Pharmacia & Upjohn
Action And Clinical Pharmacology: Minoxidil is an orally effective direct acting peripheral vasodilator that reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance.
Minoxidil does not directly stimulate the heart or electrolyte reabsorption by the kidney. However, because of peripheral dilatation, minoxidil elicits a reflex mediated increase in cardiac output, salt and water retention, and a rise in plasma renin activity. These adverse effects are diminished by the simultaneous administration of a diuretic and a beta-adrenergic blocking agent or other sympathetic nervous system suppressant.
Minoxidil is at least 95% absorbed from the gastrointestinal tract. Plasma levels of the drug reach maximum within the first hour and decline rapidly thereafter. The average plasma half-life in man is 4.2 hours. Approximately 90% of the administered drug is metabolized, predominantly by conjugation with glucuronic acid at the N-oxide position in the pyrimidine ring but also by conversion to more polar products.
Known metabolites exert much less pharmacologic effect than minoxidil itself, and all are excreted principally in the urine. Minoxidil does not bind to plasma proteins, and its renal clearance corresponds to the glomerular filtration rate. In the absence of functional renal tissue, minoxidil and its metabolites can be removed by hemodialysis, although this does not rapidly reverse its pharmacological effect.
The extent and time-course of blood pressure reduction by minoxidil do not correspond closely to its concentration in plasma. After a single oral dose, blood pressure usually starts to decline within one half hour, and reaches a minimum between 2 and 3 hours and recovers at an arithmetically linear rate of about 30%/day. The total duration of effect is approximately 72 hours. When minoxidil is administered chronically, the time required to achieve maximum effect on blood pressure is inversely related to the size of the dose.
Indications And Clinical Uses: Because of the potential for serious adverse effects, minoxidil is indicated only in the treatment of severe 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.
Contra-Indications: Pheochromocytoma because minoxidil may reflexly stimulate secretion of catecholamines from the tumor; pulmonary hypertension associated with mitral stenosis; hypersensitivity to minoxidil or any components of the preparation.
Manufacturers’ Warnings In Clinical States: Salt and water retention; congestive heart failure – concomitant use of an adequate diuretic is required: Minoxidil 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 and 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. 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. This increase can be partly or entirely prevented by the concomitant administration of a beta-adrenergic blocking drug or other sympathetic nervous system suppressant. Round-the-clock effectiveness of the sympathetic suppressant should be assured. In addition, 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. This can usually be prevented by sympathetic blockade.
Pericarditis, Pericardial effusion and Tamponade: Although there is no evidence of a causal relationship, there have been multiple reports of pericarditis occurring in association with minoxidil. 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 therapy 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 i.v. agents, can precipitate cerebrovascular accidents and myocardial infarction. 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.
Cardiac Lesions in Animals: In non-primate animal studies, minoxidil produced several types of myocardial lesions as well as other adverse cardiac effects. These included necrotic and hemorrhagic lesions of the myocardium and papillary muscles and cardiac hypertrophy and dilatation. As greater experience with minoxidil has accumulated, it has become apparent that these cardiac lesions so described in the dog, minipig and other non-primates do not occur in humans.
Human autopsy experience has revealed the following: Among 242 autopsies performed on patients who received minoxidil tablets, cardiac pathology was detected in only 8 instances. In every instance, the conclusion has been reached that the human heart lesions were decidedly different in individual elements and constellation of changes from both the atrial and ventricular lesions seen in animals. Among 224 autopsies performed on patients never exposed to minoxidil tablets, the cardiac pathology observed, especially in the right atrium, entirely encompassed the pathologic findings seen in the minoxidil cases. The inference of these observations is that the pathologic findings in hearts of minoxidil treated hypertensive patients were not attributable to minoxidil administration, but rather to disease processes which were common to patients in these 2 studies.
Precautions: Monitor fluid and electrolyte balance and body weight (see Warnings).
Observe patients for signs and symptoms of pericarditis, pericardial effusions and tamponade (see Warnings).
Abnormal hair growth is a common occurrence (see Adverse Effects). This is especially disturbing to women and children and patients should be thoroughly informed about this effect.
When using a concomitant sympatholytic to prevent tachycardia, careful attention to adjusting the dosages of the beta-blocker or other sympathetic nervous system suppressant is required for maximum safety and efficacy (see Dosage, Concomitant Therapy).
When using a concomitant diuretic to prevent or treat fluid retention, careful attention to adjusting the dosage of the diuretic is required for maximum safety and efficacy (see Dosage, Concomitant Therapy).
Minoxidil has 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.
Possible hypersensitivity to minoxidil, manifested as a skin rash, including rare reports of bullous eruptions and Stevens-Johnson syndrome, has been seen.
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.
If minoxidil therapy must be discontinued in a patient who has been treated effectively, the drug should be phased out gradually or replaced with another antihypertensive agent. Careful monitoring of the patient’s blood pressure during the treatment adjustment is necessary.
