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Product Information

REGAINE
Topical Solution 2% Topical Solution 5%

For external use only

Composition

REGAINE Topical Solution 2% contains minoxidil, at a concentration of 20 mg minoxidil per mL in a solution composed of alcohol, propylene glycol and water.

REGAINE Topical Solution 5% contains minoxidil, at a concentration of 50 mg minoxidil per mL in a solution composed of alcohol, propylene glycol and water.

Description

Minoxidil, a peripheral vasodilator, occurs as a white or off-white, odourless, crystalline solid which is readily soluble in propylene glycol or ethanol, soluble in water to the extent of 2 mg/mL and is almost insoluble in acetone, chloroform or ethyl acetate. The chemical name for minoxidil is 2, 4-diamino-6-piperidino-pyrimidine-3-oxide (MW = 209.25).

Pharmacology

Pharmacodynamics

When applied topically, REGAINE (minoxidil) has been shown to stimulate hair growth in males and females with alopecia androgenetica; however, the exact mechanism of action of REGAINE in the treatment of alopecia androgenetica is not known. The regrowth can be observed after approximately 4 or more months of use and is variable among patients. Upon discontinuation of treatment with REGAINE new hair growth stops and restoration of pre-treatment appearance may occur within 3-4 months.

Topical application of REGAINE showed no systemic effects related to absorption of minoxidil when tested in controlled clinical trials in both normotensive and untreated hypertensive patients.

Minoxidil administered orally for the treatment of hypertension has a direct peripheral vasodilator effect which reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. Reduction of peripheral arteriolar resistance and the associated fall in blood pressure induces sympathetic, vagal inhibitory, and renal homeostatic mechanisms, including an increase in renin secretion, which lead to increased heart rate and cardiac output, and salt and water retention. Minoxidil does not interfere with vasomotor reflexes and therefore does not produce orthostatic hypotension. In experimental animals, the drug does not enter the central nervous system (CNS) in significant amounts.

Pharmacokinetics

Following topical application, minoxidil is poorly absorbed from normal intact skin, with an average of approximately 1.2% (topical gel) and 1.7% (topical solution) of the total applied dose ultimately reaching the systemic circulation. In contrast, minoxidil is almost completely absorbed from the gastrointestinal tract following oral administration of minoxidil tablets. Following cessation of topical dosing of REGAINE Topical Solution 2%, and Topical Solution 5% approximately 95% of systemically absorbed minoxidil is eliminated within 4 days. The effects of concomitant dermal diseases on absorption are unknown.

The metabolic biotransformation of minoxidil absorbed following topical application has not been fully determined. But the active form of the drug appears to be a sulfated metabolite, minoxidil sulfate. Orally administered minoxidil is metabolised predominantly by conjugation with glucuronic acid at the N-oxide position in the pyrimidine ring but also by conversion to more polar products. Minoxidil does not bind to plasma proteins and its renal clearance corresponds to the glomerular filtration rate. Minoxidil does not cross the blood brain barrier. Minoxidil and its metabolites are haemodialysable, and are excreted principally in the urine.

Clinical Studies

In 2326 adults with early male pattern baldness who applied 1 mL of 2% TMS on the scalp twice daily for 12 months, cosmetically acceptable hair growth was observed in only a small % of individuals. Dense hair growth occurred in only 8% of individuals. Moderate hair growth was observed in a further 30% of subjects.

Two studies in healthy males aged 18-50 years with androgenetic alopecia showed statistically significant differences favouring 5% over 2% TMS with regard to non-vellus hair counts. Compared to mean baseline counts of 103-106/cm2, at the end of 32 weeks treatment mean increases in non-vellus hair counts were 39/cm2 in subjects who received 5% TMS (N=163), 30/cm2 in subjects who received 2% TMS (N=79), and 5/cm2 in subjects who received placebo (N=79). In the other study, compared to mean baseline counts of 144-152 /cm2, at the end of 48 weeks treatment mean increases in non-vellus hair counts were 19/cm2 in subjects who received 5% TMS (N=137), 13/cm2 in subjects who received 2% TMS (N=139), and 4/cm2 in subjects who received placebo (N=70).

