Loniten Tablets 2.5 mg, 5 mg and 10mg

Each Loniten Tablet contains 2.5 mg, 5 mg or 10 mg minoxidil USP.

Tablet

Minoxidil is indicated for the treatment of severe hypertension.

It should not be used as the sole agent to initiate therapy. It is a peripheral vasodilator and should be given in conjunction with a diuretic, to control salt and water retention, and a beta-adrenergic blocking agent, or appropriate substitute, to control reflex tachycardia.

Oral Administration

Adults and Patients over 12 years of age: An initial daily dose of 5 mg, which may be given as a single or divided dosage, is recommended. This dose may first be increased to 10 mg daily and subsequent increases should be by increments of 10 mg in the daily dose. Dosage adjustments should be made at intervals of not less than three days, until optimum control of blood pressure is achieved. It is seldom necessary to exceed 50 mg per day although, in exceptional circumstances, doses up to 100 mg per day have been used. Twice-daily dosage is satisfactory. Where diastolic pressure reduction of less than 30 mm Hg is required, once daily dosing has been reported as effective.

Dosage requirements may be lower in dialysis patients. Minoxidil is removed from the blood by dialysis, but its pharmacological action, once established is not reversed. Therefore haemodialysis patients should take minoxidil either after or at least two hours before dialysis.

Children: For patients of 12 years of age or under, the initial dose should be 200 micrograms per kilogram (0.2 mg/kg) given as a single or divided daily dosage. Incremental increases of 100 - 200 micrograms per kilogram (0.1-0.2 mg/kg) in the daily dose are recommended at intervals of not less than three days until optimum blood pressure control has been achieved, or the maximum daily dose of 1.0 mg/kg has been reached.

Rapid reduction of blood pressure: Under hospital monitoring conditions, rapid reduction of blood pressure can be achieved using continuous blood pressure monitoring and incremental doses of 5 mg every six hours.

Concomitant antihypertensive therapy: It is recommended that, where possible, antihypertensive therapy, other than a beta-adrenergic blocking agent and a diuretic be discontinued before minoxidil treatment is started. It is recognised that some antihypertensive agents should not be abruptly discontinued. These drugs should be gradually discontinued during the first week of minoxidil treatment.

Minoxidil causes sodium retention and if used alone can result in several hundred milli-equivalents of salt being retained together with a corresponding volume of water.

Therefore, in all patients who are not on dialysis, minoxidil must be given in conjunction with a diuretic in sufficient dosage to maintain salt and water balance. Examples of the daily dosages of diuretics commonly used when starting therapy with minoxidil include:

1. Hydrochlorothiazide (100 mg) - or other thiazides at equi-effective dosage.

2. Chlortalidone (100 mg).

3. Furosemide (80 mg).

If excessive water retention results in a weight gain of more than 3 pounds when a thiazide or chlortalidone is being used, diuretic therapy should be changed to furosemide, the dose of which may be increased in accordance with the patient's requirements. Diuretic dosage in children should be proportionally less in relation to weight.

Patients will require a sympathetic nervous system suppressant to limit a minoxidil-induced rise in heart rate. The preferred agent is a beta-blocker equivalent to an adult propranolol dosage of 80 - 160 mg/day. Higher doses may be required when pre-treated patients have an increase in heart rate exceeding 20 beats per minute or when simultaneous introduction causes an increase exceeding 10 beats per minute. When beta-blockers are contra-indicated, alternatives such as methyldopa may be used instead and should be started 24 hours prior to minoxidil.

Elderly patients: At present there are no extensive clinical studies with minoxidil in patients over age 65. There is data indicating that elevated systolic and diastolic pressures are important risk factors for cardiovascular disease in individuals over age 65. However, elderly patients may be sensitive to the blood pressure lowering effect of minoxidil and thus caution is urged in initiating therapy as orthostatic hypotension may occur. It is suggested that 2.5 mg per day be used as the initial starting dose in patients over 65 years of age.

Minoxidil is contra-indicated in patients with a phaeochromocytoma because it may stimulate secretion of catecholamines from the tumor through its antihypertensive action.

Minoxidil is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.

If used alone, minoxidil can cause a significant retention of salt and water leading to physical signs such as oedema, and to clinical deterioration of some patients with heart failure. Diuretic treatment alone, or in combination with restricted salt intake is, therefore, necessary for all patients taking minoxidil. The patient's bodyweight, fluid and electrolyte balance should be monitored for evidence of fluid retention.

Salt and water retention in excess of 1 to 1.5 kg may diminish the effectiveness of minoxidil. Patients should, therefore, be carefully instructed about compliance with diuretic therapy and a detailed record of body weight should be maintained.

The product should be used with particular attention to maintenance of salt and water balance in patients with renal impairment, but who are not on dialysis.

Renal failure or dialysis patients – Those patients with renal failure or on haemodialysis may require smaller doses of minoxidil.

Patients who have had myocardial infarction should only be treated with minoxidil after a stable post-infarction state has been established.

Because minoxidil is a vasodilator, reflex tachycardia may occur and possibly angina pectoris may occur in patients at risk; it is recommended that minoxidil be used in combination with beta-adrenergic blocking agent or other sympathetic nervous system suppressants to blunt or prevent such a response.

