole is a substrate and potent inhibitor of the CYP3A4 isoenzyme. In vitro, ketoconazole weakly inhibits CYP2C9 and CYP2C19; however, the in vivo inhibition potential is questionable. Ketoconazole has the ability to inhibit P-glycoprotein (P-gp) in vitro, but the potency of this inhibition may vary depending on the in vitro model or P-gp substrate used in the assay.3010 Studies have also found ketoconazole to be an inhibitor of uridine diphosphoglucuronosyltransferase UGT1A1 and UGT2B7.313233

Topical ketoconazole does not have significant systemic absorption. Repeated topical application of ketoconazole 2% shampoo, however, will lead to absorption of the drug into hair keratin. Small amounts of intravaginal ketoconazole are absorbed systemically. Peak plasma concentrations in women receiving ketoconazole as a 400 mg vaginal suppository ranged from 0—20.7 ng/mL.

Contraindications/Precautions

Minoxidil

Minoxidil has been reported to produce cardiac lesions in animals. Some lesions are characteristic of other drugs that can cause tachycardia and/or hypotension (e.g., isoproterenol, hydralazine). These effects are more likely to occur in patients with compromised renal function and in patients with connective tissue disease, uremic syndrome, CHF, or minoxidil-induced fluid retention.

Systemic minoxidil is a potent vasodilator with potential to produce hypotension and reflex tachycardia; serious complications may occur. Minoxidil is relatively contraindicated in patients with cardiac disease (including angina, coronary artery disease, recent or acute myocardial infarction), or cerebrovascular disease because a reflex increase in heart rate and decrease in blood pressure can exacerbate these conditions. Minoxidil is relatively contraindicated in patients with coronary insufficiency, including angina, to avoid the risk of reflex tachycardia and angina exacerbation. Minoxidil may cause pericardial effusion which occasionally may progress to cardiac tamponade. Reserve oral minoxidil for hypertension in patients who do not respond adequately to maximum therapeutic doses of a diuretic (loop diuretic suggested) concurrently with 2 other antihypertensive agents. In experimental animals, minoxidil has been shown to induce several types of myocardial lesions as well as other adverse cardiac effects. Minoxidil must be administered under close supervision, usually in combination with therapeutic doses of a beta-blocker to prevent reflex tachycardia and increased myocardial workload. Minoxidil is often given with a diuretic (preferably a diuretic which acts within the ascending limb of the loop of Henle) to prevent fluid accumulation and peripheral edema. When first administering minoxidil to patients with malignant hypertension and those already receiving guanethidine to avoid rapid or large orthostatic reductions in blood pressure, minoxidil use requires a specialized care setting, specifically hospitalization. Although minoxidil does not directly cause orthostatic hypotension, administration to patients receiving guanethidine can result in profound orthostatic effects. When possible, guanethidine should be discontinued well before minoxidil is initiated. Otherwise, minoxidil therapy should be started in the hospital; the patient should remain hospitalized until the risk of excessive orthostatic effects is minimized and the patient is able to avoid activities that induce orthostatic hypotension.

Minoxidil is relatively contraindicated in patients with renal disease, preexisting pulmonary hypertension, or chronic congestive heart failure not secondary to hypertension because the drug can cause an increase in pulmonary artery pressure, which could be detrimental to these patients. Use of minoxidil has been associated with the development of pericardial effusion and tamponade in some patients, and it may be more likely to occur in patients with renal disease. Since approximately only 10% of active drug is eliminated unchanged via the kidneys, minoxidil can be used safely in patients with renal impairment. Renal elimination, however, may be reduced and dosage adjustment may be necessary. Avoid use of minoxidil in patients with severe renal failure (CrCl < 10 ml/min).

Minoxidil is contraindicated in patients with pheochromocytoma because the hypotensive effects of the drug can stimulate catecholamine secretion.

