Minoxidil (oral)

Minoxidil (oral)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Black Box Warning

WARNINGS See full prescribing information for complete Boxed Warning. * Minoxidil tablets contain the powerful antihypertensive agent, minoxidil, which may produce serious adverse effects. It can cause pericardial effusion, occasionally progressing to tamponade, and angina pectoris may be exacerbated. Minoxidil should be reserved for hypertensive patients who do not respond adequately to maximum therapeutic doses of a diuretic and two other antihypertensive agents. In experimental animals, minoxidil caused several kinds of myocardial lesions as well as other adverse cardiac effects. Minoxidil must be administered under close supervision, usually concomitantly with therapeutic doses of a beta-adrenergic blocking agent to prevent tachycardia and increased myocardial workload. It must also usually be given with a diuretic, frequently one acting in the ascending limb of the loop of Henle, to prevent serious fluid accumulation. Patients with malignant hypertension and those already receiving guanethidine should be hospitalized when minoxidil is first administered so that they can be monitored to avoid too rapid, or large orthostatic, decreases in blood pressure.

Overview

Minoxidil (oral) is a vasodilator that is FDA approved for the {{{indicationType}}} of hypertension that is symptomatic or associated with target organ damage and is not manageable with maximum therapeutic doses of diuretic plus two other antihypertensive drugs. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, hirsutism, hypertrichosis, fluid retention, and hypernatremia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Refractory Hypertension Associated with End Organ Damage

• Dosing Information

• Initial Dosage

• 5 mg/day PO as single dose or 2 divided doses; adjust in 100% increments as required

• Maintenance Dosage

• 10-40 mg/day ORALLY daily in 1-2 divided doses; maximum 100 mg/day

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Minoxidil (oral) in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Minoxidil (oral) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Refractory Hypertension Associated with End Organ Damage

• Dosing Information

• Dosage
• Initial Dosage

• 0.2 mg/kg/day PO in a single dose or as 2 divided doses; adjust as required up to 50 mg/day

• Maintenance Dosage

• 0.25-1 mg/kg/day PO in a single dose or as 2 divided daily doses; maximum 50 mg/day

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Minoxidil (oral) in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Minoxidil (oral) in pediatric patients.

Contraindications

• Pheochromocytoma

• Minoxidil tablets are contraindicated in pheochromocytoma, because it may stimulate secretion of catecholamines from the tumor through its antihypertensive action.

• Hypersensitivity

• Minoxidil tablets are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.

Warnings

WARNINGS See full prescribing information for complete Boxed Warning. * Minoxidil tablets contain the powerful antihypertensive agent, minoxidil, which may produce serious adverse effects. It can cause pericardial effusion, occasionally progressing to tamponade, and angina pectoris may be exacerbated. Minoxidil should be reserved for hypertensive patients who do not respond adequately to maximum therapeutic doses of a diuretic and two other antihypertensive agents. In experimental animals, minoxidil caused several kinds of myocardial lesions as well as other adverse cardiac effects. Minoxidil must be administered under close supervision, usually concomitantly with therapeutic doses of a beta-adrenergic blocking agent to prevent tachycardia and increased myocardial workload. It must also usually be given with a diuretic, frequently one acting in the ascending limb of the loop of Henle, to prevent serious fluid accumulation. Patients with malignant hypertension and those already receiving guanethidine should be hospitalized when minoxidil is first administered so that they can be monitored to avoid too rapid, or large orthostatic, decreases in blood pressure.

Salt and Water Retention

• Congestive Heart Failure — concomitant use of an adequate diuretic is required — Minoxidil tablets must usually be administered concomitantly with a diuretic adequate to prevent fluid retention and possible congestive heart failure; a high ceiling (loop) diuretic is almost always required. Body weight should be monitored closely. If minoxidil is used without a diuretic, retention of several hundred milliequivalents of salt and corresponding volumes of water can occur within a few days, leading to increased plasma and interstitial fluid volume and local or generalized edema. diuretic treatment alone, or in combination with restricted salt intake, will usually minimize fluid retention, although reversible edema did develop in approximately 10% of nondialysis patients so treated. Ascites has also been reported. diuretic effectiveness was limited mostly by disease-related impaired renal function. The condition of patients with pre-existing congestive heart failure occasionally deteriorated in association with fluid retention although because of the fall in blood pressure (reduction of afterload), more than twice as many improved than worsened. Rarely, refractory fluid retention may require discontinuation of minoxidil. Provided that the patient is under close medical supervision, it may be possible to resolve refractory salt retention by discontinuing minoxidil for 1 or 2 days and then resuming treatment in conjunction with vigorous diuretic therapy.

