Loniten Information
Loniten (Minoxidil) Warnings
Loniten (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. Loniten (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 ).
Loniten (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 ) should be hospitalized when Loniten (Minoxidil) is first administered so that they can be monitored to avoid too rapid, or large orthostatic, decreases in blood pressure.
Loniten (Minoxidil) Description
Loniten (Minoxidil) Tablets contain minoxidil, an antihypertensive peripheral vasodilator. Minoxidil occurs as 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. The chemical name for minoxidil is 2,4-pyrimidinediamine,6-(1-piperidinyl)-,3-oxide (mw=209.25). The structural formula is represented at right:
Loniten (Minoxidil) Tablets for oral administration contain either 2.5 mg or 10 mg of minoxidil. Inactive ingredients: cellulose, corn starch, lactose, magnesium stearate, silicon dioxide.
Loniten (Minoxidil) Clinical Pharmacology
Minoxidil is an orally effective direct acting peripheral vasodilator that reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. Microcirculatory blood flow in animals is enhanced or maintained in all systemic vascular beds. In man, forearm and renal vascular resistance decline; forearm blood flow increases while renal blood flow and glomerular filtration rate are preserved.
Because it causes peripheral vasodilation, minoxidil elicits a number of predictable reactions. Reduction of peripheral arteriolar resistance and the associated fall in blood pressure trigger sympathetic, vagal inhibitory, and renal homeostatic mechanisms, including an increase in renin secretion, that lead to increased cardiac rate and output and salt and water retention. These adverse effects can usually be minimized by concomitant administration of a diuretic and a beta-adrenergic blocking agent or other sympathetic nervous system suppressant.
Minoxidil does not interfere with vasomotor reflexes and therefore does not produce orthostatic hypotension. The drug does not enter the central nervous system in experimental animals in significant amounts, and it does not affect CNS function in man.
The extent and time-course of blood pressure reduction by minoxidil do not correspond closely to its concentration in plasma. After an effective 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 75 hours. When minoxidil is administered chronically, once or twice a day, the time required to achieve maximum effect on blood pressure with a given daily dose is inversely related to the size of the dose. Thus, maximum effect is achieved on 10 mg/day within 7 days, on 20 mg/day within 5 days, and on 40 mg/day within 3 days.
The blood pressure response to minoxidil is linearly related to the logarithm of the dose administered. The slope of this log-linear doseresponse relationship is proportional to the extent of hypertension and approaches zero at a supine diastolic blood pressure of approximately 85 mm Hg.
When used in severely hypertensive patients resistant to other therapy, frequently with an accompanying diuretic and beta-blocker, Loniten (Minoxidil) Tablets usually decreased the blood pressure and reversed encephalopathy and retinopathy.
Minoxidil produces several cardiac lesions in animals. Some are characteristic of agents that cause tachycardia and diastolic hypotension (betaagonists like isoproterenol, arterial dilators like hydralazine) while others are produced by a narrower range of agents with arterial dilating properties. The significance of these lesions for humans is not clear, as they have not been recognized in patients treated with oral minoxidil at systemically active doses, despite formal review of over 150 autopsies of treated patients.
Autopsies of over 150 patients who died of various causes after receiving minoxidil for hypertension have not revealed the characteristic hemorrhagic (especially atrial) lesions seen in dogs and minipigs. While areas of papillary muscle and subendocardial necrosis were occasionally seen, they occurred in the presence of known pre-existing coronary artery disease and were also seen in patients never exposed to minoxidil in another series using similar, but not identical, autopsy methods.
Loniten (Minoxidil) Indications And Usage
Because of the potential for serious adverse effects, Loniten (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.
Loniten (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.
Loniten (Minoxidil) Contraindications
Loniten (Minoxidil) Tablets are contraindicated in pheochromocytoma, because it may stimulate secretion of catecholamines from the tumor through its antihypertensive action. Loniten (Minoxidil) is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
Loniten (Minoxidil) Warnings
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.