Two studies in healthy females aged 18 to 50 years with adrogenetic alopecia showed statistically significant differences favouring 5% over placebo, but not over 2% TMS with regard to non-vellus hair counts. Compared to mean baseline counts of 178-185 /cm2, at the end of 36 weeks treatment mean increases in non-vellus hair counts were 18/cm2 in subjects who received 5% TMS (N=64), 15/cm2 in subjects who received 2% TMS (N=74) and 3/cm2 in subjects who received placebo (N=40). In the other study, compared to mean baseline counts of 138-150/cm2, at the end of 48 weeks treatment mean increases in non-vellus hair counts were 25/cm2 in subjects who received 5% TMS (N=97), 21/cm2 in subjects who received 2% TMS (N=106), and 9/cm2 in subjects who received placebo (N=50).

Examination of efficacy data based on hair weight measurements demonstrated an overall clinical benefit of 5% TMS and 2% TMS in stimulating hair growth. Additionally, this study strongly demonstrated the stabilisation of hair loss over the 2 year treatment period.

Indications

Topical Solution 2% and Topical Solution 5% (minoxidil) is indicated for the treatment of alopecia androgenetica (pattern baldness) in healthy adult males and females

REGAINE Topical Solution 2% and Topical Solution 5% (minoxidil) is indicated for the stabilisation of hair loss.

Contraindications

REGAINE Topical Solution 2% and 5% (minoxidil) is contraindicated in patients with a history of hypersensitivity to minoxidil, propylene glycol or ethanol.

REGAINE is also contraindicated in pregnant, or nursing women.

Warnings and Precautions

Keep this and all medications out of the reach of children.

Accidental ingestion of REGAINE Topical Solution 2% or Topical Solution 5% could lead to serious adverse effects.

Before starting on REGAINE Topical Solution 2% or Topical Solution 5% the patient should have a healthy, normal scalp.

Although extensive use of topical minoxidil has not revealed evidence that enough minoxidil is absorbed to have systemic effects, greater absorption because of misuse or individual variability or unusual sensitivity could lead, at least theoretically, to a systemic effect, and patients need to be aware of this.

The following adverse effects may be observed as a result of systemic absorption:

salt and water retention,

generalised and local oedema,

pericardial effusion,

pericarditis, tamponade,

tachycardia,

increased frequency of angina or new onset of angina, or

the potentiation of the orthostatic hypotension produced by guanethidine.

REGAINE Topical Solution 2% and Topical Solution 5% are recommended for use only in healthy adults with normal cardiovascular status. The safety is unknown in patients with cerebrovascular disease, ischaemic heart disease, cardiac arrhythmias or congestive heart failure. Patients with a history of underlying heart disease should be aware that adverse effects in them might be especially serious. Patients should be alerted to the possibility of tachycardia and fluid retention and should watch for, and be monitored for, increased heart rate and weight gain or other systemic effects.

Patients treated with REGAINE Topical Solution 2% or Topical Solution 5% should be monitored after starting therapy and periodically thereafter. If systemic effects should occur, discontinue use of REGAINE Topical Solution 2% or Topical Solution 5%. If necessary, fluid retention and oedema can be managed with diuretic treatment. Tachycardia and angina can be controlled by administration of beta-adrenergic blocking drugs or other sympathetic nervous system suppressants.

Topical minoxidil therapy should be stopped if hair regrowth is not evident after 12 months of treatment.

In the event of severe dermatological reactions patients should discontinue use of REGAINE Topical Solution 2% or Topical Solution 5% and contact their physician or pharmacist.

REGAINE Topical Solution 2% and Topical Solution 5% will cause burning and irritation of the eye on contact. In the event of accidental contact with sensitive surfaces (eye, abraded skin, mucous membranes), the area should be bathed with copious amounts of cool tap water.

The effects of REGAINE Topical Solution 2% or Topical Solution 5% in patients with concomitant skin diseases, or in those using topical corticosteroids or other dermatological preparations, are unknown. There is a possibility that an increase in bioavailability, of topically administered minoxidil, may occur in the presence of inflammatory conditions of the scalp and such situations are to be avoided.

The use of REGAINE Topical Solution 2% or Topical Solution 5% in combination with any products which inflame the scalp, for example topical retinoids, is not recommended due to the possibility of enhanced minoxidil absorption and consequently, increased potential for adverse drug reactions.