Concomitant Treatment to Prevent Tachycardia is Usually Required

• Minoxidil increases the heart rate. Angina may worsen or appear for the first time during minoxidil treatment, probably because of the increased oxygen demands associated with increased heart rate and cardiac output. The increase in rate and the occurrence of angina generally can be prevented by the concomitant administration of a beta-adrenergic blocking drug or other sympathetic nervous system suppressant. The ability of beta-adrenergic blocking agents to minimize papillary muscle lesions in animals is further reason to utilize such an agent concomitantly. Round-the-clock effectiveness of the sympathetic suppressant should be ensured.

Pericarditis, Pericardial Effusion and Tamponade

• There have been reports of pericarditis occurring in association with the use of minoxidil. The relationship of this association to renal status is uncertain. Pericardial effusion, occasionally with tamponade, has been observed in about 3% of treated patients not on dialysis, especially those with inadequate or compromised renal function. Although in many cases, the pericardial effusion was associated with a connective tissue disease, the uremic syndrome, congestive heart failure, or marked fluid retention, there have been instances in which these potential causes of effusion were not present. Patients should be observed closely for any suggestion of a pericardial disorder, and echocardiographic studies should be carried out if suspicion arises. More vigorous diuretic therapy, dialysis, pericardiocentesis, or surgery may be required. If the effusion persists, withdrawal of minoxidil should be considered in light of other means of controlling the hypertension and the patient's clinical status.

Interaction with Guanethidine

• Although minoxidil does not itself cause orthostatic hypotension, its administration to patients already receiving guanethidine can result in profound orthostatic effects. If at all possible, guanethidine should be discontinued well before minoxidil is begun. Where this is not possible, minoxidil therapy should be started in the hospital and the patient should remain institutionalized until severe orthostatic effects are no longer present or the patient has learned to avoid activities that provoke them.

Hazard of Rapid Control of Blood Pressure

• In patients with very severe blood pressure elevation, too rapid control of blood pressure, especially with intravenous agents, can precipitate syncope, cerebrovascular accidents, myocardial infarction and ischemia of special sense organs with resulting decrease or loss of vision or hearing. Patients with compromised circulation or cryoglobulinemia may also suffer ischemic episodes of the affected organs. Although such events have not been unequivocally associated with minoxidil use, total experience is limited at present.

• Any patient with malignant hypertension should have initial treatment with minoxidil carried out in a hospital setting, both to assure that blood pressure is falling and to assure that it is not falling more rapidly than intended.

Precautions

General Precautions

• Monitor fluid and electrolyte balance and body weight.

• Observe patients for signs and symptoms of pericardial effusion.

• Use after myocardial infarction

• Minoxidil tablets have not been used in patients who have had a myocardial infarction within the preceding month.
• It is possible that a reduction of arterial pressure with minoxidil might further limit blood flow to the myocardium, although this might be compensated by decreased oxygen demand because of lower blood pressure.

• Hypersensitivity

• Possible hypersensitivity to minoxidil, manifested as a skin rash, has been seen in less than 1% of patients; whether the drug should be discontinued when this occurs depends on treatment alternatives.

• Renal failure or dialysis patients may require smaller doses of minoxidil and should have close medical supervision to prevent exacerbation of renal failure or precipitation of cardiac failure.

Laboratory Tests

• Those laboratory tests which are abnormal at the time of initiation of minoxidil therapy, such as urinalysis, renal function tests, EKG, chest x-ray, echocardiogram, etc., should be repeated at intervals to ascertain whether improvement or deterioration is occurring under minoxidil therapy. Initially, such tests should be performed frequently, e.g., 1 to 3 month intervals; later as stabilization occurs, at intervals of 6 to 12 months.

Unapproved Use

• Use of minoxidil tablets, in any formulation, to promote hair growth is not an approved indication.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Minoxidil (oral) in the drug label.

Postmarketing Experience

• Salt and Water Retention

• Temporary edema developed in 7% of patients who were not edematous at the start of therapy.

