Minoxidil / Melatonin / Latanoprost 3/0.2/0.01% 60 mL Dropper Bottle
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
Melatonin
Melatonin may provide some benefit and few risks for the short-term treatment of sleep irregularities in pediatric patients with neurodevelopmental disorders. In pediatric patients, there is a role for the use of melatonin in children and adolescents with autism spectrum disorder (ASD) who have not responded to behavioral strategies to improve sleep. Melatonin also has orphan drug status for neonatal hypoxic-ischemic encephalopathy. Although considered a dietary supplement in the U.S., melatonin is available by prescription in Europe under the brand name Circadin as a short-term monotherapy treatment for primary insomnia characterized by poor quality of sleep in patients 55 years of age or more. According to the British Association for Psychopharmacology guidelines, extended-release melatonin is the first-choice treatment when a hypnotic is indicated in patients over 55 years of age.
Topical melatonin solutions have been tried and shown to be effective in the treatment of scalp seborrheic dermatitis and androgenetic alopecia.4
Latanoprost
Latanoprost, an analog of prostaglandin F2alpha, is a prodrug used to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Studies have shown that latanoprost administered once daily is at least as effective as timolol in lowering intraocular pressure.56 When latanoprost and timolol were used in combination, a complete or almost complete additive effect in reducing intraocular pressure has been observed.[24740] Treatment has been associated with increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes.
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.1 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
Melatonin
Melatonin is an endogenous hormone secreted by the pineal gland. The suprachiasmatic nuclei of the hypothalamus controls the numerous physiologic and endocrine circadian rhythms of the body, including that of rest and activity. The circadian clock is set via a process called entrainment, which is a response of the suprachiasmatic nuclei to photic input. Synthesis and secretion of endogenous melatonin is controlled by enzymes secreted by the hypothalamus which are activated by darkness and depressed by environmental light. Exactly how melatonin induces sleep is not clear, but it is probably not through a direct hypnotic effect. In patients with jet lag or circadian rhythm disorders, endogenous melatonin secretion does not correspond to the social or solar sleep-wake cycles imposed by their surroundings, and they experience sleep disruption. Administration of exogenous melatonin appears to re-set the body to the environmental clock and allow patients to normalize physiologic and behavioral sleep patterns. Exogenous melatonin maximally advances delayed rhythms when administered before endogenous melatonin levels begin to increase in the evening hours. In addition to circadian phase-shifting effects, melatonin has been shown to decrease nocturnal core body temperature, which helps to facilitate sleep. To date, pharmacological tolerance to melatonin has not been described.
Melatonin also exhibits immunostimulatory and antioxidant actions. In neurodegenerative disease models, melatonin appears to neutralize oxidizing free radicals, specifically by preventing the reduction of antioxidant enzyme activity, and reducing beta-amyloid mediated lipid peroxidation of cell membranes. These actions appear to decrease apoptosis of neuronal cells. Further research is needed to determine if melatonin may preserve function in neurologic diseases where free radicals have been implicated as partially causative of the conditions.
Melatonin is a potent antioxidant and hair growth modulator and has been identified as a possible candidate to counteract the oxidative stress associated with general hair loss as well as androgenetic alopecia because of the strong anti-oxidant properties that have been described for this substance.15
Latanoprost
Latanoprost is a selective agonist at a subtype of prostaglandin receptors known as the FP receptor. By acting on the FP receptor, latanoprost increases the outflow of aqueous humor thereby reducing intraocular pressure. According to the manufacturer, studies in both animals and man suggest that increased uveoscleral outflow is the primary mechanism of action.
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.
