Minoxidil

209.25

209.25

253-874-2

5965120SH1

757106

DTXSID9040685

C47623

Crystals from methanol-acetonitrile|White to off-white, crystalline powder

D11AX01|C - Cardiovascular system|D - Dermatologicals

2933990090

88.9

1.2

White crystalline powder

1.5±0.1 g/cm3

248 °C

351.7°C at 760 mmHg

166.5±28.7 °C

1.724

soluble in water (2.2 mg/ml), 100% ethanol (29 mg/ml), propylene glycol, acetone, DMSO (6.5 mg/ml), and methanol.

Store at RT

LD50 in rats, mice (mg/kg): 49, 51 i.v. (Carlson, Feenstra)

Odorless

4.61|pKa= 4.61

146.1 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]|147.9 Ų [M+H]+ [CCS Type: DT, Method: single field calibrated]

Decomposition 259-261 °C

NONH for all modes of transport

3

22-36/37/38-26/27/28

26-36-45-36/37/39-22

UV8200000

Xn,T+

Minoxidil tablets should be stored in well-closed containers at 15-30 deg C.

P261-P305 + P351 + P338

H302-H315-H319-H335

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl minoxidil, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (98.67%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 75 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Oral LD50 in rats has ranged from 1321-3492 mg/kg; in mice, 2456-2648 mg/kg. Side effects include cardiovascular effects associated with hypotension such as sudden weight gain, rapid heart beat, faintness or dizziness.

Serum aminotransferase elevations during oral minoxidil therapy are uncommon, but have been reported even with topical administration. Despite many decades of use, oral minoxidil has not been implicated in convincing cases of clinically apparent acute liver injury. Severe rash, toxic epidermal necrolysis and Stevens Johnson syndrome have been reported after minoxidil therapy (generally arising within 2 to 6 weeks of starting), but published cases have not been marked by concurrent hepatic injury.

Topical minoxidil has been used concomitantly with topical tretinoin in a limited number of individuals for potential additive or synergistic effects on hair regrowth. In one study in a limited number of individuals with androgenetic alopecia, combined topical therapy with tretinoin and low-dose minoxidil (a 0.5% solution) appeared to be more effective than tretinoin alone in stimulating hair regrowth. However, because topical tretinoin has increased percutaneous absorption of minoxidil by threefold compared with a 1.3 to 1.4 fold increase with the vehicle, the manufacturer of minoxidil recommends that the drugs not be used concomitantly. Enhanced absorption of topical minoxidil probably resulted from tretinoin-induced alterations in the dermal barrier. The manufacturer also recommends that topical minoxidil not be applied concomitantly with other topical retinoids, topical corticosteroids, or petrolatum or agents known to enhance percutaneous absorption of drugs. Individuals receiving topical minoxidil therapy should be advised to not use the drug concurrently with other topical therapy for the scalp.|No drug interactions have been reported in patients receiving minoxidil topical solution concurrently with other drugs. However, the possibility exists theoretically that following topical application, systemically absorbed minoxidil could interact with other concomitantly administered drugs (eg; potentiation of orthostatic hypotension in patients receiving concomitant guanethidine therapy).|When minoxidil is administered with diuretics or other hypotensive drugs, the hypotensive effect of minoxidil is increased. The effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly. Minoxidil should be administered with caution to patients receiving guanethidine, since concurrent use may cause profound orthostatic hypotensive effects. If possible, guanethidine should be withdrawn several days (1-3 wk) before minoxidil therapy is begun.|Minoxidil-induced stimulation of hair growth does not appear to depend on interference with the action of androgens on the hair follicle epithelium since patients receiving the drug do not develop abnormal serum androgen concentrations or abnormal urinary excretion of 17-hydroxysteroids and 17-ketosteroids. In addition, the drug can induce hair regrowth in androgen independent forms of alopecia (eg; alopecia areata).|Minoxidil, when used with diuretics or other antihypertensive agents, may induce a profoundly hypotensive state. With guanethidine, orthostatic hypotension may be severe and prolonged.

Minoxidil does not bind to plasma proteins.

For the treatment of severe hypertension and in the topical treatment (regrowth) of androgenic alopecia in males and females and stabilisation of hair loss in patients with androgenic alopecia.|FDA Label

Minoxidil is an antihypertensive agent that is used largely for patients with severe and refractory hypertension not responding to conventional therapies. Minoxidil is also used topically to treat male pattern baldness. Despite its use for many years, minoxidil has not been convincingly linked to cases of clinically apparent liver injury.