• Pericarditis, Pericardial Effusion, and Tamponade

• Dermatologic

• Hypertrichosis (elongation, thickening, and enhanced pigmentation of fine body hair)) is seen in about 80% of patients taking minoxidil tablets. This develops within 3 to 6 weeks after starting therapy. It is usually first noticed on the temples, between the eyebrows, between the hairline and the eyebrows, or in the side-burn area of the upper lateral cheek, later extending to the back, arms, legs, and scalp. Upon discontinuation of minoxidil, new hair growth stops, but 1 to 6 months may be required for restoration to pretreatment appearance. No endocrine abnormalities have been found to explain the abnormal hair growth; thus, it is hypertrichosis without virilism. Hair growth is especially disturbing to children and women and such patients should be thoroughly informed about this effect before therapy with minoxidil is begun.

• Allergic

• Rashes have been reported, including rare reports of bullous eruptions, and Stevens-Johnson syndrome.

• Hematologic

• Thrombocytopenia and leukopenia (WBC <3000/mm³) have rarely been reported.

• Gastrointestinal

• Nausea and/or vomiting has been reported. In clinical trials the incidence of nausea and vomiting associated with the underlying disease has shown a decrease from pretrial levels.

• Miscellaneous

• Breast tenderness developed in less than 1% of patients.

• Altered Laboratory Findings

• ECG changes:

• Changes in direction and magnitude of the ECG T waves occur in approximately 60% of patients treated with minoxidil. In rare instances a large negative amplitude of the T wave may encroach upon the S-T segment, but the S-T segment is not independently altered. These changes usually disappear with continuance of treatment and revert to the pretreatment state if minoxidil is discontinued. No symptoms have been associated with these changes, nor have there been alterations in blood cell counts or in plasma enzyme concentrations that would suggest myocardial damage. Long-term treatment of patients manifesting such changes has provided no evidence of deteriorating cardiac function. At present the changes appear to be nonspecific and without identifiable clinical significance.

• Effects of hemodilution

• Hematocrit, hemoglobin, and erythrocyte count usually fall about 7% initially and then recover to pretreatment levels.

• Other

• Alkaline phosphatase increased varyingly without other evidence of liver or bone abnormality.
• Serum creatinine increased an average of 6% and BUN slightly more, but later declined to pretreatment levels.

Drug Interactions

• Guanethidine

• Although minoxidil does not itself cause orthostatic hypotension, its administration to patients already receiving guanethidine can result in profound orthostatic effects. If at all possible, guanethidine should be discontinued well before minoxidil is begun. Where this is not possible, minoxidil therapy should be started in the hospital and the patient should remain institutionalized until severe orthostatic effects are no longer present or the patient has learned to avoid activities that provoke them.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category C

• Oral administration of minoxidil has been associated with evidence of increased fetal resorption in rabbits but not rats, when administered at five times the maximum recommended oral antihypertensive human dose. There was no evidence of teratogenic effects in rats and rabbits. Subcutaneous administration of minoxidil to pregnant rats at 80 mg/kg/day was maternally toxic but not teratogenic. Higher subcutaneous doses produced evidence of developmental toxicity. There are no adequate and well controlled studies in pregnant women. Minoxidil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Minoxidil (oral) in women who are pregnant.

Labor and Delivery

• The effects on labor and delivery are unknown.

Nursing Mothers

• There has been one report of minoxidil excretion in the breast milk of a woman treated with 5 mg oral minoxidil twice daily for hypertension. Because of the potential for adverse effects in nursing infants from minoxidil absorption, minoxidil should not be administered to a nursing woman.

Pediatric Use

• Use in pediatric patients has been limited to date, particularly in infants. The recommendations can be considered only a rough guide at present and careful titration is essential.

Geriatic Use

• Clinical studies of minoxidil tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, 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.

Gender

There is no FDA guidance on the use of Minoxidil (oral) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Minoxidil (oral) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Minoxidil (oral) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Minoxidil (oral) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Minoxidil (oral) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Minoxidil (oral) in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

Monitoring

There is limited information regarding Monitoring of Minoxidil (oral) in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Minoxidil (oral) in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• There have been only a few instances of deliberate or accidental overdosage with minoxidil tablets. One patient recovered after taking 50 mg of minoxidil together with 500 mg of a barbiturate. When exaggerated hypotension is encountered, it is most likely to occur in association with residual sympathetic nervous system blockade from previous therapy (guanethidine-like effects or alpha-adrenergic blockage), which prevents the usual compensatory maintenance of blood pressure. Intravenous administration of normal saline will help to maintain blood pressure and facilitate urine formation in these patients. Sympathomimetic drugs such as norepinephrine or epinephrine should be avoided because of their excessive cardiac stimulating action. Phenylephrine, angiotensin II, vasopressin, and dopamine all reverse hypotension due to minoxidil, but should only be used if underperfusion of a vital organ is evident.

