Generic Name: MINOXIDIL
Brand Name: MINOXIDIL
- Substance Name(s):
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.
Drug interactions See ” Interaction with Guanethidine ” under WARNINGS .
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 LD 50 in rats has ranged from 1321–3492 mg/kg; in mice, 2456–2648 mg/kg.
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.
Minoxidil tablets are available as follows: Minoxidil tablets 2.5 mg are round, scored, white and debossed on one side and on the reverse side.
Bottles of 90 NDC 42291-618-90 Bottles of 100 NDC 42291-618-01 Bottles of 1000 NDC 42291-618-10 Minoxidil tablets 10 mg are round, scored, white and debossed on one side and on the reverse side.
Bottles of 90 NDC 42291-619-90 Bottles of 100 NDC 42291-619-01 Bottles of 1000 NDC 42291-619-10 Figure Figure Figure Figure Store at 20° to 25°C (68° to 77° F).
[See USP Controlled Room Temperature] DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
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 of concomitant disease or other drug therapy.
INDICATIONS AND 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.
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.
Pregnancy Teratogenic Effects 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.
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.
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.
INFORMATION FOR PATIENTS
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.
DOSAGE AND ADMINISTRATION
Patients over 12 years of age: The recommended initial dosage of minoxidil tablets is 5 mg of minoxidil given as a single daily dose.
Daily dosage can be increased to 10, 20 and then to 40 mg in single or divided doses if required for optimum blood pressure control.
The effective dosage range is usually 10 to 40 mg per day.
The maximum recommended dosage is 100 mg per day.
Patients under 12 years of age: The initial dosage is 0.2 mg/kg minoxidil as a single daily dose.
The dosage may be increased in 50 to 100% increments until optimum blood pressure control is achieved.
The effective dosage range is usually 0.25 mg to 1 mg/kg/day.
The maximum recommended dosage is 50 mg daily ( see 9.
Pediatric Use under PRECAUTIONS ).
Dose frequency: The magnitude of within-day fluctuation of arterial pressure during therapy with minoxidil is directly proportional to the extent of pressure reduction.
If supine diastolic pressure has been reduced less than 30 mm Hg, the drug need be administered only once a day; if supine diastolic pressure has been reduced more than 30 mm Hg, the daily dosage should be divided into two equal parts.
Frequency of dosage adjustment: Dosage must be titrated carefully according to individual response.
Intervals between dosage adjustments normally should be at least 3 days since the full response to a given dose is not obtained for at least that amount of time.
Where a more rapid management of hypertension is required, dose adjustments can be made every 6 hours if the patient is carefully monitored.
Concomitant therapy: Diuretic and beta-blocker or other sympathetic nervous system suppressant.
Diuretics: Minoxidil must be used in conjunction with a diuretic in patients relying on renal function for maintaining salt and water balance.
Diuretics have been used at the following dosages when starting therapy with minoxidil: hydrochlorothiazide (50 mg, b.i.d.) or other thiazides at equieffective dosage; chlorthalidone (50 to 100 mg, once daily); furosemide (40 mg, b.i.d.).
If excessive salt and water retention results in a weight gain of more than 5 pounds, diuretic therapy should be changed to furosemide; if the patient is already taking furosemide, dosage should be increased in accordance with the patient’s requirements.
Beta-blocker or other sympathetic nervous system suppressants: When therapy with minoxidil is begun, the dosage of a beta-adrenergic receptor blocking drug should be the equivalent of 80 to 160 mg of propranolol per day in divided doses.
If beta-blockers are contraindicated, methyldopa (250 to 750 mg, b.i.d.) may be used instead.
Methyldopa must be given for at least 24 hours before starting therapy with minoxidil because of the delay in the onset of methyldopa’s action.
Limited clinical experience indicates that clonidine may also be used to prevent tachycardia induced by minoxidil; the usual dosage is 0.1 to 0.2 mg twice daily.
Sympathetic nervous system suppressants may not completely prevent an increase in heart rate due to minoxidil but usually do prevent tachycardia.
Typically, patients receiving a beta-blocker prior to initiation of therapy with minoxidil have a bradycardia and can be expected to have an increase in heart rate toward normal when minoxidil is added.
When treatment with minoxidil and beta-blocker or other sympathetic nervous system suppressant are begun simultaneously, their opposing cardiac effects usually nullify each other, leading to little change in heart rate.