Antihypertensive Agents

Antihypertensive Agents; Vasodilator Agents|Minoxidil is indicated for treatment of hypertension. Because of its serious side effects, minoxidil is not considered to be a primary agent in the treatment of essential hypertension. It is recommended for use only in patients with symptomatic or organ-damaging hypertension not responsive to other treatment. /Included in US product labeling/|Minoxidil is used topically to stimulate regrowth of hair in balding areas of individuals with androgenetic alopecia (male pattern alopecia, hereditary alopecia, common male baldness). The drug is effective in promoting hair regrowth on the vertex (crown) of the scalp but appears to have little or no effect on temporal recession; the efficacy of topical minoxidil therapy for frontal alopecia has not been evaluated objectively to date. There is evidence to suggest that individuals most likely to respond to topical minoxidil therapy are those younger than 40 years of age, those in whom treatment is initiated relatively early (less than 10 years' duration of hair loss), those with a small diameter of baldness (less than 10 cm), and those who have a large number of terminal or indeterminate (intermediate) hairs before initiation of treatment. At least 4 mo of continuous therapy with minoxidil topical solution usually is required for evidence of response; however, treatment for up to a year may be warranted before deciding that the alopecia is unresponsive. While the ultimate benefit of topical minoxidil therapy depends on the subjective perceptions of the treated individual, cosmetically acceptable hair regrowth as determined by study investigators has been reported in approximately one third of individuals after 6-12 mo of twice daily therapy in most clinical studies, and complete coverage of the balding areas of the scalp occurs rarely. Current evidence suggests that such therapy must be continued indefinitely for maintenance of hair growth.|Topically applied minoxidil has been used as a 1, 3, or 5% solution, ointment, or cream to promote hair regrowth in males and females with alopecia areata, including those with the most severe forms, alopecia totalis (complete loss of scalp hair) or alopecia universalis (complete loss of body hair). Overnight petrolatum occlusion of the treated area, which has been reported to enhance efficacy, has been used in some studies. A cosmetically acceptable response to topical minoxidil therapy appears most likely to occur in patients with patchy alopecia areata; patients with total loss of scalp or body hair at baseline (eg; those with alopecia totalis or universalis) usually have the poorest and most delayed response. Efficacy of any therapy in patients with alopecia areata is difficult to evaluate because of the spontaneous hair regrowth and hair loss characteristic of the disease. As in androgenetic alopecia, some patients with alopecia areata receiving treatment with the vehicle alone in controlled studies have had regrowth of terminal hair, and hair loss has resumed in other patients during continued topical minoxidil therapy.|For more Therapeutic Uses (Complete) data for MINOXIDIL (6 total), please visit the HSDB record page.

It is particularly important that the risks versus benefits of topical minoxidil therapy be assessed carefully in individuals older than 50 yr of age; those with cardiac, renal, or hepatic disease or scalp abnormalities; and those receiving potentially interacting drugs concomitantly (eg; hypotensive agents such as guanethidine); such individuals should be closely monitored if a decision is made to initiate therapy. In addition, individuals with underlying cardiac disease, including coronary artery disease or congestive heart failure, should be informed that adverse systemic effects of topical minoxidil therapy may be particularly serious should they occur.|Individuals receiving topical minoxidil therapy and their clinician should be aware of the manifestations of common and otherwise potentially serious adverse effects associated with systemic minoxidil therapy, particularly sodium and water retention, weight gain, local or generalized edema, pericardial effusion, pericarditis, tamponade, tachycardia, and increased frequency or development of angina. ... While such effects generally appear to be unlikely during topical minoxidil therapy, certain individuals may be at increased risk of their development because of underlying disease, sensitivity to the drug, or achievement of higher than usual systemic concentrations (eg; secondary to misuse or enhanced percutaneous penetration of topical drug). Individuals receiving topical minoxidil therapy should be advised to watch for and report the occurrence of increased heart rate, weight gain, difficulty in breathing (especially when lying down), worsening or development of angina pectoris, edema (swelling) of the face, hands, ankles, or abdomen, or other systemic effects and should be monitored 1 mo after initiating therapy and at least every 6 mo thereafter for the possible development of such effects. If systemic effects occur, topical minoxidil therapy should be discontinued.|As with other topically applied drugs, inflammation or disease processes associated with decreased integrity of the epidermal barrier (eg; excoriations of the scalp, severe sunburn, scalp psoriasis) may increase percutaneous absorption of minoxidil and potentially increase the likelihood of systemic adverse effects.|In evaluating females in whom androgenetic alopecia is suspected, the possibility of an underlying endocrine abnormality such as Cushing's disease, polycystic ovary (Stein-Leventhal) syndrome, hypothyroidism, or an androgen secreting tumor should be considered.|For more Drug Warnings (Complete) data for MINOXIDIL (14 total), please visit the HSDB record page.