Systemic effects resulting from topically administered minoxidil are unlikely but theoretically could occur if the drug is overused. Skin abrasion or irritations, such as excoriations, psoriasis, or sunburn, can increase the systemic absorption of topically administered minoxidil.

Reported clinical experience has not identified differences in responses in geriatric adults vs. younger adult patients. In general, systemic dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.34 Topical minoxidil use carries no special precaution in the elderly, but any patient experiencing dizziness or faintness should discontinue topical use.1 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, antihypertensive regimens should be individualized to achieve the desired outcome while minimizing adverse effects. Antihypertensives may cause dizziness, postural hypotension, fatigue, and there is an increased risk for falls. There are many drug interactions that can potentiate the effects of antihypertensives. Some agents require a gradual taper to avoid adverse consequences caused by abrupt discontinuation.35

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.4

Azelaic acid has not been well-studied in patients with dark complexions and should be used cautiously in these patients to avoid hypopigmentation.46

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.6

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.4

Finasteride

Finasteride is not indicated for use in adolescents, children, or infants. Safety and effectiveness have not been established in pediatric patients under 18 years of age.729

Finasteride should be used with caution in patients with hepatic disease, since finasteride is metabolized extensively in the liver. Data are lacking regarding the incidence of adverse effects or drug accumulation in patients with hepatic impairment.

Finasteride reduces total serum prostate specific antigen (PSA). In a typical patient undergoing treatment for BPH with finasteride (>= 6 months), a 50% decrease in serum PSA concentrations can be expected; however, individual patients may experience varying decreases in PSA values. During treatment, serum PSA concentrations may decrease even in the presence of prostate cancer. If clinicians use serum PSA concentrations as an aid in the detection of prostate cancer in men receiving finasteride, values should be doubled for comparison with normal ranges in untreated men. Any increase from baseline, even if the value is within the normal range for untreated men, may signal the presence of prostate cancer. If clinicians elect to use percent free PSA (free to total PSA ratio) as a marker, no adjustment in PSA values appear to be necessary as the value is not significantly decreased by finasteride.7 In June 2011, a review of two large, randomized controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial prompted the FDA to alert healthcare professionals of the potential risk of an increased incidence of high-grade prostate cancer in patients receiving finasteride or dutasteride treatment. Results from the PCPT trial showed that men receiving finasteride had a 26% decreased risk of being diagnosed with prostate cancer when compared to placebo (p < 0.0001); however, the risk reduction was limited to Gleason score (GS) <= 6 cancers. There was an increased incidence of GS 8—10 prostate cancers with finasteride compared to placebo (1.8% vs. 1.1%, respectively).89Therefore, in initiating or continuing treatment with finasteride, clinicians should weigh the known benefits of treatment against the potential risk and be aware that finasteride may increase the risk of high-grade prostate cancer. Further, lower urinary tract symptoms of BPH can be indicative of other urological diseases, including prostate cancer. Patients should be assessed to rule out other urological diseases prior to treatment with finasteride. Patients with a large residual urinary volume and/or severely diminished urinary flow may not be good candidates for 5-alpha-reductase inhibitor therapy and should be carefully monitored for urinary tract obstruction.7

Men treated with finasteride should refrain from blood donation while taking finasteride. The purpose of this is to prevent administration of finasteride to a pregnant female transfusion recipient.

Clinical efficacy studies of finasteride for hair loss did not include subjects aged 65 and over. Based on the pharmacokinetics of finasteride 5 mg, no dosage adjustment is necessary in the geriatric patient. However, the efficacy of finasteride for hair loss in the elderly has not been established.

The clinical significance of finasteride’s effect on semen characteristics for an individual male patient’s fertility is not known; consider the potential effects on semen when assessing a male with infertility. Finasteride may cause spermatogenesis inhibition or oligospermia, decreased sperm motility, or decreased semen volume. In a 52-week, randomized, double-blind, placebo-controlled study in healthy men, finasteride (5 mg PO once daily) significantly decreased total sperm count (-34.3%) compared to baseline at 26 weeks but not at 52 weeks or at the 24-week follow-up. Semen volume was decreased at 52 weeks for finasteride (-14.5%), but the effect was not statistically significant. Sperm concentration was decreased by finasteride (-7.4%) but was not significant for either drug. Significant reductions of 6 to 12% in sperm motility were observed during treatment. Sperm morphology was not affected. One subject taking finasteride had decreases in sperm count of more than 90% of baseline values at 52 weeks; partial recovery was noted at the 24-week follow-up. During post marketing surveillance, male infertility and/or poor seminal quality following treatment discontinuation have been reported. It should be noted that normalization or improvement of seminal quality has also been reported after discontinuation of finasteride.72936

Ketoconazole

Due to its potent inhibition of the hepatic isoenzyme CYP3A4, oral ketoconazole coadministration with other drugs metabolized by CYP3A4 should be done with extreme caution, if at all. Ketoconazole can cause elevated plasma concentrations of selected drugs metabolized via CYP3A4 which may prolong the QT interval, sometimes resulting in life-threatening ventricular arrhythmias such as torsade de pointes; use of ketoconazole with such drugs is contraindicated. Oral ketoconazole may also inhibit the metabolism of many other drugs, which could result in serious and potentially life-threatening adverse reactions, and use with selected drugs is also contraindicated.10 Due to the potential for harmful drug interactions and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available.1314 Systemic ketoconazole can prolong the QT interval. Use ketoconazole tablets with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, older adult patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.10373839404142

Ketoconazole oral tablets may cause adrenal insufficiency at doses of 400 mg/day and higher in adults. This effect is not shared with other azole antifungals. The recommended dose of 200 to 400 mg daily in adults should not be exceeded. Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.).10 Due to the risk of adrenal insufficiency and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available.1314

Ketoconazole should be used with caution in patients with known azole antifungals hypersensitivity. Hypersensitivity reactions may be due to the various vehicles present in the different ketoconazole formulations. Ketoconazole may have a cross sensitivity with other azole derivatives such as itraconazole, fluconazole, clotrimazole, and miconazole. In rare cases, patients receiving ketoconazole have reported hypersensitivity reactions and even anaphylaxis. Ketoconazole is contraindicated in patients who have previously demonstrated these reactions.

Avoid accidental ocular exposure of topical ketoconazole products. If ocular exposure occurs, treat by immediate flushing the affected eye with cool, clean water. Contact an ophthalmologist if eye irritation persists.

Some topical ketoconazole products are flammable. Due to the alcohol content of ketoconazole topical gel (e.g., Xolegel gel) and the alcohol, butane, and proprane content of ketoconazole topical foam (e.g., Extina foam), avoid fire, flame, or tobacco smoking during and immediately after the application of these ketoconazole products.

Dizziness or drowsiness occurs in some patients receiving systemic ketoconazole. Patients should be careful driving or operating machinery if they have these reactions.

Due to the risk of severe drug interactions and other serious adverse effects with ketoconazole oral tablets, ketoconazole oral tablets should not be a first-line treatment for any fungal infection in the geriatric patient.13 10 Systemic ketoconazole can prolong the QT interval. Geriatric patients may be at increased risk for QT prolongation and for serious drug-drug interactions that may increase the risk QT prolongation risk or may increase the risk for other serious side effects.10373839404142 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, systemic azole antifungals should be used in the lowest possible dose for the shortest possible duration, particularly in patients receiving other medications known to interact with these medications. Increased monitoring may be required to identify and minimize the toxicity of warfarin, phenytoin, theophylline, or sulfonylureas when an azole antifungal is co-administered; other medications such as rifampin and cimetidine may decrease the therapeutic effect of the antifungal. Some drug-drug combinations may be contraindicated. OBRA guidelines caution that azole antifungals may cause hepatotoxicity, headaches, and GI distress.35

The safety and efficacy of oral ketoconazole have not been established in neonates, infants, or children under 2 years of age.10 Topical products (e.g., shampoo, cream) have been used in pediatric patients off-label but are not FDA-approved for use in pediatric patients; the safety and efficacy of ketoconazole topical foam and gel products have not been established in pediatric patients less than 12 years old.11434445

Pregnancy

Minoxidil

Minoxidil is classified as pregnancy risk category C. Although no adequate human studies have examined the effects of this drug on the fetus, animal reproduction studies have shown adverse effects, including reduced ability to conceive and a reduced survival of offspring. Dysmorphic facial features and hypertrichosis were observed in an infant whose mother received a daily minoxidil dosage of 10 mg during pregnancy.46 Therefore, in making the decision to administer this drug during pregnancy, the potential risks to the fetus and possible difficulty in conceiving must be weighed against the potential benefits to the mother.47

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.448

Finasteride

Finasteride is not FDA-approved for use in females of childbearing potential and is contraindicated during pregnancy. Finasteride may cause fetal harm. Finasteride and other 5-alpha-reductase inhibitors, by inhibiting the conversion of testosterone to DHT, have the ability to cause abnormalities in the external genitalia of the male fetus. Pregnant women or females trying to conceive should not handle crushed or broken finasteride tablets. The distribution of finasteride into human semen has been assessed and appears to be well below the threshold concentration associated with fetal anomalies in animals.729

Ketoconazole

There are no adequate and well-controlled studies of ketoconazole use during human pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Use ketoconazole in pregnant women only if the potential benefit justifies the potential risk to the fetus.104511 Guidelines recommend against starting oral azole antifungals, including ketoconazole, during pregnancy and to discontinue these agents in HIV-positive women who become pregnant.49 Embryotoxic and teratogenic effects (syndactylia and oligodactylia) have been demonstrated in animals receiving oral ketoconazole doses at 10-times the maximum recommended human dose. In addition, dystocia was observed in animals administered oral ketoconazole during the third trimester of gestation at doses approximately one-fourth the maximum human dose, based on body surface area comparisons. Ketoconazole is not detected in human plasma after chronic shampooing of the scalp.1011

Breast-feeding

Minoxidil

According to the manufacturer, minoxidil should not be administered to a nursing mother.[6800] The American Academy of Pediatrics (AAP) considers minoxidil to be generally compatible with breast-feeding 50; however, other experts are less comfortable with the use of this potent antihypertensive agent in nursing mothers. In one case report of a woman taking minoxidil 5 mg PO twice daily, minoxidil was rapidly excreted into the breast milk. After two months, no adverse events were reported in the nursing infant. The effect of prolonged exposure during breast-feeding is unknown.51 Examples of other antihypertensives with more data in this population that have been classified as usually compatible with breast-feeding by the AAP and may be possible alternatives for some patients include enalapril, hydrochlorothiazide, methyldopa, and propranolol.50 It is not known whether topical minoxidil is distributed into breast milk. 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.

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.452 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.

Finasteride

Finasteride is not FDA-approved for use in females of childbearing potential and is recommended to be avoided during breast-feeding. It is not known whether finasteride is excreted in human milk. Therefore, the effects of finasteride on breast-feeding or a nursing infant cannot be determined.729

Ketoconazole

Systemic ketoconazole is excreted in breast milk. In a case report of a mother prescribed 200 mg PO daily for 10 days, ketoconazole milk concentrations of 0.22 mcg/mL (peak) were observed 3.25 hours post-dose and were undetectable at 24 hours post-dose. Assuming a milk intake of 150 mL/kg/day, the daily ketoconazole dose of an exclusively breast-fed infant was calculated as 0.01 mg/kg/day or 0.4% of the mother's weight-adjusted dose. There are no data on the effects of ketoconazole on the breast-fed infant or its effects on milk production. The manufacturer recommends mothers refrain from breast-feeding their infants during oral therapy; however, previous American Academy of Pediatrics (AAP) recommendations considered ketoconazole compatible with breast-feeding. After topical application, ketoconazole concentrations in plasma are low; therefore, concentrations in human breast milk are likely to be low. Advise breast-feeding women not to apply topical ketoconazole directly to the nipple and areola to avoid direct infant exposure. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for topical ketoconazole and any potential adverse effects on the breast-fed infant from ketoconazole or the underlying maternal condition. Fluconazole may be a potential alternative to consider during breast-feeding.501045114453

Adverse Reactions/Side Effects

Minoxidil

The adverse reaction profile for minoxidil depends upon its use. Systemic adverse reactions are unlikely from topical administration. Placebo-controlled trials with topical minoxidil only showed an increase in dermatological effects from the active drug.

Minoxidil is a peripheral vasodilator. All direct vasodilators produce a marked increase in plasma renin activity, which leads to water and sodium retention and sometimes congestive heart failure. This renin release is believed to be partially mediated by the beta-adrenergic system. The degree of fluid retention is somewhat related to the potency of the vasodilator. Due to its potency, fluid retention (edema) occurs routinely with oral minoxidil and usually requires concomitant administration of a loop diuretic. Without a diuretic, rapid fluid retention can occur within a few days of minoxidil therapy. Temporary edema occurred in 7% of patients who were not edematous when minoxidil was initiated.34 Ascites also has been reported. A restricted dietary intake of sodium can minimize fluid retention and resultant peripheral edema. Rarely, fluid retention is refractory to diuresis and discontinuation of minoxidil is required. Vasodilation may also produce headache.

Minoxidil causes reflex tachycardia; sinus tachycardia may occur. Angina may become apparent, or worsen, secondary to increased myocardial oxygen demand associated with tachycardia and increased cardiac output. Tachycardia and subsequent angina usually can be prevented with the coadministration of a beta-blocker or other sympathetic nervous system suppressant.34

Minoxidil has been shown to transiently lower hematocrit, hemoglobin, and erythrocyte count by approximately 7%. Serum creatinine and BUN also have been shown to increase an average of 6% in patients on minoxidil therapy. Increases in alkaline phosphatase, without other evidence of hepatic abnormality, also has been reported. During the course of therapy, these laboratory abnormalities have been shown to return to pretreatment values. Thrombocytopenia and leukopenia also have been reported.34

Hypertrichosis (elongation, thickening, and enhancement of fine body hair), without evidence of virilism or endocrine abnormalities, is an embarrassing adverse effect that often occurs with oral minoxidil. This effect is usually evident within 3—6 weeks of therapy and occurs on the temples, between the eyebrows, or in the sideburn area. Hair growth also can appear on the arms, legs, and scalp. It is reversible following discontinuation of the drug.34

Oral minoxidil has occasionally been associated with appearance of a bullous rash and Stevens-Johnson syndrome. Topical minoxidil therapy produces local dermatological reactions including contact dermatitis, local burning, pruritus, erythema, or xerosis. Many other adverse effects have been reported during administration of topical minoxidil preparations, but none has been directly attributed to the drug.34

Gastrointestinal adverse effects associated with orally administered minoxidil include nausea and vomiting.34

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).546

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.4

Finasteride

Adverse reactions to finasteride are generally mild and transient. In a long-term (4 years) clinical trial in men with benign prostatic hypertrophy (BPH) [25064], the most frequently reported adverse reactions to finasteride were related to sexual function. At 1 year, the adverse reactions reported to be drug-related were impotence (erectile dysfunction), decreased libido, decreased ejaculate volume, ejaculation dysfunction, breast enlargement, breast tenderness (mastalgia), and rash (unspecified). There was no significant difference between finasteride and placebo in the incidences of impotence, decreased libido, and ejaculation dysfunction in years 2 to 4 of the study. However, during post marketing surveillance, continued erectile dysfunction, orgasm dysfunction or other orgasm disorders, and ejaculation dysfunction following treatment discontinuation have been reported.729 From June 1992, when finasteride was approved, until February 1995, the FDA received reports of gynecomastia in 214 men (median age: 71 yrs). Most were taking a dose of 5 mg/day PO. Gynecomastia has been the most frequently reported adverse effect of this drug since it was marketed. The onset of gynecomastia ranged from 14 days to 2.5 years (median: 180 days). Thirty percent had unilateral gynecomastia, 25% had bilateral involvement, and, in the remainder of reports, this information was not specified. Twenty-seven percent of patients were also taking other medications that are known to cause gynecomastia. Gynecomastia resolved either completely or partially in 80% of subjects after finasteride was discontinued, however, in at least 2 cases, a new primary malignancy of primary intraductal breast cancer subsequently developed.54 In a 4 to 6 year trial where patients were randomized to receive finasteride 5 mg/day, doxazosin 4 or 8 mg/day, a combination of the two drugs, or placebo, four patients reported breast cancer as an adverse experience; three of the patients were receiving finasteride therapy and one patient was receiving combination therapy. In addition, male breast cancer has been reported during post-marketing experience. Other post-marketing adverse reactions have included depression, testicular pain that continued after discontinuation of treatment, and hypersensitivity reactions including pruritus, urticaria, and angioedema (including swelling of the lips, tongue, throat, and face).7

In controlled trials of finasteride for the treatment of male pattern hair loss, 1.4% of patients discontinued therapy due to adverse events, compared with 1.6% of placebo-treated patients. Discontinuation of therapy because of a drug-related sexual adverse experience occurred in 1.2% of patients on finasteride and 0.9% of patients on placebo. The following adverse events were reported as at least possibly drug-related in finasteride-treated patients: libido decrease (1.8%), impotence (1.3%), and ejaculation disorder (1.2%), primarily decreased ejaculate volume. The incidence of each of the above adverse effects decreased to <= 0.3% by the fifth year of treatment. During post marketing surveillance, decreased libido and libido disorders that continued after discontinuation of treatment was reported.7

Finasteride may cause spermatogenesis inhibition or oligospermia, decreased sperm motility, or decreased semen volume. The clinical significance of finasteride’s effect on semen characteristics for an individual male patient’s fertility is not known; consider the potential effects on semen when assessing a male with infertility. In a 52-week, randomized, double-blind, placebo-controlled study in healthy men, finasteride (5 mg PO once daily) significantly decreased total sperm count (-34.3%) compared to baseline at 26 weeks but not at 52 weeks or at the 24-week follow-up. Semen volume was decreased at 52 weeks for finasteride (-14.5%), but the effect was not statistically significant. Sperm concentration was decreased by finasteride (-7.4%) but was not significant for either drug. Significant reductions of 6 to 12% in sperm motility were observed during treatment. Sperm morphology was not affected. One subject taking finasteride had decreases in sperm count of more than 90% of baseline values at 52 weeks; partial recovery was noted at the 24-week follow-up. During post marketing surveillance, male infertility and/or poor seminal quality following treatment discontinuation have been reported. It should be noted that normalization or improvement of seminal quality has also been reported after discontinuation of finasteride.72936

By inhibiting the conversion of testosterone to DHT, finasteride and other 5-alpha-reductase inhibitors have the ability to cause teratogenesis, specifically abnormalities in the external genitalia of the male fetus (e.g., hypospadias).7

Ketoconazole

Approximately 3% of patients receiving oral ketoconazole experience episodes of nausea and vomiting. This usually is transient and may improve when ketoconazole is given with food, which also can increase oral bioavailability. Other ketoconazole-associated gastrointestinal adverse reactions include abdominal pain and diarrhea which were reported in 1.2% and less than 1% of patients, respectively.10 Cases of cheilitis have been noted during postmarketing use of ketoconazole topical foam. Due to the voluntary nature of postmarketing reports, neither a frequency nor definitive causal relationship can be established.44

Ketoconazole can inhibit testosterone secretion at doses of 200—400 mg/day23and can inhibit cortisol synthesis in doses of 400—600 mg/day.24 Inhibition of testosterone synthesis has led to cases of gynecomastia and impotence (erectile dysfunction) in < 1% of men. Serum testosterone concentrations return to baseline and gynecomastia and impotence usually abate after ketoconazole therapy is stopped. Oligospermia has been reported in patients receiving systemic ketoconazole in investigational studies. This was mainly at doses above those approved. Oligospermia was not reported at doses up to 400 mg/day; however, sperm counts are not frequently obtained at these doses.10

Rare cases of anaphylactoid reactions have been reported following the first dose of oral ketoconazole and during post-marketing use of the 2% shampoo. Several cases of hypersensitivity reactions including urticaria and angioedema have also been reported.11 Fever and chills have been reported in < 1% of patients receiving systemic ketoconazole.10 Facial swelling has been reported in < 1% of patients using the topical gel formulation.55

Dizziness, drowsiness (somnolence), and headache have been reported in < 1% of patients receiving treatment with oral ketoconazole. Neuropsychiatric events have also been reported rarely and include suicidal ideation and severe depression.10 Headache and dizziness were also reported in < 1% of patients using the topical gel formulation.55

Photophobia occurs in < 1% of patients receiving treatment with oral ketoconazole. To minimize discomfort, the patient should wear sunglasses while outside and avoid bright light when possible.10 Treatment-related ophthalmic adverse events reported in < 1% of patients using the topical gel include ocular irritation, ocular swelling, and keratoconjunctivitis sicca.55

Post-marketing worldwide reports in patients receiving oral ketoconazole have included rare cases of paresthesias, and signs of increased intracranial pressure including bulging fontanelles and papilledema. Hypertriglyceridemia has also been reported with the oral formulation but a causal relationship with ketoconazole has not been determined.10 Paresthesias have also been reported in <= 1% of patients using the topical foam and in < 1% of patients using the topical gel.5544

Dermatologic reactions were reported with systemic and topical ketoconazole formulations. Pruritus has been reported in 1.5% of patients receiving oral ketoconazole; it has also been reported following application of the topical cream, topical foam (up to 1%), topical gel (less than 1%), and the shampoo. Alopecia has been reported with the shampoo and with worldwide postmarketing reports in patients receiving the oral formulation. Skin irritation has been reported with topical use, specifically with the cream (as pruritus, burning, and stinging), the foam (up to 1%), the gel (less than 1%), and the shampoo. Contact dermatitis was reported with use of the shampoo and postmarketing with the cream; application site dermatitis was reported with use of the gel (less than 1%). The topical foam (Extina) was associated with an increased incidence of contact sensitization, including photosensitivity in dermal safety studies. Application site reaction (6%) and burning (10%) were reported with ketoconazole foam, burning was also reported with the gel (4%) and the shampoo. Skin dryness or xerosis was reported with use of the foam (up to 1%), the gel (less than 1%), and the shampoo. Erythema was reported with use of the foam (up to 1%) and the gel (less than 1%). Rash (unspecified) was reported with use of the foam (up to 1%) and the shampoo. Warmth at the application site was noted in up to 1% of patients using the foam. Pustules were noted on the skin with application of the gel (less than 1%) and on the scalp with application of the shampoo. Other reactions noted in less than 1% of patients who used the topical gel include discharge, pain, impetigo, pyogenic granuloma, acne vulgaris, and nail discoloration. Adverse reactions specifically noted with use of the shampoo include hair discoloration, abnormal hair texture and removal of curl, rash (unspecified), and application site reactions.1110434445

Systemic ketoconazole can prolong the QT interval. Serious cardiovascular events, QT prolongation, ventricular arrhythmias, and torsade de pointes, have been observed in patients receiving ketoconazole oral tablets in combination with other QT-prolonging drugs.10

Ketoconazole alters vitamin D metabolism and may lead to vitamin D deficiency. Patients should be monitored and supplemented with vitamin D if necessary.

Storage

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

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