Hypertrichosis occurs in most patients treated with minoxidil and all patients should be warned of this possibility before starting therapy. Most patients will experience an elongation, thickening and enhanced pigmentation of fine body hair. Usually these signs will emerge 3 to 6 weeks after starting treatment. They initially emerge in the face, and they may slightly subside with continued treatment. However, hypertrichosis was hardly or not at all tolerable in less than 10% of patients. Spontaneous reversal to the pre-treatment state can be expected one to six months after cessation of therapy.

Soon after starting minoxidil therapy approximately 60% of patients exhibit ECG alterations in the direction and magnitude of their T waves. Large changes may encroach on the ST segment, unaccompanied by evidence of ischaemia. These asymptomatic changes usually disappear with continuing minoxidil treatment. The ECG reverts to the pre-treatment state when minoxidil is discontinued.

Thrombocytopenia and leukopenia have been rarely reported.

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 and occasionally tamponade, has been observed in about 3% - 5% of treated patients not on dialysis. While in many cases, the pericardial effusion is associated with other potential etiologies, there have been cases in which these potential causes of effusion were not present. Patients should be observed closely for any suggestion of a pericardial effusion and 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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

The effect of minoxidil may be additive to concurrent antihypertensive agents and other agents with blood pressure lowering effects. The interaction of minoxidil with sympathetic-blocking agents such as guanethidine or betanidine may produce excessive blood pressure reduction and/or orthostatic hypotension.

If possible guanethidine should be discontinued well before minoxidil is begun. If this is not feasible, minoxidil therapy should be instituted in the hospital and the patient monitored carefully for orthostatic events.

Pregnancy

There is limited data from the use of minoxidil in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3 Pre-clinical safety data).

Minoxidil is not recommended during pregnancy and in women of childbearing potential not using contraception. Neonatal hirsutism has been reported following exposure of minoxidil during pregnancy.

Lactation

Minoxidil has been reported to be excreted in human milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from minoxidil therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no fertility data from the use of minoxidil in humans. In a fertility study with male and female rats, a dose-dependent reduction of the conception rate was found. The dose corresponded to one to five times the maximum dose used in humans to treat hypertension.

No studies on the effect of minoxidil on the ability to drive or use machines have been performed.

The ability to drive or operate machinery may be influenced by the individual response to treatment, particularly at the start of therapy.

Most patients receiving Loniten experience a diminution of pre-existing side-effects attributable to their disease or previous therapy. New events or side-effects likely to increase are included in the following table:

Frequencies are defined as:

Salt and Water Retention – See section 4.4 Special warnings and precautions for use.

Tachycardia – See section 4.4 Special warnings and precautions for use.

Pericarditis, Pericardial Effusion and Tamponade – See section 4.4 Special warnings and precautions for use.

If exaggerated hypotension is encountered, it is most likely to occur in association with residual sympathetic nervous system blockade (guanethidine-like effects or alpha-adrenergic blockade). Recommended treatment is intravenous administration of normal saline. Sympathomimetic drugs, such as noradrenaline (norepinephrine) or adrenaline (epinephrine), should be avoided because of their excessive cardiac-stimulating action. Phenylephrine, angiotensin II and vasopressin, which reverse the effect of minoxidil, should be used only if inadequate perfusion of a vital organ is evident.

ATC Code: C02 DC01

Minoxidil is an antihypertensive agent which acts predominantly by causing direct peripheral vasodilation of the arterioles.

About 90% of an oral dose of minoxidil has been reported to associated from the GI tract.

Following oral administration the maximum hypotensive effect usually occurs after 2-3 hours. The action may persist for up to 75 hours. The plasma half life is about 4.2 hours.

Minoxidil is not bound to plasma proteins. It is extensively metabolised in the liver primarily by conjugation with glucuronic acid and is excreted in the urine mainly in the form of metabolites.

Cardiac Lesions in Animals

In non-clinical studies in a variety of species, minoxidil induces several types of cardiac lesions including necrotic and hemorrhagic lesions of the myocardium and papillary muscles, and cardiac hypertrophy and dilation. These changes occur only in the context of profound hypotension and tachycardia and reflect haemodynamic and/or hypoxic stress rather than direct cytotoxicity. As greater experience with the drug has accumulated, it has become apparent that these cardiac lesions do not occur in humans treated with minoxidil.

Reproduction toxicity

In a fertility study with male and female rats, a dose-dependent reduction of the conception rate was found. The no observed adverse effect level (NOAEL) for this finding was 1mg/kg per day in treated rats.

Teratogenicity has been demonstrated in the rat at doses above 80mg/kg/day. Oral administration of minoxidil has been associated with evidence of increased fetal resorption in rabbits at doses associated with maternal toxicity. Teratogenicity was not demonstrated in the rabbit.

Lactose hydrous, microcrystalline cellulose, starch, colloidal silicon dioxide and magnesium stearate.

None

Shelf-life of the medicinal product as packaged for sale: 36 months.

Store below 25°C.

High density polyethylene (HDPE) bottles with LDPE caps. Each bottle contains 100 tablets.

20-25 micron aluminium foil/250 micron opaque pvc blister. Pack contains 60 tablets.

No special requirements.

Pharmacia Limited, Ramsgate Road, Sandwich, CT13 9NJ, UK

PL 0032/0064 2.5mg

PL 0032/0065 5 mg

PL 0032/0066 10 mg

24 May 1995.

February 2012

POM

Company Ref: LN 6_0