If a patient wishes to wear any form of protective headgear, he should be instructed to allow 1 hour to elapse after using REGAINE Topical Solution 2% or Topical Solution 5% before covering the head.

Carcinogenicity, Mutagenicity and Impairment of Fertility

Carcinogenic activity of minoxidil has been investigated following dietary administration to mice at 10-64 mg/kg/day, and following topical administration to mice and rats at 8-80 mg/kg/day. Minoxidil treatment was associated with the development of benign pituitary tumours and malignant mammary tumours in female mice, hepatic adenomas and splenic haemangiosarcomas in male mice, and adrenal medullary and clitoral gland adenomas in female rats. The hepatic tumours were only observed at high dose levels. The development of mammary adenocarcinomas in mice may be related to stimulation of prolactin release. Tumour development in the pituitary, preputial and clitoral glands may also involve endocrine mechanisms, while the vascular wall tumours in mouse spleen and adrenal medullary tumours in rats may be related to the vasodilator activity of the drug.

In a 12-month photocarcinogenicity study in hairless mice, topical minoxidil did not accelerate the development of dermal tumours initiated by ultraviolet light.

Genetic toxicology studies showed that minoxidil does not cause gene mutation in bacterial cells, but gene mutation studies in mammalian cells have not been reported. Minoxidil had weak clastogenic activity in a cytogenetics assay in Chinese hamster lung cells in vitro, but there was no evidence of similar effects in cultured human lymphocytes, or in an in vivo assay (micronucleus test in mice). Minoxidil did not cause DNA damage in an alkaline elution assay in Chinese hamster fibroblasts or unscheduled DNA synthesis in rat hepatocytes.

In fertility studies in rats, minoxidil decreased live litter size at oral doses of 3-10 mg/kg/day and at 80 mg/kg/day SC.

Use in Pregnancy

CATEGORY C:

Oral administration of minoxidil has been associated with hypertrichosis in the newborn infant following exposure in utero. The safety of topical minoxidil in pregnancy has not been established, therefore REGAINE Topical Solution 2% and Topical Solution 5% should not be used by pregnant women.

Subcutaneous administration of minoxidil to pregnant rats during organogenesis caused foetal deaths, decreased foetal weight, and increased incidences of external, visceral and skeletal abnormalities. These effects were observed in two strains of rats at doses of 120 to 160 mg/kg/day, and were associated with mild to moderate maternal toxicity. No development effects were observed at non-maternotoxic dose levels. No teratogenic effects were observed in rabbits at oral doses up to 10 mg/kg/day or at subcutaneous doses up to 49 mg/kg/day. In a peri/postnatal study in rats, subcutaneous administration of minoxidil at 80 mg/kg/day caused an increase in gestation length, prolonged parturition, an increased incidence of stillbirths and reduced birth weight.

Use in Lactation

Systemically-absorbed minoxidil is secreted in human milk. REGAINE Topical Solution 2% and Topical Solution 5% should not be used by nursing women.

Subcutaneous administration of minoxidil at 80 mg/kg/day to lactating rats suppressed postnatal growth and increased postnatal mortality of the offspring. These effects may have been due to interference with nursing behaviour rather than to ingestion of drug-related material by the offspring.

Use in Children

Safety and efficacy of REGAINE Topical Solution 2% and Topical Solution 5% in patients under 18 years of age have not been established.

Use in Elderly

Safety and efficacy of REGAINE Topical Solution 2% and Topical Solution 5% in patients over 65 years of age have not been established.

Drug Interactions

There are currently no known drug interactions associated with the use of REGAINE Topical Solution 2% or Topical Solution 5% (minoxidil). Although it has not been clinically demonstrated, there exists the theoretical possibility of absorbed minoxidil potentiating orthostatic hypotension in patients currently taking peripheral vasodilators. In vitro studies have shown that paracetamol and diethylcarbamazine may inhibit the stimulation of hair growth by minoxidil.

Adverse Reactions

The most frequently encountered adverse effects in clinical trials with REGAINE were mild dermatitis of the scalp.

