(Minoxidil Tablets USP) 2.5 mg, 10 mg
Pfizer Canada Inc Date of Preparation:
17,300 Trans-Canada Highway 23 September 2003 Kirkland, Quebec H9J 2M5
Control No. 086830
* TM Pharmacia Enterprises S.A. Pfizer Canada Inc, Licensee
(c) Pfizer Canada Inc 2003
(Minoxidil Tablets USP) 2.5 mg, 10 mg
Antihypertensive
ACTION AND CLINICAL PHARMACOLOGY
LONITEN * (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 administration 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 ss-adrenergic blocking agent or other sympathetic nervous system suppressant. Minoxidil is at least 95% absorbed from the gastrointestinal tract. Plasma levels of the parent 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 hemo-dialysis, 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, 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 USE
Because of the potential for serious adverse effects, LONITEN (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 of the benefit-risk relationship in such patients has not been defined.
LONITEN (minoxidil) is contraindicated in pheochromocytoma because it may reflexly stimulate secretion of catecholamines from the tumor. LONITEN is also contraindicated in pulmonary hypertension associated with mitral stenosis, and in patients with known hypersensitivity to LONITEN or any of the components of the preparation.
Salt and Water Retention; Congestive Heart Failure - Concomitant Use of an Adequate Diuretic is
required
- LONITEN (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 LONITEN 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 non-dialysis patients so treated. Diuretic effectiveness was limited mostly by disease-related impaired renal function. The condition of patients with preexisting 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 LONITEN. Provided that the patient is under close medical supervision, it may be possible to resolve refractory salt retention by discontinuing LONITEN for 1 or 2 days and then resuming treatment in conjunction with vigorous diuretic therapy.
Concomitant Treatment to Prevent Tachycardia is Usually Required
LONITEN 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 LONITEN 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 LONITEN should be considered in light or other means of controlling the hypertension and the patient's clinical status.
Interaction with Guanethidine
- Although LONITEN 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 LONITEN is begun. Where this is not possible, LONITEN 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 cerebrovascular accidents and myocardial infarction. Although such events have not been unequivocally associated with LONITEN use, total experience is limited at present.
Any patient with malignant hypertension should have initial treatment with LONITEN 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 LONITEN 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 dilation (See TOXICOLOGY). 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 LONITEN 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 LONITEN Tablets, the cardiac pathology observed, especially in the right atrium, entirely encompassed the pathologic findings seen in the LONITEN cases. The inference of these observations is that the pathologic findings in hearts of LONITEN treated hypertensive patients were not attributable to LONITEN administration, but rather to disease processes which were common to patients in these two studies.
Monitor fluid and electrolyte balance and body weight (See WARNING: Salt and Water Retention). Observe patients for signs and symptoms of pericardial effusion (See WARNING: Pericarditis, Pericardial Effusion and Tamponade). Abnormal hair growth is a common occurrence with LONITEN (minoxidil) treatment (See ADVERSE REACTIONS). This is especially disturbing to women and children and patients should be thoroughly informed about this effect before therapy with LONITEN is begun. 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 AND ADMINISTRATION: 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 AND ADMINISTRATION: Concomitant Therapy) LONITEN 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 LONITEN might further limit blood flow to the myocardium, although this might be compensated by decreased oxygen demand because of lower blood pressure. Hypersensitivity to LONITEN, manifested as a skin rash including rare reports bullous eruptions and Stevens-Johnson syndrome, has been seen. Renal failure or dialysis patients may require smaller doses of LONITEN and should have close medical supervision to prevent exacerbation of renal failure or precipitation of cardiac failure. If LONITEN 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.
Use in Pregnancy
: The safety for use of LONITEN in pregnancy has not been established. LONITEN has been shown to reduce the conception rate in rats and to show evidence of increased fetal absorption in rabbits when administered at five times the human dose. There was no evidence of teratogenic effects in rats and rabbits. LONITEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
: 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 LONITEN.
Use in Children
: Use in children has been limited to date, particularly in infants. The recommendations under DOSAGE AND ADMINISTRATION 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.