Melatonin
Melatonin administration follows a different pharmacokinetic profile than that of the endogenous hormone. Melatonin crosses the blood-brain barrier, and also traverses the placenta in pregnancy. Some accumulation of melatonin in fat tissue may occur with prolonged daily administration. The primary metabolic pathway occurs via the liver via oxidative metabolism via CYP1A (isoenzymes CYP1A2 and CYP1A1), with minor roles by CYP2C19 and possibly CYP2C9. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. Elimination of melatonin is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as unchanged, active melatonin. The mean elimination half-life (T1/2) after oral administration of immediate-release melatonin is roughly 45 minutes; with intravenous administration, the half-life is approximately 28 minutes.16 The terminal half-life is 3.5 to 4 hours and the excretion of the primary metabolite is completed within 12 hours following a single oral dose of an extended-release product.17
In a study to assess the clinical tolerability and pharmacokinetics of topical melatonin solution, conducted from at the Forenap Centre Hospitalier in Rouffach, France, blood samples were collected on day 14 at 30-minute intervals for 8 hours following application and at 10, 12, 16 and 20 hours following application. The analysis of the blood samples revealed that repeated application of the cosmetic melatonin solution (0.033%) had no negative influence with respect to an increase or reduction in physiological endogenous melatonin secretion. The mean serum melatonin level over 20 hours was similar to the serum level with placebo; the maximum serum melatonin concentration in the melatonin group was somewhat higher than in the placebo group (83.4 pg/ml vs. 71.2 pg/ml) and was reached somewhat earlier.18
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP1A1
Melatonin is primarily and predominantly metabolized by CYP1A2, with some metabolism by CYP1A1, CYP1B1, and minor contributions by CYP2C9 and CYP2C19.1920 Melatonin may exhibit significant interactions with potent CYP1A2 inhibitors, such as fluvoxamine.21 Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations only; the clinical relevance of the finding is unknown.17
Latanoprost
Latanoprost is administered topically to the eye as an isopropyl ester prodrug. Once in systemic circulation, the biologically active latanoprost acid is primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4- tetranor metabolites via fatty acid beta-oxidation with an elimination half-life of 17 minutes. The metabolites are mainly eliminated by the kidneys, with 88% of the topically administered dose being recovered in the urine.
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.22 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.23
Melatonin
Patients who develop angioedema, hypersensitivity or other serious allergic-type events due to melatonin should not be rechallenged with the dietary supplement.1724 Patients with asthma should seek health care professional advice prior to melatonin use, as melatonin may play a role in the expression of asthma symptoms.24
Melatonin may cause drowsiness. Driving or operating machinery, or performing other tasks that require mental alertness should be avoided after ingestion of melatonin; patients should confine their activities to those necessary to prepare for bed. Sedation occurring after melatonin use during waking hours may indicate excessive dosage.25 Complex sleep-related behaviors such as sleep-driving (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use and have been reported in the use of melatonin analogs.26 The use of alcohol may increase the risk of such behaviors, similar to other sedative-hypnotics. Avoid melatonin coadministration with other CNS depressants (i.e., other sedative-hypnotic agents) at bedtime, as there is no evidence supporting additional efficacy and use together may increase the risk for harm. Patients should be advised to avoid ethanol ingestion in combination with melatonin at bedtime as additive effects may occur. Discontinuation of melatonin should be considered for a patient who reports any complex sleep-related behavior.
Exogenous melatonin should be used with caution in patients with hepatic disease and should be avoided in patients with severe hepatic impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment.17 Patients with hepatic disease should consult their health care provider prior to the use of melatonin.
Due to a lack of scientific data and an unknown potential for side effects, investigational protocols should govern appropriate melatonin use in neonates or infants. Several small, randomized controlled trials suggest the efficacy and relative safety of short-term supplemental melatonin in treating insomnia and sleep disturbances in pediatric patients with autism spectrum disorder (ASD) or other neurodevelopmental disorders; experts generally agree that melatonin may be useful in children and adolescents 2 years and older when behavioral strategies have failed. However, nonprescription use should be avoided; a clinician should monitor the use of melatonin in any pediatric patient.2728 Melatonin and melatonin analogs have been associated with an effect on reproductive hormones in adults (e.g., decreased testosterone levels and increased prolactin levels). It is not known what effect melatonin would have on the reproductive and gonadal function of pre-pubescent or pubescent pediatric patients and further study is needed regarding the overall safety of chronic use in pediatric patients. Clinicians should counsel parents/caregivers regarding potential adverse effects of melatonin use and the lack of long-term safety data, including an unknown effect on pubertal development. Reported side effects of melatonin in pediatric patients have included morning drowsiness, increased enuresis, headache, dizziness, diarrhea, rash, and hypothermia.262928
Latanoprost
Latanoprost should not be used in patients with closed-angle glaucoma, or inflammatory or neovascular glaucoma. There is limited experience with latanoprost in these patients.
