Biotin / Finasteride / Minoxidil Capsules

Overview of Biotin / Finasteride / Minoxidil Capsules

 

Dosage Strengths of Biotin / Finasteride / Minoxidil Capsules

Biotin / Finasteride / Minoxidil 5/2.5/0.25 mg

Biotin / Finasteride / Minoxidil 5/2.5/2.5 mg

General Information

Biotin

Biotin (vitamin H; coenzyme R; classified as a B vitamin) is a dietary component that is important for the metabolism of carbohydrates, fats, and amino acids. It is found primarily in liver, kidney, and muscle. Biotin functions as an essential cofactor for five carboxylases that catalyze steps in fatty acid, glucose, and amino acid metabolism. It is also an important factor in histone modifications, gene regulation, and cell signaling. Mammals must consume biotin to replenish stores. Sources of biotin include organ meats, eggs, fish, seeds, and nuts. As a dietary supplement, biotin has been promoted to be useful in the treatment of hair and nail problems, cradle cap (seborrheic dermatitis) in phenylketonuria patients, biotinidase deficiency, diabetes, peripheral neuropathy, candida infections, and high cholesterol. It has also been used in pregnancy, hemodialysis, and peritoneal dialysis, as biotin deficiency is more likely in these situations. Biotin is found in many cosmetics products. Radiolabeled biotin is used for pretargeted radioimmunotherapy of cancerous tumors.1

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.2 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).3 4 Finasteride 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.

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.5 Lesser growth or a halt in the worsening of alopecia are also frequent outcomes.6Due 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.6The 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.7

Mechanism of Action

Biotin

Biotin is a water-soluble B vitamin found naturally in some foods and used as a dietary supplement. It is important for the metabolism of carbohydrates, fats, and amino acids. It is found primarily in liver, kidney, and muscle. Biotin functions as an essential cofactor for five carboxylases that catalyze steps in fatty acid, glucose, and amino acid metabolism. It is mostly protein-bound in foods such as organ meats, eggs, nuts, and soybeans. Gastrointestinal enzymes break down ingested biotin via proteolysis. This creates biocytin, which is then cleaved by biotinidase into free biotin and lysine. Free biotin is then absorbed in the small intestine. Biotin can be used for metabolism issues such as biotinidase, holocarboxylase synthetase, and isolated carboxylase enzyme deficiencies due to its essential role in the metabolism of fatty acids, glucose, and amino acids.8 1

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.

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.910

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.11 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.12 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.13 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.5 Furthermore, minoxidil appears to affect only suboptimal follicles with no further stimulation of normal hair follicles.12 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.14

Pharmacokinetics

Biotin

The mechanism of biotin transport is not fully understood. An acid anion carrier is thought to be the primary transporter of biotin into liver cells. It is known that biotin is taken up by the placenta and transported to the fetus, with no harm to the fetus. About half of the biotin consumed is metabolized into bisnorbiotin and biotin sulfoxide before being excreted. The urinary excretion and serum concentrations of biotin and its metabolites increase in about the same proportion whether biotin is given orally or intravenously.8

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.15 16 2 17 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.18

Route-Specific Pharmacokinetics:

Oral Route: The mean bioavailability following a single dose of finasteride is about 63—65%; however, bioavailability is highly variable.

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.

Contraindications/Precautions

Biotin

Biotin in blood or other samples taken from patients who are ingesting higher biotin dosages (i.e., doses of 10 to 300 mg biotin/day) in dietary supplements, including multivitamins, prenatal vitamins, and supplements for hair, skin, and nail growth, can cause clinically significant incorrect lab test results (falsely high or falsely low results) in assays that use biotin-streptavidin technology. Adverse events, including one death, related to biotin interference with lab tests have been reported. Specifically, biotin lab interference has caused falsely low troponin results, which may lead to missed diagnosis and potentially serious clinical implications. One patient taking high levels of biotin died following falsely low troponin test results when a troponin test known to have biotin interference was used. Some lab test developers have been successful at mitigating the biotin interference in their assays, while others may have not addressed this. Health care providers should be aware that many lab tests, including but not limited to, cardiovascular diagnostic tests and hormone tests that use biotin technology, may be affected. Discuss dietary supplement intake, particularly those that may contain biotin, with patients and communicate to the lab conducting testing if the patient reports taking biotin containing supplements. Consider laboratory test interference from biotin as a possible source of error if the lab test result does not match the clinical presentation of the patient and report any adverse events thought to be due to biotin interference to the lab test manufacturer and the FDA. One patient reportedly had abnormal thyroid function tests (TFTs) that did not match the clinical context after starting biotin. Within 3 days of stopping supplementation with biotin, repeated TFTs were normal. Then, biotin was reintroduced to the same patient, and TFTs taken 16 hours after the last dose and after an overnight fast showed further evidence of biotin immunoassay interference.19 1 20

