Minoxidil

Minoxidil


A 14-year-old girl with alopecia areata developed bouts of

GENERAL INFORMATION

In a 1-year observational study of more than 3 million subject-days of exposure to topical minoxidil solution, patients who use topical minoxidil were no more likely to have major medical events resulting in hospitalization or death than control subjects who had never been exposed to topical minoxidil. In addition, there was no difference in the rates of cardiovascular events between the two groups [6]. Minoxidil can cause pericardial effusion [7].

Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) is a potent vasodilator effective in severe hypertension irrespective of the cause. The pattern of adverse vasodilator effects with minoxidil is similar to, but more severe than, that of hydralazine, and fluid retention can be troublesome. Topical minoxidil stimulates new hair growth and arrests loss of hair in alopecia areata and androgenic alopecia. Adverse reactions after topical application are usually limited to the application site on the scalp. They include irritant contact dermatitis, allergic contact dermatitis, and exacerbation of seborrheic dermatitis. These reactions are seen in 5.7% of patients who use a 5% solution and in 1.9% of those who use a 2% formulation [1].

palpitation and dizziness after using topical minoxidil 1% for 20 days.


A 52-year-old man with a history of chronic hypertension pre-

sented with worsening dyspnea and leg edema. He had been taking minoxidil for 10 years. The cardiac silhouette was markedly enlarged. Echocardiography and computed tomography showed a large pericardial effusion. Minoxidil was withdrawn and the effusion resolved within 1 month.

Respiratory DRUG STUDIES Placebo-controlled studies The results with a 2% solution of minoxidil are variable, but experience has suggested that higher concentrations may be more effective. Topical twice-daily minoxidil 2% and 5% have therefore been compared for 48 weeks in a double-blind, randomized, placebo-controlled, multicenter trial in 393 men (aged 18–49 years) with androgenic alopecia [2]. The higher concentration of minoxidil was significantly more effective than both the lower concentration and placebo in terms of change from baseline in non-vellus hair count, patient rating of scalp coverage and treatment benefit, and investigator rating of scalp coverage; the response to treatment occurred earlier with 5% minoxidil. However, there was more pruritus and local irritation with 5% minoxidil.

ORGANS AND SYSTEMS Cardiovascular Minoxidil is poorly absorbed through the skin (less than 4%) [3], and plasma concentrations of minoxidil are far less than 10% of the mean minoxidil concentration present 2 hours after oral ingestion of 5 mg, the lowest dose for the treatment of hypertension [4]. However, there have been reports of hypotension and tachycardia after chronic scalp application of minoxidil, suggesting that topical minoxidil can be systemically absorbed. Three young patients with alopecia areata treated with topical minoxidil 2% had cardiovascular adverse effects [5].
A 12-year-old boy with extensive alopecia areata developed a

tachycardia after using minoxidil 1% for 1 month. When minoxidil was withdrawn the tachycardia resolved.
A 10-year-old girl with alopecia totalis developed bouts of palpitation and dizziness after using topical minoxidil 1% for 1 month. The symptoms resolved on withdrawal. ã 2016 Elsevier B.V. All rights reserved.

An isolated unilateral pleural effusion secondary to minoxidil has been reported in a patient undergoing peritoneal dialysis [8]. It resolved on withdrawal and reappeared after the patient reintroduced the drug himself.

Endocrine Pseudoacromegaly has been reported in a patient who had taken large oral doses of minoxidil for about 10 years [9]. There have been no reports of pseudoacromegaly associated with topical minoxidil.

Skin Local adverse reactions to topical minoxidil (usually in an alcohol–propylene glycol base) include dryness, irritation, pruritus, contact allergy [10], and photocontact allergy [11]. Allergic contact dermatitis has been reported in about 1–3% of patients who use topical minoxidil solution.
A 72-year-old woman developed an allergic contact dermatitis

during treatment with topical minoxidil for alopecia [12].


A 24-year-old woman developed allergic contact dermatitis

while taking minoxidil and again while taking Serenoa repens (saw palmetto) solution for androgenic alopecia [13].

In many cases, propylene glycol is the causative allergen, but not always.
In a 40-year-old woman with a history of scalp desquamative

dermatitis 1 week after starting 5% minoxidil solution, patch tests showed that minoxidil itself was the inciting agent [14].

