SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Regaine for Women ONCE A DAY Scalp Foam 5% w/w Cutaneous Foam

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Minoxidil 50 mg/g (5% w/w)

Contains butylhydroxytoluene (BHT), stearyl alcohol and cetyl alcohol. For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Cutaneous foam White to off-white foam

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

This product is indicated for the treatment of alopecia androgenetica in women (also known as female pattern hair loss) in women aged between 18 and 65. Onset and degree of hair regrowth may be variable among users. Although trends in the data suggest that those users who are younger, whose hair has been thinning for a shorter period of time or who have a smaller area of thinning on the vertex are more likely to respond to the product, individual responses cannot be predicted.

4.2    Posology and method of administration

Women aged 18-65:

Hair and scalp should be thoroughly dry prior to topical application of this product. A dose of 1 g (equivalent to the volume of half a capful) of this product should be applied to the total affected areas of the scalp once daily. The total daily dosage should not exceed 1 g.

It may take once-daily applications for 12 to 24 weeks before evidence of hair growth can be expected. Users should discontinue treatment if there is no improvement seen after 24 weeks.

If hair regrowth occurs, once daily applications of this product are necessary for continued hair growth.

Clinical Trials have not investigated the efficacy of this product beyond 24 weeks. Further secondary results and safety were assessed up to 52 weeks (see section 5.1).

Special populations

There are no specific recommendations for use in older people or in patients with renal or hepatic impairment.

Paediatric population

Not recommended. The safety and effectiveness of this product in children and adolescents below the age of 18 years has not been established.

Method of administration

Hold can upside down and press nozzle to dispense foam onto the hand. Spread with fingertips over the affected areas and gently massage the foam into the scalp working from the back to the front of the scalp. Hands should be washed thoroughly after application.

4.3 Contraindications

This product is contraindicated: in men

in users with a history of sensitivity to minoxidil or any of the other ingredients

in users with treated or untreated hypertension

in users with any scalp abnormality (including psoriasis and sunburn)

in users with a shaved scalp

if occlusive dressings or other topical medical preparations are being used.

4.4 Special warnings and precautions for use

Before using this product, the user should determine that the scalp is normal and healthy. Topical minoxidil should not be applied to inflamed, infected or painful scalp skin (see section 4.3).

Topical minoxidil is not indicated when there is no family history of hair loss, hair loss is sudden and/or patchy, hair loss is due to childbirth, or the reason for hair loss is unknown.

The patient should stop using this product and see a doctor if hypotension is detected or if the patient is experiencing chest pain, rapid heartbeat, faintness or dizziness, sudden unexplained weight gain, swollen hands or feet or persistent redness or irritation of the scalp, or other unexpected new symptoms occur (see section 4.8).

Patients with known cardiovascular disease or cardiac arrhythmia should contact a physician before using this product.

Some patients have experienced changes in hair colour and/or texture with this product use.

This product is for external use only. Do not apply to areas of the body other than the scalp.

Using more than the recommended dose or more often will not improve results.

Unwanted hair growth may be caused by the transfer of the product to areas other than the scalp.

Hands should be washed thoroughly after applying the foam.

Some consumers reported increased hair shedding upon initiation of therapy with this product. This is most likely due to minoxidil’s action of shifting hairs from the resting telogen phase to the growing anagen phase (old hairs fall out as new hairs grow in their place). This temporary increase in hair shedding generally occurs two to six weeks after beginning treatment and subsides within a couple of weeks. If shedding persists (> 2 weeks), users should stop using this product and consult their doctor.

Users should be aware that, whilst extensive use of this product has not revealed evidence that sufficient minoxidil is absorbed to have systemic effects, greater absorption because of misuse, individual variability, unusual sensitivity or decreased integrity of the epidermal barrier caused by inflammation or disease processes in the skin (eg. excoriations of the scalp, or scalp psoriasis) could lead, at least theoretically, to systemic effects.