Pregnancy: The safety for use of minoxidil in pregnancy has not been established. Minoxidil has been shown to reduce the conception rate in rats and to show evidence of increased fetal absorption in rabbits when administered at 5 times the human dose. There was no evidence of teratogenic effects in rats and rabbits. Minoxidil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: This drug has been reported to be excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on minoxidil.
Children: Use in children has been limited to date particularly in infants. The recommendations under Dosage can be considered only a rough guide and careful titration is essential.
Patient Information: The patient should be made fully aware of the importance of continuing all prescribed antihypertensive medications and of the nature of symptoms that would suggest fluid overload (see Blue Section – Information for the Patient “Loniten”).
Adverse Reactions: Salt and water retention (see Warnings): Temporary edema, developed in 7% of patients who were not edematous at the start of therapy.
Pericarditis, pericardial effusion and tamponade (see Warnings).
Hypertrichosis: Elongation, thickening, and enhanced pigmentation of fine body hair are seen in about 80% of patients. 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 sideburn 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.
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 ST segment, but the ST 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.
Miscellaneous: Breast tenderness, rash (see Precautions) and gastrointestinal intolerance developed in less than 1% of patients.
Altered Laboratory Findings: Effects of hemodilution-hematocrit, hemoglobin, and erythrocyte count usually fall about 7% initially and then recover to pretreatment levels; thrombocytopenia and leukopenia have been rarely reported; 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.
Symptoms And Treatment Of Overdose: Symptoms: There have been only a few instances of deliberate or accidental overdosage with minoxidil. 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 of alpha-adrenergic blockade).
Treatment: The recommended treatment is i.v. administration of normal saline. Sympathomimetic drugs, such as norepinephrine or epinephrine, should be avoided because of their excessive cardiac stimulating action. Phenylephrine, angiotensin II, vasopressin and dopamine, which reverse the effects of minoxidil, should only be used if inadequate perfusion of a vital organ is evident.
Dosage And Administration: Adults and children over 12 years of age: The recommended initial daily dosage of minoxidil is 5 mg given in 2 divided doses. Daily dosage can be increased to 10, 20 and 40 mg in divided doses, at 3-day intervals or longer, if required for optimum blood pressure control. The effective dosage range is usually 10 to 40 mg/day. In certain patients, doses up to a maximum of 100 mg/day may be attempted, recognizing the probability of an increase in the incidence and severity of adverse reactions.
Children under 12 years of age: The initial recommended daily dosage is 0.2 mg/kg minoxidil in 2 divided doses. The dosage may be increased by 0.1 to 0.2 mg/kg/day increments, at 3-day intervals or longer, until optimum blood pressure control is achieved. The effective dosage range is usually 0.25 to 1 mg/kg/day. The maximum recommended dose is 50 mg/day.
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, a 5 mg dose can be given every 6 hours if the patient is hospitalized and carefully monitored (see Warnings).
Dose Frequency: The magnitude of within-day fluctuation of arterial pressure during therapy with minoxidil is directly proportional to the extent of pressure reduction. When the targeted blood pressure has been reached, a change from twice daily to once daily dosing with minoxidil may be tried in those patients in whom the diastolic pressure has been reduced less than 30 mmHg. If supine diastolic pressure has been reduced more than 30 mmHg, the twice daily dosage schedule should be maintained.
Concomitant Therapy: Diuretics: To prevent fluid retention and possible congestive heart failure, minoxidil must be used in conjunction with a high ceiling (loop) 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 twice daily) or other thiazides at equi-effective dosage; chlorthalidone (50 to 100 mg once daily); furosemide (40 mg twice daily).
If excessive salt and water retention results in a weight gain of more than 2 kg, 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. 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 fluid retention by discontinuing minoxidil for 1 or 2 days and then resuming treatment in conjunction with vigorous diuretic therapy.
In dialysis patients also receiving diuretic therapy, use of minoxidil may create the need to raise diuretic dosage or to increase the frequency or duration of dialysis in order to maintain salt and water balance.
Sympathetic Nervous System Suppressants: The preferred agent to achieve sympathetic nervous system suppression is a beta-blocker equivalent to a propranolol dosage of 80 to 160 mg/day. Higher doses may be required when patients, pretreated with a beta-blocker, have an increase in heart rate exceeding 20 beats/minute or when simultaneous introduction of minoxidil and a beta-blocker causes an increase in heart rate exceeding 10 beats/minute.
If beta-blockers are contraindicated, methyldopa (250 to 750 mg twice daily) 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 a 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.
Availability And Storage: 2.5 mg: Each round, white tablet scored and embossed with a “U” and 121 on one side and 2 1/2 on the other contains: minoxidil 2.5 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Bottles of 100.
10 mg: Each round, white tablet scored and embossed with a “U” and 137 on one side and 10 on the other contains: minoxidil 10 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Bottles of 100. (Shown in Product Recognition Section)
LONITEN® Pharmacia & Upjohn Minoxidil Antihypertensive