Alostil 2%

Because of the potential for serious adverse effects, Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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. Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) reduced supine diastolic blood pressure by 20 mm Hg or to 90 mm Hg or less in approximately 75% of patients, most of whom had hypertension that could not be controlled by other drugs.

Patients over 12 years of age

The recommended initial dosage of Alostil 2% tablets is 5 mg of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 mg/kg/day. The maximum recommended dosage is 50 mg daily (see Pediatric Use under PRECAUTIONS). Dose frequency: The magnitude of within-day fluctuation of arterial pressure during therapy with Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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:Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) : 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) ; 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) but usually do prevent tachycardia. Typically, patients receiving a beta-blocker prior to initiation of therapy with Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) have a bradycardia and can be expected to have an increase in heart rate toward normal when Alostil 2% is added. When treatment with Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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.

Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) tablets are contraindicated in pheochromocytoma, because it may stimulate secretion of catecholamines from the tumor through its antihypertensive action. Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.

WARNINGS

Salt and Water Retention

Congestive Heart Failure-concomitant use of an adequate diuretic is required-Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets). Provided that the patient is under close medical supervision, it may be possible to resolve refractory salt retention by discontinuing Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) for 1 or 2 days and then resuming treatment in conjunction with vigorous diuretic therapy.

Concomitant Treatment to Prevent Tachycardia is Usually Required

Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) increases the heart rate. Angina may worsen or appear for the first time during Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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.

Pericarditis, Pericardial Effusion, and Tamponade

There have been reports of pericarditis occurring in association with the use of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets). 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) should be considered in light of other means of controlling the hypertension and the patient's clinical status.

Interaction with Guanethidine

Although Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% is begun. Where this is not possible, Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) use, total experience is limited at present.

Any patient with malignant hypertension should have initial treatment with Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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

General Precautions

1. Monitor fluid and electrolyte balance and body weight (see WARNINGS: Salt and Water Retention).
2. Observe patients for signs and symptoms of pericardial effusion (see WARNINGS: Pericarditis, Pericardial Effusion, and Tamponade).
3. Use after myocardial infarction-Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) tablets have 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) might further limit blood flow to the myocardium, although this might be compensated by decreased oxygen demand because of lower blood pressure.
4. Hypersensitivity-Possible hypersensitivity to Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) , manifested as a skin rash, has been seen in less than 1% of patients; whether the drug should be discontinued when this occurs depends on treatment alternatives.
5. Renal failure or dialysis patients may require smaller doses of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) and should have close medical supervision to prevent exacerbation of renal failure or precipitation of cardiac failure.

Information for Patients

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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) package. The text of this brochure is reprinted at the end of the insert.

Laboratory Tests

Those laboratory tests which are abnormal at the time of initiation of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) therapy. Initially such tests should be performed frequently, e.g., 1-3 month intervals; later as stabilization occurs, at intervals of 6-12 months.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Two-year carcinogenicity studies of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) has not been shown to cause hyperprolactinemia in women on clinical trials. Absorption of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) through rodent skin is greater than would be experienced by patients treated topically with Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) for hair loss. Dietary administration of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) to mice for up to 2 years was associated with an increased incidence of malignant Iymphomas 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Iymphomas, liver nodules/adenomas in mice). Based on differences in absorption of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) for hair loss.

There was no evidence of epithelial hyperplasia or tumorigenesis at the sites of topical application of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) in either species in the two-year dermal carcinogenesis studies. No evidence of carcinogenicity was detected in rats or rabbits treated topically with Alostil 2% for one year. Topical Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) (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.

Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) (multiples based on a 50 kg patient) there was a dose-dependent reduction in conception rate.

Pregnancy

Teratogenic Effects

Pregnancy Category C. Oral administration of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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. Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and delivery

The effects on labor and delivery are unknown.

Nursing Mothers

There has been one report of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) excretion in the breast milk of a woman treated with 5 mg oral Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) twice daily for hypertension. Because of the potential for adverse effects in nursing infants from Alostil 2% absorption, Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) should not be administered to a nursing woman.

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.

Geriatric Use

Clinical studies of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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.

Unapproved Use

Use of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) tablets, in any formulation, to promote hair growth is not an approved indication. While clinical trials with Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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.

. This product may cause dizziness or hypotension. If affected, patients should not drive or operate machinery.

1. Salt and Water Retention (see WARNINGS: Concomitant Use of an 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) , 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) is begun. Allergic-Rashes have been reported, including rare reports of bullous eruptions, and Stevens-Johnson Syndrome.
4. Hematologic-Thrombocytopenia and leukopenia (WBC < 3000/mm³) 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets). 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 Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) is discontinued. No symptoms have been associated with these changes, nor have there been alterations in blood cell counts or in plasma enzymeconcentrations 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.

There have been only a few instances of deliberate or accidental overdosage with Alostil 2% tablets. One patient recovered after taking 50 mg of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 ll, vasopressin, and dopamine all reverse hypotension due to Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) , but should only be used if underperfusion of a vital organ is evident.

Radioimmunoassay can be performed to determine the concentration of Alostil 2% (Alostil 2% (Alostil 2% (Alostil 2% tablets) tablets) tablets) 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 LD₅₀ in rats has ranged from 1321-3492 mg/kg; in mice, 2456-2648 mg/kg.

Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AX.

