Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3862
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Loniten (Tablet)
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Patients over 12 years of age: The recommended initial dosage of LONITEN 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.<br/>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 to 1.0 mg/kg/day. The maximum recommended dosage is 50 mg daily .<br/>Dose frequency: The magnitude of within-day fluctuation of arterial pressure during therapy with LONITEN 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.<br/>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.<br/>Concomitant therapy: Diuretic and beta-blocker or other sympathetic nervous system suppressant.<br/>Diuretics: LONITEN 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 LONITEN: 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.<br/>Beta-blocker or other sympathetic nervous system suppressants: When therapy with LONITEN 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 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 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.
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LONITEN 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 Tablets for oral administration contain either 2.5 mg or 10 mg of minoxidil. Inactive ingredients: cellulose, corn starch, lactose, magnesium stearate, silicon dioxide.
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1. General Pharmacologic Properties: 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.<br/>2. Effects on Blood Pressure and Target Organs: 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 Tablets usually decreased the blood pressure and reversed encephalopathy and retinopathy.<br/>3. Absorption and Metabolism: Minoxidil is at least 90% absorbed from the GI tract in experimental animals and man. 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; 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.<br/>4. Cardiac Lesions in Animals: 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.
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LONITEN Tablets are contraindicated in pheochromocytoma, because it may stimulate secretion of catecholamines from the tumor through its antihypertensive action. LONITEN is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
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LONITEN Tablets are available as follows: 2.5 mg (white, round, scored, imprinted U/121 and 2��) Bottles of 100 NDC 0009-0121-01 10 mg (white, round, scored, imprinted LONITEN 10) Bottles of 100 NDC 0009-0137-01 Store at controlled room temperature 20��to 25��C (68��to 77��F) [see USP].
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WARNINGS: LONITEN 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 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 Cardiac Lesions in Animals). LONITEN 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 should be hospitalized when LONITEN is first administered so that they can be monitored to avoid too rapid, or large orthostatic, decreases in blood pressure.
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1. General Precautions:<br/>2. Information for Patient: The patient should be fully aware of the importance of continuing all of his antihypertensive medications and of the nature of symptoms that would suggest fluid overload. A patient brochure has been prepared and is included with each LONITEN package. The text of this brochure is reprinted at the end of the insert.<br/>3. Laboratory Tests: Those laboratory tests which are abnormal at the time of initiation of minoxidil therapy, such as urinalysis, renal function tests, EKG, chest x-ray, echocardiogram, etc., should be repeated at intervals to ascertain whether improvement or deterioration is occurring under minoxidil therapy. Initially such tests should be performed frequently, eg, 1���3 month intervals; later as stabilization occurs, at intervals of 6���12 months.<br/>4. Drug interactions: See "Interaction with Guanethidine" under WARNINGS.<br/>5. Carcinogenesis, Mutagenesis and Impairment of Fertility: 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<0.05) reduce the latency period of UV light-initiated skin tumors in hairless mice, as compared to controls, in a 12-month photocarcinogenicity study. Minoxidil was not mutagenic in the Salmonella (Ames) test, the DNA damage alkaline elution assay, the in vitro 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 in vitro 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.<br/>6. Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. Oral administration of minoxidil has been associated with evidence of increased fetal resorption in rabbits, but not rats, when administered at five times the maximum recommended oral antihypertensive human dose. There was no evidence of teratogenic effects in rats and rabbits. Subcutaneous administration of minoxidil to pregnant rats at 80 mg/kg/day was maternally toxic but not teratogenic. Higher subcutaneous doses produced evidence of developmental toxicity. There are no adequate and well controlled studies in pregnant women. LONITEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>7. Labor and Delivery: The effects on labor and delivery are unknown.<br/>8. Nursing Mothers: There has been one report of minoxidil excretion in the breast milk of a woman treated with 5 mg oral minoxidil twice daily for hypertension. Because of the potential for adverse effects in nursing infants from minoxidil absorption, LONITEN should not be administered to a nursing woman.<br/>9. Pediatric Use: Use in pediatric patients has been limited to date, particularly in infants. The recommendations under DOSAGE AND ADMINISTRATION can be considered only a rough guide at present and a careful titration is essential.<br/>10. Geriatric Use: Clinical studies of LONITEN Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.<br/>11. Unapproved Use: Use of LONITEN Tablets, in any formulation, to promote hair growth is not an approved indication. While clinical trials with ROGAINE Topical Solution 2% demonstrated that formulation and dosage were safe and effective, the effects of extemporaneous formulations and dosages have not been shown to be safe or effective. Because systemic absorption of topically applied drug may occur and is dependent on vehicle and/or method of use, extemporaneous topical formulations made from LONITEN should be considered to share in the full range of CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS listed in this insert. In addition, skin intolerance to drug and/or vehicle may occur.
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There have been only a few instances of deliberate or accidental overdosage with LONITEN 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, 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 LDin rats has ranged from 1321���3492 mg/kg; in mice, 2456���2648 mg/kg.
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minoxidil
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Loniten (Tablet)
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1. Salt and Water Retention: ���Temporary edema developed in 7% of patients who were not edematous at the start of therapy.<br/>2. Pericarditis, Pericardial Effusion, and Tamponade: .<br/>3. Dermatologic: Hypertrichosis���Elongation, thickening, and enhanced pigmentation of fine body hair are seen in about 80% of patients taking LONITEN 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, 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 is begun. Allergic���Rashes have been reported, including rare reports of bullous eruptions, and Stevens-Johnson Syndrome.<br/>4. Hematologic: Thrombocytopenia and leukopenia (WBC<3000/mm) have rarely been reported.<br/>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.<br/>6. Miscellaneous: Breast tenderness���This developed in less than 1% of patients.<br/>7. Altered Laboratory Findings:
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LONITEN 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 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 Cardiac Lesions in Animals). LONITEN 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 should be hospitalized when LONITEN is first administered so that they can be monitored to avoid too rapid, or large orthostatic, decreases in blood pressure.
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Because of the potential for serious adverse effects, LONITEN 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 milderdegrees of hypertension is not recommended because the benefit-risk relationship in such patients has not been defined. LONITEN 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.
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Loniten
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