A patient brochure has been prepared for this purpose, the text of which is reprinted below.
Salt and Water Retention (See WARNING: Concomitant Use of Adequate Diuretic is Required) - 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 taking LONITEN (minoxidil). 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 LONITEN, 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 LONITEN. 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 pre-treatment state if LONITEN 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 - (a) Effects of hemodilution-hematocrit, hemoglobin and erythrocyte count usually fall about 7% initially and then recover to pre-treatment levels. Thrombocytopenia and leukopenia have been reported rarely. (b) 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 pre-treatment levels.
There have been only a few instances of deliberate or accidental overdosage with LONITEN (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 "-adrenergic blockade). The recommended treatment is intravenous 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 LONITEN, should only be used if inadequate perfusion of a vital organ is evident.
Patients Over 12 Years of Age
: The recommended initial daily dosage of LONITEN (minoxidil) is 5 mg given in two divided doses. Daily dosage can be increased to 10, 20 and then to 40 mg per day 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 per day. In certain patients, doses up to a maximum of 100 mg per day may be attempted, recognizing the probability of an increase in the incidence and severity of adverse reactions.
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 1.0 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 LONITEN 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 LONITEN may be tried in those patients in whom the diastolic pressure has been reduced less than 30 mm Hg. If supine diastolic pressure has been reduced more than 30 mm Hg, the twice daily dosage schedule should be maintained.
Concomitant Therapy.
Diuretics:
To prevent fluid retention and possible congestive heart failure, LONITEN 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 LONITEN: hydrochlorothiazide (50 mg b.i.d.) or other thiazides at equi-effective dosage; chlorthalidone (50 to 100 mg once daily); furosemide (40 mg b.i.d).
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 LONITEN. Provided that the patient is under close medical supervision, it may be possible to resolve refractory fluid retention by discontinuing LONITEN for 1 or 2 days and then resuming treatment in conjunction with vigorous diuretic therapy. In dialysis patients also receiving diuretic therapy, use of LONITEN 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 ss-blocker equivalent to an adult propranolol dosage of 80 to 160 mg/day. Higher doses may be required when patients, pretreated with a ss-blocker, have an increase in heart rate exceeding 20 beats per minute or when simultaneous introduction of LONITEN and a ss-blocker causes an increase in heart rate exceeding 10 beats per minute.
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 LONITEN 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 LONITEN; 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 LONITEN but usually do prevent tachycardia. Typically, patients receiving a beta blocker prior to initiation of therapy with LONITEN have a bradycardia and can be expected to have an increase in heart rate toward normal when LONITEN is added. When treatment with LONITEN and a beta blocker or usually nullify each other, leading to little change in heart rate.
minoxidil
2,4,-Pyrimidinediamine,6-(1-piperidinyl)-3,oxide
209.25
Molecular Formula: C9H15N5O
A white or off-white, odorless, crystalline solid that is soluble in water to the extent of approximately 2 mg/ml; is readily soluble in propylene glycol or ethanol, and is almost insoluble in acetone, chloroform or ethyl acetate. It has a melting point of 248degC, a pKa of 4.60, a logP of 0.6 (octanol/water partition coefficient), and a pH in an aqueous solution of 7.0 (due to very low solubility in water).
Loniten should be stored at controlled room temperature (15 to 30degC).
LONITEN tablets (minoxidil tablets) are round, scored, white tablets with the dosage strength debossed on one convex surface. LONITEN tablets are supplied as 2.5 mg and 10 mg tablets, in bottles of 100.
LONITEN tablets contain minoxidil, a powerful medicine for the treatment of high blood pressure. LONITEN is used for the treatment of severe hypertension that is difficult to control. It is taken with other medicines. Be sure to take all of your medicines for high blood pressure according to your doctor's instructions. Your doctor will need to see you regularly while you are taking LONITEN. Be sure to keep all your appointments or to arrange for new ones if you must miss one. Do not stop taking LONITEN unless your doctor tells you to. Do not give any of your medication to other people.
