SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Boots Hair Loss Treatment Regular Strength

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Minoxidil 20mg/ml (2% w/v).

For excipients, see 6.1.

3.    PHARMACEUTICAL FORM

Cutaneous Solution.

A clear, colourless to light yellow solution.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Minoxidil 2% Solution is indicated for the treatment of alopecia androgenetica in men and 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, who have been balding for a shorter period of time or who have a smaller area of baldness on the vertex are more likely to respond to Minoxidil 2% Solution, individual responses cannot be predicted.

4.2. Posology and method of administration

Men and women aged 18 - 65.

Hair and scalp should be thoroughly dry prior to topical application of Minoxidil 2% Solution. A dose of 1ml Minoxidil 2% Solution should be applied to the total affected areas of the scalp twice daily. The total dosage should not exceed 2ml. If fingertips are used to facilitate drug application, hands should be washed afterwards.

It may take twice-daily applications for four months before evidence of hair growth can be expected.

If hair regrowth occurs, twice daily applications of Minoxidil 2% Solution are necessary for continued hair growth. Anecdotal reports indicate that regrown hair may disappear three to four months after stopping Minoxidil 2% Solution and the balding process will continue.

Users should discontinue treatment if there is no improvement after one year.

The method of application varies according to the disposable applicator being used:

Pump spray applicator

This is useful for large areas. Aim the pump at the centre of the bald area, press once and spread with fingertips over the entire bald area. Repeat for a total of six times to apply a dose of 1ml. Avoid breathing spray mist.

Extended spray tip applicator

This is useful for small areas, or under hair. The pump spray applicator must be in place in order to use this additional applicator. Use in the same way as the pump spray.

Dropper

Fill the dropper to the 1ml mark and apply the Minoxidil 2% Solution to the bald area until the entire dose has been delivered.

Children and the Elderly

Not recommended. The safety and effectiveness of Minoxidil 2% Solution in users aged under 18 or over 65 has not been established.

The solution is flammable and exposure of the container and contents to naked flames should be avoided during use, storage and disposal.

4.3. Contraindications

Minoxidil 2% Solution is contra-indicated:

-    in users with a history of sensitivity to Minoxidil, ethanol or propylene glycol

-    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 Minoxidil 2% Solution the user should determine that the scalp is normal and healthy.

Minoxidil is only indicated for the treatment of alopecia androgenetica and should not be used in other types of hair loss for example, when 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 Minoxidil and see a doctor if hypotension is detected or if the patient is experiencing chest pain, rapid heart beat, faintness or dizziness, sudden unexplained weight gain, swollen hands or feet or persistent redness.

Patients with known cardiovascular disease or cardiac arrhythmia should contact a physician before using minoxidil 2% w/v.

Minoxidil 2% Solution is for external use only. Do not apply to areas of the body other than the scalp.

Hands should be washed thoroughly after applying the solution. Inhalation of the spray mist should be avoided.

Minoxidil 2% Solution contains 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 amount of cool tap water.

Minoxidil 2% Solution contains propylene glycol. May cause skin irritation.

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

Patients should be advised to consult their doctor or pharmacist if they are concerned at any time during treatment with minoxidil 2% w/v.

Some consumers reported increased hair shedding upon initiation of therapy with minoxidil 2% w/v. This is most likely due to minoxidil’s action of shifting hairs from the resting telogen phase to the growth 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 minoxidil 2% w/v and consult their doctor.

Users should be aware that, whilst extensive use of Minoxidil 2% Solution 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 (e.g. 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.

4.5.    Interactions with other medicinal products and other forms of interaction

This product should not be used concomitantly with other medications applied topically on the scalp.

Topical drugs, such as corticosteroids, tretinoin, 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.    Pregnancy and lactation

There are no adequate and well controlled studies in pregnant women.

Animal studies have shown a risk to the foetus at exposure levels that are very high compared to those intended for human exposure (see section 5.3). The potential risk in humans in unknown.

Systemically absorbed minoxidil is secreted in human milk.

There is no evidence as to drug safety in human pregnancy nor is there evidence from animal work that it is free from hazard.

Minoxidil 2% Solution should not be used during pregnancy or lactation.

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 Minoxidil 2% Solution would interfere with the ability to drive or operate machinery.

4.8. Undesirable effects

In placebo-controlled trials, the overall frequency of medical events in females in all body system categories was approximately five times that of males.

Several thousand patients have used topical Minoxidil in clinical trials where a comparison with an inactive solution was made. Dermatological reactions (eg. irritation, itching) occurred in patients using both solutions. This has been explained by the presence of propylene glycol in both the active and inactive solution.