Latanoprost should be used with caution in patients with aphakia, pseudophakic patients with a torn posterior lens capsule, and patients with known risk factors for macular edema. Macular edema, including cystoid macular edema, has been reported during treatment with this drug.78
Recipients of latanoprost may experience a gradual increase in pigmentation (i.e., brown coloration) of the iris and periorbital tissue (eyelids), which may not be noticeable for several months to years. Patients who develop increased pigmentation may continue to receive treatment; however, these patients should be examined regularly as they may develop photophobia or be more sensitive to sunlight (UV) exposure. After discontinuing latanoprost, the change in iris color is likely to be permanent, while the pigmentation change in the periorbital tissue may be reversible in some patients. Eyelash changes (i.e., increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes) has also been associated with the use of latanoprost. Eyelash changes are usually reversible upon treatment discontinuation. Inform drug recipients of the possibility of iridal and eyelid discoloration, and of the potential for eyelash changes.78
Latanoprost should be used with caution in patients with active intraocular inflammation (e.g., iritis, uveitis). Use of latanoprost in these patient may exacerbate inflammation.7 8
Instruct drug recipients to remove contact lenses before instilling latanoprost ophthalmic drops. Lenses may be reinserted 15 minutes after drug administration. The ophthalmic solution is formulated with the preservative benzalkonium chloride, which may be absorbed by soft contact lenses.78
The use of multiple dose containers of ophthalmic products has been associated with bacterial keratitis. Inadvertent contamination of the latanoprost containers may increase the risk of infection in ocular surgery patients, or in patients who develop an ocular infection or ocular trauma, including corneal abrasion. If there is any damage to the ocular epithelial surface, latanoprost should be used with caution. Reactivation of herpes simplex keratitis has been reported during latanoprost therapy. Use caution in patients with a history of herpetic keratitis; avoid use in patients with active herpes simplex keratitis due to the potential for exacerbation of inflammation.7
Latanoprost is classified as FDA pregnancy risk category C. Although there are no adequate and well-controlled studies in pregnant women, limited experience in human pregnancy has not resulted in clinically significant risk to the fetus. A minimal amount of drug reaches systemic circulation after ophthalmic administration, suggesting exposure of the drug to the fetus is low.30 According to the manufacturer, latanoprost should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.7
According to the manufacturer, it is not known whether latanoprost or its metabolites are excreted in breast milk. Because systemic plasma concentrations of latanoprost are low and the half-life is short after ophthalmic administration, clinically significant amounts of the drug would not be expected to be excreted in breast-milk.30 To further minimize the amount of drug that reaches the systemic circulation and breast milk, apply pressure over the tear duct by the corner of the eye for 1 minute after ophthalmic administration. According to the manufacturer, caution should be exercised when latanoprost is administered during breast-feeding.7 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.
Safety and efficacy of latanoprost have not been established in the pediatric population (i.e., neonates, infants, children, or adolescents).78
Latanoprost should be used cautiously in patients with renal disease (e.g., renal failure, renal impairment) or hepatic disease. There have been no studies on safe use in these patients.
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.31 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.32
Melatonin
Melatonin should be considered to be contraindicated in pregnancy at this time.24 In pregnant women, endogenous melatonin crosses the placenta and enters the fetal circulation, and appears to be responsible for setting circadian rhythm influences in utero. Melatonin receptors in the fetus are widespread in both central and peripheral tissues from the third week of fetal development. The administration of exogenous melatonin could potentially disrupt circadian entrainment and other pineal gland influences.[47168] Thus, fetal exposure to exogenous melatonin use in the mother may be of concern. Effects in non-clinical animal studies of melatonin were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use; however, the data are limited.17 In animal studies, ramelteon, a melatonin analog, produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose.26 The potential effects of melatonin on the duration of labor and/or obstetric delivery, for either the mother or the fetus, have not been studied. Melatonin has no established use in labor and delivery.