What is LONITEN? LONITEN tablets contain minoxidil which is a powerful drug for lowering the blood pressure. It works by relaxing and enlarging certain small blood vessels so that blood flows through them more easily.
Who Should Take LONITEN? There are many people with high blood pressure, but most of them do not need LONITEN. LONITEN is
Your high blood pressure is severe;
Your high blood pressure is causing symptoms or damage of vital organs and
Other medicines did not work well enough or had very disturbing side effects.
LONITEN should be taken only when a doctor prescribes it. Never give any of your LONITEN tablets, or any other high blood pressure medicine, to a friend or a relative.
Pregnancy:
In some cases, doctors may prescribe LONITEN for women who are pregnant or who are planning to have children. However, its safe use in pregnancy has not been established. If you are pregnant or are planning to become pregnant, be sure to tell your doctor.
How to Take LONITEN: Usually, your doctor will prescribe two other medicines along with LONITEN. These will help lower blood pressure and will help prevent undesired effects of LONITEN. Often, when a medicine like LONITEN lowers blood pressure, your body tries to return the blood pressure to the original, higher level. It does this by holding on to water and salt (so there will be more fluid to pump) and by making your heart beat faster. To prevent this, your doctor will usually prescribe a water tablet to remove the extra salt and water from your body and another medicine to slow your heart beat. You must follow your doctor's instructions exactly, taking all the prescribed medicines, in the right amounts, each day. These medicines will decrease the side effects you might otherwise have and will also help keep your blood pressure down. You may take LONITEN with water or with other liquids, either with or between meals. LONITEN tablets come in two strengths (21/2 mg and 10 mg) that are marked on each tablet. Pay close attention to the tablet markings to be sure you are taking the correct strength. Your doctor may prescribe half a tablet; the tablets are scored (partly cut on one side) so that you can easily break them. When you first start taking LONITEN, your doctor may need to see you often in order to adjust your dosage. Take all your medicine according to the schedule prescribed by your doctor. Do not skip any doses. If you should forget a dose of LONITEN, wait until it is time for your next dose, then continue with your regular schedule. Remember, do not stop taking LONITEN, or any of your other high blood pressure medicines, without checking with your doctor. Make sure that any doctor treating or examining you knows that you are taking high blood pressure medicines, including LONITEN.
WARNING SIGNALS:
Even if you take all your medicines correctly, you may have side effects. If any of the following warning signals occur, you must call your doctor immediately as your treatment may have to be adjusted.
Increase in heart rate:
You should measure your heart rate by counting your pulse rate while you are resting. If you have an increase of 20 beats or more per minute over your normal pulse, contact your doctor. Ask your doctor how often to check your pulse. Weight Gain: You should weigh yourself daily. If you quickly gain five or more pounds (two or more kg), or if there is any swelling or puffiness in the face, hands, ankles, or stomach area, this could be a sign that you are retaining body fluids and you should call your doctor. A smaller weight gain ( 2 or 3 pounds or 1 to 1.5 kg) often occurs when treatment is started. You may lose this extra weight with continued treatment. Also call your physician if you notice:
increased difficulty in breathing, especially when lying down,
new or worsening of pain in the chest, arm or shoulder or signs of severe indigestion and
dizziness, lightheadedness or fainting.
Hair Growth: About 8 out of 10 patients who have taken LONITEN noticed that fine body hair grew darker or longer on certain parts of the body. This happened about three to six weeks after beginning treatment. The hair may first be noticed on the forehead and temples, between the eyebrows, or on the upper part of the cheeks. Later, hair may grow on the back, arms, legs, or scalp. Although hair growth may not be noticeable to some patients, it often is bothersome in women and children. Unwanted hair can be controlled with a hair remover or by shaving. The extra hair is not permanent it disappears within 1 to 6 months of stopping LONITEN. Nevertheless, you should not stop taking LONITEN without first talking to your doctor. A few patients have developed a rash or breast tenderness while taking LONITEN tablets, but this is unusual.