Particular attention has been paid to body systems, such as cardiovascular and metabolic, which might have some relevance based on the pharmacology of Minoxidil. There was no increased risk to users due to drug related medical reactions in these, or other, body system categories.

Data from the brand leader: 7 placebo controlled trials are presented with a population of 1,197 males and females treated with topical minoxidil solution where adverse events were assessed. Additionally, adverse events reported in post-marketing are included.

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

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'.

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).

Hypertrichosis (unwanted non-scalp hair including facial hair growth in women),

		application site, generalised and eye pruritus), rash (including pustular, papular,generalised, vestibular and macular rash) Dermatitis (including contact, allergic, atopic and seborrheic dermatitis)
	Uncommon	Temporary hair loss (see Section 4.4), changes in hair texture and hair colour, skin exfoliation (including application site, exfoliative rash and dermatitis exfoliative), acne (acne form rash), and dry skin
	Common	Oedema peripheral
General disorders and administration site conditions	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)
Immune System	Common	Hypersensitivity reactions (including face oedema, generalised erythema, pruritus generalised, swelling face, and throat tightness)
Disorders	Uncommon	Angioedema (including lip oedema, lip swelling, oedema mouth, oropharyngeal swelling, pharyngeal oedema, swollen tongue and tongue oedema)
Eye disorders	Uncommon	Eye irritation
Gastrointestinal Disorders	Uncommon	Nausea, Vomiting
Investigations	Common	Weight Increased

Users should stop using minoxidil 2% w/v if they experience redness or irritation of the scalp

Users should stop using Minoxidil if they experience chest pain, tachycardia, faintness, dizziness, sudden unexplained weight gain, or swollen hands or feet or persistent redness or irritation of the scalp. Rare cases of hypotension have been reported.

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 Minoxidil 2% Solution are applied to larger surface areas of the body or areas other than the scalp. There are no known cases of Minoxidil overdosage resulting from topical administration of Minoxidil 2% Solution.

Because of the concentration of Minoxidil in Minoxidil 2% Solution, accidental ingestion has the potential of producing systemic effects related to the pharmacological action of the drug (5 ml of Minoxidil 2% Solution contains 100 mg; 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. Fluid retention can be managed with appropriate diuretic therapy. Clinically significant tachycardia can be controlled by administration of beta-adrenergic blocking agent.

Treatment

Treatment of minoxidil overdosage should be symptomatic and supportive.

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: other dermatologicals, ATC code: D11AX

Individual responses to Minoxidil are variable and unpredictable.

The effect of Minoxidil 2% Solution has been assessed in phase III clinical trials in both men and women conducted over a 48 week treatment period. In these studies Minoxidil 2% was compared to the product vehicle without the Minoxidil active ingredient. The primary efficacy criterion was non-vellus hair count in a 1.0 cm² reference area of affected scalp. The mean changes observed in this parameter in these studies were significantly in favour of Minoxidil 2% and were as follows -

Females

₂

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

	Minoxidil 2%	Vehicle	Pairwise comparison
Baseline	150.4	138.4
	Mean change from baseline	Mean change from baseline
16 weeks	+35.9	+20.0	2%> vehicle
32 weeks	+26.7	+15.2	2%> vehicle
48 weeks	+20.7	+9.4	2%> vehicle

Using non-vellus hair count as an efficacy criterion, Minoxidil 2% has also been shown to stabilise hair loss (defined as regrowth or no loss) in 88% of patients compared with 69% of patients who received vehicle in one trial following 48 weeks treatment and in 87% of patients compared to 73 % of patients who received vehicle in a further trial following 32 weeks treatment.

Female patients own evaluation in clinical studies have shown that hair growth was reported by approximately 60% of females after eight months of Minoxidil 2% usage.

Patient Evaluation of Visible Hair Growth

	% of Females reporting regrowth after 8 months Minoxidil 2% Solution	% of Females reporting regrowth after 4 months Product vehicle usage
Minimal re-growth	30 - 40	29 - 33
Moderate to dense regrowth	20 - 25	7 - 12
Total	55 - 59	40 - 41

In addition, Minoxidil 2% has also shown to stabilise hair loss (shown as regrowth or no loss) in four out of five females as calculated from two clinical studies that showed stabilisation with 88 and 87% respectively while corresponding figures for vehicle were 69 and 74%.

Males

Mean change in non-vellus hair count in reference 1 cm² area of scalp compared with baseline.

