SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Regaine Extra Strength 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 men.

4.2    Posology and method of administration

Men aged 18-49:

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 twice daily. The total daily dosage should not exceed 2 g.

Hold can upside down and press nozzle to dispense foam onto the hand. Spread with fingertips over entire bald area. Hands should be washed thoroughly after application.

It may take twice-daily applications for 8 weeks or more before evidence of hair growth can be expected. Users should discontinue treatment if there is no improvement seen after 16 weeks.

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

Clinical Trials have not investigated the efficacy of this product beyond 16 weeks.

Children and men over 49 years

Not recommended. The safety and effectiveness of this product in users aged under 18 or over 49 has not been established.

4.3 Contraindications

This product is contraindicated: in women

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)

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.

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 (2 g of this product contains 100 mg minoxidil; the

maximum recommended adult dose for oral minoxidil administration in the treatment of hypertension). Signs and symptoms of minoxidil overdosage would primarily be cardiovascular effects associated with sodium and water retention, and tachycardia, hypotension and dizziness can also occur. Fluid retention can be managed with appropriate diuretic therapy. Clinically significant tachycardia can be controlled by administration of a beta-adrenergic blocking agent.

Treatment

Treatment of minoxidil overdosage should be symptomatic and supportive.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 cm ) 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).

₂

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

	Regaine for Men Extra Strength Foam (n=180)	Placebo (n=172)	Difference (p-value)
Baseline haircount	170.8	168.9
	Mean change from baseline	Mean change from baseline
8 weeks	16.0	4.9	11.1 (<0.0001)
12 weeks	19.9	4.5	15.4 (<0.0001)
16 weeks	21.0	4.3	16.7 (<0.0001)

5.2 Pharmacokinetic properties

The failure to detect evidence of systemic effects during treatment with Regaine 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 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 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.

5.3 Preclinical safety data

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.

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 extremely flammable.

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

The contents are under pressure. The container should not be punctured or incinerated. The product is extremely flammable and exposure of the container and contents to naked flames should be avoided during use, storage and disposal. Do not expose to temperatures above 50°C.

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

03/07/2015