SPL UNCLASSIFIED

Rx only

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.

OVERDOSAGE

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.

DOSAGE & 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.

HOW SUPPLIED

Minoxidil tablets are available as follows:

Minoxidil tablets 2.5 mg are round, scored, white and debossed on the reverse side.

Minoxidil tablets 10 mg are round, scored, white and debossed

Store at 20° to 25°C (68° to 77° F). [See USP Controlled Room Temperature]

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

SPL PATIENT PACKAGE INSERT

Minoxidil tablets contain minoxidil, a medicine for the treatment of high blood pressure in the patient who has not been controlled or is experiencing unacceptable side effects with other medications. It must usually be taken with other medicines.

Be absolutely sure to take all of your medicines for high blood pressure according to your doctor's instructions. Do not stop taking minoxidil unless your doctor tells you to. Do not give any of your medicine to other people.

It is important that you look for the warning signals of certain undesired effects of minoxidil. Call your doctor if they occur. Your doctor will need to see you regularly while you are taking minoxidil. Be sure to keep all your appointments or to arrange for new ones if you must miss one.

Do not hesitate to call your doctor if any discomforts or problems occur.

The information here is intended to help you take minoxidil properly. It does not tell you all there is to know about minoxidil. There is a more technical leaflet that you may request from the pharmacist; you may need your doctor's help in understanding parts of that leaflet.

What is Minoxidil?

Minoxidil tablets contain minoxidil which is a drug for lowering the blood pressure. It works by relaxing and enlarging certain small blood vessels so that blood flows through them more easily.

Why lower blood pressure?

Your doctor has prescribed minoxidil to lower your blood pressure and protect vital parts of your body. Uncontrolled blood pressure can cause stroke, heart failure, blindness, kidney failure and heart attacks.

Most people with high blood pressure need to take medicines to treat it for their whole lives.

Who should take minoxidil tablets?

There are many people with high blood pressure, but most of them do not need minoxidil. Minoxidil is used ONLY when your doctor decides that:

1. your high blood pressure is severe;
2. your high blood pressure is causing symptoms or damage to vital organs; and
3. other medicines did not work well enough or had very disturbing side effects.

Minoxidil should be taken only when a doctor prescribes it. Never give any of your minoxidil tablets, or any other high blood pressure medicine, to a friend or relative.

Pregnancy: In some cases doctors may prescribe minoxidil for women who are pregnant or who are planning to have children. However, its safe use in pregnancy has not been established. Laboratory animals had a reduced ability to become pregnant and a reduced survival of offspring while taking minoxidil. If you are pregnant or are planning to become pregnant, be sure to tell your doctor.

How to take minoxidil tablets.

Usually, your doctor will prescribe two other medicines along with minoxidil. These will help lower blood pressure and will help prevent undesired effects of minoxidil.

Often, when a medicine like minoxidil 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 (a diuretic: dye-u-RET-tic) 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 help keep your blood pressure down. The water tablet and heart beat medicine will help prevent the undesired effects of minoxidil.

Minoxidil tablets come in two strengths (2.5 milligrams and 10 milligrams) 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 minoxidil, 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 minoxidil, wait until it is time for your next dose, then continue with your regular schedule. Remember: do not stop taking minoxidil, 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 minoxidil.

WARNING SIGNALS

Even if you take all your medicines correctly, minoxidil tablets may cause undesired effects. Some of these are serious and you should be on the lookout for them. If any of the following warning signals occur, you must call your doctor immediately:

1. 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 a minute over your normal pulse, contact your doctor immediately. If you do not know how to take your pulse rate, ask your doctor. Also ask your doctor how often to check your pulse.

Rapid weight gain of more than 5 pounds — You should weigh yourself daily. If you quickly gain five or more pounds, 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. Your doctor may have to change your drugs or change the dose of your drugs. You may also need to reduce the amount of salt you eat. A smaller weight gain (2 to 3 pounds) often occurs when treatment is started. You may lose this extra weight with continued treatment.

Increased difficulty in breathing, especially when lying down. This too may be due to an increase of body fluids. It can also happen because your high blood pressure is getting worse. In either case, you might require treatment with other medicines.

4. New or worsening of pain in the chest, arm, or shoulder or signs of severe indigestion — These could be signs of serious heart problems.

5. Dizziness, lightheadedness or fainting — These can be signs of high blood pressure or they may be side effects from one of the medicines. Your doctor may need to change or adjust the dosage of the medicines you are taking.

OTHER UNDESIRED EFFECTS

Minoxidil tablets can cause other undesired effects such as nausea and/or vomiting that are annoying but not dangerous. Do not stop taking the drug because of these other undesired effects without talking to your doctor.

Hair growth: About 8 out of every 10 patients who have taken minoxidil noticed that fine body hair grew darker or longer on certain parts of the body. This happened about 3 to 6 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 minoxidil. Nevertheless, you should not stop taking minoxidil without first talking to your doctor.

A few patients have developed a rash or breast tenderness while taking minoxidil tablets, but this is unusual.

SPL UNCLASSIFIED

Manufactured by:
MUTUAL PHARMACEUTICAL CO., INC.
Philadelphia, PA 19124 USA

Rev 01, June 2009

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

DRUG: MINOXIDIL

GENERIC: minoxidil

DOSAGE: TABLET

ADMINSTRATION: ORAL

NDC: 52125-170-02

STRENGTH:10 mg

COLOR: white

SHAPE: ROUND

SCORE: Two even pieces

SIZE: 7 mm

IMPRINT: 30

QTY: 30