Accidental ingestion may cause serious cardiac adverse events. Therefore this product has to be kept out of the reach of children.

This product contains ethanol (alcohol), which will cause burning and irritation of the eye. In the event of accidental contact with sensitive surfaces (eye, abraded skin and mucous membranes) the area should be bathed with large amounts of cool tap water.

This product also contains butylated hydroxytoluene, which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes or mucous membranes, and cetyl and stearyl alcohol, which may cause local skin reactions (e.g. contact dermatitis)

4.5 Interaction with other medicinal products and other forms of interaction

This product should not be used concomitantly with other medications applied topically on the scalp (see section 4.3).

Topical drugs, such as corticosteroids, tretinoin or dithranol or petrolatum, which alter the stratum corneum barrier, could result in increased absorption of minoxidil if applied concurrently. Although it has not been demonstrated clinically, there exists the theoretical possibility of absorbed minoxidil potentiating orthostatic hypotension caused by peripheral vasodilators.

Guanethidine has been reported to interact with oral formulations of minoxidil resulting in rapid and pronounced lowering of blood pressure. There is a theoretical possibility that topical minoxidil may also interact with guanethidine.

4.6 Fertility, pregnancy and lactation

This product should not be used during pregnancy or lactation.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Studies in animals have shown a risk to the foetus at exposure levels that are very high compared to those intended for human exposure. There is potentially a risk of foetal harm in humans (see section 5.3).

Lactation

Systemically absorbed minoxidil is secreted in human milk. The effect of minoxidil on newborns/infants is unknown.

4.7 Effects on ability to drive and use machines

Based on the pharmacodynamic and overall safety profile of minoxidil, it is not expected that this product would interfere with the ability to drive or operate machinery.

4.8 Undesirable effects

The safety of topical minoxidil from clinical trials data is based on data from 7 placebo-controlled randomised clinical trials in adults evaluating either 2% or 5% minoxidil solution, and two placebo-controlled randomised clinical trials in adults evaluating a 5% foam formulation.

Adverse drug reactions (ADRs) identified during clinical trials and postmarketing experience with minoxidil are included in the table below by System Organ Class (SOC).

The frequencies are provided according to the following convention:

Very common (>1/10); common (>1/100,<1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

ADRs are presented by frequency category based on 1) incidence in adequately designed clinical trials or epidemiology studies, if available, or 2) when incidence cannot be estimated, frequency category is listed as ‘Not known’.

Body System (SOC)	Frequency	Adverse Drug Reaction (Preferred Term)
Immune System Disorders	Common	Hypersensitivity reactions (The manifestations of Hypersensitivity reactions may include the following MedDRA PTs: Face oedema, Generalised erythema, Pruritus generalized, Swelling face, and Throat tightness)
	Uncommon	Angioedema (The manifestations of angioedema may include following PTs: Lip oedema, Lip swelling,

		Oedema mouth, Oropharyngeal swelling, Pharyngeal oedema, Swollen tongue and Tongue oedema)
Nervous System Disorders	Very common	Headache
	Uncommon	Dizziness
Eye disorders	Uncommon	Eye irritation
Cardiac disorders	Common	Chest pain
	Uncommon	Tachycardia Palpitations
Vascular disorders	Uncommon	Hypotension
Respiratory, thoracic and mediastinal disorders	Uncommon	Dyspnoea
Gastrointestinal Disorders	Uncommon	Nausea Vomiting
Skin and subcutaneous tissue disorders	Common	Hypertrichosis (unwanted non-scalp hair including facial hair growth in women) Pruritus (including rash pruritic generalised and eye pruritus) Rash (including pustular, papular, generalised, vestibular and macular rash) Dermatitis (including contact, allergic, atopic and seborrhoeic dermatitis)
	Uncommon	Dry skin Skin exfoliation (including

		exfoliative rash and dermatitis exfoliative) Acne (acneform rash) Temporary hair loss (see section 4.4) Changes in hair texture and hair colour
General disorders and administration site conditions	Common	Oedema peripheral
	Uncommon	Application site reactions (These sometimes involve nearby structures like the ears and face and typically consist of pruritus, irritation, pain, rash, oedema, dry skin, erythema and rash erythematous but can sometimes be more severe and include exfoliation, dermatitis, blistering, bleeding and ulceration)
Investigations	Common	Weight increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Increased systemic absorption of minoxidil may potentially occur if higher-than-recommended doses of this product are applied to larger surface areas of the body or areas other than the scalp.