Loniten (Minoxidil) Precautions
Two-year carcinogenicity studies of minoxidil have been conducted by the dermal and oral (dietary) routes of administration in mice and rats. There were no positive findings with the oral (dietary) route of administration in rats.
In the two-year dermal study in mice, an increased incidence of mammary adenomas and adenocarcinomas in the females at all dose levels (8, 25 and 80 mg/kg/day) was attributed to increased prolactin activity. Hyperprolactinemia is a well-known mechanism in the enhancement of mouse mammary tumors, but has not been associated with mammary tumorigenesis in women. Additionally, topical minoxidil has not been shown to cause hyperprolactinemia in women on clinical trials. Absorption of minoxidil through rodent skin is greater than would be experienced by patients treated topically with minoxidil for hair loss. Dietary administration of minoxidil to mice for up to 2 years was associated with an increased incidence of malignant lymphomas in females at all dose levels (10, 25 and 63 mg/kg/day) and an increased incidence of hepatic nodules in males (63 mg/kg/day). There was no effect of dietary minoxidil on the incidence of malignant liver tumors.
In the two-year dermal study in rats there were significant increases in incidence of pheochromocytomas in males and females and preputial gland adenomas in males. Changes in incidence of neoplasms found to be increased in the dermal or oral carcinogenicity studies were typical of those expected in rodents treated with other hypotensive agents (adrenal pheochromocytomas in rats), treatment-related hormonal alterations (mammary carcinomas in female mice; preputial gland adenomas in male rats) or representative of normal variations within the range of historical incidence for rodent neoplasms (malignant lymphomas, liver nodules/adenomas in mice). Based on differences in absorption of minoxidil and mechanisms of tumorigenesis in these rodent species, none of these changes were considered to be relevant to the safety of patients treated topically with minoxidil for hair loss.
There was no evidence of epithelial hyperplasia or tumorigenesis at the sites of topical application of minoxidil in either species in the 2-year dermal carcinogenesis studies. No evidence of carcinogenicity was detected in rats or rabbits treated topically with minoxidil for one year. Topical minoxidil (2% and 5%) did not significantly (p
Minoxidil was not mutagenic in the (Ames) test, the DNA damage alkaline elution assay, the rat hepatocyte unscheduled DNA synthesis (UDS) assay, the rat bone marrow micronucleus assay, or the mouse bone marrow micronucleus assay. An equivocal result was recorded in an cytogenetic assay using Chinese hamster cells at long exposure times, but a similar assay using human lymphocytes was negative.
In a study in which male and female rats received one or five times the maximum recommended human oral antihypertensive dose of minoxidil (multiples based on a 50 kg patient) there was a dose-dependent reduction in conception rate.
Loniten (Minoxidil) Adverse Reactions
Hypertrichosis—Elongation, thickening, and enhanced pigmentation of fine body hair are seen in about 80% of patients taking Loniten (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 Loniten (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 Loniten (Minoxidil) is begun.
Allergic—Rashes have been reported, including rare reports of bullous eruptions, and Stevens-Johnson Syndrome.
Loniten (Minoxidil) Overdosage
There have been only a few instances of deliberate or accidental overdosage with Loniten (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 Loniten (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 in rats has ranged from 1321 – 3492 mg/kg; in mice, 2456 – 2648 mg/kg.
Loniten (Minoxidil) Dosage And Administration
When therapy with Loniten (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 Loniten (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 Loniten (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 Loniten (Minoxidil) but usually do prevent tachycardia. Typically, patients receiving a beta-blocker prior to initiation of therapy with Loniten (Minoxidil) have a bradycardia and can be expected to have an increase in heart rate toward normal when Loniten (Minoxidil) is added. When treatment with Loniten (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.
Loniten (Minoxidil) How Supplied
Loniten (Minoxidil) Tablets are available as follows:
Bottles of 100 NDC 0009-0121-01
Bottles of 100 NDC 0009-0137-01
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
Loniten (Minoxidil)
Loniten (Minoxidil)
