1. 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 milli-equivalents 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.
2. 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.
3. 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.
4. 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.
5. 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.
1. General Precautions
- (a) Monitor fluid and electrolyte balance and body weight (see WARNINGS: Salt and Water Retention).
- (b) Observe patients for signs and symptoms of pericardial effusion (see WARNINGS: Pericarditis, Pericardial Effusion, and Tamponade).
- (c) 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.
- (d) 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.
- (e) 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.
2. Information for patient
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. A patient brochure has been prepared and is included with each minoxidil package. The text of this brochure is reprinted at the end of the insert.
3. 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., 1-3 month intervals; later as stabilization occurs, at intervals of 6-12 months.
4. Drug interactions
See "Interaction with guanethidine" under WARNINGS.
5. Carcinogenesis, Mutagenesis, 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 two-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 or 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.
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 development 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.
7. Labor and delivery
The effects on labor and delivery are unknown.
8. 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.
9. Pediatric Use
Use in pediatric patients has been limited to date, particularly in infants. The recommendations under DOSAGE AND ADMINISTRATION can be considered only a rough guide at present and a careful titration is essential.
10. Geriatric Use
Clinical studies of minoxidil tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified the 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 concomitant disease or other drug therapy.
11. Unapproved Use
Use of minoxidil tablets, in any formulation, to promote hair growth is not an approved indication. While clinical trials with Minoxidil Topical Solution 2% demonstrated that formulation and dosage were safe and effective, the effects of extemporaneous formulations and dosages have not been shown to be safe or effective. Because systemic absorption of topically applied drug may occur and is dependent on vehicle and/or method of use, extemporaneous topical formulations made from minoxidil should be considered to share in the full range of CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS listed in this insert. In addition, skin intolerance to drug and/or vehicle may occur.