• Radioimmunoassay can be performed to determine the concentration of minoxidil in the blood. At the maximum adult dose of 100 mg/day, peak blood levels of 1641 ng/mL and 2441 ng/mL were observed in two patients, respectively. Due to patient-to-patient variation in blood levels, it is difficult to establish an overdosage warning level. In general, a substantial increase above 2000 ng/mL should be regarded as overdosage, unless the physician is aware that the patient has taken no more than the maximum dose.

• Oral LD50 in rats has ranged from 1321 to 3492 mg/kg; in mice, 2456 to 2648 mg/kg.

Chronic Overdose

There is limited information regarding Chronic Overdose of Minoxidil (oral) in the drug label.

Pharmacology

There is limited information regarding Minoxidil (oral) Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Minoxidil (oral) Mechanism of Action in the drug label.

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Minoxidil (oral) in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Minoxidil (oral) in the drug label.

Nonclinical Toxicology

Carcinogenesis and Mutagenesis and Impairment of Fertility

• Two-year carcinogenicity studies of minoxidil have been conducted by the dermal and oral (dietary) routes of administration in mice and rats. There were no positive findings with the oral (dietary) route of administration in rats.

• In the two-year dermal study in mice, an increased incidence of mammary adenomas and adenocarcinomas in the females at all dose levels (8, 25 and 80 mg/kg/day) was attributed to increased prolactin activity. Hyperprolactinemia is a well-known mechanism in the enhancement of mouse mammary tumors, but has not been associated with mammary tumorigenesis in women. Additionally, topical minoxidil has not been shown to cause hyperprolactinemia in women on clinical trials. Absorption of minoxidil through rodent skin is greater than would be experienced by patients treated topically with minoxidil for hair loss. Dietary administration of minoxidil to mice for up to 2 years was associated with an increased incidence of malignant lymphomas in females at all dose levels (10, 25 and 63 mg/kg/day) and an increased incidence of hepatic nodules in males (63 mg/kg/day). There was no effect of dietary minoxidil on the incidence of malignant liver tumors.

• In the two-year dermal study in rats there were significant increases in incidence of pheochromocytomas in males and females and preputial gland adenomas in males. Changes in incidence of neoplasms found to be increased in the dermal or oral carcinogenicity studies were typical of those expected in rodents treated with other hypotensive agents (adrenal pheochromocytomas in rats), treatment-related hormonal alterations (mammary carcinomas in female mice; preputial gland adenomas in male rats) or representative of normal variations within the range of historical incidence for rodent neoplasms (malignant lymphomas, liver nodules/adenomas in mice). Based on differences in absorption of minoxidil and mechanisms of tumorigenesis in these rodent species, none of these changes were considered to be relevant to the safety of patients treated topically with minoxidil for hair loss.

• There was no evidence of epithelial hyperplasia or tumorigenesis at the sites of topical application of minoxidil in either species in the 2-year dermal carcinogenesis studies. No evidence of carcinogenicity was detected in rats or rabbits treated topically with minoxidil for one year. Topical minoxidil (2% and 5%) did not significantly (p<0.05) reduce the latency period of UV light-initiated skin tumors in hairless mice, as compared to controls, in a 12-month photocarcinogenicity study.

• Minoxidil was not mutagenic in the Salmonella (Ames) test, the DNA damage alkaline elution assay, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) assay, the rat bone marrow micronucleus assay, or the mouse bone marrow micronucleus assay. An equivocal result was recorded in an in vitro cytogenetic assay using Chinese hamster cells at long exposure times, but a similar assay using human lymphocytes was negative.

• In a study in which male and female rats received one to five times the maximum recommended human oral antihypertensive dose of minoxidil (multiples based on a 50 kg patient) there was a dose-dependent reduction in conception rate.

Clinical Studies

There is limited information regarding Clinical Studies of Minoxidil (oral) in the drug label.

How Supplied

This image is provided by the National Library of Medicine.

Storage

There is limited information regarding Minoxidil (oral) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• The patient should be fully aware of the importance of continuing all of his antihypertensive medications and of the nature of symptoms that would suggest fluid overload. The patient brochure below has been prepared and is included with each minoxidil package.

This image is provided by the National Library of Medicine.

Precautions with Alcohol

• Alcohol-Minoxidil (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Loniten®

Look-Alike Drug Names

• Loniten® — Lipitor®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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