	Minoxidil 2%	Vehicle	Pairwise comparison
Baseline	143.6	152.4
	Mean change from baseline	Mean change from baseline
16 weeks	+29.8	+15.3	2%> vehicle
32 weeks	+22.2	+7.7	2%> vehicle
48 weeks	+12.7	+3.9	2%> vehicle

In addition, in males efficacy was further assessed by comparing photographs taken at various timepoints with baseline. Assessment was undertaken by patients using a 100 mm visual analogue scale where point 0 represented much less scalp coverage. The results were as follows -

Patient Evaluation of Change in Scalp Coverage

	Minoxidil 2%	Vehicle	Pairwise comparison
	mm	mm
16 weeks	58.2	51.4	2%> vehicle
32 weeks	58.0	52.0	2%> vehicle
48 weeks	56.9	51.0	2%> vehicle

Also in males, assessment was undertaken by two blinded reviewers who compared photographs taken at baseline after 48 weeks. Differences were assessed using a seven point categorical scale viz:

Dense growth Moderate growth Minimal growth No change Minimal loss Moderate loss Dense loss

The results were as follows -

Photographic Evaluation of Clinical Response (Reviewer 1)

	Dense Growth %	Moderate Growth %	Minimal Growth %	No Change %	Hair Loss %	Unable to Rate %
Minoxidil 2%	2.8	19.7	21.1	50.0	2.8	3.5
Placebo	0	7.0	22.5	60.6	9.9	0

Photographic Evaluation of Clinical Response (Reviewer 2)

	Dense Growth %	Moderate Growth %	Minimal Growth %	No Change %	Hair Loss %	Unable to Rate %
Minoxidil 2%	3.5	12.0	22.5	47.2	1.4	13.4
Placebo	0	7.0	9.9	60.6	14.1	8.5

Based upon the photographic data around 40% of the patients experienced an increased scalp coverage after 48 weeks treatment with Minoxidil 2% defined by regrowth of hair compared with 23% at an average for those who received vehicle alone. Around 19% treated with Minoxidil 2% experienced dense or moderate growth compared with around 7% who received vehicle alone. In addition 49% of patients who received Minoxidil 2% were adjudged to have no change between photographic assessments of hair growth compared with 60% who received vehicle alone. Stabilisation of hair loss (i.e. regrowth or no loss) can therefore be expected in about four out of five patients using Minoxidil 2% compared with three out of four using vehicle alone.

The mechanism by which Minoxidil stimulates hair growth is not fully understood, but Minoxidil can reverse the hair loss process of androgenetic alopecia by the following means:

Increase the diameter of the hair shaft Stimulate anagen growth Prolong the anagen phase

Stimulate anagen recovery from the telogen 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

The failure to detect evidence of systemic effects during treatment with Minoxidil 2% Solution reflects the poor absorption of topical Minoxidil, which averages about 1.4% (range 0.3 - 4.5%) of the total applied dose from normal intact skin. Absorption is about 2% when applied topically to shaved scalps of hypertensive users. Increasing the amount of drug applied or increasing the frequency of application of Minoxidil 2% Solution also results in increased absorption.

Results of the extensive pharmacokinetic studies indicate that the three major factors by which topical Minoxidil absorption are increased by are: increasing the dose applied, increasing the frequency of dosing and decreasing the barrier function of the stratum corneum.

In a study in males, the minoxidil serum concentration time curve (AUC) for the 2% solution averaged 7.54 ngh/ml compared to a mean AUC of 35.1 ngh/ml for the 2.5 mg oral formulation. The mean peak plasma concentration (C_max) for the topical solution was 1.25 ng/ml, compared to 18.5 ng/ml following the 2.5 mg oral dose.

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.

Serum Minoxidil levels and systemic effects resulting from administration of Minoxidil 2% Solution are governed by the drug’s absorption rate through the skin. 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

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 the 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.

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 (from 19 to 570-fold human exposure). A low, albeit remote, risk of foetal harm is possible in humans.

Fertility

Preclinical fertility studies in rats have shown minoxidil doses equal to or greater than 3 mg/kg/day (at least 21-fold human exposure) when administered orally and greater than 9 mg/kg/day (at least 64-fold human exposure) when administered subcutaneously were associated with reduced conception and implantation rates as well as a reduction in the number of live pups.

6.    PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Propylene Glycol

Ethanol

Water

6.2. Incompatibilities

None applicable.

6.3. Shelf Life

Four years.

6.4. Special precautions for storage

Minoxidil 2% Solution is flammable. Store below 25°C.

Protect from light.

Store upright.

6.5. Nature and contents of container

HDPE bottle with 24mm polypropylene white cap and spray-pump/dropper applicator containing 60ml of solution.

6.6 Special precautions for disposal

Not applicable.

7. MARKETING AUTHORISATION HOLDER

Wrafton Laboratories Limited

Wrafton

Braunton

North Devon EX33 2DL

8. MARKETING AUTHORISATION NUMBER

PL 12063/0038

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/12/2010

10    DATE OF REVISION OF THE TEXT

13/10/2016