Minoxidil is an orally effective direct acting peripheral vasodilator that reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. Minoxidil is also used topically to treat androgenetic alopecia. Microcirculatory blood flow in animals is enhanced or maintained in all systemic vascular beds. In man, forearm and renal vascular resistance decline; forearm blood flow increases while renal blood flow and glomerular filtration rate are preserved. The predominant site of minoxidil action is arterial. Venodilation does not occur with minoxidil; thus, postural hypotension is unusual with its administration. The antihypertensive activity of minoxidil is due to its sulphate metabolite, minoxidil sulfate.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)|Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)

Minoxidil is at least 90% absorbed from the GI tract in experimental animals and man.|Minoxidil is almost completely absorbed (95%) from the GI tract. Peak plasma levels are reached in 1 hr. Protein binding does not occur. Minoxidil is widely distributed in the tissues, with an apparent volume of distribution of about 2.8-3.3 l/kg. Placental passage and distribution into breast milk have not been established. The elimination half-life of minoxidil is2.77-4.2 hr. About 90% of an oral dose of minoxidil is metabolized in the liver. The drug and its metabolites are largely excreted in the urine. Renal clearance is 73.9 ml/min.|Percutaneous absorption of minoxidil appears to be minimal following topical application of minoxidil solution to intact scalp. However, systemic absorption of topically applied minoxidil is variable and depends on several factors, including the vehicle used in the formulation, the area of application, condition of the skin (eg; being increased with local abrasion or inflammation), and interindividual variation in the extent of percutaneous absorption. Percutaneous absorption of the drug does not appear to be altered by use of a hot-air hair dryer. Although limited in vitro evidence suggests comparable release of minoxidil from solutions with different proportions of propylene glycol, alcohol, and water, release of the drug from a cream base differs substantially from that from solution formulations, and water-in-oil creams appear to differ markedly from oil-in-water creams or ointments in terms of the rate and concentration dependency of drug permeation through human skin. Absorption of minoxidil from extemporaneously prepared solutions, ointments, creams, or other such topical formulations may not be comparable to that from the commercially available topical minoxidil solution.|Percutaneous absorption of minoxidil following topical application of 2% hydroalcoholic, propylene glycol-containing solutions of the drug generally has been reported to average 0.3-4.5% of the applied dose. In a preliminary study in healthy balding men, the systemic bioavailability of minoxidil 2 or 3% topical solution (20 or 30 mg doses, respectively) at steady state relative to that of a 2.5 mg oral tablet averaged 1.4 or 1.2%, respectively. Based on urinary excretion of radiolabeled drug administered to healthy men in another study, percutaneous absorption of minoxidil after application of 1 or 5% minoxidil solutions to the scalp generally averaged 1.6-3.9% of the applied dose, based on urinary recovery of radiolabeled drug. In studies in animals, 5-36% of topically applied doses was absorbed systemically. Serum concentrations achieved after topical application of minoxidil solutions are variable, and clinical studies of topical minoxidil therapy have found no correlation between serum minoxidil concentrations and hair growth. In controlled studies in individuals with androgenetic alopecia or alopecia areata, serum concentrations of minoxidil after topical application of 1, 2, 3, or 5% solution formulations (with or without nightly petrolatum occlusion) generally averaged 2 ng/ml or less. However, about 1% of individuals receiving a 2% topical solution achieved peak serum concentrations of 5 ng/ml or greater, and a few patients achieved concentrations approaching 30 ng/ml. In part, increased percutaneous absorption of the drug in some individuals may have resulted from alterations in the stratum corneum (eg; secondary to irritation and inflammation from shaving of the scalp). In addition, some individuals may have a propensity for enhanced percutaneous absorption of the drug. Data from healthy balding men indicate that peak serum concentrations of unchanged minoxidil after oral doses of 5 mg daily generally are 20-30 times higher than mean serum concentrations achieved after twice daily topical application of approximately 20 mg (1 ml) of minoxidil as a 2% solution.|The distribution of topically applied minoxidil has not been fully determined. Limited evidence suggests that intact stratum corneum serves as a barrier that inhibits substantial diffusion of topically applied minoxidil into systemic circulation, but additional study is needed. Skin biopsy specimens obtained after topical application of a radiolabeled minoxidil 1 or 5% solution to the scalp of healthy balding men indicate an average retention in the skin of 2.6% or less of the applied dose after 24 hr, with twice as much radioactivity in the dermis as in the epidermis. The remainder of the dose remained on the skin or presumably was lost to the environment.|For more Absorption, Distribution and Excretion (Complete) data for MINOXIDIL (8 total), please visit the HSDB record page.