Because of the concentration of minoxidil in this product, accidental ingestion has the potential of producing systemic effects related to the pharmacological action of the drug (1 g of this product contains 50 mg minoxidil; the maximum recommended adult dose for oral minoxidil administration in the treatment of hypertension is 100mg per day).

Signs and symptoms of minoxidil overdosage would primarily be cardiovascular effects associated with sodium and water retention, and tachycardia, hypotension, dizziness and lethargy can also occur.

Treatment

Treatment of minoxidil overdosage should be symptomatic and supportive.

Fluid retention can be managed with appropriate diuretic therapy. Clinically significant tachycardia can be controlled by administration of a beta-adrenergic blocking agent.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other dermatologicals, ATC code: D11AX.

Individual responses to Regaine for Women ONCE A DAY are variable and unpredictable. The efficacy of 5 % minoxidil topical foam for the treatment of androgenic alopecia in women has been assessed in two phase 3 clinical trials, each studying women with FPHL with scalp hair density on the top of the scalp D3 to D6 on the Savin Density Scale.

Comparative Efficacy vs. Placebo

In a randomised, controlled, double-blind, multi-centre study, 5 %Minoxidil Topical Foam ONCE A DAY (MTF OD) was compared to a foam vehicle containing no active product. Each was applied once daily, for 24 weeks.

Primary efficacy criterion was assessed by the mean change in non-vellus hair count in a 1.0 cm² reference area of affected scalp, as measured by macrophotography at baseline and Week 24, and subject assessment of scalp coverage from global photographs, as measured by the change from baseline at Week 24 on a 7-point scale. After 24 weeks of treatment, the 5% MTF OD group re-grew 13.4 hairs/cm and the foam vehicle group re-grew 4.3 hairs/cm², a treatment difference of 9.1 hairs/cm² (p<0.0001). After 24 weeks of treatment, subjects in the 5% MTF OD group observed improved scalp coverage from baseline. The adjusted mean scalp coverage scores were 0.75 versus 0.06 for the 5% MTF OD and the foam vehicle groups, respectively, a significant treatment difference of 0.69 (p<0.0001).

Mean change in non-vellus hair count in reference 1 cm area of scalp compared with baseline

	Regaine for Women Once a Day Foam -5% MTF OD (n= 200)	Vehicle (n= 197)	Difference (p value)
Baseline Mean Hair Count	158.6	152.7
	Adjusted Mean Change from Baseline	Adjusted Mean Change from Baseline
Week 12	+16.2	+5.3	<0.0001
Week 24	+13.4	+4.3	<0.0001

Comparative Efficacy vs. 2% Minoxidil Topical Solution twice daily In a randomised, controlled evaluator-blind multicentre study, 5 % minoxidil topical foam (MTF) applied once a day (OD) was compared to 2% minoxidil topical solution (MTS) applied twice daily (BID), each for 52 weeks.

Primary efficacy criterion was assessed by the mean change in non-vellus hair count in a 1.0 cm² reference area of affected scalp with baseline, as measured by macrophotography at Week 24.

5% MTF OD was concluded to be at least as effective as 2% MTS BID. Both 5% MTF OD and 2% MTS BID increased the total non-vellus hair diameters at all measuring time points, and after 24 and 52 weeks of treatment, the experts observed improved scalp coverage in both the 5% MTF OD and 2% MTS BID groups.