Animal Studies: Minoxidil produces a dose-related reduction in mean arterial blood pressure following oral administration to rats, dogs, monkeys, and minipigs. The onset of action was within 2 hours regardless of the route of administration, and the activity persisted at near maximum for more than 24 hours. Minoxidil acts on vascular smooth muscle to reduce resistance to blood flow. This effect appears to be direct since it was not antagonized by beta-adrenergic, cholinergic, or histaminergic blocking agents or by decentralization with higher spinal anesthesia. The vasculature of dogs remained responsive to the vasoconstrictor action of norepinephrine, angiotensin II and vasopressin and to vasodilator action of acetylcholine, histamine, glyceryl-trinitrate, and isoproterenol. In dogs measurements with radiolabelled microspheres indicated that minoxidil increased blood flow to the myocardium 8 - 11 fold, 60 - 70% to skin, skeletal muscle, pancreas and gastrointestinal tract whereas blood flow to the adrenals, kidneys, spleen, liver and the central nervous system was unchanged. Vascular resistance was reduced in all tissues studied with the exception of the liver. The administration of minoxidil to intact dogs markedly increased cardiac output, heart rate and left ventricular dp/dt in association with the decreased total peripheral resistance. These changes in cardiac function did not appear to be a direct effect. Sympathetic nerve tone was increased as evidenced by increased urinary excretion of norepinephrine and augmented blood pressure reduction in response to ganglionic blockade, but sympathetic activity alone did not account for the increase in heart rate and cardiac output. Chronic stimulation of the carotid sinus nerves or ganglionic blockade more effectively prevented the cardiac hyperactivity associated with minoxidil treatment suggesting an important component of the heart changes is withdrawal of vagal tone. Minoxidil produced an acute reduction in renal salt and water excretion in rats and dogs but did not significantly influence renal hemodynamics. At approximately a 15% expansion of total body exchangeable sodium in chronically treated animals, salt and water balance were re-established at an expanded, extracellular fluid volume. Hypersecretion of mineralocorticosteroids which occurred during minoxidil treatment did not explain this salt retaining action. Also sodium clearance increased when minoxidil was delivered directly into the renal artery and, thus direct activation of electrolyte reabsorptive transport in the kidney did not account for the retention phenomenon. Minoxidil-induced salt and water retention and attendant extracellular fluid volume expansion was reduced by concomitant administration of hydrochlorothiazide. Minoxidil elevated plasma glucose concentration in rats at doses of 1.5 mg/kg. Minoxidil did not alter intravenous glucose tolerance to any extent unless very large doses (100 mg/kg) were used.
| SPECIES | ROUTE | LD 50 (mg/kg) |
| Mouse | Oral | 2457 |
| Intraperitoneal Intravenous | 1001 51 | |
| Rat | Oral Intraperitoneal Intravenous | 1321 759 49 |
Signs of Toxicity: CNS depression and acute pulmonary congestion. Concomitant therapy with either prednisone and anti-thymocyte globulin, hydrochlorothiazide and propranolol or digoxin and furosemide did not appreciably alter the LD50 for minoxidil.
Minoxidil was administered orally to rats and dogs at daily doses up to 100 and 10 mg/kg respectively for 3 days. In rats, a dose related slight increase in the number of mitoses in hepatocytes was seen. In Beagle dogs, epicardial and myocardial cellular infiltrations, hypertrophy and hyperplasia of the mesothelial cells, small focal hemorrhages and myocardial atrial lesions were observed at 1.0 and 10 mg/kg doses. These findings were more frequent and severe at the higher dose. In mongrel dogs, there were minimal to mild subepicardial hemorrhages present in the right atrium and/or right auricle which may represent the early stages of right atrial lesions as seen in the longer term studies.