Minoxidil stimulates hair growth in persons with early and moderate stages of hereditary hair loss (alopecia androgenetica). This hair loss appears in men as a receding hairline and balding in the vertex area. The exact mechanism of action of minoxidil for topical treatment of alopecia is not fully understood, but minoxidil can reverse the hair loss process of androgenetic alopecia by the following means:

- increasing the diameter of the hair shaft

- stimulating anagen growth

- prolonging the anagen phase

- stimulating anagen recovery from the telegen phase

As a peripheral vasodilator minoxidil enhances microcirculation to hair follicles. The Vascular Endothelial Growth Factor (VEGF) is stimulated by minoxidil and VEGF is presumably responsible for the increased capillary fenestration, indicative of a high metabolic activity, observed during the anagen phase.

The efficacy of 5% minoxidil foam has been assessed in a Phase 3 clinical trial conducted over a 16-week treatment period. In this study 5% minoxidil foam was compared to the product vehicle without the minoxidil active ingredient.

The primary efficacy endpoints were a) mean change in non-vellus hair count within the target region between Baseline and Week 16, as determined by validated computer-assisted dot-mapping technique; and b) subject rating of treatment benefit via use of global photographs of the vertex region, assessed as an overall improvement from baseline, collected on a subject questionnaire.

The active treatment showed a statistically significant greater increase in hair count than the vehicle foam group (21.0 versus 4.3 hairs cm²) at week 16. A clear difference between treatment groups was already evident at week 8, increasing at week 12 and again at week 16. The subject`s rating of treatment benefit was statistically significantly better for the 5% minoxidil foam treatment group than placebo (1.4 vs 0.5) at week 16.

The secondary efficacy endpoints were a) expert panel review (EPR) of hair regrowth when comparing global photographs obtained at baseline with photographs obtained at Week 16 and b) percent change from baseline in non-vellus hair counts within a pre-specified area of clipped hair.

The 5% minoxidil foam group showed a better score in the expert panel review (EPR) than the placebo foam group (adjusted mean 0.5 vs 0.1, p<0.0001).

At weeks 8, 12 and 16, the difference in adjusted means for percent change in non-vellus hair counts between vehicle foam and minoxidil foam were statistically significant (p<0.0001 at all 3 visits).

Alostil 2% Foam Data: Mean change in non-vellus hair count in reference 1cm² area of scalp compared with baseline

The failure to detect evidence of systemic effects during treatment with Alostil 2% Foam reflects the poor absorption of topically applied minoxidil from normal intact skin. Systemic absorption of minoxidil from topically applied solution ranges between 1% and 2% of the total applied dose.

The systemic absorption of minoxidil from a 5% foam formulation has been estimated in a pharmacokinetic study in subjects with androgenetic alopecia, which included 5% topical solution as a comparator. This demonstrated that in men, the systemic absorption of minoxidil from twice daily application of 5% minoxidil foam was about half of that observed with 5% minoxidil solution. The mean steady state AUC (0-12 hr) and Cmax for 5% minoxidil foam, 8.81 ng·hr/mL and 1.11 ng/mL, respectively, were both approximately 50 % of AUC (0-12 hr) and Cmax of the 5% solution, 18.71 ng·hr/mL and 2.13 ng/mL, respectively. The time to maximum minoxidil concentration (Tmax) for the 5% foam, 5.42 hr, was similar to Tmax for the 5% solution, 5.79 hr.

There is some evidence from in vitro studies that minoxidil reversibly binds to human plasma proteins. However, since only 1 - 2% of topically applied minoxidil is absorbed, the extent of plasma protein binding occurring in vivo after topical application would be clinically insignificant. The volume of distribution of minoxidil after intravenous administration has been estimated at 70 litres.

Approximately 60% minoxidil absorbed after topical application is metabolised to minoxidil glucuronide, primarily in the liver. Minoxidil and its metabolites are excreted almost entirely in the urine, with a very minor degree of elimination via the faeces. Following cessation of dosing, approximately 95% of topically applied minoxidil will be eliminated within four days.

Mutagenicity

Minoxidil showed no evidence of mutagenic/genotoxic potential in a number of in vitro and in vivo assays.

Carcinogenicity

A high incidence of hormone-mediated tumours was observed in mice and rats. These tumours are due to the secondary hormonal (hyperprolactinemia) effects observed only in the rodents at extremely high doses by a mechanism similar to that seem with reserpine. Application of topical minoxidil has not demonstrated any effect on hormonal status in women. Therefore, hormonally mediated tumour promotion by minoxidil does not represent a carcinogenic risk to humans.

Teratogenicity

Animal reproduction toxicity studies in rats and rabbits have shown signs of maternal toxicity and a risk to the foetus at exposure levels that are very high compared to those, intended for human exposure. A low, albeit remote, risk of foetal harm is possible in humans.

Fertility

Minoxidil doses greater than 9 mg/kg (at least 25-fold human exposure) administered subcutaneously in rats were associated with reduced conception and implantation rates as well as reduction in the number of live pups.

Not applicable.

Precautions during use, storage and disposal:

Pressurized container: May burst if heated. Protect from sunlight and do not expose to temperatures above 50°C. Do not pierce or burn, even after use. Do not spray on a naked flame or any incandescent material. Keep away from heat, hot surfaces, sparks, open flames and other ignition sources. No smoking. Do not use near or place container on polished or painted surfaces.

Any unused product or waste material should be disposed of in accordance with the local requirements.