Infrequently reported adverse reactions include irritant dermatitis (redness, scaling and burning), non-specific allergic reactions, hives, allergic rhinitis, facial swelling, sensitivity, shortness of breath, headache, neuritis, dizziness, light-headedness, syncope, vertigo, oedema, chest pain, blood pressure changes, palpitations and pulse rate changes.

Rarely reported adverse reactions included allergic contact dermatitis, folliculitis, alopecia, unwanted hypertrichosis and seborrhoea.

REGAINE has been used by over 3500 patients enrolled in placebo-controlled trials. In comparative trials between topical minoxidil 5% solution, 2% solution, and placebo, dermatological events were more frequent in the topical minoxidil 5% group (see Table 1). The events were of similar type and severity in the 5% and 2% groups, but the incidence was greater in the 5% group. Hypertrichosis (including facial hair growth) was reported particularly in studies involving women. In two comparative trials between 5% solution, 2% solution and placebo in women, hypertrichosis was reported in 37% in the combined groups who received 5% solution, compared to 21% in the combined groups who received 2% solution, and 15% who received placebo.

Additional events reported with 2% minoxidil in postmarketing clinical experience include: eczema, local erythema, pruritus, dry skin/scalp flaking, sexual dysfunction, visual disturbances including decreased visual acuity, exacerbation of hair loss, alopecia.

Except for dermatological events, no individual or reactions within a body system were meaningfully or clinically increased in the minoxidil group

Dosage and Administration

For external use only.

Use REGAINE Topical Solution 2% and Topical Solution 5% only as directed. Do not apply REGAINE to any area of the body other than the scalp.

A total dose of 1 mL REGAINE Topical Solution 2% or Topical Solution 5% should be applied twice per day to the scalp, beginning at the centre of the affected area. This dose should be used regardless of the size of the affected area. The total daily dose should not exceed 2 mL. After applying REGAINE Topical Solution 2% or Topical Solution 5%, wash hands thoroughly.

Apply REGAINE Topical Solution 2% or Topical Solution 5% when the hair and scalp are thoroughly dry. Do not use a hairdryer to speed the drying of REGAINE , because blowing air on the scalp may decrease the effectiveness of REGAINE . REGAINE Topical Solution 2% and Topical Solution 5% must remain in contact with the scalp for several hours (up to 4 hours).

At least four months of twice daily applications of REGAINE are generally required before evidence of hair regrowth can be expected. Onset and degree may be variable among patients.

Note: Following discontinuation of medication, relapse to pre-treatment appearance has been reported to occur within 3-4 months.

Directions for Use

Make sure the scalp is dry and that the skin is healthy and intact.

Dropper

This applicator is designed to deliver a measured amount (1 mL or 1 dose) of solution.

Remove the large outer cap off the bottle; unscrew the child-resistant cap.

Hold the bottle upright. Whilst ensuring that the dropper is immersed in the solution, squeeze the bulb to fill the dropper to the black line. The applicator now contains one full dose (1 mL) of REGAINE Topical Application and is ready for use.

Aim the dropper to the area of the scalp you wish to treat, lifting any hair out of the way with your fingers or comb. Gently squeeze the dropper bulb and apply the solution dropwise.

Massage the solution into the scalp gently with your fingers. Wash your hands after you have finished massaging the solution into your scalp.

Replace the child-resistant dropper by screwing the dropper firmly onto the bottle. Place the larger outer cap on the bottle when not in use.

Overdosage and Accidental Ingestion

Due to the high concentration of minoxidil in REGAINE Topical Solution 2% and Topical Solution 5% accidental ingestion may produce systemic effects related to the vasodilatory action of minoxidil. Signs and symptoms of drug overdosage would most likely be cardiovascular effects associated with fluid retention, tachycardia or lowered blood pressure. Fluid retention can be managed with appropriate diuretic therapy. Tachycardia can be controlled by administration of a beta-adrenergic blocking agent. Symptomatic hypotension should be treated by intravenous administration of normal saline. Sympathomimetic drugs, such as noradrenaline and adrenaline should be avoided because of their excessive cardiac stimulating activity.

Package Quantities

REGAINE Topical Solution 2%, containing 20 mg minoxidil per mL is available in a 60 mL bottle.

REGAINE Topical Solution 5%, containing 50 mg minoxidil per mL is available in a 60 mL bottle.

Medicine Classification

Pharmacist Only Medicine

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