Minoxidil was administered orally to monkeys at 20 mg/kg/day; to dogs at 0.5 and 1 mg/kg/day, and at 20 and 100 mg/kg/day; to minipigs at 20 mg/kg/day and to rats at 300 mg/kg/day. Grossly observed cardiac hypertrophy was reported in the monkey study (the 4-OH metabolite of minoxidil at the same dose showed no effect). In dogs, lesions of the right atrium and/or auricle were seen at all doses. Local myocardial cell atrophy and/or degeneration was reported at doses as low as 1 mg/kg/day. The 20 mg/kg dose produced degenerative right auricular heart lesions as did the 4-OH metabolite of minoxidil. The high dose resulted in the death of all dogs probably due to profound alteration in electrolyte balance. In the minipig study blood pressure was depressed, heart rate elevated and total body water and exchangeable sodium were increased. Cardiac hypertrophy was observed. In rats, repression of body weight gain, decreased food consumption reduced erythrocyte levels, increased liver and heart weights, indications of cardiac hypertrophy and electrolyte imbalance were observed.
Minoxidil was administered orally to rats at 10, 30, and 100 mg/kg/day, monkeys at 3.5, 7 and 14 mg/kg/day and dogs at 3, 10 and 30 mg/kg/day. In rats, repression in body weight gain occurred at 100 mg/kg/day and a dose related increase in liver, kidney, adrenal and heart weights were seen. One high dose female monkey with chronic glomerulonephritis died from cardiac failure and minoxidil probably contributed because of its salt and water retaining action. In the dog study, degenerative right auricular heart lesions were found at all dose levels. Evidence of chronic electrolyte disturbance were noted in dogs at the highest dose.
Minoxidil was administered orally to rats at 3, 10 and 30 mg/kg/day. Increased heart weights were observed at the highest dose. No carcinogenic potential was apparent.
No evidence of alteration in toxicity when minoxidil was given concomitantly with (a) hydrochlorothiazide and propranolol in rats and monkeys for up to 1 month, and (b) furosemide and digoxin in rats for 1 month. Hydrochlorothiazide partially reduced increases in heart weight and total body exchangeable sodium produced by minoxidil in a 1 month monkey study.
Oral doses of 0.5 mg/kg for several days up to 1 month or longer produced a grossly visible hemorrhagic lesion of the right atrium of the dog. Replacement of myocardial cells by proliferating fibroblasts and angioblasts; phagocytosis; and hemosiderin accumulation in macrophages was observed.
In dog, rat and minipig necrosis of the papillary muscles and, in some cases, subendocardial areas of the left ventricle were seen following a few days treatment. Beta-adrenergic receptor blockade reduced the incidence and severity.
were seen in the epicardium, endocardium and walls of small coronary arteries and arterioles after acute minoxidil treatment in dogs. Left atrial hemorrhagic lesions were seen in minipigs.
Longer term treatment in rats, dogs and monkeys showed cardiac hypertrophy and cardiac dilation (in rats). Hydrochlorothiazide partly reversed the increased heart weight in monkeys.
Male rats received minoxidil in oral doses of 3 or 10 mg/kg/day for 60 days prior to and during the 14 day breeding period. Female rats received the same dose for 14 days prior to and during breeding, and throughout gestation. A reduction in conception rate was observed. No increase in the incidence of fetal resorption in treated dams was seen. The average number of live pups per litter was significantly decreased in both treatment groups, but live pups from treated dams were significantly heavier than live pups from control dams. Minoxidil, when given orally to pregnant rats and rabbits on gestation days 6 through 15 and 18 respectively, at dose levels of 3 and 10 mg/kg/day showed no teratogenic effect. Increased fetal resorption occurred in rabbits. The same dose administered to rats from the 15th day of gestation until pups were weaned at 21 days showed no effect of treatment on various parameters related to gestation, parturition and lactation. When a minoxidil suspension was given subcutaneously to pregnant rats in doses of 0,1,11, and 120 mg/kg, no teratogenic changes were found in the fetuses from the rats dosed at 0,1 and 11 mg/kg of minoxidil. Increased fetal mortality, still birth, external malformations and skeletal anomalies and variations were observed at 120 mg/kg. This dose also caused decreased maternal weight gain and food consumption and thus the fetal effects noted could have resulted from maternal toxicity.
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