Mean change in non-vellus hair count in reference 1 cm area of scalp compared with baseline

	Regaine for Women Once a Day Foam -5% MTF OD (n= 161)	2% MTS BID (n= 161)	Difference (p value)
Baseline Mean Hair Count	169.7	167.3
	Adjusted Mean Change from Baseline	Adjusted Mean Change from Baseline
Week 12	+24.6	+22.2	0.4158
Week 24	+23.9	+24.2	0.9170

The 2 efficacy studies demonstrated that 5% MTF OD provided benefits to women with FPHL after 12-24 weeks of treatment, including promotion of hair regrowth, improvement in scalp coverage, increase in hair density and hair diameter.

Minoxidil stimulates hair growth in persons with early and moderate stages of hereditary hair loss (alopecia androgenetica). This hair loss appears in women with a reduction in hair density (thinning) and widening of the part line on the central part of the scalp, which may include a breach of the frontal hairline (female pattern hair loss). 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 telegon 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.

5.2 Pharmacokinetic properties

Absorption

The systemic absorption of topically applied minoxidil from normal intact skin is low. Systemic absorption of minoxidil from topically applied solution ranges between 1% and 2% of the total applied dose compared to 90-100% of the oral formulation.

The systemic absorption of minoxidil from a 5% foam formulation has been estimated in a 2-arm pharmacokinetic study in subjects with androgenetic alopecia, which included twice daily 5% topical solution or 2% topical solution as comparators.

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 nghr/mL and 1.11 ng/mL, respectively, were both approximately 50 % of AUC (0-12 hr) and Cmax of the 5% solution, 18.71 nghr/mL and 2.13 ng/mL, respectively.

The AUC of 5% minoxidil foam used once daily was found to be similar to that of 2% minoxidil solution used twice daily in female subjects.

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. The haemodynamic effects of minoxidil do not become evident until mean serum minoxidil concentrations reach 21.7 ng/mL.

Distribution

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 doses between 1.37 mg and 27.4 mg at steady state after 12-hour intravenous administration ranges from 76.0 to 82.8, respectively.

Metabolism

Approximately 60% minoxidil absorbed after topical application is metabolised to minoxidil glucuronide, primarily in the liver.

Elimination

The half-life of topical minoxidil averaged 22 hours, compared to 1.49 hours for the oral formulation. Minoxidil and its metabolites are excreted almost entirely in the urine (97%), with a very minor degree of elimination via the faeces (3%).

Renal clearance of minoxidil and minoxidil glucuronide calculated from oral data averaged 261 mL/min and 290 mL/min, respectively.

Following cessation of dosing, approximately 95% of topically applied minoxidil will be eliminated within four days.

5.3 Preclinical safety data

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Cardiac effects of minoxidil in dogs are species-specific in terms of low doses that cause profound haemodynamic effects and associated changes in the heart. Available data indicate that similar cardiac effects do not occur in humans treated topically or orally with minoxidil.

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. There is a risk of foetal harm in humans.

Fertility

Preclinical fertility studies in rats have shown minoxidil doses equal or greater than 3 mg/kg/day (at least 8 fold human exposure) when administered orally and 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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Ethanol, Anhydrous Purified Water

Butylated hydroxytoluene (E321)

Lactic acid

Citric acid anhydrous

Glycerol

Cetyl alcohol

Stearyl Alcohol

Polysorbate 60

Propane/n-Butane/Iso-butane (as propellant)

6.2 Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for storage

Store below 25°C.

This product is an extremely flammable aerosol.

6.5    Nature and contents of container

A lined aluminium pressurised container with a child-resistant plastic or polypropylene overcap, containing 60 gram of product.

Packs contain either one or two cans. Not all pack sizes may be marketed.

6.6    Special precautions for disposal

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.

7    MARKETING AUTHORISATION HOLDER

McNeil Products Limited Foundation Park Roxborough Way Maidenhead Berkshire SL6 3UG United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 15513/0135

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/10/2014

10    DATE OF REVISION OF THE TEXT

27/11/2015