Genital ulceration, probably due to inadvertent local contamination from topical minoxidil used for androgenic baldness, has been described [15]. Leukoderma has been reported in two men from India who used 2% minoxidil lotion for 2–3 months to treat baldness [16]. The depigmentation was localized to the scalp. Other possibilities of leukoderma were ruled out, as was vitiligo. There was repigmentation of the

1054 Minoxidil leukodermic area within 3 months of minoxidil withdrawal in both cases. Oral minoxidil for the treatment of uncontrolled hypertension was associated with Stevens–Johnson syndrome in a 50-year-old man with chronic renal insufficiency [17].

positive patch tests to minoxidil in alcohol, but not to minoxidil in petrolatum, piperidine, pyrimidine, or diaminopyrimidine.

The authors of the last report suggested that the whole structure of minoxidil is required for sensitization and that propylene glycol in the formulation of minoxidil that is used therapeutically increases the penetration of minoxidil into the skin, enhancing the risk of a reaction.

Hair A particular feature of minoxidil is excessive hair growth [18], which occurs in about 70% of patients who take oral minoxidil, usually within 2 months of the start of therapy. Severe hypertrichosis, unacceptable even to men, has complicated the otherwise successful antihypertensive treatment of six patients after renal transplantation, for which ciclosporin was also used. Since hypertrichosis has also been described with ciclosporin, there may be an additive pharmacodynamic interaction [19]. Severe hypertrichosis of the face and the limbs occurred in three women with androgenic alopecia after 2–3 months of treatment with 5% topical minoxidil [20]. The hypertrichosis disappeared from the face and arms within 1–3 months of withdrawal and from the legs after 4–5 months. A review of clinical trials of minoxidil topical solution showed that about 4% of women noted hypertrichosis/ facial hair. Excessive hair growth was reported primarily on the face (including cheeks, chin, forehead, upper lip, sideburns and around the eyes), but also on the neck, chest, back and extremities. However, post-marketing data showed a lower occurrence (0.5%) of hypertrichosis/facial hair than in the trials. There was a dose-related pattern of response. The hypertrichotic effect of minoxidil is reversible, and does not necessarily require withdrawal of therapy [21].

Immunologic A “polymyalgia syndrome”, characterized by fatigue, anorexia, weight loss, and severe pain in the shoulders and the pelvic girdle, was attributed to minoxidil in four men [22]. In 11 patients allergic to topical minoxidil lotion, patch tests showed that four were positive to minoxidil itself [23]. Propylene and butylene glycol are used as solvents for minoxidil in topical formulations. Nine of the 11 patients appeared to have positive patch tests to propylene glycol and one of the 11 reacted to its alternative butylene glycol.
A 57-year-old man developed a pigmented contact dermatitis

after using topical minoxidil 5% for 2 years [24]. Patch tests were negative with the European standard series and with a textile and finishes series, but positive with minoxidil 5% on days 3 and 7. However, withdrawal of the minoxidil did not lead to improvement after 10 months.
A 24-year-old woman with androgenic alopecia became sensitized to topical minoxidil after using minoxidil 4% with retinoic acid in a propylene glycol base [25]. She subsequently also became sensitized to saw palmetto (Serenoa repens), a topical herbal extract commonly promoted for the treatment of hair loss.
Allergic contact dermatitis occurred in a 54-year-old man who had used 1% minoxidil on the scalp for 8 months [26]. He had ã 2016 Elsevier B.V. All rights reserved.

LONG-TERM EFFECTS Drug withdrawal A hypertensive crisis occurred in one patient after withdrawal of topical minoxidil [27].

SECOND-GENERATION EFFECTS Pregnancy There was no indication of increased risk of adverse pregnancy outcomes in women who used topical minoxidil during their pregnancy. However, it should be noted that this study was not designed to determine whether subjects continued to use topical minoxidil solution after they became pregnant [6].

Teratogenicity Caudal regression syndrome is a rare anomaly, a continuum of congenital malformations ranging from isolated sacral agenesis to absence of the lumbosacral spine and major visceral anomalies. While the exact cause of this syndrome is unclear, maternal diabetes, genetic factors, teratogens, and vascular anomalies that alter blood flow have been hypothesized to play a role. A case has been attributed to maternal minoxidil exposure [28]. A fetus had an extremely hypotrophic caudal body pole, aplasia of the lower spine, and complete renal agenesis diagnosed in the second trimester by ultrasound. The mother had used minoxidil solution to prevent hair loss for 4 years before and during gestation. She had also taken co-trimoxazole during the first trimester. She was not diabetic and had no history of familial genetic disorders. A 28-year-old pregnant woman who applied daily minoxidil 2% to her scalp because of hair loss. A routine ultrasound test at the 22nd gestational week showed significant brain, heart and vascular malformations of the fetus; pregnancy was interrupted. The most evident pathological event was formation of abnormal vessels [29]. However, this could have been due to coincidence.