Approximately 90% of the administered drug is metabolized, predominantly by conjugation with glucuronic acid at the N-oxide position in the pyrimidine ring, but also by conversion to more polar products. Known metabolites exert much less pharmacologic effect than minoxidil itself.|Preliminary evidence suggests that the activity of minoxidil sulfotransferase (the enzyme that converts the drug to its sulfate) is higher in the hair follicle than in epidermis or dermis. Minoxidil sulfate, which may be formed preferentially in the hair follicle following topical application of the drug, exhibits more potent vasodilatory activity than the parent drug.|About 90% of an oral dose of minoxidil is metabolized, primarily by conjugation with glucuronic acid and also by conversion to more polar metabolites. Minoxidil's metabolites are considerably less active than the parent drug.|The biotransformation of minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) was studied in the rat, dog, and monkey and compared to reported results in the human. Chromatographic profiles of urinary metabolites show that each species excreted substantially the same metabolites but in quite different relative amounts. The monkey and the human exhibited similar metabolite profiles, whereas the dog and rat were quantitatively different from each other and from the monkey and human. The major excretory product for the monkey and human was a glucuronide conjugate of minoxidil. Substantially smaller amounts of unchanged minoxidil, 2,4-diamino-6-(4'-hydroxypiperidino)pyrimidine 3-oxide, and more polar metabolites also were excreted by these two species. The major excretory product in the rat was unchanged minoxidil. Almost as much (combined) of the two acidic metabolites, 2,4-diamino-6-(4'-carboxy-n-butylamino)pyrimidine and its 3-oxide, also were produced. Smaller amounts of the glucuronide of minoxidil, 2,4-diamino-6-(4'-hydroxypiperidino)pyrimidine 3-oxide, its 3'-hydroxy isomer, and 2,4-diamino-6-piperidinopyrimidine also were excreted by the rat. The major metabolite of minoxidil excreted by the dog was the 4'-hydroxy metabolite. Smaller amounts of unchanged minoxidil and polar metabolites and much smaller amounts of the glucuronide of minoxidil, the 3'-hydroxy metabolite, and 2,4-diamino-6-piperidinopyrimidine also were excreted by the dog. Evidence was obtained for a glucuronide conjugate of the 4'-hydroxy metabolite in this species. The major circulatory material in dog plasma was the 4'-hydroxy metabolite, whereas it was the glucuronide of minoxidil in monkey plasma.|Minoxidil has known human metabolites that include 2-Pyrimidinamine, 1,6-dihydro-6-imino-4-(1-piperidinyl)-1-(sulfooxy)-.

4.2 hours|In one study in patients with various degrees of renal function (eg; normal to uremic), the mean plasma half-life of minoxidil and its metabolites was 4.2 hr.