Latanoprost
Latanoprost is classified as FDA pregnancy risk category C. Although there are no adequate and well-controlled studies in pregnant women, limited experience in human pregnancy has not resulted in clinically significant risk to the fetus. A minimal amount of drug reaches systemic circulation after ophthalmic administration, suggesting exposure of the drug to the fetus is low.30 According to the manufacturer, latanoprost should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 33; 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.34 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.33 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.
Melatonin
Melatonin should generally be avoided in women who are breast-feeding their infants.1724 Reports describing the use of melatonin dietary supplements in women who are breast-feeding are lacking; however, it is likely to be excreted in human milk. Endogenous melatonin passes into human milk and concentrations have been measured in the breast-milk of lactating women; the results coincided with the women’s daily circadian rhythm of melatonin with undetectable levels during the day and high levels at night.35
Latanoprost
According to the manufacturer, it is not known whether latanoprost or its metabolites are excreted in breast milk. Because systemic plasma concentrations of latanoprost are low and the half-life is short after ophthalmic administration, clinically significant amounts of the drug would not be expected to be excreted in breast-milk.30 To further minimize the amount of drug that reaches the systemic circulation and breast milk, apply pressure over the tear duct by the corner of the eye for 1 minute after ophthalmic administration. According to the manufacturer, caution should be exercised when latanoprost is administered during breast-feeding.7 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.
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.22 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.22
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.22
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.22
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.22
Gastrointestinal adverse effects associated with orally administered minoxidil include nausea and vomiting.22
Melatonin
Melatonin may rarely cause allergic or dermatologic reactions. Rash (unspecified), including fixed drug eruptions and exanthema, with or without pruritus, have been reported after melatonin administration; rash has also been reported in pediatric patients. Other reported dermatologic effects include hyperhidrosis (increased sweating) and hot flashes.3628 Rarely, angioedema and anaphylactoid reactions have been reported with the melatonin analog, ramelteon; however, no reports of such reactions to melatonin are found in the published literature.26 A report of “difficulty swallowing and breathing” was reported in one clinical study of melatonin for jet lag; this might have represented an allergic response.36 Patients experiencing a serious allergic reaction to melatonin should discontinue the agent and not be rechallenged.
Infrequent or rare cardiovascular (CV) reactions reported in the published literature include palpitations and sinus tachycardia.36 Most clinical trials have involved 6 months or less of daily melatonin administration. Much less is known regarding the long term administration of this hormone.
Melatonin and melatonin analogs have been associated with an effect on reproductive hormones in adults (e.g., decreased testosterone levels and increased prolactin levels). It is not known what effect melatonin would have on the reproductive and gonadal function of pre-pubescent or pubescent pediatric patients. Further study is needed regarding the overall safety of chronic use of melatonin in adult and pediatric patients, including melatonin’s effects on reproductive health.28
Treatment with topical melatonin solution has been shown to be well tolerated because no significant changes were detected in the various laboratory tests and circulatory system parameters nor were any effects on the central nervous system identified in comparison with placebo. Adverse reactions such as moderately severe headache and gastrointestinal problems have been observed.37
Latanoprost
Asthma or asthma exacerbations (bronchospasm) and dyspnea have been reported during postmarketing experience with latanoprost.7
Infection (i.e., upper respiratory tract infection, naso-pharyngitis, influenza) was reported in 3% of patients receiving latanoprost during clinical trials. Cases of herpes keratitis have been reported with postmarketing use.7
Postmarketing use of latanoprost has been associated with cases of palpitations, unstable angina, and chest pain (unspecified).7
Myalgia, arthralgia, musculoskeletal pain, and back pain were reported in 1% of patients during latanoprost clinical trials.7
Rash and other allergic skin reactions were reported at a rate of 1% during latanoprost clinical trials. Cases of pruritus and toxic epidermal necrolysis have been reported during postmarketing use of latanoprost.7
Dizziness and headache have been reported during postmarketing experience with latanoprost.
Store this medication in a refrigerator between 36°F to 46°F (2°C – 8°C). Do not freeze. Protect from light. Keep all medicine out of the reach of children. Throw away any medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.