DRUG ADMINISTRATION Drug administration route Despite the poor transdermal absorption of minoxidil, in 7 out of 30 non-hypertensive patients treated with 3%

Minoxidil minoxidil solution twice daily, there was a “significant” fall in blood pressure [30]. Some patients using minoxidil solution had increased hair growth outside the area of topical drug application, which suggests a systemic effect [31] (see also Hair above). The sudden death of a patient using topical minoxidil [32] was probably not drug-related but due to cardiovascular disease and hypertension. Nevertheless, in patients who are known to be hypertensive and who are also receiving other antihypertensive medication extra caution is warranted when topical minoxidil is used [33]. Smoking intolerance possibly related to topical minoxidil has been observed rarely [34].

Drug overdose In some countries, an extra-strength solution of minoxidil is available over the counter for hair regrowth treatment in men. Ingestion of a large dose in a suicide attempt has been reported [35].
A 26-year-old woman took 60 ml of minoxidil solution 5% and

1 hour later developed hypotension (75/40 mmHg) and tachycardia (130/minute). She was alert and oriented and physical examination was unremarkable. She was given a saline infusion, oral activated charcoal, and sorbitol, and had worsening hypotension (40 mmHg systolic) and bradycardia (20/minute), developed chest pain and T wave inversion on the electrocardiogram, and lost consciousness. Atropine and dopamine restored a heart rate of 120/minute, but she remained hypotensive (54/36 mmHg). Her blood ethanol concentration was 5.64 mmol/l and other toxicological screening tests were negative. The addition of phenylephrine up to a dose of 200 micrograms/minute restored her systolic blood pressure to 90– 100 mmHg.

REFERENCES [1] Rogaine extra strength for Men slide lecture kit. Pharmacia & Upjohn Company, 1998: M-7909P. [2] Olsen EA, Dunlap FE, Funicella T, Koperski JA, Swinehart JM, Tschen EH, Trancik RJ. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol 2002; 47(3): 377–85. [3] Franz TJ. Percutaneous absorption of minoxidil in man. Arch Dermatol 1985; 121(2): 203–6. [4] Vanderveen EE, Ellis CN, Kang S, Case P, Headington JT, Voorhees JJ, Swanson NA. Topical minoxidil for hair regrowth. J Am Acad Dermatol 1984; 11(3): 416–21. [5] Georgala S, Befon A, Maniatopoulou E, Georgala C. Topical use of minoxidil in children and systemic side effects. Dermatology 2007; 214(1): 101–2. [6] Shapiro J. Safety of topical minoxidil solution: a one-year, prospective, observational study. J Cutan Med Surg 2003; 7: 322–9. [7] Shirwany A, D’Cruz IA, Munir A. Very large pericardial effusion attributable to minoxidil: resolution without drainage of fluid. Echocardiography 2002; 19(6): 513–6. [8] Palomar R, Morales P, Sanz de Castro S, Tasis A, Rodrigo E, Pinera C, Ruiz JC, Fernandez-Fresnedo G, Martin de Francisco AL, Arias M. Pleural effusion secondary to minoxidil in a peritoneal dialysis patient. Nephrol Dial Transplant 2004; 19(10): 2688.

ã 2016 Elsevier B.V. All rights reserved.

1055

[9] Nguyen K, Marks J. Pseudoacromegaly induced by the long-term use of minoxidil. J Am Acad Dermatol 2003; 48: 962–5. [10] Degreef H, Hendrickx I, Dooms-Goossens A. Allergic contact dermatitis to minoxidil. Contact Dermatitis 1985; 13: 194. [11] Tosti A, Bardazzi F, De Padova MP, Caponeri GM, Melino M, Veronesi S. Contact dermatitis to minoxidil. Contact Dermatitis 1985; 13(4): 275–6. [12] Hagemann T, Schlutter-Bohmer B, Allam JP, Bieber T, Novak N. Positive lymphocyte transformation test in a patient with allergic contact dermatitis of the scalp after short-term use of topical minoxidil solution. Contact Dermatitis 2005; 53(1): 53–5. [13] Sinclair R, Mallair R, Tate B. Sensitization to saw palmetto and minoxidil in separate topical extemporaneous treatments for androgenetic alopecia. Aust J Dermatol 2002; 43: 311–2. [14] Carreno P, Martin E, Trabado A, Peral C, Timon S, Arbeiza FJ, Lopez RC. Allergic contact dermatitis due to minoxidil itself. Allergol Immunol Clin 2003; 18: 225–8. [15] Spenatto N, Alibert M, Cambon L, Viraben R. Ulce´ration ge´nitale originale d0 origine toxique. [Toxic genital ulceration.] Nouv Dermatol 2004; 23(3): 111. [16] Malakar S, Dhar S. Leucoderma associated with the use of topical minoxidil: a report of two cases. Dermatology 2000; 201(2): 183–4. [17] Callen EC, Church CO, Hernandez CL, Thompson ED. Stevens–Johnson syndrome associated with oral minoxidil: a case report. J Nephrol 2007; 20(1): 91–3. [18] Toriumi DM, Konior RJ, Berktold RE. Severe hypertrichosis of the external ear canal during minoxidil therapy. Arch Otolaryngol Head Neck Surg 1988; 114(8): 918–9. [19] Sever MS, Sonmez YE, Kocak N. Limited use of minoxidil in renal transplant recipients because of the additive sideeffects of cyclosporine on hypertrichosis. Transplantation 1990; 50(3): 536. [20] Peluso AM, Misciali C, Vincenzi C, Tosti A. Diffuse hypertrichosis during treatment with 5% topical minoxidil. Br J Dermatol 1997; 136(1): 118–20. [21] Dawber R, Rundegren J. Hypertrichosis in females applying minoxidil topical solution and in normal controls. J Eur Acad Dermatol Venereol 2003; 17: 271–5. [22] Colamarino R, Dubost JJ, Brun P, Flori B, Tournilhac M, Eschalier A, Sauvezie B. Etats polyalgiques induits par le minoxidil topique. [Polymyalgia induced by topical minoxidil.] Ann Med Interne (Paris) 1990; 141(5): 425–8. [23] Friedman ES, Friedman PM, Cohen DE, Washenik K. Allergic contact dermatitis to topical minoxidil solution: etiology and treatment. J Am Acad Dermatol 2002; 46(2): 309–12. [24] Trattner A, David M. Pigmented contact dermatitis from topical minoxidil 5%. Contact Dermatitis 2002; 46(4): 246. [25] Sinclair RD, Mallari RS, Tate B. Sensitization to saw palmetto and minoxidil in separate topical extemporaneous treatments for androgenetic alopecia. Australas J Dermatol 2002; 43(4): 311–2. [26] Suzuki K, Suzuki M, Akamatsu H, Matsungaga K. Allergic contact dermatitis from minoxidil: study of the crossreaction to minoxidil. Am J Contact Dermat 2002; 13(1): 45–6. [27] Montoya-Cabrera MA. Crisis hipertensiva como manifestacion de supression de minoxidil topico. [Hypertensive crisis as a manifestation of suppression of topic minoxidil.] Rev Med Inst Mex Seg Soc 1990; 28(1): 37–9. [28] Rojansky N, Fasouliotis SJ, Ariel I, Nadjari M. Extreme caudal agenesis. Possible drug-related etiology? J Reprod Med 2002; 47(3): 241–5.

1056 Minoxidil [29] Smorlesi C, Caldarella A, Caramelli L, Di Lollo S, Moroni F. Topically applied minoxidil may cause fetal malformation: a case report. Birth Defects Res 2003; 67: 997–1001. [30] Ranchoff RE, Bergfeld WF. Topical minoxidil reduces blood pressure. J Am Acad Dermatol 1985; 12(3): 586–7. [31] Gonzalez M, Landa N, Gardeazabal J, Calderon MJ, Bilbao I, Diaz Perez JL. Generalized hypertrichosis after treatment with topical minoxidil. Clin Exp Dermatol 1994; 19(2): 157–8. [32] Baral J. Minoxidil and sudden death. J Am Acad Dermatol 1985; 13(2 Pt 1): 297–9.

ã 2016 Elsevier B.V. All rights reserved.

[33] Vanderveen EE. Minoxidil and sudden death: reply. J Am Acad Dermatol 1985; 13(2 Pt 1): 298. [34] Trattner A, Ingber A. Topical treatment with minoxidil 2% and smoking intolerance. Ann Pharmacother 1992; 26(2): 198–9. [35] Farrell SE, Epstein SK. Overdose of Rogaine Extra Strength for Men topical minoxidil preparation. J Toxicol Clin Toxicol 1999; 37(6): 781–3.