Biotin during pregnancy at the recommended adequate intake (AI) is recommended. Supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed and no deficiency has been diagnosed.8

Breastfeeding females may consume biotin within the recommended adequate intake (AI) parameters. Supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed and no deficiency has been diagnosed.8

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.2 17

Finasteride is not FDA-approved for use in females of childbearing potential and is recommended to be avoided during breastfeeding. It is not known whether finasteride is excreted in human milk. Therefore, the effects of finasteride on breastfeeding or a nursing infant cannot be determined.2 17

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.2 17

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.2 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).34 Therefore, 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.2

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.2 17 [33165]

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.21 Topical minoxidil use carries no special precaution in the elderly, but any patient experiencing dizziness or faintness should discontinue topical use.5 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.22

Pregnancy

Biotin

Biotin during pregnancy at the recommended adequate intake (AI) is recommended. Supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed and no deficiency has been diagnosed.8

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.2 17

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.23 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.24

Breastfeeding

Biotin

Breastfeeding females may consume biotin within the recommended adequate intake (AI) parameters. Supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed and no deficiency has been diagnosed.8

Finasteride

Finasteride is not FDA-approved for use in females of childbearing potential and is recommended to be avoided during breastfeeding. It is not known whether finasteride is excreted in human milk. Therefore, the effects of finasteride on breastfeeding or a nursing infant cannot be determined.2 17

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 breastfeeding 25; 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 breastfeeding is unknown.26 Examples of other antihypertensives with more data in this population that have been classified as usually compatible with breastfeeding by the AAP and may be possible alternatives for some patients include enalapril, hydrochlorothiazide, methyldopa, and propranolol.25 It is not known whether topical minoxidil is distributed into breast milk. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Adverse Reactions/Side Effects

Biotin

Biotin has been very rarely associated with any adverse effects, even with high doses. There is one case report of life-threatening eosinophilic pleuro-pericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid for two months.8

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) 27, 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.2 17 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.[24660] 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).2

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.2

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.2 17 [33165]

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).2

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.21 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.21

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.21

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.21

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.21

Gastrointestinal adverse effects associated with orally administered minoxidil include nausea and vomiting.21

Storage

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

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  • 7. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebo-controlled, double-blind clinical trial of a novel formulation of 5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol 2007;57(5):767-74. Epub 2007 Aug 29
  • 8. a. b. c. d. e. f. g. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes-Panel on Folate, Other B Vitamins, and Choline and the Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board, Institute of Medicine (IOM). Dietary Reference Intakes for Thiamine, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. 1999, 2000. The National Academy of Sciences Press, Washington DC.
  • 9. Bauer JH, Alpert MA. Rapid reduction of severe hypertension with minoxidil. J Cardiovasc Pharmacol 1980;2 Suppl:S189-99.
  • 10. Alpert MA, Bauer JH. Rapid control of severe hypertension with minoxidil. Arch Intern Med 1982;142(12):2099-104.
  • 11. Pogatsa-Murray G, Varga L, Varga A, et al. Changes in left ventricular mass during treatment with minoxidil and cilazapril in hypertension patients with left ventricular hypertrophy. J Hum Hypertens 1997;11(3):149-56.
  • 12. a. b. Buhl AE. Minoxidil's action in hair follicles. J Invest Dermatol 1991;96:73S-4S.
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  • 15. Kaplan SA, Holtgrewe HL, Bruskewitz R, et al. Comparison of the efficacy and safety of finasteride in older versus younger men with benign prostatic hyperplasia. Urology 2001;57:1073-7.
  • 16. Steiner JF. Clinical Pharmacokinetics and pharmacodynamics of finasteride. Clin Pharmacokinet 1996;30:16-27.
  • 17. a. b. c. d. e. f. g. h. i. Propecia (finasteride) package insert. Whitehouse Station, NJ: Merck and Co., INC.; 2013 Sept.
  • 18. Lee SJ, Park JB, Kim D,et al. In vitro selective inhibition of human UDP-glucuronosyltransferase (UGT) 1A4 by finasteride, and prediction of in vivo drug-drug interactions. Toxicol Lett. 2015;232:458-465.
  • 19. US Food and Drug Administration (FDA). FDA Safety Communication: Update: The FDA warns that biotin may interfere with lab tests.
  • 20. Elston MS, Sehgal S, Toit SD, et al. Factitious graves’ disease due to biotin immunoassay interference - a case and review of the literature. J Clin Endocrinol Metab 2016;101(9):3251-3255.
  • 21. a. b. c. d. e. f. g. Loniten (minoxidil) tablets package insert. Kalamazoo, MI: Pharmacia; 2006 Feb.
  • 22. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
  • 23. Kaler SG, Patrinos ME, Lambert GH, et al. Hypertrichosis and congenital anomalies associated with maternal use of minoxidil. Pediatrics 1987;79:434-6.
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