MINOXIDIL (minoxidil 10 mg) Dailymed

Spl Unclassified

Rx only

 

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 (see Cardiac Lesions in Animals ).

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 (see WARNINGS ) 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.

 

Description

Minoxidil tablets contain minoxidil, an antihypertensive peripheral vasodilator. Minoxidil occurs as a white to off-white, crystalline powder, soluble in alcohol and propylene glycol; sparingly soluble in methanol; slightly soluble in water; practically insoluble in chloroform, acetone and ethyl acetate. The chemical name for minoxidil is 2,4-Pyrimidinediamine, 6-(1-piperidinyl)-, 3-oxide. The structural formula is represented below:

Minoxidil tablets for oral administration contain either 2.5 mg or 10 mg of minoxidil. Inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

Clinical Pharmacology

Indications & Usage

Because of the potential for serious adverse effects, minoxidil tablets are indicated only in the treatment of hypertension that is symptomatic or associated with target organ damage and is not manageable with maximum therapeutic doses of a diuretic plus two other antihypertensive drugs. At the present time use in milder degrees of hypertension is not recommended because the benefit-risk relationship in such patients has not been defined.

Minoxidil reduced supine diastolic blood pressure by 20 mm Hg or to 90 mm Hg or less in approximately 75% of patients, most of who had hypertension that could not be controlled by other drugs.

 

Contraindications

Minoxidil tablets are contraindicated in pheochromocytoma, because it may stimulate secretion of catecholamines from the tumor through its antihypertensive action. Minoxidil tablets are contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.

 

Warnings

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.

 

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.

 

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.

 

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.

 

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

Adverse Reactions

1. Salt and Water Retention (see WARNINGS: Concomitant use of Adequate Diuretic is Required) — Temporary edema developed in 7% of patients who were not edematous at the start of therapy.

2. Pericarditis, Pericardial Effusion and Tamponade (see WARNINGS ).

3. Dermatologic — Hypertrichosis — Elongation, thickening, and enhanced pigmentation of fine body hair are 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.

4. Hematologic — Thrombocytopenia and leukopenia (WBC<3000/mm ³) have rarely been reported.

5. 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.

6. Miscellaneous — Breast tenderness — This developed in less than 1 % of patients.

7. Altered Laboratory Findings — (a) 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. (b) Effects of hemodilution — hematocrit, hemoglobin and erythrocyte count usually fall about 7% initially and then recover to pretreatment levels. (c) 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.