Minoxidil is thought to promote the survival of human dermal papillary cells (DPCs) or hair cells by activating both extracellular signal-regulated kinase (ERK) and Akt and by preventing cell death by increasing the ratio of BCl^-2/Bax. Minoxidil may stimulate the growth of human hairs by prolonging anagen through these proliferative and anti-apoptotic effects on DPCs. Minoxidil, when used as a vasodilator, acts by opening adenosine triphosphate-sensitive potassium channels in vascular smooth muscle cells. This vasodilation may also improve the viability of hair cells or hair follicles.|The mechanism(s) by which topically applied minoxidil and/or a metabolite of the drug stimulate vertex hair regrowth in androgenetic (male-pattern) alopecia or other forms of alopecia has not been fully elucidated. However, because minoxidil has stimulated hair regrowth in several forms of alopecia, it appears that the drug acts at the level of the hair follicle, possibly involving direct stimulation of hair follicle epithelial growth. ... While increased scalp blood flow resulting from local vasodilation often has been proposed as a principal mechanism of minoxidil's effect on hair growth, this mechanism has not been substantiated consistently and not all vasodilators produce hypertrichosis.|Studies in animal cell cultures indicate that minoxidil directly induces proliferation of hair epithelial cells near the base of the hair follicle and increases incorporation of cysteine and glycine into the follicle; cysteine residues crosslink to form cystine, which provides strength to the hair shaft. The drug also appears to induce hypertrophy of existing small follicles, prolong the anagen phase of the hair follicle, and accelerate the cyclic turnover of vellus hair follicles, enabling these follicles to produce thick, terminal hair; these effects result in a decrease in vellus hair follicles, an increase in terminal hair follicles, and an increase in the diameter of the hair shaft. Biopsy specimens obtained after topical treatment with minoxidil demonstrate enlargement of preexisting hair follicles but no evidence of new hair follicle formation.|In vitro studies demonstrate different effects of minoxidil on epithelial cells and lymphocytes, which may lead to synergistic effects on hair growth in patients with alopecia areata. In cultures of murine epithelial cells, minoxidil increased cell proliferation, prolonged cell passage time (delayed senescence), and altered cell morphology; the latter 2 effects also have been observed in cultures of human keratinocytes. Human lymphocytes exposed to minoxidil in cell culture demonstrated a modest suppression of mitogen-induced blast formation.|Minoxidil reduces peripheral vascular resistance and blood pressure as a result of a direct vasodilating effect on vascular smooth muscle; like diazoxide and hydralazine, minoxidil's effect on arterioles is greater than on veins. Minoxidil delays the hydrolysis of cyclic 3',5'-adenosine monophosphate and cyclic guanosine monophosphate by inhibiting the enzyme phosphodiesterase, and relaxation of arterial smooth muscle by the drug may be, at least partly, mediated by cyclic 3',5'-adenosinemonophospate. Animal studies indicate that minoxidil does not have CNS or adrenergic neuronal blocking effects.

Treatment of Overdose: Administration of iv sodium chloride injection is recommended to maintain blood pressure and facilitate urine formation. Sympathomimetics such as norepinephrine or epinephrine should be avoided because of the risk of excessive cardiac stimulation. Hypotension may be treated with phenylephrine, vasopressin, or dopamine, but they are recommended only if lack of perfusion of a vital organ occurs.|Maintain an open airway and assist ventilation if necessary.Hypotension usually respondes to supine positioning and iv crystalloid fluids. Occasionally pressor therapy is needed. there is no specific antidote. Administer activated charcoal.

/CASE REPORTS/ Sinus tachycardia and unusual ST-T wave changes have been reported in a patient following overdosage with minoxidil. A 20 year old woman developed ST depressions (leads II, III, and aVF) and inverted T waves (leads I, II, III, and aVF, and V3 through V6) in the absence of hypotension or documented electrolyte abnormalities. The ECG abnormalities were resolving 10 hours after admission.|/CASE REPORTS/ A patient treated for 2 months with the antihypertensive agent minoxidil developed pleural and pericardial effusions in association with a positive antinuclear antibody titer. No evidence of CNS or renal involvement was present, and results of specific tests for idiopathic systemic lupus erythematosus, including anti-double-stranded DNA and anti-Smith antibodies, were negative. Complement levels were normal. The patient's clinical picture improved and titers of antinuclear antibody decreased after discontinuation of minoxidil therapy, suggesting that minoxidil induced a lupus-like syndrome in this patient.

Loniten

Tablets, 2.5 and 10 mg (Loniten). Topical soluton, 2% (Rogaine)|Oral tablets: 2.5 and 10 mg (scored)-Loniten (also Australia, United Kingdom).|Topical Solution, 2% Hair Regrowth /SRP: retail pharmaceutical distributor/; Rogaine Hair Regrowth Treatment for Men (with alcohol 60% and propylene glycol), Pharmacia; Rogaine Hair Regrowth Treatment for Women (with alcohol 60% and propylene glycol), Pharmacia. 5% Rogaine Extra Strength for Men (with alcohol 30% and propylene glycol), Pharmacia.|Oral Tablets, 2.5 mg, Loniten (scored), Pharmacia; 10 mg, Loniten (scored), Pharmacia.

Analyte: minoxidil; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: minoxidil; matrix: chemical purity; procedure: liquid chromatography with detection at 254 nm and comparison to standards|Analyte: minoxidil; matrix: pharmaceutical preparation (topical solution); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)|Analyte: minoxidil; matrix: pharmaceutical preparation (topical solution); procedure: retention time of liquid chromatogram with comparison to standards (chemical identification)|For more Analytic Laboratory Methods (Complete) data for MINOXIDIL (7 total), please visit the HSDB record page.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals